Fingolimod for Multiple Sclerosis: Mechanism of Action, Clinical Outcomes, and Future Directions

The oral sphingosine 1-phosphate receptor (S1PR) modulator fingolimod functionally antagonizes S1PR hereby blocking lymphocyte egress from secondary lymphoid organs to the peripheral blood circulation. This results in a reduction in peripheral lymphocyte counts, including potentially encephalitogenic T cells. In patients with relapsing multiple sclerosis fingolimod has been shown to be an effective treatment. In phase 2 and phase 3 studies fingolimod-treated patients had reduced disease activity clinically and in MRI. Although severe infectious complications occurred in single cases treated with fingolimod, the frequency of overall infections was comparable in fingolimod-treated patients and controls. Overall, in clinical studies fingolimod was well tolerated and had a favorable safety profile. In follow-up studies with continuous fingolimod, treatment showed sustained efficacy while being well tolerate

Relation between functional brain imaging, cognitive impairment and cognitive rehabilitation in patients with multiple sclerosis

Abstract : Cognitive impairment belongs to the core symptoms in MS affecting quality of life, self-esteem, and social as well as occupational functioning. Due to this high impact on patients' well-being efficient treatment concepts are required. Imaging studies on cognition have shown that functional reorganisation takes place spontaneously to compensate for deficits. In mildly to moderately impaired patients these processes may support coping with emerging deficits. However, these compensatory processes seem to be limited as brain activation of cognitively severely impaired patients is characterised by decreased additional recruitment of brain regions. Cognitive rehabilitation concentrates on the question whether induction of brain plasticity is possible for both the support of the spontaneous processes and the initiation of new ones. Combining cognition, brain imaging and cognitive rehabilitation in MS, an intriguing question is whether fMRI can provide further insights into the mechanisms of induced plasticity and serve as objective outcome measures for efficient cognitive interventio

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

Abstract. : 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 α-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 M

Screening for balance disorders in mildly affected multiple sclerosis patients

Multiple sclerosis (MS) patients often complain about balance problems when Romberg's test and tandem gait are normal. The aim of the study was to determine if measures of trunk sway taken during a battery of stance and gait tasks could be used to detect subclinical balance disorders. We recorded trunk angular sway in the pitch and roll directions from 20 MS patients (EDSS 1.4±0.5) and 20 age- and gender-matched healthy controls (HCs), during 12 stance and gait tasks. We filmed 22 subjects simultaneously. Two neurologists assessed the videos, deciding whether task performance was pathological. Sway measures were significantly different between patients and HCs in eight out of 12 balance tasks. The most significant differences between MS patients and HCs were pitch angle range standing on one leg with eyes open on a firm surface (mean 3.13° vs. 2.09°, p=0.005), and on a foam support surface (mean 6.24° vs. 2.96°, p=0.006), pitch velocity range walking 8m with eyes closed (mean 75.5 vs. 50.2°/s, p<0.001) and pitch velocity range walking 3m on heels (mean 85.37 vs. 60.9°/s, p=0.002). Multivariate analysis revealed a model with three tasks which detected balance disorders in 84% of the MS patients and 90% of the HCs correctly. The neurologists achieved accuracies of 30% for the MS patients and 82% for the HCs. Using trunk sway measures during stance and gait tasks is a sensitive screening method for balance problems in MS patients, and is more accurate than assessment by trained neurologist