WILLIAM STUART, MD: Hello, and welcome this evening to MS Conversations. My name is Dr. William Stuart and I am the medical director of the MS Center in Atlanta.

Tonight, we're going to discuss the use of MRI for MS diagnosis and management. And with me tonight is Dr. Rob Bakshi from the Buffalo Neuroimaging and Analysis Center. I've heard Rob speak many times and I think you're going to enjoy him.

Obviously, we all use MRI, it's been around for a number of years. It has evolved substantially in terms of our attitudes about it.

Rob, how are you this evening?

ROHIT BAKSHI, MD: Excellent.

WILLIAM STUART, MD: Good.

ROHIT BAKSHI, MD: Nice to be with you, Dr. Stuart.

WILLIAM STUART, MD: Well, it's good to be with you. I know you're doing some very exciting things and we're going to talk about them.

What I'd like to establish at the beginning is what we would consider to be the minimum study that one should do for a clinical MRI of the brain and of the spinal cord.

ROHIT BAKSHI, MD: Yes, I think that's an excellent question, because a lot of times we are confused as to what are the best sequences. And of course, different MRI centers will have different standard protocols, so this can lead to variability within the same patient or comparing a whole group of patients. So, what we have found very useful at our comprehensive MS center is we are working fairly exclusively with one outpatient MRI center, which is located in close proximity to us and we're very comfortable with the quality of those images. And we have set up a standard MS protocol that all of our patients receive.

And that includes a T1-weighted axial, a T2-weighted axial, a flare axial, a flare sagittal and T1-weighted sagittal images. Those are the non-contrast images we think every patient should get. Then after contrast administration, we have a five-minute delay. And then the patient receives an axial postcontrast image. And this allows us to get really all the key information that we use clinically in taking care of MS patients.

WILLIAM STUART, MD: Do you think that the precontrast T1 sequence is necessary?

ROHIT BAKSHI, MD: Yes, we do. And the reason for that is primarily because there is a phenomenon that is associated with a certain percentage of MS lesions, probably 20 or 30% of lesions that we've seen, which is a T1-shortening phenomenon. And this simply means that the lesions are going to appear bright on a non-contrast T1 scan. This is felt to be perhaps the effect of free radicals or macrophage activity at the lesion periphery and this can lead to misjudging enhancement that is present on a postcontrast study. So one has to verify that there is no hyperintensity on the non-contrast image in that lesion.

WILLIAM STUART, MD: That accounts for some of those -- sometimes you put your films up and you see what appears to be contrast enhancement in the non-contrast scan.

ROHIT BAKSHI, MD: That's right. And we have called this the T1-shortening phenomenon and we actually showed a poster on this last year at Denver at the American Academy of Neurology. So we'll hopefully have a paper on that very soon.

WILLIAM STUART, MD: Now, one of the things that comes up frequently is the flare image, which is such a sensitive part of the MS study. And I like your idea of there being a sagittal sequence, which gives us a much better look at the corpus callosum and the corona radiata. But what about the posterior fossa and flare imaging relative to T2 imaging?

ROHIT BAKSHI, MD: That's an excellent point and that is why I raised -- in the protocol that I outlined -- the importance of using T2 fast-spin echo axial images. We still do that on every patient, because the flare is not sufficiently sensitive or specific for the posterior fossa anatomy. The reason for this is that the flare is affected by CSF and venous pulsation, which occurs predominantly in the posterior fossa. This is related, for example, to the transverse sinuses and the CSF flowing up and down the basal cisterns. The T2 axial, when compared side-by-side with flare, gives you much more confidence in evaluating the posterior fossa.

WILLIAM STUART, MD: So when you're kind of trying to establish the T2 load, you need to combine your flare sequencing with your T2 for the posterior fossa.

ROHIT BAKSHI, MD: That's exactly how we do it. And of course, I must also say -- which you alluded to, which is that the flare is superior to T2 imaging for the super-tentorial lesion load.

WILLIAM STUART, MD: Right, mm-hm.

ROHIT BAKSHI, MD: There's no question about that.

WILLIAM STUART, MD: Okay, well, so let's move down to the neck.

