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L Kappos

Publications and source records attributed to L Kappos.

At least 55 records · Page 3Linked to original sources
PubMed2001

Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis.

Matrix metalloproteinases (MMPs) are a family of Zn2+-dependent endopeptidases targeting extracellular matrix (ECM) compounds as well as a number of other proteins. Their proteolytic activity acts as an effector mechanism of tissue remodeling in physiologic and pathologic conditions, and as modulator of inflammation. In the context of neuro-inflammatory diseases, MMPs have been implicated in processes such as (a) blood-brain barrier (BBB) and blood-nerve barrier opening, (b) invasion of neural tissue by blood-derived immune cells, (c) shedding of cytokines and cytokine receptors, and (d) direct cellular damage in diseases of the peripheral and central nervous system. This review focuses on the role of MMPs in multiple sclerosis (MS) and bacterial meningitis (BM), two neuro-inflammatory diseases where current therapeutic approaches are insufficient to prevent severe disability in the majority of patients. Inhibition of enzymatic activity may prevent MMP-mediated neuronal damage due to an overactive or deviated immune response in both diseases. Downregulation of MMP release may be the molecular basis for the beneficial effect of IFN-beta and steroids in MS. Instead, synthetic MMP inhibitors offer the possibility to shut off enzymatic activity of already activated MMPs. In animal models of MS and BM, they efficiently attenuated clinical disease symptoms and prevented brain damage due to excessive metalloproteinase activity. However, the required target profile for the therapeutic use of this novel group of compounds in human disease is not yet sufficiently defined and may be different depending on the type and stage of disease. Currently available MMP inhibitors show little target-specificity within the MMP family and may lead to side-effects due to interference with physiological functions of MMPs. Results from human MS and BM indicate that only a restricted number of MMPs specific for each disease is up-regulated. MMP inhibitors with selective target profiles offer the possibility of a more efficient therapy of MS and BM and may enter clinical trials in the near future.

Animals↗
PubMed2001

Evoked potentials for evaluation of multiple sclerosis.

The role of evoked potentials (EP) in the assessment of multiple sclerosis (MS) has changed over the last decade. This is largely due to progress in imaging techniques. But while MRI has a greater diagnostic sensitivity, EP remain a useful diagnostic tool in many clinical situations. Moreover, recent studies demonstrate the utility of EP for monitoring and predicting the course of the disease in patient groups, although not yet in individuals. For these purposes, EP show better results than conventional MRI. In the near future, new developments in electrophysiology, immunology and imaging may allow to differentiate between different subtypes of MS early in the course, and consequently to tailor therapeutic measures more precisely to the individual patients.

Evoked Potentials↗
PubMed2001

Visual and motor evoked potentials in the course of multiple sclerosis.

While evoked potentials are sensitive tools for diagnosing multiple sclerosis, little is known about their prognostic value and their role in determining the course of the disease. To validate the visual and motor evoked potentials (VEP and MEP) as measures for the course of multiple sclerosis, we examined prospectively 30 patients with relapsing-remitting or secondary progressive multiple sclerosis. The Expanded Disability Status Scale (EDSS), VEP and MEP were measured at entry and after 6, 12 and 24 months. The Spearman rank correlation was used for statistical analysis. Applying multiple regression in 15 randomized patients allowed derivation of a formula for predicting changes in EDSS score based on changes in MEP and VEP. Validation was done by comparing the predicted with the real changes in EDSS in the other 15 patients. The number of pathological VEP and MEP results correlated at all four measurement points with the EDSS (rho > or = 0.6, P < or = 0.01). When the latencies of VEP and MEP were combined using the sum of their Z scores, correlation with the EDSS was even more significant (rho > or = 0.6, P < 0.001). Changes over time of electrophysiological data and EDSS were also correlated (rho = 0.43, P < 0.05). Moreover, VEP and MEP at baseline correlated with the EDSS after 2 years (rho = 0.43,P = 0.03). Reliable prediction of the course of multiple sclerosis for individual patients is not possible from VEP and MEP data. However, we conclude that, for groups of patients with secondary progressive or relapsing-remitting multiple sclerosis the combined testing of VEP and MEP yields numerical data that allow objective estimation of the course and prognosis of the disease.

Adult↗
PubMed2001

T(1) hypointense lesions in secondary progressive multiple sclerosis: effect of interferon beta-1b treatment.

