Floriana Angelis - Academia.edu (original) (raw)

Papers by Floriana Angelis

OBJECTIVE: To assess the discriminatory value of the central vein sign (CVS) on susceptibility-we... more OBJECTIVE: To assess the discriminatory value of the central vein sign (CVS) on susceptibility-weighted imaging (SWI) acquired on a clinical scanner (3T) between neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS). BACKGROUND: It would be useful to identify brain magnetic resonance imaging (MRI) features that help to differentiate between NMOSD and MS. A previous study at 7T has suggested that central vein is not commonly seen in NMOSD lesions, but it is typical of MS. METHODS: 18 NMOSD (14F, mean [SD] age 52 [±11] yrs, all except two AQP4 antibody positive) and 16 relapsing remitting MS patients (12F, mean [SD] age 41 [±9] yrs) were scanned at 3T. White matter (WM) lesions were first identified on the T2 image and classified as infratentorial, periventricular or subcortical. Subsequently, the presence of at least one vein , depicted as a dark line coursing through the lesion or a dot tracked on contiguous slices, was assessed on SWI. Logistic regression mode...

Efficacy and Mechanism Evaluation

Background Neuroprotective drugs are needed to slow or prevent neurodegeneration and disability a... more Background Neuroprotective drugs are needed to slow or prevent neurodegeneration and disability accrual in secondary progressive multiple sclerosis. Amiloride, fluoxetine and riluzole are repurposed drugs with potential neuroprotective effects. Objectives To assess whether or not amiloride, fluoxetine and riluzole can reduce the rate of brain volume loss in people with secondary progressive multiple sclerosis over 96 weeks. The secondary objectives that were assessed were feasibility of a multiarm trial design approach, evaluation of anti-inflammatory effects, clinician- and patient-reported efficacy and three mechanistic substudies. Design A multicentre, multiarm, randomised, double-blind, placebo-controlled, parallel-group Phase IIb trial with follow-up at 4, 8, 12, 24, 36, 48, 72 and 96 weeks. Patients, investigators (including magnetic resonance imaging analysts), and treating and independent assessing neurologists were blinded to the treatment allocation. The target sample size...

The Lancet Neurology

Background Neurodegeneration is the pathological substrate that causes major disability in second... more Background 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. Methods 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.

Magnetic Resonance in Medicine

Clinical Pharmacology & Therapeutics

CNS Drugs

Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system ... more Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system characterised by demyelination, neuro-axonal loss, and a heterogeneous clinical course. MS presents with different phenotypes, most commonly a relapsing-remitting course (RRMS) and, less frequently, a progressive accumulation of disability from disease onset (primary progressive MS [PPMS]). The majority of people with RRMS, after a variable time, switch to a stage characterised by gradual neurological worsening known as secondary progressive MS (SPMS). We have a limited understanding of the mechanisms underlying MS, and it is believed that multiple genetic, environmental and endogenous factors are elements driving inflammation and ultimately neurodegeneration. Axonal loss and grey matter damage have been regarded as amongst the leading causes of irreversible neurological disability in the progressive stages. There are over a dozen disease-modifying therapies currently licenced for RRMS, but none of these has provided evidence of effectiveness in SPMS. Recently, there has been some early modest success with siponimod in SPMS and ocrelizumab in PPMS. Finding treatments to delay or prevent the courses of SPMS is an unmet and essential goal of the research in MS. In this review, we discuss new findings regarding drugs with immunomodulatory, neuroprotective or regenerative properties and possible treatment strategies for SPMS. We will look at the field broadly to include trials where participants have progressive or relapsing phenotypes. We will summarise the most relevant results from newer investigations from phase 2 and 3 randomised-controlled trials over the past decade, with particular attention to the last five years. 3 Key Points  Many anti-inflammatory, reparative or neuroprotective agents are currently in the pipeline for secondary and primary progressive MS.  New trial design may expedite the discovery of therapeutic compounds for progressive MS.  The use of repurposed drugs and combination therapies are promising strategies to prevent or mitigate SPMS.

Practical neurology, Jan 22, 2018

The diagnosis of multiple sclerosis, after exclusion of its mimics, is based on the objective evi... more The diagnosis of multiple sclerosis, after exclusion of its mimics, is based on the objective evidence of central nervous system involvement and dissemination of demyelinating lesions in time and space. The correct application of the current diagnostic criteria enables early diagnosis of MS and prompt commencement of disease-modifying therapies. We provide a diagram that summarises the McDonald 2017 diagnostic criteria, which may serve both MS experts and general neurologists in the diagnostic process of multiple sclerosis. We also briefly comment on the advantages of using the new diagnostic criteria and stress the uncertain fields that warrant further research.

