Establishing a Diagnosis of Multiple Sclerosis Relapse

Stephen Krieger, MD: With all that said, how do you diagnose a relapse? I know we’re going to talk in this program about a new algorithm, but let’s start with first principles. You said you speak to the people on the phone and you ask these questions. What are the next steps in actually distinguishing relapse, at least the basics?

Amy Perrin Ross, APN, MSN, CNRN, MSCN: Again, if I need to, I’m going to get these folks in to see them for a clinical exam, to see if I can find any physical changes that may or may not be present as a result of the relapse. You’re going to evaluate them, but again, as I said, the key issue here is listening to what they’re telling you and how they’re telling you things. Usually when we bring them in, we’re going to ideally have a urine specimen done before they ever come in, so that we can rule out the urinary tract infection [UTI] that they all deny that they have because they don’t have burning, or frequency, or anything that’s just part of their normal MS [multiple sclerosis]. But in fact, when we look at it, we probably get 70% of them with an underlying UTI. We get some of those things treated, and amazingly, they do better.

Our big issue, in terms of diagnosing MS, is trying to tease out what’s a pseudo relapse and what’s a true relapse. And 1 of the things that I think is really important, particularly as we’re starting to establish a relationship with a patient, whether they’re newly diagnosed by us or they’re coming to us for a second opinion, is to help them identify what might be a true relapse and what might be a pseudo relapse. I have people who come to us for a second opinion, and I’ll ask them about their history. And I say, “Have you had any relapses?” “I have 2 or 3 a week.” Well, obviously, we’ve got to tease out some information there and help them understand really what’s the difference between a relapse and a symptom.

From there we may or may not choose to add MRI [magnetic resonance imaging] findings. One of the things about looking for a true relapse with an MRI is, yes, we might be looking for gad [gadolinium]-enhancing lesions, but just because they’re not there, doesn’t mean this isn’t a new relapse. It may be something that just hasn’t shown up right away or isn’t available for our imaging. I think the big issue for us in diagnosing is that the diagnosis is a clinical diagnosis, first and foremost, followed by use of ancillary testing, such as MRI, if and when we need it.

Stephen Krieger, MD: In that way, recognizing each individual relapse as a microcosm for how we make the diagnosis of MS. In the grand scheme, it’s still a clinical diagnosis, and we use our ancillary testing to fill that out. After a relapse or after the first event, when do you feel comfortable saying that this has declared itself as multiple sclerosis, a disease disseminated across space and time?

Joseph R. Berger, MD: Right. So that gets me back to the history of medicine, because prior to the era of the MRIs and prior to the availability of disease-modifying therapies, there was generally reluctance on the part of neurologists to establish a diagnosis of multiple sclerosis because it was vested with lamentable results, as used to be said. You would tell the patient they had multiple sclerosis, and they envision being wheelchair bound in a short period of time, and there was little you were capable of doing. You really didn’t make that diagnosis after that first event, even when you really strongly suspected it. And not everybody actually with those first events went on to develop a second event, which would have been the clue that, indeed, they had multiple sclerosis.

And the diagnosis of relapsing-remitting multiple sclerosis, which is what 80% or 85% of the patients are diagnosed with when first diagnosed with multiple sclerosis, was really not codified until the early 1960s, when people started looking at drugs to determine whether or not these drugs had any value in the treatment of multiple sclerosis. Then you had to have a disease that was well framed, very well defined. And that led to the Schumacher criteria, and the Schumacher criteria evolved into other criteria that ultimately became the McDonald criteria. We now have 3 iterations of the McDonald criteria, the most recent coming out in 2017. Fundamentally, what you want to see is dissemination in space and dissemination in time. And that went to the very earliest definitions, and we use various criteria to do that. You can do it on the basis of clinical features, so for the person who has 2 events, you don’t even need an MRI. But you’d like to see objective abnormalities on the physical examination, and that’s critical.

Otherwise, we buttress what we see with paraclinical findings. These include MRI findings in which you want to see at least T2 lesions in 2 or 4 areas, juxtacortical, periventricular, and so on. You don’t necessarily have to have gadolinium-enhancing lesions, and we now use spinal fluid, the presence of oligoclonal bands to help us with respect to dissemination in time. There are criteria that are well established that we use. They’ve been, as Dr Fred Lublin has stated, used and abused. So you have to be careful in their application. But there are criteria that help us establish this diagnosis.

Stephen Krieger, MD: I think you’re right: the goal has been to establish it earlier and earlier. And the tension that’s there, as Dr Andy Solomon has written about, is the tension between making an early diagnosis and making a missed diagnosis.

Joseph R. Berger, MD: Absolutely. In fact, there have been studies that have looked at this. In the 1980s, the time to establish the diagnosis in multiple sclerosis was actually quite long. With every succeeding decade, actually every succeeding 5-year interval, the time from first presentation to the establishment of a diagnosis of multiple sclerosis has shortened. And there’s a value to that because the earlier you treat a person—and this has been repeatedly demonstrated—the earlier you treat a person with a disease-modifying therapy, the better they do.

Stephen Krieger, MD: It makes sense. It also draws on what Rob said earlier, that relapses early on are a concerning prognostic feature.

Robert Bermel, MD: Yes.

Stephen Krieger, MD: So we try to shut them down.

Robert Bermel, MD: I think that 1 of the major pitfalls, if we talk about diagnosing relapsing-remitting MS in applying the McDonald or the International Advisory Committee on Clinical Trials in MS, the major pitfall is identifying a typical clinically isolated syndrome, or CIS. Where people trip up is applying the diagnostic criteria to situations in which people do not have a syndrome, including physical exam findings that are typical of inflammatory demyelination. The diagnostic criteria were meant to be applied to people who, just as Amy was talking about, have symptoms typical of a relapse. And that means that they have a typical optic neuritis, the typical brain stem syndrome, or a typical syndrome for partial myelitis—something like this, where you can trace the event back to an inflammatory demyelination event.

And that’s the situation where the diagnostic criteria apply. It’s not in the person who gets an MRI after having classic migraine headaches and has white spots on the MRI. It’s only in those cases in which we’ve already applied what we’ve talked about today, which is identifying this as a typical relapse, even though it’s the first 1 ever. The nomenclature gets confusing. Why are we calling it a relapse? But it’s still what we do.

Stephen Krieger, MD: Right, it’s still a relapse even when it’s the first event.

Robert Bermel, MD: Yes.

Stephen Krieger, MD: But the clinical thinking and parsing out the characteristic symptoms of MS relapse are important in distinguishing relapses in people who have known MS, just as it’s important in recognizing what constitutes a first diagnosis of multiple sclerosis.