Smouldering multiple sclerosis: the 'real MS'.

Using a philosophical approach or deductive reasoning, we challenge the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central nervous system (CNS). We provide a range of evidence to argue that the 'real MS' is in fact driven primarily by a smouldering pathological disease process. In natural history studies and clinical trials, relapses and focal activity revealed by magnetic resonance imaging (MRI) in MS patients on placebo or on disease-modifying therapies (DMTs) were found to be poor predictors of long-term disease evolution and were dissociated from disability outcomes. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. Many putative pathological drivers of smouldering MS can be potentially modified by specific therapeutic strategies, an approach that may have major implications for the management of MS patients. We hypothesise that therapeutically targeting a state of 'no evident inflammatory disease activity' (NEIDA) cannot sufficiently prevent disability accumulation in MS, meaning that treatment should also focus on other brain and spinal cord pathological processes contributing to the slow loss of neurological function. This should also be complemented with a holistic approach to the management of other systemic disease processes that have been shown to worsen MS outcomes.

Ocrelizumab treatment in multiple sclerosis: A Danish population-based cohort study.

BACKGROUND AND PURPOSE: Real-world evidence regarding the effectiveness and safety of ocrelizumab for the treatment of multiple sclerosis (MS) is limited. The aim was to evaluate the effectiveness and safety of ocrelizumab treatment for MS in a real-world setting. METHODS: A nationwide population-based cohort study was conducted where clinical and magnetic resonance imaging data of MS patients enrolled prospectively in the Danish Multiple Sclerosis Registry who initiated ocrelizumab treatment between January 2018 and November 2020 were analyzed. RESULTS: A total of 1104 patients (85.7% relapsing-remitting MS [RRMS], 8.8% secondary progressive MS [SPMS], 5.5% primary progressive MS [PPMS]) were included, with a median follow-up period of 1.3 years. At baseline, the mean age was 41.4 years in the RRMS group, 44.5 years in the PPMS group and 50.3 years in the SPMS group. Median Expanded Disability Status Scale score was 2.5, 3.5 and 5.5, respectively. Most RRMS and SPMS patients had received previous disease-modifying therapies (87.5% and 91.8%, respectively), whereas PPMS patients were mostly treatment naïve (78.7%). After ocrelizumab initiation, 9.3% of the patients experienced a relapse and 8.7% a 24 weeks confirmed disability worsening. Conversely, 16.7% showed a 24 weeks confirmed disability improvement. After ~1 year of treatment, most patients (94.5%) were free of magnetic resonance imaging activity. Ocrelizumab was generally well tolerated, as side effects were only reported for 10% of patients, mostly consisting of infusion-related reactions and infections. CONCLUSIONS: It is shown that most MS patients treated with ocrelizumab are clinically stabilized and with an adverse event profile consistent with the experience from the pivotal clinical trials.

The effectiveness of natalizumab vs fingolimod-A comparison of international registry studies.

BACKGROUND: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. METHODS: By re-analyzing original published results from MSBase, France, and Denmark using uniform methodologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. RESULTS: The pooled analyses comprised 968 natalizumab- and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. CONCLUSION: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed.

Surface EMG crosstalk during phasic involuntary muscle activation in the nociceptive withdrawal reflex.

The human nociceptive withdrawal reflex is typically assessed using surface electromyography (sEMG). Based on sEMG, the reflex receptive field (RRF) can be mapped. However, EMG crosstalk can cause erroneous results in the RRF determination. Single differential (SD) vs. double differential (DD) surface EMG were evaluated. Different electrode areas and inter-electrode-distances (IED) were evaluated. The reflexes were elicited by electrical stimulation of the sole of the foot. EMG was obtained from both tibialis anterior (TA) and soleus (SOL) using both surface and intramuscular EMG (iEMG). The amount of crosstalk was significantly higher in SD recordings than in DD recordings (P < 0.05). Crosstalk increased when electrode measuring area increased (P < 0.05) and when IED increased (P < 0.05). Reflex detection sensitivity decreases with increasing measuring area and increasing IED. These results stress that for determination of RRF and similar tasks, DD recordings should be applied.