Recently, the clinical efficacy of interferon beta-1b (IFNbeta-1b) was demonstrated for secondary progressive (SP) multiple sclerosis in a European multicentre study. We evaluated the effect of IFNbeta-1b treatment on the rate of development of hypointense T(1) MRI lesions, a putative marker of axonal damage. Unenhanced T(1)-weighted images were obtained in a subgroup of 95 multiple sclerosis patients from five centres at 6-month intervals; this subgroup was similar to the total study population for all demographic, clinical and MRI parameters. An experienced observer blinded to the clinical data and treatment allocation measured volumes. The median baseline lesion load for hypointense T(1) lesions was 5.1 cm(3) for placebo-treated and 4.9 cm(3) for IFNbeta-1b-treated patients (P = 0.56). Placebo-treated patients showed an increase in T(1) lesion load by a median of 14% per year (P = 0.0002 compared with baseline); this was reduced to 7.7% per year in the IFNbeta-1b-treated patients (P = 0.003 versus placebo). In the IFNbeta-1b arm there was a statistically significant correlation between absolute change in Expanded Disability Status Scale scores and T(1) lesion load by month 36 (r = 0.38, P = 0.0015). In patients with SP multiple sclerosis, IFNbeta-1b treatment reduces the development of hypointense T(1) lesions, suggesting that reduced axonal damage in lesions may play a part in the beneficial effect that is observed clinically.

Adult↗
PubMed2001

The expression profile of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in lesions and normal appearing white matter of multiple sclerosis.

In multiple sclerosis, matrix metalloproteinases (MMPs) are effectors of crucial pathogenetic steps, such as blood-brain barrier breakdown, invasion of brain parenchyma by immune cells and demyelination. However, only limited data are available on the types of MMPs induced in the course of multiple sclerosis, and on the role of their endogenous antagonists, the tissue inhibitors of metalloproteinases (TIMPs). We quantified the transcriptional expression of six MMPs and the four TIMPs in lesions and in normal appearing white matter (NAWM) from post-mortem multiple sclerosis brain tissue by real-time polymerase chain reaction, and compared levels with those in brain tissue from six control patients without neurological disease. The mRNA expression of MMP-7 and -9, but not of other metalloproteinases [MMP-2 and -3, and tumour necrosis factor (TNF)-alpha-converting-enzyme] was equally upregulated throughout all stages of lesion formation with active inflammation, and in most of matched NAWM tissue. The transcription of cytokines TNF-alpha/beta and IL (interleukin)-2, known modulators of MMPs, was upregulated only in distinct stages of lesion formation, while their receptors were not induced at all, which suggests that additional signalling molecules participate in the sustained upregulation of MMP-7 and -9 in multiple sclerosis. None of the TIMPs showed a significant induction over baseline expression of controls. We hypothesize that an imbalance between MMP and TIMP expression may cause a persistent proteolytic overactivity in multiple sclerosis, that may be a factor for continuous tissue destruction, and hence for secondary disease progression.

ADAM Proteins↗
PubMed2000

[Late manifestation of radiation injury to the plexus brachialis and plexus lumbosacralis].

Radiotherapy of breast cancer, cervical cancer, testicular tumours and lymphoma is one of the most effective therapy options. Damage to the nervous system, in particular the brachial and lumbar plexus, is rare and typically leads to development of progressive sensory disturbances and motor weakness after years-long latency. We present two cases exemplifying the diagnostic problems in differentiating between radiation-induced injury and recurrence of the primary tumour. A clinical course with sensorimotor symptoms and signs progressing over months, electomyographic recording of myokymic discharges, and absence of a space-occupying mass suggest late-onset radiation-induced plexopathy. The literature on pathogenesis and incidence of radiation-induced plexopathy is reviewed.

Aged↗
PubMed2000

[Neurological complications of HIV infection. Review: new diagnostic, therapeutic and prognostic aspects].

About one third of patients with HIV infection show neurological complications with considerable morbidity and high mortality. This is an actualized review of the most important neurological manifestations resulting from primary HIV infection, from secondary opportunistic infections, or as complications of antiretroviral therapy. The primary neurological manifestations, including HIV-associated dementia complex, myelopathies, peripheral neuropathies and myopathies, the more common opportunistic infections, primary central nervous system lymphoma and cerebrovascular diseases, are discussed in the light of new evidence in diagnosis, therapy and prognosis. Cognitive and psychiatric symptoms, visual changes, headache, seizures, dizziness, involuntary movements, gait disturbances, cranial neuropathies and focal deficits are the common neurological symptoms in HIV infection which are described under the aspect of differential diagnosis. It is important to bear in mind that nearly all information available to date on this subject concerns HIV patients in the period before combination therapies (including protease inhibitors). The introduction of highly active antiretroviral therapy (HAART) with protease inhibitors in 1995, and non-nucleoside reverse transcriptase inhibitors, have opened up new therapeutic modalities with a new emphasis on earlier detection and treatment of neurological complications. The prognosis of different HIV-associated neurological diseases has considerably improved, as recently shown in the case, for example, of progressive multifocal leucoencephalopathy.