BMJ Open

IntroductionThe major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that... more IntroductionThe major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network (CTN) was initiated in 2007 with the purpose of developing a national, efficient, multiarm trial of repurposed drugs. Key underpinning work was commissioned by the CTN to inform the design, outcome selection and drug choice including animal models and a systematic review. This identified seven leading oral agents for repurposing as neuroprotective therapies in secondary progressive MS (SPMS). The purpose of the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) will be to evaluate the neuroprotective efficacy of three of these drugs, selected with distinct mechanistic actions and previous evidence of likely efficacy, against a common placebo arm. The interventions chosen were: amiloride (acid-sensing ion channel antagonist); fluoxetine (selective serotonin...

Neurology, Jan 3, 2018

To assess the value of the central vein sign (CVS) on a clinical 3T scanner to distinguish betwee... more To assess the value of the central vein sign (CVS) on a clinical 3T scanner to distinguish between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Eighteen aquaporin-4-antibody-positive patients with NMOSD, 18 patients with relapsing-remitting MS, and 25 healthy controls underwent 3T MRI. The presence of a central vein in white matter lesions on susceptibility-weighted imaging, defined as a thin hypointense line or a small dot, was recorded. The proportion of lesions with the CVS was higher in MS than NMOSD (80% vs 32%, < 0.001). A greater proportion of lesions with the CVS predicted the diagnosis of MS, rather than NMOSD (odds ratio 1.10, 95% confidence interval [CI] 1.04 to 1.16, = 0.001), suggesting that each percent unit increase in the proportion of lesions with the CVS in an individual patient was associated with a 10% increase in the risk of the same patient having MS. If more than 54% of the lesions on any given scan show the CVS, then the pati...

F1000 - Post-publication peer review of the biomedical literature

Objective: Neurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebro... more Objective: Neurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebrospinal fluid (CSF), and are detectable at low concentrations in peripheral blood. Various diseases causing neuronal damage have resulted in elevated CSF concentrations. We explored the value of an ultrasensitive single-molecule array (Simoa) serum NfL (sNfL) assay in multiple sclerosis (MS). Methods: sNfL levels were measured in healthy controls (HC, n 5 254) and two independent MS cohorts: (1) crosssectional with paired serum and CSF samples (n 5 142), and (2) longitudinal with repeated serum sampling (n 5 246, median follow-up 5 3.1 years, interquartile range [IQR] 5 2.0-4.0). We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes. Results: sNfL levels were higher in both MS cohorts than in HC (p < 0.001). We found a strong association between CSF NfL and sNfL (b 5 0.589, p < 0.001). Patients with either brain or spinal (43.4pg/ml, IQR 5 25.2-65.3) or both brain and spinal gadolinium-enhancing lesions (62.5pg/ml, IQR 5 42.7-71.4) had higher sNfL than those without (29.6pg/ml, IQR 5 20.9-41.8; b 5 1.461, p 5 0.005 and b 5 1.902, p 5 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (b 5 1.105, p < 0.001) and presence of relapses (b 5 1.430, p < 0.001). sNfL levels were lower under disease-modifying treatment (b 5 0.818, p 5 0.003). Patients with sNfL levels above the 80th, 90th, 95th, 97.5th, and 99th HC-based percentiles had higher risk of relapses (97.5th percentile: incidence rate ratio 5 1.94, 95% confidence interval [CI] 5 1.21-3.10, p 5 0.006) and EDSS worsening (97.5th percentile: OR 5 2.41, 95% CI 5 1.07-5.42, p 5 0.034). Interpretation: These results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS.

F1000 - Post-publication peer review of the biomedical literature

F1000 - Post-publication peer review of the biomedical literature

F1000 - Post-publication peer review of the biomedical literature

Objective: Grey matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investig... more Objective: Grey matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS. Methods: We analysed 3,604 brain high-resolution T1-weighted MRI scans from 1,417 participants: 1,214 MS patients (253 clinically-isolated syndrome [CIS], 708 relapsing-remitting [RRMS], 128 secondary-progressive [SPMS], 125 primary-progressive [PPMS]), over an average follow-up of 2.41 years (standard deviation [SD]=1.97), and 203 healthy controls (HCs) [average follow-up=1.83 year, SD=1.77], attending 7 European centres. Disability was assessed with the Expanded-Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem and cerebral white matter. Hierarchical mixed-models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time-to-E...

