Body fluid biomarkers for multiple sclerosis: the long road to clinical application

There is a strong unmet clinical need for objective body fluid biomarkers to assist early diagnosis and estimate long-term prognosis, monitor treatment response and predict potential adverse effects in multiple sclerosis (MS). Here, we review recent studies (focusing on 2012 to early 2015) on body fluid markers in MS from the perspective of their clinical utility. Because the first step towards clinical implementation of a newly discovered biomarker is independent replication, we focus on biomarkers that have been validated in at least two independent cohorts. We also discuss recent data challenging earlier findings, and biomarkers for which new clinical uses are suggested. For early MS diagnosis and prediction of conversion from clinically isolated syndrome to MS, several new B-cell-associated candidate blood biomarkers have emerged. For prognosis, several novel axonal damage markers should be adopted to biomarker panels. The number of disease-modifying treatments for MS has increased sharply, but biomarkers for treatment response monitoring and adverse effect prediction are scarce, and markers for subtyping and staging of MS are still lacking. In view of the availability and implementation of several standardized protocols to optimize biomarker studies, we expect biomarker development for MS to be improved and accelerated, with clinical implementation in the near future.

via Nature Reviews Neurology : Nature Publishing Group.


Review of “Brain MRI Atlas” App for the iPad

Review of the app published in the Journal of Digital Imaging

Quick Review

(1 star: lowest / 5 stars: highest)

Overall rating (1–5): 4

Content (1–5): 4
Usability (1–5): 4

Pros Extremely clear and detailed delineation of complex neuroanatomy. Ability to select for specific neuroanatomical categories (e.g., nerves, ventricles).

Cons Axial FLAIR sequence only. Cannot search by label. At a Glance A great overview of detailed neuroanatomical

structures as seen on MRI, in the axial plane only.

via Online First – Springer.

The Effect of Three Times a Week Glatiramer Acetate on Cerebral T1 Hypointense Lesions in Relapsing-Remitting Multiple Sclerosis


Two definitions of T1 hypointense (T1H) lesions can be derived from pre-contrast images: those that may or may not have a corresponding gadolinium-enhancing correlate on post-contrast images (T1H total), and those that are simultaneously non-gadolinium-enhancing on post-contrast scans (T1H non-enhancing). To determine the differences in lesion evolution between these two T1H definitions, we examined the effect of glatiramer acetate 40 mg/mL three times weekly subcutaneous injection (GA40) on the number of new or enlarging T1H total and T1H non-enhancing lesions in patients with relapsing-remitting multiple sclerosis (RRMS).


The Phase III GALA study randomized 1404 RRMS subjects 2:1 to receive GA40 or placebo for 12 months. MRI scans were obtained at baseline and at months 6 and 12. Cumulative numbers of T1H total and of T1H non-enhancing lesions were analyzed using an adjusted negative binomial regression model. A total of 1,357 patients had MRI data collected at either the month 6 or month 12 visit.


Among the 1,357 patients with MRI scans performed at either the month 6 or month 12 visit, 883 treated with GA40 developed an adjusted cumulative mean of 1.72 T1H total lesions versus 2.62 in 440 placebo controls (risk ratio, .66; 95% CI, .54-.80; P < .0001). On T1H non-enhanced scans, GA40-treated patients developed an adjusted cumulative mean of 1.35 T1H non-enhancing lesions versus 1.91 in placebo controls (risk ratio, .71; CI, .58-.87; P = .0009).


GA40 significantly reduced the number of new or enlarging T1H total lesions and T1H non-enhancing lesions compared with placebo. Although the treatment effect magnitude was comparable with both definitions, the use of T1H non-enhancing lesions may be more relevant for more uniform standardization in future clinical trials.

via Journal of Neuroimaging – Wiley Online Library.

Natalizumab in the pediatric MS population: results of the Italian registry


Natalizumab is a promising option for pediatric multiple sclerosis (MS) patients with active evolution and a poor response to Interferon-beta or Glatiramer Acetate. However, no data are available in large cohorts of patients and after a long-term follow up. Our study was planned to shed lights on this topic.


A registry was established in 2007 in Italy to collect MS cases treated with Natalizumab (NA) before 18 years of age.


101 patients were included (69 females), mean age of MS onset 12.9 ± 2.7 years, mean age at NA initiation 14.7 ± 2.4 years. Mean treatment duration was 34.2 ± 18.3 months.

