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Ludwig Kappos

Publications and source records attributed to Ludwig Kappos.

33 records · Page 2Linked to original sources
PubMed2004

Alternatives to current disease-modifying treatment in MS: what do we need and what can we expect in the future?

Disease-modifying treatments (DMTs) for multiple sclerosis (MS) are now widely available, and their beneficial effects on relapse rates, magnetic resonance imaging outcomes and, in some cases, relapse-related disability have been shown in numerous clinical studies. However, as these treatments are only partially effective in halting the MS disease process, the search for improved treatment regimens and novel therapies must continue. Strategies to improve our therapeutic armamentarium have to take into account the different phases or parts of the pathogenesis of the disease. Available treatments address systemic immune dysfunction, blood-brain barrier permeability and the inflammatory process in the central nervous system. Currently, patients who fail to respond adequately to first-line DMTs are often considered as candidates for intensive immunosuppression with cytostatic agents or even autologous stem cell transplantation. However, new approaches are being developed. Combination therapies offer an alternative approach that may have considerable potential to improve therapeutic yield and, although likely to present considerable challenges in terms of trial design, this certainly seems to be a logical step forward in view of the complex pathology of MS. Several new drugs are also being developed with the aim of providing more effective, convenient and/or specific modulation of the inflammatory component of the disease. These treatments include humanised monoclonal antibodies such as the anti-VLA-4 antibody natalizumab, inhibitors of intracellular activation, signalling pathways and T-cell proliferation, and oral immunomodulators such as sirolimus, teriflunomide or statins. There remains, however, an urgent need for treatments that protect against demyelination and axonal loss, or promote remyelination/regeneration. Due to the chronicity of MS, the therapeutic window for neuroprotective agents is wider than that following stroke or acute spinal cord injury, and may therefore allow the use of some drugs that have proven disappointing in other situations. Novel potential neuroprotective agents such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonists and ion-channel blockers will be entering Phase II trials in MS in the near future, and it is hoped that these agents will mark the start of a new era for DMTs for MS.

Adjuvants, Immunologic↗
PubMed2004

Multiple sclerosis as a generalized CNS disease--comparative microarray analysis of normal appearing white matter and lesions in secondary progressive MS.

We used microarrays to compare the gene expression profile in active lesions and donor-matched normal appearing white matter (NAWM) from brain autopsy samples of patients with secondary progressive multiple sclerosis (MS) with that from controls who died from non-neurological diseases. The 123 genes in lesions, and 47 genes in NAWM(MS) were differentially expressed. Lesions distinguished from NAWM(MS) by a higher expression of genes related to immunoglobulin synthesis and neuroglial differentiation, while cellular immune response elements were equally dysregulated in both tissue compartments. Current results provide molecular evidence of a continuum of dysfunctional homeostasis and inflammatory changes between lesions and NAWM(MS), and support the concept of MS pathogenesis being a generalised process that involves the entire CNS.

Brain↗
PubMed2004

Effect of drugs in secondary disease progression in patients with multiple sclerosis.

Secondary progressive multiple sclerosis (SPMS) is a form of MS characterized by continuously worsening disability with or without superimposed relapses that occurs after a variable period of relapsing remitting disease and results in limited ambulation for almost all patients. The use of interferon beta (IFN beta) for immunomodulation in patients with SPMS has been evaluated in four recent clinical trials: The European multicentre trial on IFN beta-1b in SPMS (EUSPMS), the Secondary Progressive Efficacy Trial of Rebif (IFN beta-1a) in MS (SPECTRIMS), the North American Study of IFN beta-1b in SPMS (NASPMS), and the International MS Secondary Progressive Avonex Clinical Trial (IMPACT). EUSPMS was the only trial to demonstrate a significant positive effect of therapy on disease progression as measured by the expanded disability status scale (EDSS). However, results from all studies demonstrated significant positive effects of treatment on relapse, T2 lesion load, and gadolinium enhancement. Immunomodulation with IFN beta has the potential to significantly slow disease progression and improve quality of life for patients with SPMS. While results with monthly i.v. Ig were disappointing, positive effects on disease progression have been reported with the application of immunosuppressants, especially Mitoxantrone. The risk-benefit ratio of these cytostatic agents remains controversial. New strategies addressing the important neurodegenerative aspects of the disease are urgently needed.