Grey matter atrophy is present from the earliest clinical stages of multiple sclerosis (MS), but ... more Grey matter atrophy is present from the earliest clinical stages of multiple sclerosis (MS), but the temporal ordering is poorly understood. We aimed to determine the sequence in which grey matter regions become atrophic in MS, and its association with disability accumulation. In this longitudinal study, we included 1,417 subjects: 253 with clinically-isolated syndrome (CIS), 708 relapsing-remitting MS (RRMS), 128 secondary-progressive MS (SPMS), 125 primary-progressive MS (PPMS), and 203 healthy controls from 7 European centres. Subjects underwent repeated MRI scanning (total number of scans 3,604); the mean follow-up for patients was 2.41yrs (SD1.97). Disability was scored using the Expanded Disability Status Scale (EDSS). We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template. We used an established data-driven event-based model (EBM) to determine the sequence of occurrence of atrophy and its uncertainty. We assigned each sub...

CNS drugs, Jan 19, 2016

Cognitive impairment is a disabling symptom in multiple sclerosis (MS). While its management rema... more Cognitive impairment is a disabling symptom in multiple sclerosis (MS). While its management remains challenging, beneficial effects on cognition of interferon beta (IFN-β) have been reported and a positive effect from estroprogestins has been hypothesised, suggesting that the combination of the two medications in women with MS could offer a promising treatment strategy. We investigated whether a combination of estroprogestins and IFN-β can improve cognition in women with MS. Women with relapsing-remitting (RR) MS were randomly assigned (1:1:1) to receive subcutaneous IFN-β-1a (Rebif(®), Merck Serono, Geneva, Switzerland) 44 mcg three times a week (tiw) (group 1), subcutaneous IFN-β-1a 44 mcg tiw plus ethinyl estradiol 20 mcg and desogestrel 150 mcg (Mercilon(®), MSD Italia SRL, Rome, Italy) (group 2) or subcutaneous IFN-β-1a 44 mcg tiw plus ethinyl estradiol 40 mcg and desogestrel 125 mcg (Gracial(®), Organon Italia S.p.A., Rome, Italy) (group 3) in a randomised controlled trial, f...

Therapeutic advances in neurological disorders, 2016

OBJECTIVE: To assess the discriminatory value of the central vein sign (CVS) on susceptibility-we... more OBJECTIVE: To assess the discriminatory value of the central vein sign (CVS) on susceptibility-weighted imaging (SWI) acquired on a clinical scanner (3T) between neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS). BACKGROUND: It would be useful to identify brain magnetic resonance imaging (MRI) features that help to differentiate between NMOSD and MS. A previous study at 7T has suggested that central vein is not commonly seen in NMOSD lesions, but it is typical of MS. METHODS: 18 NMOSD (14F, mean [SD] age 52 [±11] yrs, all except two AQP4 antibody positive) and 16 relapsing remitting MS patients (12F, mean [SD] age 41 [±9] yrs) were scanned at 3T. White matter (WM) lesions were first identified on the T2 image and classified as infratentorial, periventricular or subcortical. Subsequently, the presence of at least one vein , depicted as a dark line coursing through the lesion or a dot tracked on contiguous slices, was assessed on SWI. Logistic regression mode...

Efficacy and Mechanism Evaluation

Background Neuroprotective drugs are needed to slow or prevent neurodegeneration and disability a... more Background Neuroprotective drugs are needed to slow or prevent neurodegeneration and disability accrual in secondary progressive multiple sclerosis. Amiloride, fluoxetine and riluzole are repurposed drugs with potential neuroprotective effects. Objectives To assess whether or not amiloride, fluoxetine and riluzole can reduce the rate of brain volume loss in people with secondary progressive multiple sclerosis over 96 weeks. The secondary objectives that were assessed were feasibility of a multiarm trial design approach, evaluation of anti-inflammatory effects, clinician- and patient-reported efficacy and three mechanistic substudies. Design A multicentre, multiarm, randomised, double-blind, placebo-controlled, parallel-group Phase IIb trial with follow-up at 4, 8, 12, 24, 36, 48, 72 and 96 weeks. Patients, investigators (including magnetic resonance imaging analysts), and treating and independent assessing neurologists were blinded to the treatment allocation. The target sample size...

The Lancet Neurology

Background Neurodegeneration is the pathological substrate that causes major disability in second... more Background 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. Methods 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.

