Background: Spasticity is a disabling complication of multiple sclerosis, affecting many patients with the condition. We report the first Phase 3 placebo‐controlled study of an oral antispasticity ...agent to use an enriched study design.
Methods: A 19‐week follow‐up, multicentre, double‐blind, randomized, placebo‐controlled, parallel‐group study in subjects with multiple sclerosis spasticity not fully relieved with current antispasticity therapy. Subjects were treated with nabiximols, as add‐on therapy, in a single‐blind manner for 4 weeks, after which those achieving an improvement in spasticity of ≥20% progressed to a 12‐week randomized, placebo‐controlled phase.
Results: Of the 572 subjects enrolled, 272 achieved a ≥20% improvement after 4 weeks of single‐blind treatment, and 241 were randomized. The primary end‐point was the difference between treatments in the mean spasticity Numeric Rating Scale (NRS) in the randomized, controlled phase of the study. Intention‐to‐treat (ITT) analysis showed a highly significant difference in favour of nabiximols (P = 0.0002). Secondary end‐points of responder analysis, Spasm Frequency Score, Sleep Disturbance NRS Patient, Carer and Clinician Global Impression of Change were all significant in favour of nabiximols.
Conclusions: The enriched study design provides a method of determining the efficacy and safety of nabiximols in a way that more closely reflects proposed clinical practice, by limiting exposure to those patients who are likely to benefit from it. Hence, the difference between active and placebo should be a reflection of efficacy and safety in the population intended for treatment.
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MRI studies have provided valuable insights into the structure and function of neural networks, particularly in health and in classical neurodegenerative conditions such as Alzheimer disease. ...However, such work is also highly relevant in other diseases of the CNS, including multiple sclerosis (MS). In this Review, we consider the effects of MS pathology on brain networks, as assessed using MRI, and how these changes to brain networks translate into clinical impairments. We also discuss how this knowledge can inform the targeting of MS treatments and the potential future directions for research in this area. Studying MS is challenging as its pathology involves neurodegenerative and focal inflammatory elements, both of which could disrupt neural networks. The disruption of white matter tracts in MS is reflected in changes in network efficiency, an increasingly random grey matter network topology, relative cortical disconnection, and both increases and decreases in connectivity centred around hubs such as the thalamus and the default mode network. The results of initial longitudinal studies suggest that these changes evolve rather than simply increase over time and are linked with clinical features. Studies have also identified a potential role for treatments that functionally modify neural networks as opposed to altering their structure.
Background:
Understanding long-term disability in multiple sclerosis (MS) is a key goal of research; it is relevant to how we monitor and treat the disease.
Objectives:
The Magnetic Imaging in MS ...(MAGNIMS) collaborative group sought to determine the relationship of brain lesion load, and brain and spinal cord atrophy, with physical disability in patients with long-established MS.
Methods:
Patients had a magnetic resonance imaging (MRI) scan of their brain and spinal cord, from which we determined brain grey (GMF) and white matter (WMF) fractional volumes, upper cervical spinal cord cross-sectional area (UCCA) and brain T2-lesion volume (T2LV). We assessed patient disability using the Expanded Disability Status Scale (EDSS). We analysed associations between EDSS and MRI measures, using two regression models (dividing cohort by EDSS into two and four sub-groups).
Results:
In the binary model, UCCA (p < 0.01) and T2LV (p = 0.02) were independently associated with the requirement of a walking aid. In the four-category model UCCA (p < 0.01), T2LV (p = 0.02) and GMF (p = 0.04) were independently associated with disability.
Conclusions:
Long-term physical disability was independently linked with atrophy of the spinal cord and brain T2 lesion load, and less consistently, with brain grey matter atrophy. Combinations of spinal cord and brain MRI measures may be required to capture clinically-relevant information in people with MS of long disease duration.
Background and purpose
The literature provides contrasting results on the efficacy of levetiracetam (LEV) in multiple sclerosis (MS) patients with cerebellar signs. It was sought to evaluate the ...efficacy of LEV on upper limb movement in MS patients.
Methods
In this multicenter double‐blind placebo‐controlled crossover study, MS patients with prevalently cerebellar signs were randomly allocated into two groups: LEV followed by placebo (group 1) or placebo followed by LEV (group 2). Clinical assessments were performed by a blinded physician at T0 (day 1), T1 (day 22), T2 (2‐week wash‐out period, day 35) and T3 (day 56). The primary outcome was dexterity in the arm with greater deficit, assessed by the nine‐hole peg test (9HPT). Secondary clinical outcomes included responders on the 9HPT (∆9HPT >20%), tremor activity of the daily living questionnaire and self‐defined upper limb impairment, through a numeric rating scale. Kinematic evaluation was performed using a digitizing tablet, providing data on normalized jerk, aiming error and centripetal acceleration.
Results
Forty‐eight subjects (45.2 ± 10.4 years) were randomly allocated into two groups (n = 24 each). 9HPT significantly improved in the LEV phase in both groups (P < 0.001). The LEV treatment phase led to a significant improvement (P < 0.01) of all clinical outcomes in group 1 and in dexterity in group 2. No significant changes were reported during both placebo phases in the two groups. Considering the kinematic analysis, only normalized jerk significantly improved after treatment with LEV (T0–T1) in group 1.
Conclusions
Levetiracetam treatment seems to be effective in improving upper limb dexterity in MS patients with cerebellar signs.
The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for ...many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting.
We collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0-10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months.
A total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3-2.4 p<0.001). During the 6 months observation period, 631(39.5%) patients discontinued treatment. The main reasons for discontinuation were lack of effectiveness (n=375, 26.2%) and/or adverse events (n=268, 18.7%).
Sativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.
The aspiration technique has gained a prominent role in mechanical thrombectomy. The thrombectomy goal is successful revascularization (modified TICI ≥ 2b) and first-pass effect. The purpose of this ...study was to evaluate the impact of the vessel-catheter ratio on the modified TICI ≥ 2b and first-pass effect.
This was a retrospective, single-center, cohort study. From January 2018 to April 2020, 111/206 (53.9%) were eligible after applying the exclusion criteria. Culprit vessel diameters were measured by 2 neuroradiologists, and the intraclass correlation coefficient was calculated. The receiver operating characteristic curve was used for assessing the vessel-catheter ratio cutoff for modified TICI ≥ 2b and the first-pass effect. Time to groin puncture and fibrinolysis were weighted using logistic regression. All possible intervals (interval size, 0.1; sliding interval, 0.01) of the vessel-catheter ratio were plotted, and the best and worst intervals were compared using the χ
test.
Modified TICI ≥ 2b outcome was achieved in 75/111 (67.5%), and first-pass effect was achieved in 53/75 (70.6%). The MCA diameter was 2.1 mm with an intraclass correlation coefficient of 0.92. The optimal vessel-catheter ratio cutoffs for modified TICI ≥ 2b were ≤1.51 (accuracy = 0.67; 95% CI, 0.58-0.76;
= 0.001), and for first-pass effect, they were significant (≤1.33;
= .31). The modified TICI ≥ 2b odds ratio and relative risk were 9.2 (95% CI, 2.4-36.2;
= 0.002) and 3.2 (95% CI, 1.2-8.7;
= .024). The odds ratio remained significant after logistic regression (7.4; 95% CI, 1.7-32.5;
= .008). First-pass effect odds ratio and relative risk were not significant (2.1 and 1.5;
> .05, respectively). The modified TICI ≥ 2b best and worst vessel-catheter ratio intervals were not significantly different (55.6% versus 85.7%,
= .12). The first-pass effect best vessel-catheter ratio interval was significantly higher compared with the worst one (78.6% versus 40.0%,
= .03).
The aspiration catheter should be selected according to culprit vessel diameter. The optimal vessel-catheter ratio cutoffs were ≤1.51 for modified TICI ≥ 2b with an odds ratio of 9.2 and a relative risk of 3.2.
Quercus spp. are one of the most important tree genera in temperate deciduous forests in terms of biodiversity, economic and cultural perspectives. However, natural regeneration of oaks, depending on ...specific environmental conditions, is still not sufficiently understood. Oak regeneration dynamics are impacted by climate change, but these climate impacts will depend on local forest management and light and temperature conditions.
Here, we studied germination, survival and seedling performance (i.e. aboveground biomass, height, root collar diameter and specific leaf area) of four oak species (Q. cerris, Q. ilex, Q. robur and Q. petraea). Acorns were sown across a wide latitudinal gradient, from Italy to Sweden, and across several microclimatic gradients located within and beyond the species’ natural ranges. Microclimatic gradients were applied in terms of forest structure, distance to the forest edge and experimental warming.
We found strong interactions between species and latitude, as well as between microclimate and latitude or species. The species thus reacted differently to local and regional changes in light and temperature ; in southern regions the temperate Q. robur and Q. petraea performed best in plots with a complex structure, whereas the Mediterranean Q. ilex and Q. cerris performed better in simply structured forests with a reduced microclimatic buffering capacity. The experimental warming treatment only enhanced height and aboveground biomass of Mediterranean species.
Our results show that local microclimatic gradients play a key role in the initial stages of oak regeneration; however, one needs to consider the species‐specific responses to forest structure and the macroclimatic context.
Initial regeneration responses of oak are strongly influenced by the macroclimate as well as local gradients in light and temperature, which suggests that management interventions can be used to create more optimal conditions for acorn germination and seedling establishment.
In a multicenter cross-sectional study, the authors assessed pain in patients with multiple sclerosis (MS) using a symptom-oriented approach. Out of 2,077 questionnaires, we used 1,672 for data ...analysis. Pain and frequencies included trigeminal neuralgia 2%, Lhermitte's sign 9%, dysesthetic pain 18.1%, back pain 16.4%, and painful tonic spasms 11%. Comparison between different groups showed significant differences for age, Expanded Disability Status Scale, disease duration, and disease course, but not for sex. This study underlines the relevance of pain in the clinical history of MS.
The prevalence of trigeminal neuralgia (TN) in patients with Multiple Sclerosis (MS) is higher than in the general population and its management can be particularly challenging due to a number of ...reasons including high recurrence rates, lack of MS-specific treatment guidelines and uncertainties about pain pathophysiology.
Aim of this cross-sectional, multicentre survey was to gather information on the current treatment modalities and options of MS-related TN across 23 Italian MS centres.
Initial medical management (carbamazepine or oxcarbazepine) of MS-related TN was fairly homogeneous throughout Italian centres. The most commonly available surgical procedure was microvascular decompression, but the frequency and types of surgical procedures available locally differed considerably throughout MS centers, and were unavailable in one quarter of them.
This survey reveals some of the issues that could hamper an optimal patient management and underlines the need for a consensus on MS-related TN to support health-care professionals in their approach to this challenging condition and to facilitate the development of local guidelines aimed at ensuring equity in access to care and treatment optimization.
•Multiple Sclerosis (MS)-related trigeminal neuralgia (TN) management is challenging.•MS-related TN treatment guidelines are lacking.•There are considerable differences amongst Italian centres in the surgical options available locally.
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