AIDS Dementia Complex↗
PubMed2000

The contribution of magnetic resonance imaging in the differential diagnosis of the damage of the cerebral hemispheres.

There are presently many magnetic resonance (MR) measures that can aid the assessment of damage to the brain. The conventional measures include T2 lesion volume, T1 enhanced lesion volume, and brain atrophy. Newer methodologies include magnetization transfer measures and proton spectroscopy. These methods have the potential for improving the specificity of MR with respect to the underlying pathology. MR spectroscopy offers the ability to quantitate the component of axonal loss in multiple sclerosis. MR techniques can be implemented to assess the effectiveness of treatment algorithms.

Blood-Brain Barrier↗
PubMed2000

Dynamic susceptibility contrast MR imaging of plaque development in multiple sclerosis: application of an extended blood-brain barrier leakage correction.

Since the pathogenesis of multiple sclerosis (MS) lesions is not yet fully understood, we investigated the potential of dynamic susceptibility contrast (DSC) magnetic resonance (MR) perfusion imaging for a better characterization of lesion pathology. Twenty-five MS patients were examined on a 1.5 T scanner. A single dose of gadolinium (Gd)-DOTA contrast agent was injected, and echoplanar images were acquired every 0.5 seconds for 1 minute. From the signal intensity-versus-time curves, the relative cerebral blood volume (rCBV) was evaluated for regions in plaques and in gray and white matter. The rCBV calculated for acute, Gd-enhancing plaques was corrected for the effects of blood-brain barrier leakage, using a new correction algorithm. Acute plaques had significantly higher blood volumes than normal-appearing white matter (P < = 0.01). Chronic plaques that appeared hypointense on T(1)-weighted images had lower rCBV than T(1)-isointense plaques (P < = 0.03). Our results indicate that the acute phase in MS is accompanied by vasodilation. In later stages of gliosis, the perfusion decreases with increasing axonal injury. Although the DSC technique is less sensitive than conventional MR imaging, the information provided is essentially different from that obtained with any other MR method.

Adult↗
PubMed2000

[Multiple sclerosis. Current review of failed and discontinued clinical trials of drug treatment].

Recent immunobiological findings together with advances in biotechnology, ameliorations in clinical trial design, and MRI developments have led to a variety of therapeutical approaches in multiple sclerosis (MS). However, in contrast to successfully introduced new treatments, a number of therapeutical failures exist as well: despite impressive data from animal models, convincing concepts, and promising phase I/II studies, some investigated drugs and strategies showed no positive effects in clinical trials, or trials had to be terminated because of unexpected side effects. This article provides an overview of clinical studies that have failed or been abandoned for other reasons. Tumor necrosis factor (TNF) alpha-antagonists which have led to negative effects in two studies (Lenercept, Infliximab) are discussed in detail. These results raise critical questions concerning the hypothetical pathogenesis of MS lesions and the value of MRI in the assessment of clinically relevant therapeutic drug effects. In addition to a description of the immunobiological background, studies on the immunosuppressive agents linomide, deoxyspergualin, sulfasalazine and cladribine, trials for the cytokines interleukin-10 and TGF-beta 2, the studies on remyelination by intravenous immunoglobulins (IVIg), oral tolerance, and extracorporeal photopheresis are discussed.

Adjuvants, Immunologic↗
PubMed2000

The use of magnetic resonance imaging in multiple sclerosis treatment trials: power calculations for annual lesion load measurement.

