This Is MS Multiple Sclerosis Community: Knowledge & Support

Gray matter involvement in multiple sclerosis 27 February 2007
Istvan Pirko, MD, Claudia F. Lucchinetti, MD, Subramaniam Sriram, MD and Rohit Bakshi, MD

From the Department of Neurology (I.P.), University of Cincinnati, OH; Department of Neurology (C.F.L.), Mayo Clinic College of Medicine, Rochester, MN; Department of Neurology (S.S.), Vanderbilt Medical Center, Nashville, TN; and Departments of Neurology and Radiology (R.B.), Partners MS Center, Center for Neurological Imaging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

Gray matter (GM) involvement is detected even in the earliest stages of multiple sclerosis (MS), and GM atrophy occurs at a faster rate than white matter (WM) atrophy early in the disease course.

Studies published to date establish that 1) GM involvement and in particular cortical demyelination can be extensive in MS; 2) GM pathology may occur in part independently of WM lesion formation; 3) a primarily GM-related process may be the earliest manifestation of MS; 4) GM involvement is associated with physical disability, fatigue, and cognitive impairment in MS; and 5) GM disease might help explain the observed dissociation between markers of inflammatory demyelination (relapses, WM gadolinium enhancement, WM lesion burden) and disease progression.

It remains likely that GM damage is related to WM damage. However, continued studies of GM pathology as well as neuronal and axonal involvement in MS and related experimental models are necessary to better understand the etiology and pathogenesis of the degenerative components.

Source: Neurology 2007 68: 628-629. [Full Text] © 2007 American Academy of Neurology

For years, clinical drug trials for MS have used MRI results of the white matter lesion activity to gauge how effective the medication may be.

Now we are being told that disease activity has taken place in the gray matter, perhaps much earlier. Does anyone know if MRI's have been used to scan gray matter?

Harry

Functional MRIs are used for this as is are diffusion tensor (DT) MRI and MR spectroscopy.

Standard MRI can't cut it and this is why, IMO, there is a big discrepancy between what you can see (or not see) on an MRI and people's symptoms. Just because an MRI shows no lesions doesn't mean there isn't damage. Unfortunately FMRI and others such as proton MR spectoscopy are much more expensive to buy and run.

This is far from the first study I have seen that considers grey matter damage takes place early in the disease process or indeed long before the first symptoms become apparent.

Manchester

On the other hand, there are those patients with MS who have many lesions but few symptoms and little to no disability. So the issue of gray matter involvement seems even more complicated than studies such as this suggest.

Yes and No. It depends how you define symptoms.

The EDSS doesn't pay as much attention to cognitive deficits (except very overt ones ) as it does to physical symptoms.

Cognitive deficits caused by grey matter changes can be much more subtle and take a lot more time to become apparent.

Also it depends on the area of grey matter affected just as with white matter.

I have no disability when measured by EDSS but plenty lesions and I have had subtle cognitive changes. If I had an fMRI the reasons may become much more evident for this.

Manchester

Another technology that seems to be getting some consideration for looking at gray matter is optical coherence tomography, based on this info from Dr. Freedman...



Dr. Freedman: There's a general belief that we're lacking in not only clinical trials to help us see repair or regenerative capacity, but in agents capable of doing so. The challenge is going to be to design clinical trials and methodologies that will allow us to test agents, see the ability of treatments to bolster the person's own endogenous ability to repair, and to investigate agents that we think act to stimulate repair.

In that regard, one of the up and coming technologies is something called OCT, optical coherence tomography. There were several posters and presentations on this topic; one was by my own group (Costello and colleagues[15]), in which we're looking at OCT as a possible window to examine the integrity of axons in the brain by looking at the retina. In a nutshell, this is a fancy ultrasound that uses infrared technology, and it can measure the thickness of the retinal nerve fiber layer, made up exclusively of unmyelinated axons. So the real question is this: Will measuring the thickness of the nerve fiber layer, which is sort of a surrogate marker for axonal density, be indicative of what's going on in the brain? Theoretically, if you can make the axons look better in the eye, maybe they'll look better in the brain.

http://www.thisisms.com/ftopicp-21251-fty720.html#21251

Manchester,



If standard MRI can't really tell us all that much about what is going on in an MS patient's brain, then I start to wonder about the accuracy of the clinical trial results that state a "X" percentage in the reduction of lesions over placebo had taken place.

Harry

A good question and I would agree that the trials cannot definitively be seen as 100% accurate in their data because of this.

This doesn't mean the DMDs are completely ineffective but it raises the issue that they could be less effective than the trial date would always suggest.

I think the rationalisation goes that MS is immune mediated but to what extent is still unknown. DMDs have some effect on this immune aspect. Even though this is not the only area involved in the overall disease process perhaps by keeping this aspect, somewhat, in abeyance it helps to slow the disease process and gives time for repair. The excerpt says that 'It remains likely that GM damage is related to WM damage' so I assume this is where the DMDs come in.

It would seem, to me, it also explains why DMDs are far from 100% effective but I wouldn't throw the baby out with the bathwater completely.

Manchester