Magnetic Resonance in Medicine

Clinical Pharmacology & Therapeutics

CNS Drugs

Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system ... more Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system characterised by demyelination, neuro-axonal loss, and a heterogeneous clinical course. MS presents with different phenotypes, most commonly a relapsing-remitting course (RRMS) and, less frequently, a progressive accumulation of disability from disease onset (primary progressive MS [PPMS]). The majority of people with RRMS, after a variable time, switch to a stage characterised by gradual neurological worsening known as secondary progressive MS (SPMS). We have a limited understanding of the mechanisms underlying MS, and it is believed that multiple genetic, environmental and endogenous factors are elements driving inflammation and ultimately neurodegeneration. Axonal loss and grey matter damage have been regarded as amongst the leading causes of irreversible neurological disability in the progressive stages. There are over a dozen disease-modifying therapies currently licenced for RRMS, but none of these has provided evidence of effectiveness in SPMS. Recently, there has been some early modest success with siponimod in SPMS and ocrelizumab in PPMS. Finding treatments to delay or prevent the courses of SPMS is an unmet and essential goal of the research in MS. In this review, we discuss new findings regarding drugs with immunomodulatory, neuroprotective or regenerative properties and possible treatment strategies for SPMS. We will look at the field broadly to include trials where participants have progressive or relapsing phenotypes. We will summarise the most relevant results from newer investigations from phase 2 and 3 randomised-controlled trials over the past decade, with particular attention to the last five years. 3 Key Points  Many anti-inflammatory, reparative or neuroprotective agents are currently in the pipeline for secondary and primary progressive MS.  New trial design may expedite the discovery of therapeutic compounds for progressive MS.  The use of repurposed drugs and combination therapies are promising strategies to prevent or mitigate SPMS.

Practical neurology, Jan 22, 2018

The diagnosis of multiple sclerosis, after exclusion of its mimics, is based on the objective evi... more The diagnosis of multiple sclerosis, after exclusion of its mimics, is based on the objective evidence of central nervous system involvement and dissemination of demyelinating lesions in time and space. The correct application of the current diagnostic criteria enables early diagnosis of MS and prompt commencement of disease-modifying therapies. We provide a diagram that summarises the McDonald 2017 diagnostic criteria, which may serve both MS experts and general neurologists in the diagnostic process of multiple sclerosis. We also briefly comment on the advantages of using the new diagnostic criteria and stress the uncertain fields that warrant further research.

BMJ Open

IntroductionThe major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that... more IntroductionThe major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network (CTN) was initiated in 2007 with the purpose of developing a national, efficient, multiarm trial of repurposed drugs. Key underpinning work was commissioned by the CTN to inform the design, outcome selection and drug choice including animal models and a systematic review. This identified seven leading oral agents for repurposing as neuroprotective therapies in secondary progressive MS (SPMS). The purpose of the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) will be to evaluate the neuroprotective efficacy of three of these drugs, selected with distinct mechanistic actions and previous evidence of likely efficacy, against a common placebo arm. The interventions chosen were: amiloride (acid-sensing ion channel antagonist); fluoxetine (selective serotonin...

Neurology, Jan 3, 2018

To assess the value of the central vein sign (CVS) on a clinical 3T scanner to distinguish betwee... more To assess the value of the central vein sign (CVS) on a clinical 3T scanner to distinguish between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Eighteen aquaporin-4-antibody-positive patients with NMOSD, 18 patients with relapsing-remitting MS, and 25 healthy controls underwent 3T MRI. The presence of a central vein in white matter lesions on susceptibility-weighted imaging, defined as a thin hypointense line or a small dot, was recorded. The proportion of lesions with the CVS was higher in MS than NMOSD (80% vs 32%, < 0.001). A greater proportion of lesions with the CVS predicted the diagnosis of MS, rather than NMOSD (odds ratio 1.10, 95% confidence interval [CI] 1.04 to 1.16, = 0.001), suggesting that each percent unit increase in the proportion of lesions with the CVS in an individual patient was associated with a 10% increase in the risk of the same patient having MS. If more than 54% of the lesions on any given scan show the CVS, then the pati...