Phase III definitive treatment trials of new multiple sclerosis (MS) therapies now routinely incorporate an annual magnetic resonance imaging protocol, with change in T2-weighted brain lesion load providing an important outcome measure. To date the accepted strategy has been to perform a core imaging protocol on all patients in such studies. The aim of this study was to provide power calculations based on this MRI endpoint. Serial MRI data from 128 patients with either relapsing remitting (RR) or secondary progressive (SP) MS were used to calculate sample size requirements using a repeated measures analysis of variance design. We provide sample size calculations based on various follow-up intervals and effect sizes. Sample sizes for the SPMS cohort were substantially larger than for the RRMS group, reflecting the greater variance in lesion load changes between patients in the SPMS group. With a follow-up of 3 years, we estimate that only 12 and 33 patients per arm are needed to show stabilisation of MRI lesion load in the RRMS and SPMS groups, respectively. Our results suggest that ongoing phase III treatment trials are more than adequately powered to detect even subtle treatment effects, and indicate that incorporating measurements from longer follow-up durations increases power substantially. We conclude that an annual imaging protocol provides a robust and powerful tool for assessing effects on the radiological appearance of the disease process.

Brain↗
PubMed2000

Guidelines for autologous blood and marrow stem cell transplantation in multiple sclerosis: a consensus report written on behalf of the European Group for Blood and Marrow Transplantation and the European Charcot Foundation. BMT-MS Study Group.

Recent reports suggest the possible beneficial effects of haemopoietic stem cell transplantation (HSCT) in autoimmune diseases such as multiple sclerosis (MS). The definition of the risk/benefit ratio for such a treatment is perceived as a major issue for the neurological community worldwide. The First Consensus Conference on Bone Marrow Transplantation in Patients with Multiple Sclerosis was held in Milan, Italy on 21 February 1998. Participants from 16 European, North American, and South American countries discussed the guidelines for performing HSCT in MS. This conference was organized in order to: (a) define criteria for patient selection; (b) define transplantation procedures to maximize efficacy of the treatment and minimize its toxicity; (c) standardize patient outcome evaluation; and (d) establish an international working group to evaluate the efficacy and safety of HSCT in MS and to study the immunological changes related to HSCT in MS patients. During the meeting in Milan agreement was reached on: (a) the preparation and distribution of a consensus report on HSCT in MS and (b) the design of an open trial for an initial assessment of the safety and efficacy of HSCT in MS. The consensus reached during the meeting and the design of the clinical trial are summarized in this contribution.

Blood Transfusion, Autologous↗
PubMed2000

The alphabeta T cell response to self-glycolipids shows a novel mechanism of CD1b loading and a requirement for complex oligosaccharides.

The structural basis for the T cell recognition of lipoglycans remains to be elucidated. We have described autoreactive T cells responsive to GM1 ganglioside presented by CD1b. We show that glycosphingolipids bind to CD1b on the cell surface at neutral pH and are recognized without internalization or processing. Furthermore, soluble GM-CD1b complexes stimulate specific T cells. Oligosaccharide groups containing five or more sugars are required to build a minimal epitope for TCR recognition. This suggests a mechanism for T cell recognition of glycosphingolipids in which much of the CD1b-bound ligand is exposed. Binding to CD1b is a highly reversible process and other ceramide-containing glycosphingolipids displace GM1. These nonantigenic compounds act as blockers and may prevent harmful autoreactivity in vivo.

Antigen Presentation↗
PubMed2000

Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial. The Altered Peptide Ligand in Relapsing MS Study Group.

In this 'double-blind', randomized, placebo-controlled phase II trial, we compared an altered peptide ligand of myelin basic protein with placebo, evaluating their safety and influence on magnetic resonance imaging in relapsing-remitting multiple sclerosis. A safety board suspended the trial because of hypersensitivity reactions in 9% of the patients. There were no increases in either clinical relapses or in new enhancing lesions in any patient, even those with hypersensitivity reactions. Secondary analysis of those patients completing the study showed that the volume and number of enhancing lesions were reduced at a dose of 5 mg. There was also a regulatory type 2 T helper-cell response to altered peptide ligand that cross-reacted with the native peptide.

Dose-Response Relationship, Drug↗
PubMed2000

The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis. European Study Group on Interferon beta-1b in secondary progressive multiple sclerosis.