ROHIT BAKSHI, MD: Now in the spine -- first of all, let me state upfront that we believe that spinal imaging -- that being cervical and thoracic -- should be part of, first of all, establishing a baseline for a patient who's about to start therapy or for making the diagnosis of MS. We think that information is a comprehensive way to study the total disease burden of the CNS. Approximately 40 to 50% of patients with MS will have spinal cord lesions at any one time when you take a snapshot of them. And then if you follow them longitudinally, you get into 60, 70% will ultimately have cord involvement. So the protocol is very important to standardize and also to execute.

What we do at our center is, first of all, in the sagittal plane, non-contrast T1 and fast-spin echo T2 axial. Then we -- T2 sagittal. So T1 sagittal, T2 sagittal. And then, in the axial view, we do a fast-spin echo T2-weighted axial image. That is the minimum non-contrast that the patient should have for cervical and thoracic.

Now, if the patient has disk disease, if you're suspecting disk disease, it's also good to have a T2-star, gradient-echo study, which looks like a T2, but it actually is a gradient-echo --

WILLIAM STUART, MD: Which one is more like a proton density?

ROHIT BAKSHI, MD: The, the proton density is a little different from the T2 star and the T2 axial. And we actually have dropped the proton density and we also don't use flare, at all, in the spinal cord.

WILLIAM STUART, MD: Okay, right, neither do we. What do you substitute, then, for the proton density as your sensitive sequence? Because so often, we don't see the lesions on the regular T2 and we do on the proton density.

ROHIT BAKSHI, MD: That is absolutely true and that is especially true with conventional spin-echo T2 sequences. You really had to have proton density five, ten years ago or if you're on an older platform. But we have found, though, with the modern platforms, with good fast-spin echo T2 images and 3 or 4 mm slice thickness that this obviates the need for proton density or flare.

WILLIAM STUART, MD: Okay.

ROHIT BAKSHI, MD: You can have a very high sensitivity with a good T2 sequence.

WILLIAM STUART, MD: You get a better resolution, I would presume.

ROHIT BAKSHI, MD: Yes. Better signal-to-noise ratio.

WILLIAM STUART, MD: Right. Then you also believe that the thoracic spine should be imaged in new-onset patients.

ROHIT BAKSHI, MD: We sure do. And the reason for that is that is yet another site where a patient can have lesions that come and go. Can have enhancement, can have thoracic spinal cord atrophy. And all of these things can have certainly a bearing on clinical progression.

WILLIAM STUART, MD: As this becomes a somewhat costly operation. Could one make an argument against not needing the thoracic MRI, in the sense that most spinal cord lesions are symptomatic and that only constitutes about 5% of the volume of the central nervous system. So that if you had the brain and the cervical cord, that you presumably would have pretty well screened the volume of disease.

ROHIT BAKSHI, MD: I think that's certainly reasonable. And if patient tolerability is an issue or cost becomes an issue, then that certainly is a reasonable approach. We've chosen to err on the side of getting more information rather than less, because of the -- one main reason for that, of course, is that MRI has no biologic harm associated with it. Unlike if you're doing CTs of the spine, you really have to justify that.

WILLIAM STUART, MD: Mm-hm. Now this is a loaded question, so be ready. Do you think we can identify or diagnose MS -- or are we at a time where we can do this without MR? Or only with MR and without clinical symptoms?

ROHIT BAKSHI, MD: The simplest answer I can give you to that is definitely not. MRI by itself, in isolation is not sufficient to make a diagnosis of MS with any confidence. Certainly there are features on the MRI that will strongly suggest the diagnosis, that will make you suspicious of the diagnosis. And then if you correlate that clinically, you're on firm ground.

And I can also present that from the opposite viewpoint, which is that if a patient has symptoms and you suspect MS, if the MRI -- done on a high-quality scanner, covering the whole nervous system -- is normal, I think that brings the diagnosis into doubt, quite strongly. Certainly ...

WILLIAM STUART, MD: If the MRI is normal.

ROHIT BAKSHI, MD: That's right.

WILLIAM STUART, MD: Right. So you --

ROHIT BAKSHI, MD: So MRI by itself still has to be correlated clinically.

WILLIAM STUART, MD: So you would be of a mind that there are probably no patients who have MS that have negative MRI.

ROHIT BAKSHI, MD: I would just add one word to that sentence: There are no patients that I've ever heard of or that have been written up or that I've seen who have normal, repeated MRI.

WILLIAM STUART, MD: Uh-huh.

