Lesions on MRI, now you see it now you don’t


Gadolinium  enhancement of MS lesions on MRI scans is only used outcome measure in therapeutic trials. However, enhancement depends on MRI acquisition parameters that might significantly alter detectability. We investigated how the difference in blood-brain barrier (BBB) permeability threshold between MRI protocols affects lesion detection and apparent enhancement time using dynamic-contrast-enhanced (DCE) MRI. We examined forty-four relapsing-remitting MS patients with two MRI protocols: ‘standard sensitivity’ (SS) (1.5 T, single-dose Gd) and ‘high sensitivity’ (HS) (3 T, triple-dose Gd, delayed acquisition). Eleven patients had at least one enhancing lesion and completed the 1-month follow-up. We acquired DCE-MRI during the HS protocol and calculated BBB permeability. Sixty-five lesions were enhanced with the SS vs. 135 with the HS protocol. The detection threshold of the HS was significantly lower than that of the SS protocol (K trans = 2.64 vs. 4.00E-3 min(-1), p < 0.01). Most lesions (74 %) were in the recovery phase; none were in the onset phase and 26 % were at the peak of enhancement. The estimated duration of detectability with the HS protocol was significantly longer than for the SS protocol (6-12 weeks vs. 3 weeks). Our observations on the protocol-dependent threshold for detection and time-course help explain discrepancies in the observed effects of anti-inflammatory therapies on MS lesions.
This study tells us that lesions enhance for various amounts of time indicating the blood brain barrier is leaking. Depending on how the imaging is done dictates what is seen. We (ProfG & Kappoor) based the optic neuritis trial on the idea that the barrier was leaking for 2-3 weeks. This study suggests that with a different imaging technology the lesions may leak for longer. This suggests that they grumble for longer than was first thought. However, we have got people on drug within a couple of weeks from onset of symptoms. 

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  • Does your conclusion mean that the Phenytoin trial might eventually fail because the BBB stays open longer than what you estimated (hence the treatment would not be as effective) or does it mean that actually more people than originally thought could take advantage of such a treatment for optic neuritis as the window of time to treat it would be longer?
    Another side question: Do you think the Phenytoin trial approach (blocking Na channels) might also be valid for other relapses different than optic neuritis?

    • Perhaps the opposite because our animal work suggested optimum effect with occurred during blood brain barrier problems. If the barrier is leaky for longer more optimum benefit. It would also mean that we could start treatment later and so make it easierr to recruit. Phenytonin was my least preferred sodium channel blocker, however it was selected because of the ability to get drug on board quickly. Lets hope for success.. I think most people have been recruited so hopefully results by research day 2015.

      As to your second question we think the approach is of value for other relapses and the PROXIMUS trial is ready to go..there was a delay in getting started because of issues with the biomarker test, but I think we have now got ethical approval forr us to start. The aim is neurorotection on top of immunomodulation.

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