Adjuvants, Immunologic↗
PubMed2003

Neutralizing antibodies against IFN-beta in multiple sclerosis: antagonization of IFN-beta mediated suppression of MMPs.

Neutralizing antibodies (NAb) against interferon-beta (IFN-beta) develop in about a third of treated multiple sclerosis patients and are believed to reduce therapeutic efficacy of IFN-beta on clinical and MRI measures. The expression of the interferon acute-response protein, myxovirus resistance protein A (MxA) is a sensitive measure of the biological activity of therapeutically applied IFN-beta and of its reduced bioavailability due to NAb. However, MxA may not be operative in the pathogenesis of multiple sclerosis or the therapeutic effect of IFN-beta. Instead, matrix metalloproteinases (MMPs) are increased in brain tissue, CSF and blood circulation of multiple sclerosis patients and function as effector molecules in several steps of multiple sclerosis pathogenesis. One of the molecular mechanisms by which IFN-beta exerts its beneficial effect in multiple sclerosis is reduction of MMP-9 expression and increase of its endogenous tissue inhibitor, TIMP-1. Quantitative PCR measurements of MMP-2 and MMP-9, TIMP-1 and TIMP-2, and MxA were performed in peripheral mononuclear cells from clinically stable multiple sclerosis patients with relapsing remitting disease course after short-term and long-term treatment with IFN-beta. IFN-beta therapy down-regulated the expression of MMP-9 and abolished that of MMP-2 in long-term, but not short-term treated multiple sclerosis, while levels of MxA were increased in both instances. The presence of NAb reversed these effects, i.e. led to reduced MxA and increased MMP-2/MMP-9 expression levels compared with NAb- patients. In contrast, expression of TIMPs in peripheral blood mononuclear cells remained unaffected by IFN-beta therapy and the presence of NAb. While MxA is able to detect the biological action and reduced bioavailability of IFN-beta on the basis of single injections, only MMP-9 shows quantitative correlation with the NAb titre. Together with evidence that an imbalance between MMP and TIMP expression is a crucial pathogenetic feature in multiple sclerosis, these findings support the concept of a significant role of NAb in reducing the therapeutic efficacy of IFN-beta.

Antibodies↗
PubMed2003

Atrophy is detectable within a 3-month period in untreated patients with active relapsing remitting multiple sclerosis.

BACKGROUND: Atrophy is recognized as a measure of destructive changes in multiple sclerosis (MS). The time course and pathologic mechanisms of atrophy development are not well understood. Significant atrophy was reported to occur within 9 to 12 months in relapsing remitting MS. OBJECTIVES: To test whether atrophy can be detected over short time intervals, and to evaluate its relationship to inflammation. DESIGN AND METHODS: Prior to randomization to a treatment trial, 138 untreated patients with relapsing remitting MS had 3 magnetic resonance imaging scans within a mean +/- SD follow-up of 76 +/- 20.2 days. Brain parenchymal fraction (BPF), a normalized measure of whole brain volume, the proportion of active (gadolinium-enhancing) scans, and the volume of T1-weighted gadolinium-enhancing and T2-weighted hyperintense lesions were determined at all time points. An annualized atrophy rate was estimated by calculating a regression slope. RESULTS: The median Expanded Disability Status Scale score was 3.5, the mean disease duration was 7.6, and the mean age was 38.5 years. The BPF decreased significantly by -0.229% from scan 1 to scan 3, while the proportion of active scans remained high (65%, 63%, and 67%). The BPF change was only weakly correlated to the volume of T1-weighted gadolinium-enhancing lesions in scan 1 (r = -0.185). The estimated annualized atrophy rate was -1.06% (95% confidence interval, -1.50% to -0.62%). CONCLUSIONS: The annualized atrophy rate found in this study is comparable with rates reported previously. Measurements of BPF allow detection of atrophy over short time intervals in active disease. The short-term relationship of inflammation to atrophy development was weak. Brain parenchymal fraction might be a promising measure in future phase 2 studies of agents, with an expected effect on tissue-destructive pathologic mechanisms of MS.

Adult↗
PubMed2003

Analysis of impairment related functional architecture in MS patients during performance of different attention tasks.