ROHIT BAKSHI, MD: So that means if the patient still has symptoms, you bring the patient back a year later, the MRI is still normal, then you can rest fairly comfortably that you're probably not dealing with MS. Now there can be a lag; there are a few cases I've seen where the MRI may lag a few months behind the clinical symptoms. So that's why I like to at least repeat it one other time.

WILLIAM STUART, MD: Can we -- at the outset, in a clinical isolated syndrome that has a positive MRI, can we draw any conclusions relative to disease risk -- disease-progression risk and decide treatment protocols on that basis?

ROHIT BAKSHI, MD: Yes, I think we can. And this has been one of the major dilemmas that we face in managing patients. Which is: after the first attack, how do we decide what the patient's risk for having a second attack or for developing disease progression versus a patient who is going to do well in long-term followup and have a benign course. That has always been a dilemma and now in the last five years or so, there is mounting MRI data that tells us that from the very beginning, during the time of the first attack, the MRI lesion load, first of all, on T2 or flare images and secondly the enhancing lesion load, both of these are factors that very reliably correlate with two-year, five-year and eight-year rates of conversion to MS. So that's the long answer to your question.

The short answer is that if somebody comes in with a first attack and they meet the CHAMPS criteria with at least two lesions in the brain, one of which is periventricular or ovoid. Or if they have at least one enhancing lesion in the brain, either one of those two findings, that patient is going to have a very high risk for developing MS.

WILLIAM STUART, MD: So there are some lesions that we consider to be more specific -- or sensitive, rather, for the diagnosis of MS. Is that --

ROHIT BAKSHI, MD: Yes. The presence of enhancement, for example, is more specific and also the topography of the lesion, if it's ovoid in configuration or if it's perivenular or if it's periventricular. I think those -- all of those weigh in favor of it being MS.

WILLIAM STUART, MD: Do you think that the so-called Dawson's finger is specific enough for MS that it can be -- or can it be used that way? Or have you ever seen it in any other disease states?

ROHIT BAKSHI, MD: For the most part, I think it's a relatively specific finding. I find it to be very useful. The exceptions are diseases that are relatively rare that involve the perivascular space or perivenular areas, like a sarcoid, like Susac syndrome, which is a vasculopathy of the retina and the brain. Those are -- and certain -- maybe certain infections processes like Lyme disease, you may see Dawson's fingers. I've -- we have not seen Dawson's fingers; they're not usually seen or described in the garden-variety type of lesions you see with chronic ischemia, with age-related changes, with normal variants that occur as hyperintensities.

WILLIAM STUART, MD: Personally, I don't think I've ever seen a Dawson's finger that wasn't in an MS patient. I was curious about your experience.

ROHIT BAKSHI, MD: I think you're right. I think -- like I said, just a few -- there are a few rare situations where we've seen it in non-MS cases.

WILLIAM STUART, MD: Right. Well, let's move down to the next subject. Now that we have a patient who has been accurately diagnosed and we've used our MRI as we've just discussed. How are we going to use it beyond the diagnosis? Where is its application in disease monitoring?

ROHIT BAKSHI, MD: It has a very important role and I think a really pivotal role in managing patients. The reason for this is that the clinical symptomatology we see in MS, relapses and disease progression, are -- in many instances are, first of all, only the tip of the iceberg as far as what is going on with the underlying biology of the disease. That being -- an example of that being relapses. Patients will have disease activity on MRI despite the fact that they're not having obvious relapses.

And number two, disease progression, sustained disability is a more delayed and protracted phenomenon that can take several months or several years to develop. And by the time it develops, it is very difficult to do anything to reverse that disability.

So MRI gives us a way, number one, to monitor the disease more sensitively. And number two, to get ahead of the disease, to target biologic events, biologic activity -- like enhancement and brain atrophy -- which are going to predict or portend this disease progression down the road. So I think it's a very powerful tool.

WILLIAM STUART, MD: How do we use the different markers? That is gad enhancement, T2 load, atrophy in the newer studies in magnetic trans- -- magnetization transfer spectroscopy. How do we use them in the various periods of the disease? How would we sequence them in terms of their value?

ROHIT BAKSHI, MD: Well, my opinion on this may not be the same as everyone else. I have really --

WILLIAM STUART, MD: All the more reason you're entitled to it.

ROHIT BAKSHI, MD: Well, I really feel that brain atrophy is the most important marker that we have. And I think that brain atrophy is still felt to be a relatively new marker. But there is so much evidence that's come out in the past five years or so, which tells us several things about brain atrophy.

