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.

Clinical relevance of brain volume measures in multiple sclerosis.

Multiple sclerosis (MS) is a chronic disease with an inflammatory and neurodegenerative pathology. Axonal loss and neurodegeneration occurs early in the disease course and may lead to irreversible neurological impairment. Changes in brain volume, observed from the earliest stage of MS and proceeding throughout the disease course, may be an accurate measure of neurodegeneration and tissue damage. There are a number of magnetic resonance imaging-based methods for determining global or regional brain volume, including cross-sectional (e.g. brain parenchymal fraction) and longitudinal techniques (e.g. SIENA [Structural Image Evaluation using Normalization of Atrophy]). Although these methods are sensitive and reproducible, caution must be exercised when interpreting brain volume data, as numerous factors (e.g. pseudoatrophy) may have a confounding effect on measurements, especially in a disease with complex pathological substrates such as MS. Brain volume loss has been correlated with disability progression and cognitive impairment in MS, with the loss of grey matter volume more closely correlated with clinical measures than loss of white matter volume. Preventing brain volume loss may therefore have important clinical implications affecting treatment decisions, with several clinical trials now demonstrating an effect of disease-modifying treatments (DMTs) on reducing brain volume loss. In clinical practice, it may therefore be important to consider the potential impact of a therapy on reducing the rate of brain volume loss. This article reviews the measurement of brain volume in clinical trials and practice, the effect of DMTs on brain volume change across trials and the clinical relevance of brain volume loss in MS.

Fatigue and sleep-disordered breathing in multiple sclerosis: a clinically relevant association?

Background. Fatigue in patients with multiple sclerosis (MS) is highly prevalent and severely impacts quality of life. Recent studies suggested that sleep-disordered breathing (SDB) significantly contributes to fatigue in MS. Study Objective. To evaluate the importance of routine respirography in MS patients with severe fatigue and to explore the effects of treatment with continuous positive airway pressure (CPAP). Patients and Methods. We prospectively assessed the presence of severe fatigue, as defined by a score of ≥5.0 on the Fatigue Severity Scale (FSS), in 258 consecutive MS patients. Ninety-seven patients (38%) suffered from severe fatigue, whereof 69 underwent overnight respirography. Results. We diagnosed SDB in 28 patients (41%). Male sex was the only independent associate of SDB severity (P = 0.003). CPAP therapy in 6 patients was associated with a significant reduction of FSS scores (5.8 ± 0.5 versus 4.8 ± 0.6, P = 0.04), but the scores remained pathological (≥4.0) in all patients. Conclusion. Respirography in MS patients with severe fatigue should be considered in daily medical practice, because SDB frequency is high and CPAP therapy reduces fatigue severity. However, future work is needed to understand the real impact of CPAP therapy on quality of life in this patient group.

Elevated CSF histamine levels in multiple sclerosis patients.

BACKGROUND Histamine is an ubiquitous inflammatory mediator of numerous physiological processes. Histamine and its receptors have been implicated in multiple sclerosis (MS) disease pathogenesis. We prospectively enrolled 36 MS patients and 19 age and gender-matched healthy volunteers for cerebrospinal fluid (CSF) histamine analysis. FINDINGS CSF HISTAMINE LEVELS IN MS PATIENT SAMPLES WERE SIGNIFICANTLY HIGHER (MEDIAN: 35.6 pg/ml) than in controls (median: 5.5 pg/ml; Beta = 0.525, p < 0.001). In addition, histamine increased with age (Pearson's correlation, p < 0.003). CONCLUSIONS Histamine may be an important factor for both the initiation and maintenance of chronic inflammatory diseases of the central nervous system. Our observation encourages a deeper investigation of the role of histamine in MS.