More than 50 % of patients with multiple sclerosis (MS) suffer from cognitive deficits. Attention is one of the most frequently affected cognitive functions. It has been shown that MS patients suffer from a specific but not necessarily from a generalized decrease in performance and that different severity grades of impaired attentional processing can be distinguished. Little is known about patterns of brain activation in MS patients with different grades of attentional deficits. The objective was to examine if different severity grades in attentional impairment are reflected by altered patterns of brain activation in specific attention tasks. In the present study cerebral activation induced by three attention tasks of different complexity was assessed in 14 MS patients and seven healthy controls by functional MRI (fMRI). Based on their performance on the tests recorded off-line with a computerized test battery and during the fMRI investigation, patients were classified as mildly and severely impaired. MS patients with mild impairment showed increased and additional activation of brain areas which were in part not activated in normal subjects. Those were located mainly in the frontal cortex and posterior parietal cortex. This effect decreased with increasing task complexity and was strongest for the alertness task. In MS patients with severe impairment no additional activation was found in prefrontal structures and activation in the premotor cortex was not significantly different from controls. These findings suggest that compensation in MS patients is in part achieved by functional integration of frontal and parietal association areas. The extent of compensation seems to depend on the brain's capacity to access additional brain structures. Exhaustion of this capacity may finally lead to severe cognitive impairment.

Adult↗
PubMed2003

Immune-mediated neuropathies: etiology and pathogenic relationship to aging processes.

Immune-mediated peripheral neuropathies are more frequent in aged populations. Equally, underlying diseases such as vasculitis and paraproteinemia are more prevalent in the elderly. Accumulating evidence is linking the aging process of the immune system, immunosenescence, to the susceptibility of older individuals for paraproteinemic, vasculitic and inflammatory demyelinating neuropathies. Why an individual develops a particular disease is likely due to a number of factors. These include mutations in neural tissue-specific B and T cells, decreased central tolerance, increased proinflammatory environment due to cytokine shifts and higher functional capacity of innate immune cells.

Aging↗
PubMed2003

Endonasal surgery for contact point headaches: a 10-year longitudinal study.

OBJECTIVE: Some migraine and cluster headaches may be triggered by stimulation of intranasal contact points via the trigeminovascular system. Endonasal surgery is successful in some patients, but long-term outcomes have not been reported. STUDY DESIGN: Prospective. METHODS: This investigation included 20 patients with a mean 18-year history of refractory cluster or migraine headaches who were selected for surgery. All had endoscopically visible endonasal contact as well as a positive preoperative cocaine test result. Changes in pain severity and frequency and duration of headache attacks were statistically rated using a MANOVA. Follow-up averaged 112 months. RESULTS: Almost 10 years after surgery, six patients remained completely free of pain, seven had significant symptom improvement, and seven received no benefit from surgery (65% improvement). Two patients had been free of all symptoms for 7 and 8 years, respectively, before complaints returned. CONCLUSION: Our data suggest that some patients with refractory headaches and endonasal contact areas benefit from surgery, thereby supporting the existence of a connection between the two. Even though it is clear that surgery should be considered only if all other treatments have failed, a success rate of 65% over almost 10 years justifies evaluation of this option. Preoperative patient selection remains crucial and warrants further investigation.

Adult↗
PubMed2003

Extraocular blood flow and endothelin-1 plasma levels in patients with multiple sclerosis.

In order to evaluate whether plasma levels of the potent vasoconstrictor endothelin-1 (ET-1) are increased in patients with multiple sclerosis (MS) and whether these patients exhibit an ET-1-mediated vascular dysregulation, ET-1 plasma levels were measured in 30 patients with MS. Blood flow velocities in the ophthalmic artery, central retinal artery, central retinal vein, short lateral posterior ciliary artery, and short medial posterior ciliary artery were assessed in parallel. ET-1 plasma levels were significantly increased in MS patients when compared to sex- and age-matched healthy controls (2.0 +/- 0.4 pg/ml, range 1.1-2.8 vs. 1.5 +/- 0.2 pg/ml, range 0.9-2.0; p < 0.001). Moreover, the patients exhibited significant alterations of extraocular blood flow. The role of ET-1 in the inflammatory process remains to be clarified.

Adult↗
PubMed2003

Vancouver Consortium of MS Centers' Magnetic Resonance Imaging Guidelines.

The increasing use of magnetic resonance imaging (MRI) as a diagnostic tool for multiple sclerosis (MS) as recently enforced in the McDonald committee criteria--and the importance of MRI measurements in therapeutic studies both demonstrate the value of MRI findings. MRI aids our understanding of MS and management of patients.

Gadolinium↗