First of all, once you develop brain atrophy, you don't get that tissue back. It's very unlikely that that is going to recover. The rare exception to that would be if you do an MRI right after you give IV steroids. Within two or three of steroids, there are reversible changes in brain volume that occur. But other than that, once you lose brain tissue, it doesn't come back.

Number two, when you develop brain atrophy early in the disease process, you are at high risk for developing sustained disability two, five, eight years later.

And number three, brain atrophy shows robust correlations with many of the manifestations of disease that we all care about: quality of life, cognition, physical disability and even mood changes like depression.

So I've put atrophy upfront as the key marker. Now, of course, it's not the only important marker.

WILLIAM STUART, MD: No, we -- you know, we're learning so much more about the pathology of MS and we know now that it's not just a patchy disease, but it's a global and that there may actually be gray matter changes.

Which -- which of these different pathologic components is contributing mostly to the atrophy?

ROHIT BAKSHI, MD: That has been looked at by several studies recently. And what seems to be the most striking correlation is gadolinium enhancement; early gadolinium enhancement is a predictor of subsequent brain atrophy. That was shown, for example, very nicely in Jack Simon's study of third ventricular width. There is also paper which is going to be shown in Hawaii at the American Academy meeting which tells us that ring enhancement -- if you see the phenomenon of ring enhancement, that predicts atrophy six months later.

WILLIAM STUART, MD: But, but -- Rob, but the -- those are markers that are present early on that reflect a certain kind of pathology. But what I was referring to is, is more of the atrophy related to the abnormalities we see in the normal-appearing white matter on immunopathologic studies or is it T2 lesion load, is it black hole? Or is it -- or is it everything?

ROHIT BAKSHI, MD: I think it's a sum total of several different events and I think it's related to overt lesions, number one, which cause tissue destruction, as Bruce Trapp has shown. Which cause wallerian degeneration, as Jack Simon has shown. But also, the point that you raised: disease in normal-appearing brain tissue -- that being normal-appearing white matter and normal-appearing gray matter -- let me take those two one at a time.

First of all, there is no question that -- work that Doug Arnold has done that N-acetylaspartate measured in normal-appearing white matter is related to corpus callosum atrophy. So there is damage in normal-appearing white matter, which is probably leading to wallerian degeneration and causing this degeneration of the whole brain.

And finally, let me turn to normal-appearing gray matter, because -- as you alluded to -- that is an area where there has been little attention paid to in, you know, the past 100 years. But we now know that the gray matter is involved in the disease process. We see hypometabolism there, we see plaque formation directly there by flare studies and by histologic -- advanced histologic techniques.

And finally, there's a suggestion that there may be iron deposition -- pathologic, abnormal iron deposition in the gray matter. And we have done work which has correlated brain hypointensity of the gray matter, which suggests iron deposition, with brain atrophy, whole brain atrophy.

So to answer your question the simplest way: MS is a whole brain disease. There are a wide variety of factors that are all contributing to this destructive potential of the disease.

WILLIAM STUART, MD: Well, now we've -- you've made a strong case for atrophy. And the poor doc out in the community has got this patient that he's trying to make some decisions about and he doesn't have a computer program to measure brain parenchymal fraction and other, other programs to measure atrophy. How is he going to use this marker?

ROHIT BAKSHI, MD: Well, this certainly can be done with clinical images at the bedside. We conducted a study which we published in 2001 in The Journal of Neuroimaging. And we have presented a relatively simple way to be able to identify atrophy and follow patients with simply looking at MRI scans.

And the gist of it is we know that, as the brain tissue degenerates and as axons are transected, there is less brain tissue and there's more CSF. So if you look at MR scans, clinically-done scans by looking on view boxes or PAC systems, whatever. And you see that patients are developing ventriculomegaly, prominence of the cortical sulci and decreased volume of brain structures, like the corpus callosum. This is a determination you can make relatively easily and relatively quickly from MRI scans.

WILLIAM STUART, MD: Do you think that you can put 'em up side-by-side and eyeball them and do that or do you need to do some simple measurements of third ventricular width and that sort of thing? Anterior horn?

ROHIT BAKSHI, MD: I think this can be done by the human eye. And I think that what is important is, number one, you do the same sequences on the patient, longitudinally, preferably on the same scanner. So that way you're comparing apples to apples. And number two, that you make sure to read your own films; have the patient bring in old films. And put the images up side-by-side so you can see the third ventricular width during the old study and compare it to the new study. You can do the corpus callosum area by looking at it and seeing if there are dramatic changes. This is all a very useful way to manage patients.

