Wednesday, 25 November 2015

ResearchSpeak: brain volume loss and disability progression

Do you want to know if you are losing brain volume? #BrainHealth #ResearchSpeak #MSBlog #MSResearch

"I am a big proponent of brain atrophy, or brain volume loss, as an integrator of end-organ damage in MS. Brain volume loss occurs in MS at a rate of between 2-7x the normal rate. Brain volume loss is linked to previous inflammatory activity and is a poor prognostic variable. In other words MSers with progressive brain volume loss do badly; brain volume loss is associated with cognitive impairment and physical disability progression. The analysis below from the fingolimod clinical studies shows that brain volume at baseline was predictive of brain volume loss over 2 years and was highly predictive of disability progression and reaching hard disability outcomes, for example needing to use a walking stick."

"I am not surprised by this data. Why? Disability progression must be linked to loss of axons and nerve cells and this is manifested in brain volume loss. The implications of this is that we need to use treatments to slow, or preferably normalise, brain atrophy rates. The good news is that emerging data suggests we can achieve this with current licensed DMTs. Unfortunately, we are not yet able to reliably implement brain atrophy measures into clinical practice at the individual patient level. This will change with emerging algorithms, or setting thresholds above what occurs as part of day to day variability that occurs as part of the measurement. These latter thresholds will get lower with multiple measurements that will be able to exclude day-to-day variability, particularly if they show a consistent trend over time. Our centre is in the process of testing brain atrophy measurements to see if we can start using them in clinical practice. Would you want your brain volume measured as part of your annual assessment?"

Epub: Jeffery et al. The relationship between the rate of brain volume loss during first 24 months and disability progression over 24 and 48 months in relapsing MS. J Neurol. 2015 Nov 14.

Background: Clinical evidence in patients with relapsing-remitting multiple sclerosis suggests an association between MRI outcome measures and disability progression (DP). 

Objective: Post hoc analysis to investigate the association and potential predictive value of brain volume loss (BVL) with long-term DP in FREEDOMS (Gilenya study). 

Methods: Patients were categorized into quartiles by SIENA-calculated percent brain volume change from baseline to month (M) 24. Patient characteristics at baseline were determined for each quartile, as were the proportions of patients at M24 and M48 reaching Expanded Disability Status Scale (EDSS) scores of ≥4.0 or ≥6.0 or DP confirmed at 3 months (CDP3) or 6 months (CDP6), and change in EDSS and Multiple Sclerosis Functional Composite. 

Results: MS disease activity and severity as well as brain volume at baseline were predictive of subsequent BVL over 24 months. The quartiles of patients with greater BVL at 24 months were at highest risk (odds ratio, p value) for reaching EDSS ≥4 (2.8, p = 0.001) or ≥6 (5.73, p = 0.0005) and experienced more DP at M24 (CDP3 2.13, p = 0.002; CDP6 2.17, p = 0.003) and M48 (CDP3 1.98, p = 0.006; CDP6 1.87, p = 0.018) compared to the quartile of patients with the least amount of BVL. 

Conclusions: These findings confirm the clinical relevance of early brain volume changes for long-term DP.

CoI: multiple

Spasticity treatment that doesn't cut the mustard

Rommer PS, Kamin F, Abu-Mugheisib M, Koehler W, Hoffmann F, Winkelmann A, Benecke R, Zettl UK. Long-Term Effects of Repeated Cycles of Intrathecal Triamcinolone Acetonide on Spasticity in MS Patients. CNS Neurosci Ther. 2015 doi: 10.1111/cns.12474. [Epub ahead of print]

MAIN PROBLEM:Spasticity is a common feature in patients with multiple sclerosis (MS). Although options have broadened over the last years, there are still patients with no response to common therapeutic agents. Intrathecal administered triamcinolone acetonide (TCA) has been tested for spasticity in patients with MS. However, the long run effects are not known so far. The aim of this study was to evaluate the effects of repeated cycles of intrathecal TCA instillations on clinical parameters.
METHODS:A total of 54 patients with clinically definite MS and no response to commonly utilized antispastic drugs were enrolled. TCA was administered every 3 months for a period of 9 months. Clinical assessments including spasticity, disability (EDSS), mobility (walking distance, and timed 25-foot walk), bladder function, and quality of life were carried out prior to and at the end of each treatment cycle.
RESULTS:Repeated TCA treatment led to repeated effects on spasticity (P < 0.01). Bladder function improved in every 10th patient. Quality of life improved during each cycle but did not reach significance at the end of study (P = 0.09). However, long-lasting improvement on spasticity or EDSS was not shown at end of the study. Effects diminished over 3 months.
CONCLUSION: Repeated TCA instillations led to replicable effects on spasticity; subgroup analyses suggest that higher spasticity, more frequent treatments, and higher EDSS may lead to pronounced effects on spasticity and EDSS. Intrathecal TCA treatment was safe and no severe side effects occurred. We hypothesize a significant time dependence of re-administration of TCA and that an interval of 3 months between the treatments might be too long.

So not every thing works in spasticity here is one example, will we be next?.... hope not.

CoI we are developing a novel anti-spastic agent

Translating Basic Science

Here are slides from the Meeting in Harwell