Microglial activation is an important component of the neuroinflammatory response to ischemic stroke. Experimental studies have outlined such patterns temporally and spatially. In vivo studies in ...stroke patients have relied on positron emission tomography and (R)-PK11195, a ligand that binds peripheral benzodiazepine binding sites. In this study we sought to establish temporal and spatial patterns of microglial activation in ischemic stroke with particular emphasis on a defined peri-infarct zone.
Using this technique, we studied carotid territory ischemic stroke patients in 3 time windows up to 30 days after ictus. Controls were studied in a single session. 11C(R)-PK11195 injection was followed by 3-dimensional acquisition over 60 minutes. Cerebral blood volume (CBV) was measured afterward with the use of standard C15O paradigms. Analysis employed the reference tissue model in which ipsilateral cerebellum was used to generate parametric binding potential maps corrected for CBV. Data were coregistered to T1-based MRI. Using control data to identify 99% confidence limits, a region of interest analysis was applied to identify significant binding in core infarction, contralateral hemisphere, and within a defined peri-infarct zone.
Four patients (mean age, 66 years) were imaged across 9 sessions. Four age-matched controls were studied. Within this model, ipsilateral cerebellum was validated as a reference tissue. With the use of control-derived confidence limits and correction for CBV, significant binding potential rises were identified beyond 72 hours and extending to 30 days in core infarction, contralateral hemisphere, and peri-infarct zone.
In ischemic stroke patients, minimal activation of microglia is seen before 72 hours. Beyond this, binding potential rises in core infarction, peri-infarct zone, and contralateral hemisphere to 30 days. This may represent a therapeutic opportunity that extends beyond time windows traditionally reserved for neuroprotection.
Twenty percent of patients with Sjögren's syndrome experience associated neurological disease. Transverse myelitis (TM) frequently forms part of a neuromyelitis optica spectrum disorder associated ...with the presence of anti-aquaporin 4 (AQP4) antibodies. We report the first described case of a patient who developed TM and the presence of a newly recognized antibody, anti-myelin oligodendrocyte protein (MOG), who went on to develop Sjögren's syndrome. AQP4 and MOG antibodies should be tested to guide prognostically the chances of further relapse as well as the type and duration of immunotherapy in patients with coexisting Sjögren's syndrome and TM.
Hermann Oppenheim described the 'Useless Hand' in 1911 as a classical but uncommon presentation of multiple sclerosis, in which a hand loses useful function due to proprioceptive loss, with ...relatively preserved motor function. Light touch perception may be subjectively altered or can be relatively intact. The lesion is (usually) a demyelinating plaque in the posterior columns of the cervical spinal cord. Depending on its location, it may affect one limb, or if more central, may produce a bilateral (if asymmetrical) picture. This article reviews a clinical case, historical background, pathophysiology as well as examination tips to aid its recognition.
Background
Recent changes in the understanding and management of multiple sclerosis (MS) have increased the role of MRI in supporting diagnosis and disease monitoring. However, published guidelines ...on the use of MRI in MS do not translate easily into different clinical settings and considerable variation in practice remains. Here, informed by published guidelines for the use of MRI in MS, we identified a clinically informative MRI protocol applicable in a variety of clinical settings, from district general hospitals to tertiary centres.
Methods
MS specialists geographically representing the UK National Health Service and with expertise in MRI examined existing guidelines on the use of MRI in MS and identification of challenges in their applications in various clinical settings informed the formulation of a feasible MRI protocol.
Results
We identified a minimum set of MRI information, based on clinical relevance, as well as on applicability to various clinical settings. This informed the selection of MRI acquisitions for scanning protocols, differentiated on the basis of their purpose and stage of the disease, and indication of timing for scans. Advice on standardisation of MRI requests and reporting, and proposed timing and frequency of MRI scans were generated.
Conclusions
The proposed MRI protocol can adapt to a range of clinical settings, aiding the impetus towards standardisation of practice and offering an example of research-informed service improvement to support optimisation of resources. Other neurological conditions, where a gap still exists between published guidelines and their clinical implementation, may benefit from this same approach.
Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three ...neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource.
We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25–65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0–6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259.
Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% 95% CI −0·4 to 0·5; p=0·99; fluoxetine vs placebo −0·1% –0·5 to 0·3; p=0·86; riluzole vs placebo −0·1% –0·6 to 0·3; p=0·77). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten 9% patients in the amiloride group, seven 6% in the fluoxetine group, 12 11% in the riluzole group, and 13 12% in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes.
The absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine.
Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.
There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might ...enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort.
SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18–65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5–6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29).
From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15–27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 95% CI 0·81–2·26). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (<1%) person died in the MD1003 group and there were no deaths in the placebo group. Despite use of mitigation strategies, MD1003 led to inaccurate laboratory results for tests using biotinylated antibodies.
This study showed that MD1003 did not significantly improve disability or walking speed in patients with progressive multiple sclerosis and thus, in addition to the potential of MD1003 for deleterious health consequences from interference of laboratory tests, MD1003 cannot be recommended for treatment of progressive multiple sclerosis.
MedDay Pharmaceuticals.
Background: Over 80% of individuals with multiple sclerosis (MS) experience MS-associated spasticity (MSS). In many European countries, after failure of first-line treatments, moderate or severe MSS ...can be treated with nabiximols, a cannabis-based add-on treatment. Objective: This post hoc analysis assessed the shift of participants treated with nabiximols from higher (severe or moderate) to lower (moderate or mild/none) spasticity. Methods: Previously published data from two randomised controlled trials (RCTs), GWSP0604 (NCT00681538) and SAVANT (EudraCT2015-004451-40), and one large real-world study (consistent with EU label), all enriched for responders, were re-analysed. Spasticity severity, measured using the 0–10 numerical rating scale (spasticity NRS), was categorised as none/mild (score <4), moderate (score ⩾4–7), or severe (score ⩾7). Results: In the two RCTs, the shift of participants with severe MSS into a lower category was significantly greater at week 12 for those receiving nabiximols versus placebo GWSP0604: OR (95% CI), 4.4 (1.4, 14.2), p = 0.0125; SAVANT: 5.2 (1.2, 22.3), p = 0.0267. In all three studies, over 80% of assessed patients with severe spasticity at baseline reported a shift into a lower category of spasticity after 12 weeks. Conclusions: A meaningful proportion of MSS patients treated with nabiximols shifted to a lower category of spasticity severity, typically maintained to the end of the 12-week study period.
Background:
Over 80% of individuals with multiple sclerosis (MS) experience MS-associated spasticity (MSS). In many European countries, after failure of first-line treatments, moderate or severe MSS ...can be treated with nabiximols, a cannabis-based add-on treatment.
Objective:
This post hoc analysis assessed the shift of participants treated with nabiximols from higher (severe or moderate) to lower (moderate or mild/none) spasticity.
Methods:
Previously published data from two randomised controlled trials (RCTs), GWSP0604 (NCT00681538) and SAVANT (EudraCT2015-004451-40), and one large real-world study (consistent with EU label), all enriched for responders, were re-analysed. Spasticity severity, measured using the 0–10 numerical rating scale (spasticity NRS), was categorised as none/mild (score <4), moderate (score ⩾4–7), or severe (score ⩾7).
Results:
In the two RCTs, the shift of participants with severe MSS into a lower category was significantly greater at week 12 for those receiving nabiximols versus placebo GWSP0604: OR (95% CI), 4.4 (1.4, 14.2), p = 0.0125; SAVANT: 5.2 (1.2, 22.3), p = 0.0267. In all three studies, over 80% of assessed patients with severe spasticity at baseline reported a shift into a lower category of spasticity after 12 weeks.
Conclusions:
A meaningful proportion of MSS patients treated with nabiximols shifted to a lower category of spasticity severity, typically maintained to the end of the 12-week study period.
The trouble is that the health care of a population is a big financial cake, the private sector able to cherrypick the best bits for optimal profit. ...the cost effectiveness of independent sector ...treatment centres needs rigorous ongoing scrutiny, especially in a tax funded healthcare system.
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