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Objective: Smartphone devices may enable out-of-clinic assessments in chronic neurological diseases. We describe the Draw a Shape (DaS) Test, a smartphone-based and remotely administered test of Upper Extremity (UE) function developed for people with multiple sclerosis (PwMS). This work introduces DaS-related features that characterise UE function and impairment, and aims to demonstrate how multivariate modelling of these metrics can reliably predict the 9-Hole Peg Test (9HPT), a clinician-administered UE assessment in PwMS. Approach: The DaS Test instructed PwMS and healthy controls (HC) to trace predefined shapes on a smartphone screen. A total of 93 subjects (HC, n = 22; PwMS, n = 71) contributed both dominant and non-dominant handed DaS tests. PwMS subjects were characterised as those with normal (nPwMS, n = 50) and abnormal UE function (aPwMS, n = 21) with respect to their average 9HPT time (≤ or > 22.7 (s), respectively). L1-regularization techniques, combined with linear least squares (OLS, IRLS), or non-linear support vector (SVR) or random forest (RFR) regression were investigated as functions to map relevant DaS features to 9HPT times. Main results: It was observed that average non-dominant handed 9HPT times were more accurately predicted by DaS features (r2 = 0.41, 0.05; MAE: 2.08 ± 0.34 (s)) than average dominant handed 9HPTs (r2 = 0.39, 0.05; MAE: 2.32 ± 0.43 (s)), using simple linear IRLS (0.01). Moreover, it was found that the Mean absolute error (MAE) in predicted 9HPTs was comparable to the variability of actual 9HPT times within HC, nPwMS and aPwMS groups respectively. The 9HPT however exhibited large heteroscedasticity resulting in less stable predictions of longer 9HPT times. Significance: This study demonstrates the potential of the smartphone-based DaS Test to reliably predict 9HPT times and remotely monitor UE function in PwMS. [ABSTRACT FROM AUTHOR]

Background and purpose Impaired ambulation is a prominent disabling symptom of multiple sclerosis and can lead to reduced quality of life. Whether natalizumab, a monoclonal antibody shown to reduce disease activity in relapsing−remitting multiple sclerosis, could impact ambulation performance was examined. Methods A prospective open-label study, TIMER, was conducted in natalizumab-naive patients ( n = 215). The timed 25-foot walk ( T25 FW) and timed 100-m walk ( T100 MW) were assessed at baseline and at weeks 24 and 48 of natalizumab therapy, together with Expanded Disability Status Scale scores. The effects of natalizumab on T25 FW performance were also examined in a retrospective analysis of natalizumab-treated patients ( n = 627) and placebo control patients ( n = 315) from the AFFIRM study. Results In TIMER, a significant increase from baseline in T25 FW speed was seen at week 24 ( P = 0.0074) and in T100 MW speed at weeks 24 and 48 (both P < 0.001). A greater proportion of patients showed clinically meaningful increases (≥20%) in walking speed on the T100 MW (25%) than on the T25 FW (13%) at week 48 ( P = 0.032). In AFFIRM, natalizumab increased the proportion of patients with ≥20% confirmed improvement in T25 FW speed at year 2 by 78% versus placebo ( P = 0.0133). Conclusions Natalizumab increased walking speed in patients with relapsing−remitting multiple sclerosis. The T100 MW may be more sensitive to changes in ambulation capacity than the T25 FW, and both tests appear to detect clinically meaningful improvements in ambulatory function. [ABSTRACT FROM AUTHOR]

Background: No clinical test is currently available and validated to measure the maximum walking speed (WS) of multiple sclerosis (MS) patients. Since the Timed 25-Foot Walk Test (T25FW) is performed with a static start, it takes a significant proportion of the distance for MS patients to reach their maximum pace. Objectives: In order to capture the maximum WS and to quantify the relative impact of the accelerating phase during the first meters, we compared the classical T25FW with a modified version (T25FW{+}) allowing a dynamic start after a 3 meters run-up. Methods: Sixty-four MS patients and 30 healthy subjects performed successively the T25FW and the T25FW{+}. Results: The T25FW{+} was performed faster than the T25FW for the vast majority of MS and healthy subjects. In the MS population, the mean relative gain of speed due to the dynamic start on T25FW{+} was independent from the EDSS and from the level of ambulation impairment. Compared to healthy subjects, the relative difference between dynamic versus static start was more important in the MS population even in patients devoid of apparent gait impairment according to the T25FW. Conclusion: The T25FW{+} allows a more accurate measurement of the maximum WS of MS patients, which is a prerequisite to reliably evaluate deceleration over longer distance tests. Indirect arguments suggest that the time to reach the maximum WS may be partially influenced by the cognitive impairment status. The maximum WS and the capacity of MS patients to accelerate on a specific distance may be independently regulated and assessed separately in clinical trials and rehabilitation programs. [ABSTRACT FROM AUTHOR]

Background: No clinical test is currently available and validated to measure the maximum walking speed (WS) of multiple sclerosis (MS) patients. Since the Timed 25-Foot Walk Test (T25FW) is performed with a static start, it takes a significant proportion of the distance for MS patients to reach their maximum pace. Objectives: In order to capture the maximum WS and to quantify the relative impact of the accelerating phase during the first meters, we compared the classical T25FW with a modified version (T25FW^{+}) allowing a dynamic start after a 3 meters run-up. Methods: Sixty-four MS patients and 30 healthy subjects performed successively the T25FW and the T25FW^{+}. Results: The T25FW^{+} was performed faster than the T25FW for the vast majority of MS and healthy subjects. In the MS population, the mean relative gain of speed due to the dynamic start on T25FW^{+} was independent from the EDSS and from the level of ambulation impairment. Compared to healthy subjects, the relative difference between dynamic versus static start was more important in the MS population even in patients devoid of apparent gait impairment according to the T25FW. Conclusion: The T25FW^{+} allows a more accurate measurement of the maximum WS of MS patients, which is a prerequisite to reliably evaluate deceleration over longer distance tests. Indirect arguments suggest that the time to reach the maximum WS may be partially influenced by the cognitive impairment status. The maximum WS and the capacity of MS patients to accelerate on a specific distance may be independently regulated and assessed separately in clinical trials and rehabilitation programs. [ABSTRACT FROM AUTHOR]