The Coin Rotation Task: A Valid Test for Manual Dexterity in Multiple Sclerosis

BACKGROUND: Impaired manual dexterity is frequent and disabling in patients with multiple sclerosis (MS). Therefore, convenient, quick and validated tests for manual dexterity in MS patients are needed. OBJECTIVE: The aim of this study was to validate the Coin Rotation task (CRT) to examine manual dexterity in patients with MS. DESIGN: Cross-sectional study. METHODS: 101 outpatients with MS were assessed with the CRT, the Expanded Disability Status Scale (EDSS), the Scale for the assessment and rating of ataxia (SARA), the Modified Ashworth Scale (MAS), and their muscle strength and sensory deficits of the hands were noted. Concurrent validity and diagnostic accuracy of the CRT were determined by comparison with the Nine Hole Peg Test (9HPT). Construct validity was determined by comparison with a valid dexterity questionnaire. Multiple regression analysis was done to explore correlations of the CRT with the EDSS, SARA, MAS, muscle strength and sensory deficits. RESULTS: The CRT correlated significantly with the 9HPT (r=.73, p<.0001) indicating good concurrent validity. The cut-off values for the CRT relative to the 9HPT were 18.75 seconds for the dominant (sensitivity: 81.5%; specificity 80.0%) and 19.25 seconds for the non-dominant hand (sensitivity: 90.3%; specificity: 81.8%) demonstrating good diagnostic accuracy. Furthermore, the CRT correlated significantly with the dexterity questionnaire (r=-.49, p<.0001) indicating moderate construct validity. Multiple regression analyses revealed that the EDSS was the strongest predictor for impaired dexterity. LIMITATIONS: Mostly relapsing-remitting MS patients with an EDSS up to 7 were examined. CONCLUSIONS: This study validates the CRT as a test that can be used easily and quickly to evaluate manual dexterity in patients with MS.

Multiple Sclerosis: Current Knowledge and Future Outlook

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and axonal loss. The etiology of MS is unknown; however, environmental and genetic factors play a key role in the development of MS. Diagnostic criteria have been adapted to facilitate earlier diagnosis with increased sensitivity and specificity. Our understanding of the pathophysiology of MS has deepened considerably in recent years, resulting in different therapies to modify the disease course. Furthermore, several drugs have lately shown efficacy in phase III studies and their approval is expected in the near future. As treatment options expand, a future challenge will be to find the optimal treatment for the individual patient. Summary: This mini-review gives an overview of the current knowledge of MS with emphasis on the latest diagnostic criteria and both current and upcoming treatment options. Key Messages: Treatment of MS changes rapidly as the knowledge and therapeutic options in MS expand. Clinical Impact: Diagnosis of MS is based on McDonald criteria. MS therapy can be divided into relapse, disease-modifying and symptomatic treatment. Relapses are commonly treated with intravenous methylprednisolone. First-line therapy consists of either interferon-β, glatiramer acetate or teriflunomide. In general, agents used as escalation therapies (natalizumab, fingolimod and mitoxantrone) are more potent than the agents used for first-line therapy; however, these have potentially serious side effects and should be used with care.

Extracorporeal shock wave therapy for injection site panniculitis in multiple sclerosis patients.

BACKGROUND Painful cutaneous injection site reactions may hamper treatment with interferon β (IFN-β) and glatiramer acetate (GA) in multiple sclerosis (MS) patients. OBJECTIVE To maintain therapy adherence, efficient therapeutic modalities for these subcutaneous inflammatory lesions are urgently needed. We tested the application of local extracorporeal shock wave therapy (ESWT). METHODS We applied 5 sessions of ESWT to 8 patients suffering from MS who had developed painful panniculitis at the injection sites of either IFN-β or GA. Clinical outcomes, i.e. pain reduction and regression of induration, were assessed 3 and 6 months after completion of the ESWT using a visual analogue score. RESULTS All patients showed both significant pain reduction and reduction of the skin induration in the treated lesions, while in untreated control lesions there was no improvement. CONCLUSION ESWT proved to be a non-invasive, safe and efficient physical treatment modality for injection-induced painful cutaneous side effects of disease-modifying drugs in MS. © 2014 S. Karger AG, Basel.

Quality control for retinal OCT in multiple sclerosis: validation of the OSCAR-IB criteria.

BACKGROUND Retinal optical coherence tomography (OCT) permits quantification of retinal layer atrophy relevant to assessment of neurodegeneration in multiple sclerosis (MS). Measurement artefacts may limit the use of OCT to MS research. OBJECTIVE An expert task force convened with the aim to provide guidance on the use of validated quality control (QC) criteria for the use of OCT in MS research and clinical trials. METHODS A prospective multi-centre (n = 13) study. Peripapillary ring scan QC rating of an OCT training set (n = 50) was followed by a test set (n = 50). Inter-rater agreement was calculated using kappa statistics. Results were discussed at a round table after the assessment had taken place. RESULTS The inter-rater QC agreement was substantial (kappa = 0.7). Disagreement was found highest for judging signal strength (kappa = 0.40). Future steps to resolve these issues were discussed. CONCLUSION Substantial agreement for QC assessment was achieved with aid of the OSCAR-IB criteria. The task force has developed a website for free online training and QC certification. The criteria may prove useful for future research and trials in MS using OCT as a secondary outcome measure in a multi-centre setting.