During NA treatment, a total of 15 relapses were recorded in 9 patients, annualized relapse rate was 2.3 ± 1.0 in the year prior to NA and decreased to 0.1 ± 0.3 (p < 0.001) at last NA infusion.

Mean Expanded Disability Status Scale (EDSS) decreased from 2.6 ± 1.3 at initiation of NA to 1.8 ± 1.2 at the time of last visit (p < 0.001). At brain MRI, new T2 or Gd enhancing lesions were observed in 10/91 patients after 6 months, 6/87 after 12 months, 2/61 after 18 months, 2/68 after 24 months, 3/62 after 30 months, and 5/43 at longer follow up. At the time of last observation, 58 % of patients were free from clinical (relapses/increased EDSS) and/or MRI activity (new T2 or gadolinium-enhancing lesions). No relevant adverse events were recorded.


NA was safe, well tolerated and very efficacious in the large majority of patients. Our data support the use of this medication in subjects with pediatric MS and an aggressive course.


A relevant reduction of relapse rate and EDSS was observed during NA treatment, compared to pre-treatment period. No evidence of disease activity (NEDA) occurred in 58 % of cases.

via BMC Neurology.

Ocrelizumab first investigational medicine to show efficacy in people with primary progressive multiple sclerosis in large Phase III study

Very important result for progressive MS management.

For the first time, a drug revealed to be effective in preventing disability worsening in primary progressive MS in a large phase III trial.

Complete results are expected at the ECTRIMS congress in Barcelona next week.

via Roche 

‘Hidden’ factors influencing quality of life in patients with multiple sclerosis

Traditional outcome measures for patients with multiple sclerosis (MS), whether in clinical trials or clinical practice, are currently in question. The combination of relapses, physical disability progression and magnetic resonance imaging (MRI) disease activity reflect only part of the impact that MS has on a patient’s daily life. Quality of life (QoL) is considered by many to be the ideal outcome measure. Since it captures the patient’s own perspective of well-being, QoL should be the primary focus when evaluating a patient and the main objective of MS management. Nevertheless, whilst numerous instruments to measure QoL in MS patients are available or proposed, there is no current consensus regarding which is the best tool to use and under what circumstances. QoL in patients with MS is determined by several factors beyond the more obvious; these include coping with the MS diagnosis, understanding the disease and the disease process, dealing with so-called ‘hidden’ symptoms such as fatigue, cognitive impairment and sexual disturbances, and managing the many associated personal challenges such as social isolation, family issues and working difficulties. Evidence is emerging that psychological interventions may be beneficial in MS patients although more research is required to confirm their utility. This article examines some factors that influence QoL in MS patients which may be overlooked in the general busyness of routine clinical practice.

via European Journal of Neurology – Wiley Online Library.

Automated Quantification of Stroke Damage on Brain Computed Tomography Scans: e-ASPECTS

Emergency radiological diagnosis of acute ischaemic stroke requires the accurate detection and appropriate interpretation of relevant imaging findings. Non-contrast computed tomography (CT) provides fast and low-cost assessment of the early signs of ischaemia and is the most widely used diagnostic modality for acute stroke. The Alberta Stroke Program Early CT Score (ASPECTS) is a quantitative and clinically validated method to measure the extent of ischaemic signs on brain CT scans. The CE-marked electronic-ASPECTS (e-ASPECTS) software automates the ASPECTS score. Anglia Ruskin Clinical Trials Unit (ARCTU) independently carried out a clinical investigation of the e-ASPECTS software, an automated scoring system which can be integrated into the diagnostic pathway of an acute ischaemic stroke patient, thereby assisting the physician with expert interpretation of the brain CT scan. Here we describe a literature review of the clinical importance of reliable assessment of early ischaemic signs on plain CT scans, and of technologies automating these processed scoring systems in ischaemic stroke on CT scans focusing on the e-ASPECTS software. To be suitable for critical appraisal in this evaluation, the published studies needed a sample size of a minimum of 10 cases. All randomised studies were screened and data deemed relevant to demonstration of performance of ASPECTS were appraised. The literature review focused on three domains: i) interpretation of brain CT scans of stroke patients, ii) the application of the ASPECTS score in ischaemic stroke, and iii) automation of brain CT analysis. Finally, the appraised references are discussed in the context of the clinical impact of e-ASPECTS and the expected performance, which will be independently evaluated by a non-inferiority study conducted by the ARCTU.

via European Medical Journal.