The recently completed European trial of interferon beta-1b (IFNbeta-1b) in patients with secondary progressive multiple sclerosis (SP multiple sclerosis) has given an opportunity to assess the impact of treatment on cerebral atrophy using serial MRI. Unenhanced T(1)-weighted brain imaging was acquired in a subgroup of 95 patients from five of the European centres; imaging was performed at 6-month intervals from month 0 to month 36. A blinded observer measured cerebral volume on four contiguous 5 mm cerebral hemisphere slices at each time point, using an algorithm with a high level of reproducibility and automation. There was a significant and progressive reduction in cerebral volume in both placebo and treated groups, with a mean reduction of 3.9 and 2.9%, respectively, by month 36 (P = 0.34 between groups). Exploratory subgroup analyses indicated that patients without gadolinium (Gd) enhancement at the baseline had a greater reduction of cerebral volume in the placebo group (mean reduction at month 36: placebo 5.1%, IFNbeta-1b 1.8%, P < 0.05) whereas those with Gd-enhancing lesions showed a trend to greater reduction of cerebral volume if the patient was on IFNbeta-1b (placebo 2.6%, IFNbeta-1b 3.7%; P > 0.05). These results are consistent with ongoing tissue loss in both arms of this study of secondary progressive multiple sclerosis. This finding is concordant with previous observations that disease progression, although delayed, is not halted by IFNbeta. The different pattern seen in patients with and without baseline gadolinium enhancement suggests that part of the cerebral volume reduction observed in IFNbeta-treated patients may be due to the anti-inflammatory/antioedematous effect of the drug. Longer periods of observation and larger groups of patients may be needed to detect the effects of treatment on cerebral atrophy in this population of patients with advanced disease.

Adult↗
PubMed2000

Increase in serum levels of uric acid, an endogenous antioxidant, under treatment with glatiramer acetate for multiple sclerosis.

Free radicals including peroxynitrite are induced in Multiple Sclerosis (MS). Antioxidant and peroxynitrite inhibitor uric acid (UA), suppresses the MS animal model experimental autoimmune encephalomyelitis (EAE). MS patients have lower average serum UA than controls. An inverse relationship exists between MS and gout Glatiramer acetate (GA) suppresses EAE and is beneficial in relapsing MS. We investigated serum UA changes during open-label treatment of relapsing MS with GAA. Ten patients (six females, four males, aged 19 to 39 years, mean age 32 years) completed 6 months of GAA (Copaxone 20 mg s.c daily). Of these, nine completed 12 months. After 6 months on GAA, serum UA (normal, 173359 micromol/ml for women, 258-491 micromol/ml for men) increased in nine and marginally decreased (302 to 300 micromol/ml) in a single patient. Mean UA significantly increased from 240 to 303 micromol/ml (P=0.0014). At 12 months, UA remained significantly higher than at start (P=0.006) decreasing in only one patient. In contrast, we found no significant UA changes after 6 and 12 months of treatment in 21 MS patients treated with interferon beta1-a (Avonex), or in 11 treated with interferon beta1-a (Rebif), or in five placebo-treated controls. Increasing UA, a natural inhibitor of free radicals, may represent a mechanism of action of glatiramer acetate in MS.

Adjuvants, Immunologic↗
PubMed2000

Serial proton MR spectroscopy of contrast-enhancing multiple sclerosis plaques: absolute metabolic values over 2 years during a clinical pharmacological study.

BACKGROUND AND PURPOSE: The time courses of total creatine (Cr), N-acetylaspartate (NAA), choline (Cho), and myo-inositol have not previously been investigated in the follow-up of contrast-enhancing multiple sclerosis (MS) plaques. Therefore, over a period of 2 years, we compared the absolute concentrations of these metabolites between patients treated with a placebo or 15 +/- deoxyspergualin (DSG) and between clinical groups with relapsing-remitting or secondary-progressive MS. METHODS: Sixteen patients, recruited from a pharmacological study of DSG, and 11 healthy control subjects were investigated by a stimulated-echo acquisition mode sequence (TR/TE = 3000/20). The selected volume initially contained a contrast-enhancing plaque, which was followed up for a period of 2 years. RESULTS: In contrast-enhancing plaques, Cho was significantly elevated and showed a significant reduction after both 3 and 12 months. The initially normal Cr significantly increased between 3 and 12 months, and was negatively correlated with plaque volume on T1-weighted MR images. NAA initially showed normal values, a significant decrease at 1 month, and a slow recovery over 2 years. Myo-inositol did not show a clear tendency. The placebo group did not differ from the treated group, nor did the relapsing-remitting group differ from the secondary-progressive group. CONCLUSION: The contradictory time courses of Cr and NAA show that an absolute quantification in proton MR spectroscopy in MS is necessary to avoid a false interpretation of reduced NAA/Cr ratios. The increase in Cr is probably due to remyelination. The initial dip and later recovery of NAA seem to be related to diminishing edema and remyelination.

Adult↗