F1000 - Post-publication peer review of the biomedical literature

Objective: Neurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebro... more Objective: Neurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebrospinal fluid (CSF), and are detectable at low concentrations in peripheral blood. Various diseases causing neuronal damage have resulted in elevated CSF concentrations. We explored the value of an ultrasensitive single-molecule array (Simoa) serum NfL (sNfL) assay in multiple sclerosis (MS). Methods: sNfL levels were measured in healthy controls (HC, n 5 254) and two independent MS cohorts: (1) crosssectional with paired serum and CSF samples (n 5 142), and (2) longitudinal with repeated serum sampling (n 5 246, median follow-up 5 3.1 years, interquartile range [IQR] 5 2.0-4.0). We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes. Results: sNfL levels were higher in both MS cohorts than in HC (p < 0.001). We found a strong association between CSF NfL and sNfL (b 5 0.589, p < 0.001). Patients with either brain or spinal (43.4pg/ml, IQR 5 25.2-65.3) or both brain and spinal gadolinium-enhancing lesions (62.5pg/ml, IQR 5 42.7-71.4) had higher sNfL than those without (29.6pg/ml, IQR 5 20.9-41.8; b 5 1.461, p 5 0.005 and b 5 1.902, p 5 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (b 5 1.105, p < 0.001) and presence of relapses (b 5 1.430, p < 0.001). sNfL levels were lower under disease-modifying treatment (b 5 0.818, p 5 0.003). Patients with sNfL levels above the 80th, 90th, 95th, 97.5th, and 99th HC-based percentiles had higher risk of relapses (97.5th percentile: incidence rate ratio 5 1.94, 95% confidence interval [CI] 5 1.21-3.10, p 5 0.006) and EDSS worsening (97.5th percentile: OR 5 2.41, 95% CI 5 1.07-5.42, p 5 0.034). Interpretation: These results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS.

F1000 - Post-publication peer review of the biomedical literature

F1000 - Post-publication peer review of the biomedical literature

F1000 - Post-publication peer review of the biomedical literature

Objective: Grey matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investig... more Objective: Grey matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS. Methods: We analysed 3,604 brain high-resolution T1-weighted MRI scans from 1,417 participants: 1,214 MS patients (253 clinically-isolated syndrome [CIS], 708 relapsing-remitting [RRMS], 128 secondary-progressive [SPMS], 125 primary-progressive [PPMS]), over an average follow-up of 2.41 years (standard deviation [SD]=1.97), and 203 healthy controls (HCs) [average follow-up=1.83 year, SD=1.77], attending 7 European centres. Disability was assessed with the Expanded-Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem and cerebral white matter. Hierarchical mixed-models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time-to-E...

Grey matter atrophy is present from the earliest clinical stages of multiple sclerosis (MS), but ... more Grey matter atrophy is present from the earliest clinical stages of multiple sclerosis (MS), but the temporal ordering is poorly understood. We aimed to determine the sequence in which grey matter regions become atrophic in MS, and its association with disability accumulation. In this longitudinal study, we included 1,417 subjects: 253 with clinically-isolated syndrome (CIS), 708 relapsing-remitting MS (RRMS), 128 secondary-progressive MS (SPMS), 125 primary-progressive MS (PPMS), and 203 healthy controls from 7 European centres. Subjects underwent repeated MRI scanning (total number of scans 3,604); the mean follow-up for patients was 2.41yrs (SD1.97). Disability was scored using the Expanded Disability Status Scale (EDSS). We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template. We used an established data-driven event-based model (EBM) to determine the sequence of occurrence of atrophy and its uncertainty. We assigned each sub...

CNS drugs, Jan 19, 2016

Cognitive impairment is a disabling symptom in multiple sclerosis (MS). While its management rema... more Cognitive impairment is a disabling symptom in multiple sclerosis (MS). While its management remains challenging, beneficial effects on cognition of interferon beta (IFN-β) have been reported and a positive effect from estroprogestins has been hypothesised, suggesting that the combination of the two medications in women with MS could offer a promising treatment strategy. We investigated whether a combination of estroprogestins and IFN-β can improve cognition in women with MS. Women with relapsing-remitting (RR) MS were randomly assigned (1:1:1) to receive subcutaneous IFN-β-1a (Rebif(®), Merck Serono, Geneva, Switzerland) 44 mcg three times a week (tiw) (group 1), subcutaneous IFN-β-1a 44 mcg tiw plus ethinyl estradiol 20 mcg and desogestrel 150 mcg (Mercilon(®), MSD Italia SRL, Rome, Italy) (group 2) or subcutaneous IFN-β-1a 44 mcg tiw plus ethinyl estradiol 40 mcg and desogestrel 125 mcg (Gracial(®), Organon Italia S.p.A., Rome, Italy) (group 3) in a randomised controlled trial, f...

Therapeutic advances in neurological disorders, 2016