Home-based training to improve manual dexterity in patients with multiple sclerosis: A randomized controlled trial.

BACKGROUND Impaired manual dexterity is frequent and disabling in patients with multiple sclerosis (MS), affecting activities of daily living (ADL) and quality of life. OBJECTIVE We aimed to evaluate the effectiveness of a standardized, home-based training program to improve manual dexterity and dexterity-related ADL in MS patients. METHODS This was a randomized, rater-blinded controlled trial. Thirty-nine MS patients acknowledging impaired manual dexterity and having a pathological Coin Rotation Task (CRT), Nine Hole Peg Test (9HPT) or both were randomized 1:1 into two standardized training programs, the dexterity training program and the theraband training program. Patients trained five days per week in both programs over a period of 4 weeks. Primary outcome measures performed at baseline and after 4 weeks were the CRT, 9HPT and a dexterous-related ADL questionnaire. Secondary outcome measures were the Chedoke Arm and Hand Activity Inventory (CAHAI-8) and the JAMAR test. RESULTS The dexterity training program resulted in significant improvements in almost all outcome measures at study end compared with baseline. The theraband training program resulted in mostly non-significant improvements. CONCLUSION The home-based dexterity training program significantly improved manual dexterity and dexterity-related ADL in moderately disabled MS patients. Trial Registration NCT01507636.

Usability and Acceptability of ASSESS MS: Assessment of Motor Dysfunction in Multiple Sclerosis Using Depth-Sensing Computer Vision

Background: Sensor-based recordings of human movements are becoming increasingly important for the assessment of motor symptoms in neurological disorders beyond rehabilitative purposes. ASSESS MS is a movement recording and analysis system being developed to automate the classification of motor dysfunction in patients with multiple sclerosis (MS) using depth-sensing computer vision. It aims to provide a more consistent and finer-grained measurement of motor dysfunction than currently possible. Objective: To test the usability and acceptability of ASSESS MS with health professionals and patients with MS. Methods: A prospective, mixed-methods study was carried out at 3 centers. After a 1-hour training session, a convenience sample of 12 health professionals (6 neurologists and 6 nurses) used ASSESS MS to capture recordings of standardized movements performed by 51 volunteer patients. Metrics for effectiveness, efficiency, and acceptability were defined and used to analyze data captured by ASSESS MS, video recordings of each examination, feedback questionnaires, and follow-up interviews. Results: All health professionals were able to complete recordings using ASSESS MS, achieving high levels of standardization on 3 of 4 metrics (movement performance, lateral positioning, and clear camera view but not distance positioning). Results were unaffected by patients’ level of physical or cognitive disability. ASSESS MS was perceived as easy to use by both patients and health professionals with high scores on the Likert-scale questions and positive interview commentary. ASSESS MS was highly acceptable to patients on all dimensions considered, including attitudes to future use, interaction (with health professionals), and overall perceptions of ASSESS MS. Health professionals also accepted ASSESS MS, but with greater ambivalence arising from the need to alter patient interaction styles. There was little variation in results across participating centers, and no differences between neurologists and nurses. Conclusions: In typical clinical settings, ASSESS MS is usable and acceptable to both patients and health professionals, generating data of a quality suitable for clinical analysis. An iterative design process appears to have been successful in accounting for factors that permit ASSESS MS to be used by a range of health professionals in new settings with minimal training. The study shows the potential of shifting ubiquitous sensing technologies from research into the clinic through a design approach that gives appropriate attention to the clinic environment.

Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke

Each year about 650,000 Europeans die from stroke and a similar number lives with the sequelae of multiple sclerosis (MS). Stroke and MS differ in their etiology. Although cause and likewise clinical presentation set the two diseases apart, they share common downstream mechanisms that lead to damage and recovery. Demyelination and axonal injury are characteristics of MS but are also observed in stroke. Conversely, hallmarks of stroke, such as vascular impairment and neurodegeneration, are found in MS. However, the most conspicuous common feature is the marked neuroinflammatory response, marked by glia cell activation and immune cell influx. In MS and stroke the blood-brain barrier is disrupted allowing bone marrow-derived macrophages to invade the brain in support of the resident microglia. In addition, there is a massive invasion of auto-reactive T-cells into the brain of patients with MS. Though less pronounced a similar phenomenon is also found in ischemic lesions. Not surprisingly, the two diseases also resemble each other at the level of gene expression and the biosynthesis of other proinflammatory mediators. While MS has traditionally been considered to be an autoimmune neuroinflammatory disorder, the role of inflammation for cerebral ischemia has only been recognized later. In the case of MS the long track record as neuroinflammatory disease has paid off with respect to treatment options. There are now about a dozen of approved drugs for the treatment of MS that specifically target neuroinflammation by modulating the immune system. Interestingly, experimental work demonstrated that drugs that are in routine use to mitigate neuroinflammation in MS may also work in stroke models. Examples include Fingolimod, glatiramer acetate, and antibodies blocking the leukocyte integrin VLA-4. Moreover, therapeutic strategies that were discovered in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, turned out to be also effective in experimental stroke models. This suggests that previous achievements in MS research may be relevant for stroke. Interestingly, the converse is equally true. Concepts on the neurovascular unit that were developed in a stroke context turned out to be applicable to neuroinflammatory research in MS. Examples include work on the important role of the vascular basement membrane and the BBB for the invasion of immune cells into the brain. Furthermore, tissue plasminogen activator (tPA), the only established drug treatment in acute stroke, modulates the pathogenesis of MS. Endogenous tPA is released from endothelium and astroglia and acts on the BBB, microglia and other neuroinflammatory cells. Thus, the vascular perspective of stroke research provides important input into the mechanisms on how endothelial cells and the BBB regulate inflammation in MS, particularly the invasion of immune cells into the CNS. In the current review we will first discuss pathogenesis of both diseases and current treatment regimens and will provide a detailed overview on pathways of immune cell migration across the barriers of the CNS and the role of activated astrocytes in this process. This article is part of a Special Issue entitled: Neuro inflammation: A common denominator for stroke, multiple sclerosis and Alzheimer's disease, guest edited by Helga de Vries and Markus Swaninger.

Cognitive rehabilitation of working memory in juvenile multiple sclerosis-effects on cognitive functioning, functional MRI and network related connectivity.

PURPOSE To assess possible effects of working memory (WM) training on cognitive functionality, functional MRI and brain connectivity in patients with juvenile MS. METHODS Cognitive status, fMRI and inter-network connectivity were assessed in 5 cases with juvenile MS aged between 12 and 18 years. Afterwards they received a computerized WM training for four weeks. Primary cognitive outcome measures were WM (visual and verbal) and alertness. Activation patterns related to WM were assessed during fMRI using an N-Back task with increasing difficulty. Inter-network connectivity analyses were focused on fronto-parietal (left and right), default-mode (dorsal and ventral) and the anterior salience network. Cognitive functioning, fMRI and inter-network connectivity were reassessed directly after the training and again nine months following training. RESULTS Response to treatment was seen in two patients. These patients showed increased performance in WM and alertness after the training. These behavioural changes were accompanied by increased WM network activation and systematic changes in inter-network connectivity. The remaining participants were non-responders to treatment. Effects on cognitive performance were maintained up to nine months after training, whereas effects observed by fMRI disappeared. CONCLUSIONS Responders revealed training effects on all applied outcome measures. Disease activity and general intelligence may be factors associated with response to treatment.

New insights into the pharmacokinetics and pharmacodynamics of natalizumab treatment for patients with multiple sclerosis, obtained from clinical and in vitro studies.

BACKGROUND The monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the blood-brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central nervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT treatment regimens. METHODS We developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression levels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after the cessation of therapy. RESULTS In paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately 100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable with those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression levels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free and cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be identified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo and in vitro. Intercellular NAT exchange was detected in vitro. CONCLUSIONS Incorporating assays to measure free and cell-bound NAT into clinical practice can help to determine the optimal individual NAT dosing regimen for patients with MS.