WILLIAM STUART, MD: When you do your brain atrophy measures, which sequence do you generally use?

ROHIT BAKSHI, MD: The most useful sequence is the T1-weighted non-contrast image. When you give contrast, this generates a lot of noise in the image and makes the atrophy determinations difficult. So that's another reason why we always include a T1 non-contrast. And that lends itself very well to volumetric analysis.

Also, the T1 axial and sagittal that you get from hard copy films are very nice for doing a visual analysis of atrophy.

WILLIAM STUART, MD: How close are we to this being an available clinical measurement? Where it can be -- the software can be placed on the community scanners?

ROHIT BAKSHI, MD: We're getting very close. I'm very happy to tell you that there probably are six or seven major groups across the world, including our group, that has been working very hard to try to standardize the software algorithms. To make sure that they're available and to keep the costs as low as possible, to try to find the most efficient way to apply these.

One example of this is a software package that we're using at our center, which will come out in a publication in The Journal of the Neurological Sciences in the next month or two. We have described a commercially-available software package which takes thirty minutes per patient to get a BPF score. This -- it's a -- the issue here is they need to, you know, buy the software, you need to train somebody to do it and they need to pay a technician to spend thirty minutes doing it. So what is going to limit us here is not availability, it's not the technology, it's going to be the cost.

WILLIAM STUART, MD: Is there human error?

ROHIT BAKSHI, MD: There is a small degree of human error. And our human error in -- with our package is about 0.3% intrarater and about 0.4% interrater between two technicians. Which is an acceptable amount of error, because with a typical patient with MS, they have -- on average -- 0.6 to 1.2% decreased brain volume or decreased normalized atrophy every year. So our error rate should be small enough to still detect that.

WILLIAM STUART, MD: If cost -- and certainly cost is a major issue in using the MRI as a monitoring technique in MS. But if cost is what it is and atrophy can be measured on T1 images, we know we can get T1 off of lower-cost scanners, even some of the open magnets with lower field strength. Why can't we do atrophy measures, then, on a cheaper piece of equipment and keep some cost down?

ROHIT BAKSHI, MD: That would definitely help to limit cost. The major cost is really the postprocessing time and the software required to do the postprocessing.

WILLIAM STUART, MD: What --

ROHIT BAKSHI, MD: What I would propose to you and what I think we're going to see happening in the next few years is MRI center, MRI operational entrepreneurs are going to invest in this kind of quantitative analysis and make it available to their referring physicians. And those centers who can offer this are going to have an advantage competitively in the market. Because they're going to be offering a higher quality of patient care.

WILLIAM STUART, MD: But I -- what I was referring to is, is if you can establish that atrophy is such a delicate, sensitive measure, why can't we design an MS protocol that can be simpler than what we might have proposed at the beginning of this talk? And do it on scanners that don't have the high maintenance costs and the high purchase prices?

ROHIT BAKSHI, MD: That is a study that has yet to be done. And what your question gets to is: How much does the type of sequence affect the validity of the BPF or other atrophy measurements?

WILLIAM STUART, MD: Right, right.

ROHIT BAKSHI, MD: How much does field strength affect it? These are questions that have not been answered yet and those studies need to be done?

WILLIAM STUART, MD: Okay. Well, I think this has been very interesting. I've -- I certainly have learned a lot and I do every time I talk and listen to you. Rob, do you have any other things you would like to bring out to our audience?

ROHIT BAKSHI, MD: Well, I think that this has been really delightful to speak with you and participate in this. So I thank you for that, Dr. Stuart. It's always a pleasure to visit with you.

WILLIAM STUART, MD: Well, I thank you for that. I certainly as -- I certainly was here at the beginning a number of years ago when we first had CT and then MRI came along. And it's been an interesting experience to watch it evolve. I remember very well when we first began using MRI in the '80s and that everybody said all it was going to be useful for was the diagnosis of MS. I always felt like you could look at your first patient with the MRI and not have believed that to be the case. So I think your work and others' work has certainly proved this to be the case.

Again, thank you, and I want to thank our audience. We hope this has been useful to you and we have certainly enjoyed the evening. Thank you very much.

Good night, Rob.

ROHIT BAKSHI, MD: And good night.