Novel cross correlation technique allows crosstalk resistant reflex detection from surface EMG.

Existing methods for withdrawal reflex detection from surface electromyography (sEMG) do not consider the potential presence of electrical crosstalk, which in practical applications may entail reduced detection accuracy. This study estimated muscle fiber conduction velocities (CV) for the tibialis anterior (TA) and soleus (SOL) muscles of both genuine reflexes and identified crosstalk, measured during antagonistic reflex responses. These estimations were used to develop and assess a novel method for reflex detection resistant to crosstalk. Cross correlations of two single differential (SD) sEMG signals recorded along the muscle fibers were performed and two features were extracted from the resulting correlograms (average CV and maximal cross correlation). Reflex detection based on evaluation of the extracted features was compared to a conventional reflex detection method (thresholding of interval peak z-scores), applied on both SD and double differential (DD) sEMG. Intramuscular electromyography (iEMG) was used as validation for reflex detection. Apparent CV due to electrical crosstalk alone were more than one order of magnitude higher than CV estimated for genuine reflexes. Conventional reflex detection showed excellent sensitivity but poor specificity (0.19-0.76) due to the presence of crosstalk. In contrast, cross correlation analysis allowed reflex detection with significantly improved specificity (0.91-0.97). The developed methodology may be readily implemented for more reliable reflex detection.

Introducing the reflex probability maps in the quantification of nociceptive withdrawal reflex receptive fields in humans.

The aim of the present study was to improve the assessment of reflex receptive fields (RRF) in humans, using reflex sensitivity and reflex probability maps. Repeated electrical stimulation was applied to elicit the nociceptive withdrawal reflex (NWR) in fifteen healthy volunteers using two stimulation paradigms: fixed (FSI) and adjusted (ASI) stimulation intensities. Stimulation was applied on sixteen sites in the foot sole, and pain intensity ratings and EMG responses were recorded. RRF sensitivity and probability maps were derived, and RRF areas were calculated. During FSI, the stimulation intensities were constant and the pain ratings dropped significantly (p<0.01). In contrast, during ASI the pain ratings were stable, but there was a significant increase in the stimulation intensities (p<0.01). None of the paradigms altered significantly the RRF areas, but the FSI paradigm had lower estimation error (p<0.01). In all cases, the estimation error remained under 10% and 5% after five and ten repetitions, respectively. The 2nd stimulus in the train consistently rendered larger and more reliable RRF areas than the 1st stimulus. The present analysis can be useful in order to identify the most adequate stimulation parameters and quantification variables for RRF assessment in experimental and clinical pain research.

Phospholipases A2 and inflammatory responses in the central nervous system.

Phospholipases A2 (PLA2s) belong to a superfamily of enzymes responsible for hydrolyzing the sn-2 fatty acids of membrane phospholipids. These enzymes are known to play multiple roles for maintenance of membrane phospholipid homeostasis and for production of a variety of lipid mediators. Over 20 different types of PLA2s are present in the mammalian cells, and in snake and bee venom. Despite their common function in hydrolyzing fatty acids of phospholipids, they are diversely encoded by a number of genes and express proteins that are regulated by different mechanisms. Recent studies have focused on the group IV calcium-dependent cytosolic cPLA2, the group VI calcium-independent iPLA2, and the group II small molecule secretory sPLA2. In the central nervous system (CNS), these PLA2s are distributed among neurons and glial cells. Although the physiological role of these PLA2s in regulating neural cell function has not yet been clearly elucidated, there is increasing evidence for their involvement in receptor signaling and transcriptional pathways that link oxidative events to inflammatory responses that underline many neurodegenerative diseases. Recent studies also reveal an important role of cPLA2 in modulating neuronal excitatory functions, sPLA2 in the inflammatory responses, and iPLA2 with childhood neurologic disorders associated with brain iron accumulation. The goal for this review is to better understand the structure and function of these PLA2s and to highlight specific types of PLA2s and their cross-talk mechanisms in these inflammatory responses under physiological and pathological conditions in the CNS.