“In response to my post yesterday on ‘Brain atrophy: the ultimate outcome in MS‘ I thought it would be worthwhile revisiting the pivotal IFNbeta-1b (Betaseron/Betaferon) long-term follow-up data. In the 16-year follow-up baseline 3rd ventricular width, a crude measure of brain atrophy, correlated with disability progression and cognitive impairment at 16 years. Please note that the abstract states it does not correlate with physical disability progression; however in the table in the paper the p-value is significant albeit it with a low R-squared value. For those of you who are not statisticians this means that brain atrophy at baseline is not a very good predictor of EDSS progression but does explain a small component of it.”
“Unfortunately, the on-study changes in the MRI variables did not explain much change at 16 years; why not? Firstly, IFN-beta-1b subsequently was not been shown to affect brain atrophy, the drug is only a moderately effective DMT and the placebo-controlled part of the trial was relatively short. I therefore would not put too much weight on this studies conclusions. With the more effective DMTs on study changes are predictive of long-term outcomes; despite the follow-up being shorter than 16 years at present. What is also important to note is that the average disease duration of the MSers in this IFN-beta-1b study, when it started, was over 8 years, which is far too far along the disease course to have a major impact. We need to hit this disease earlier before too much reserve capacity is lost to have an impact. This study supports the concept of brain atrophy being the integrator of end-organ damage in MS; those who came into the study with end-organ damage did worst.”
“Who wouldn’t want to protect their brain from shrinking?”
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| Note the enlargement of the 3rd ventricle between the two scans. This is a crude index of brain atrophy that can be seen in serial scans done as part of routine clinical care. |
BACKGROUND: Evaluating the long term benefit of therapy in MS is challenging. Although randomised controlled trials (RCTs) demonstrate therapeutic benefits on short term outcomes, the relationship between these outcomes and late disability is not established.
METHODS: In a MSer cohort from the pivotal interferon β-1b trial, the value of clinical and MRI measures were analysed, both at baseline and during the RCT, for predicting long term physical and cognitive outcome.
RESULTS: Baseline disability correlated with both physical (R(2)=0.22; p<0.0001) and cognitive (R(2)=0.12; p<0.0001) outcome after 16 years. Accrual of disability during the RCT (R(2)=0.12; p<0.0001) and annualised relapse rates during the trial correlated with physical outcome (R(2)=0.12; p<0.0001) but not with cognition. In contrast, baseline MRI measures of atrophy and lesion burden correlated with cognitive (R(2)=0.21; p<0.0001), but not with physical, outcome. Accumulation of plaque burden measured by MRI did not correlate with late physical disability or with cognitive outcome. Multivariate regression analysis using stepwise elimination demonstrated that baseline variables contributed independently to predicting long term outcomes while trial outcome variables contributed little. Overall, and considerably dependent on baseline measures, the models developed by this method accounted for approximately half of the variance in long term cognitive and disability outcome.
CONCLUSIONS: Although on-trial change in some short term clinical measures correlated with long term physical and disability outcomes, the proportion of the variance explained by single commonly employed on-study variables was often small or undetectable. Better correlations were observed for several baseline measures, suggesting that long term outcome in MS may be largely determined early in the disease course. Trial registration number http://Clinical Trials.gov, study registration NCT00206635.
Your observations are extremely valid and very exciting.My question is: How can brain atrophy be quantified?The other day my neurologist looked at my MRI and said, with a big smile, "your brain is shrinking".Thanks again for this blog. It is so informative, I really love it.
I think that sadly many neurologists were trained and practiced in a time when there were very few treatments available for neurological diseases. This may seem cynical, but I feel they seemed to be extremely good at documenting and recording people's decline, but not doing much or anything to slow it.I think this mindset absolutely has toy change. The mindset has finally changed with stroke with the availability of drug and increasingly commonly mechanical treatments (the latter moreso outside of the UK). Unlike those with stokre, people with MS don't usually wake up one morning, suddenly having developed a disability that requires the use of a wheelchair, but for many this is exactly what happens to them over a long period of time. I would argue that while both diseases are potentially devastating, MS inflicts its problems over a much longer period of time and is therefore arguably more burdensome for the individual affected. This longer time period appears to make it an easier to ignore by treating doctors and those bodies responsible for advising on which drugs should be available. I don't really want to argue about the nastiness of various diseases, but I would like to see the devastating disability inflicted by MS from even early on recognised and appropriate early treatment made available for the many young sufferers of this disease.Sorry for hijacking your comment – it just felt that that would be a very irritating thing to be announced about a scan if done the wrong way, particularly if no particular solution was avilable or offered.
They've invented scales to measure how disabled were are getting (EDSS), our cognitive decline, our spasticity, the number of lesions, the brain shrinkage, the slowing of our walking…. All we wanted was to get better again and be normal. Massive gap between what researchers are interested in and what those with this disease want.
I understand your frustration. I asked for a long time why we cared so much about dots on an MRI if they don't correlate well with symptoms. As an MS patient for more than 8 years, I don't care much about the dots on my MRI. Still, I can appreciate the goal the study. When attempting to solve a problem, one must first define exactly what the problem is. For us patients, the temptation is to think problem begins and ends with our symptoms. Over the past few years, I have come to appreciate the inherant logic in dealing with complex systems. Complex systems are different from complicated systems in that, one can never accurately predict the impact of damage to any one place in the system. They are different from the a->b->c…->z complicated systems where one knows the impact of breaking the chain. A complex system is more akin to a road system. Interestingly enough, the complex system theory was designed to replicate the brain, but is more commonly used today for other system models like roads.Brain shrinkage would imply a less able system simply by reducing the size of the system. Even if we can not identify the specific area of defecit, the sum of all the paths now reaches less than it once did. If the brain shrinks, the number of alternate paths for signals to take likely shrinks too. The alternate routes for trafic disaapear and the fragility of the system increases, even if it appears traffic is moving at the time. Shrinkage would seem likely to predict future problems. This study seems to be validating this assumption. In doing so, it redefines the problem and measurment of MS. It is no longer enough to simply look for a flare (think car crash). One must also look to see if the map still needs folding to carry.