Natalizumab (Tysabri) is a monoclonal antibody that was recently approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Our primary objective was to analyse the efficacy of natalizumab on disability status and ambulation after switching patients with RRMS from other disease-modifying treatments (DMTs). A retrospective, observational study was carried out. All patients ( n = 45) initiated natalizumab after experiencing at least 1 relapse in the previous year under interferon-beta (IFNB) or glatiramer acetate (GA) treatments. The patients also had at least 1 gadolinium-enhancing (Gd+) lesion on their baseline brain MRI. Expanded Disability Status Scale (EDSS) scores, and performance on the Timed 25-Foot Walk Test and on the Timed 100-Metre Walk Test were prospectively collected every 4 weeks during 44 weeks of natalizumab treatment. Brain MRI scans were performed after 20 and 44 weeks of treatment. Sixty-two per cent of patients showed no clinical and no radiological signs of disease activity, and 29% showed a rapid and confirmed EDSS improvement over 44 weeks of natalizumab therapy. Patients with improvement on the EDSS showed similar levels of baseline EDSS and active T1 lesions, but had a significantly higher number of relapses, and 92% of them had experienced relapse-mediated sustained EDSS worsening in the previous year. A clinically meaningful improvement in ambulation speed was observed in approximately 30% of patients. These results indicate that natalizumab silences disease activity and rapidly improves disability status and walking performance, possibly through delayed relapse recovery in patients with RRMS who had shown a high level of disease activity under other DMTs. [ABSTRACT FROM AUTHOR]

1 In this study in vitro and in vivo approaches were combined in order to investigate if the anti-epileptic mechanism(s) of action of levetiracetam (LEV; Keppra*) may involve modulation of inhibitory neurotransmission. 2 GABA- and glycine-gated currents were studied in vitro using whole-cell patch-clamp techniques applied on cultured cerebellar granule, hippocampal and spinal neurons. Protection against clonic convulsions was assessed in vivo in sound-susceptible mice. The effect of LEV was compared with reference anti-epileptic drugs (AEDs): carbamazepine, phenytoin, valproate, clonazepam. pheno-barbital and ethosuximide. 3 LEV contrasted the reference AEDs by an absence of any direct effect on glycine-gated currents. At high concentrations, beyond therapeutic relevance, it induced a small reduction in the peak amplitude and a prolongation of the decay phase of GABA-gated currents. A similar action on GABA-elicited currents was observed with the reference AEDs, except ethosuximide. 4 These minor direct effects contrasted with a potent ability of LEV (EC50 =1-10 μM) to reverse the inhibitory effects of the negative allosteric modulators zinc and β-carbolines on both GABAA and glycine receptor-mediated responses. 5 Clonazepam, phenobarbital and valproate showed a similar ability to reverse the inhibition of β-carbolines on GABA-gated currents. Blockade of zinc inhibition of GABA responses was observed with clonazepam and ethosuximide. Phenytoin was the only AED together with LEV that inhibited the antagonism of zinc on glycine-gated currents and only clonazepam and phenobarbital inhibited the action of DMCM. 6 LEV (17 mg kg) produced a potent suppression of sound-induced clonic convulsions in mice. This protective effect was significantly abolished by co-administration of the β-carboline FG 7142, from a dose of 5 mg kg1. In contrast, the benzodiazepine receptor antagonist flumazenil (up to 10 mg kg 1) was without any effect on the protection afforded by LEV. 7 The results of the present study suggest that a novel ability to oppose the action of negative modulators on the two main inhibitory ionotropic receptors may be of relevance for the anti-epileptic mechanism(s) of action of LEV. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 38-year-old woman with multiple sclerosis (MS). The patient's serum hepatic enzyme tests found that she had grade 4 liver failure. She was treated with glatiramer acetate, a disease-modifying therapy approved for treatment of MS, in October 2006. She was also taking ibuprofen 400 milligram twice a day to treat her influenza. However, asthenia developed within three days.

Background: Newborn granule neurons are generated from proliferating neural stem/progenitor cells and integrated into mature synaptic networks in the adult dentate gyrus of the hippocampus. Since light/dark variations of the mitotic index and DNA synthesis occur in many tissues, we wanted to unravel the role of the clock-controlled Period2 gene (mPer2) in timing cell cycle kinetics and neurogenesis in the adult DG.Results: In contrast to the suprachiasmatic nucleus, we observed a non-rhythmic constitutive expression of mPER2 in the dentate gyrus. We provide evidence that mPER2 is expressed in proliferating neural stem/progenitor cells (NPCs) and persists in early post-mitotic and mature newborn neurons from the adult DG. In vitro and in vivo analysis of a mouse line mutant in the mPer2 gene (Per2Brdm1), revealed a higher density of dividing NPCs together with an increased number of immature newborn neurons populating the DG. However, we showed that the lack of mPer2 does not change the total amount of mature adult-generated hippocampal neurons, because of a compensatory increase in neuronal cell death.Conclusion: Taken together, these data demonstrated a functional link between the constitutive expression of mPER2 and the intrinsic control of neural stem/progenitor cells proliferation, cell death and neurogenesis in the dentate gyrus of adult mice. [ABSTRACT FROM AUTHOR]