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Published: March 8, 2016, 5:31 p.m.

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Host \u2013 Dan Keller

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Hello, and welcome to Episode Seventy of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I\u2019m Dan Keller.

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In today's interview, we'll talk with Dr. Brian Weinshenker of the Mayo Clinic about new diagnostic criteria for neuromyelitis optica spectrum disorder and how it differs from MS. The new criteria build upon and broaden the definition of NMO that was based, in part, on the presence of antibodies to aquaporin-4.

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But to begin, let\u2019s sample a few of the new studies we found in our weekly PubMed search of the world\u2019s largest medical library, the National Library of Medicine. You can link to each week\u2019s list of curated papers at msdiscovery.org.

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On topic with our interview, an international team led by researchers in Tianjin, China, found a unique group of people with neuromyelitis optica spectrum disorder, or NMOSD, who carried autoantibodies to both aquaporin-4 and myelin oligodendrocyte glycoprotein or MOG, a minor component of myelin. Among the 125 patients, 10 were double positive for both sets of antibodies, and 14 were positive only for MOG. The double-positive patients had a worse disease course, most having MS-like brain lesions and more disability. Those with only MOG antibodies had a milder disease and less disability. If verified in other studies, the findings may help predict the clinical course of NMOSD or even define a new phenotype somewhere between the two very different diseases of NMOSD and MS. The authors say their paper also raises a new challenge of how to diagnose and treat such patients. Three double-negative patients did not respond to rituximab, a highly effective anti-B cell therapy used off label for MS and NMO. The study is published in the journal Science China Life Sciences.

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For people with MS and other demyelinating conditions, bladder issues can play an oversized role in the quality of life. A pair of review articles addresses the \u201cneurogenic bladder.\u201d One from Duke University researchers in North Carolina, USA, recommend an evaluation known as urodynamics, calling it the gold standard in helping to break down the complex problem into basic and treatable factors. In the other paper, researchers from Western University in Ontario, Canada, review the 16 different ways to measure patient reported outcomes for neurogenic bladder, and how to choose the best one to track patients\u2019 quality of life. Both reviews are published in the journal Translational Andrology and Urology.

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In the news section, MS Discovery Forum correspondent Stephani Sutherland wrote about the recent negative results of fingolimod in a large Phase 3 clinical trial of people with primary progressive MS. Even in failure, studies can be informative and can help researchers design better investigations to test potential therapeutics for progressive disease.

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Now, let\u2019s move on to our drug development database. The drugs with important additions and changes are daclizumab, fingolimod, and ocrelizumab. One update reflects findings presented at last month\u2019s ECTRIMS conference in New Orleans suggesting that in primary progressive MS, the experimental drug ocrelizumab reduces disease activity in subgroups of individuals with and without gadolinium-enhancing images at baseline.

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And now to our interview. It\u2019s been 11 years since neuromyelitis optica, or NMO, was redefined as a separate disease from MS. Thanks to the discovery of the first biomarker for NMO, an antibody against aquaporin-4, diagnostic criteria for neuromyelitis optica, or NMO, were revised. In today's discussion, Dr. Brian Weinshenker of the Mayo Clinic in Rochester, Minnesota, USA, lays out further revisions to the criteria and the reasons for them. He uses a couple of terms that may warrant definition. One is IgG, which is immunoglobulin G, a particular class of antibody. Other terms are seropositive, meaning, in this case, the presence of antibodies to aquaporin-4, and conversely, seronegative, the absence of such antibodies. Finally, ADEM, A-D-E-M, is acute disseminated encephalomyelitis, a sudden, widespread attack of inflammation in the brain and spinal cord, usually seen in children. I spoke with Dr. Weinshenker at the ECTRIMS meeting last fall in Barcelona about the new consensus diagnostic criteria for NMO.

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Interviewer \u2013 Dan Keller

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Is there something that was lacking before?

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Interviewee \u2013 Brian Weinshenker

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Well, the first diagnostic criteria for neuromyelitis optica were proposed by our group at Mayo Clinic in 1999. And in 2006, with the advent of the first diagnostic biomarker for neuromyelitis optica, an antibody which we now know is directed against aquaporin-4 \u2013 I\u2019ll call it aquaporin-4 IgG \u2013 the criteria were revised. But there was a need to revise them. We became increasingly confident in this diagnostic biomarker, and it was possible to make an earlier diagnosis, often after the very first symptom. So that was one key driving factor.

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And furthermore, with the advent of this biomarker, we\u2019ve appreciated that the spectrum of this disease is far broader than we had previously recognized. And there are a number of clinical syndromes that were previously not recognized as being part of the neuromyelitis optica spectrum that we now know are, and those needed to be integrated. Another key factor was the fact that a number patients that we recognize have this same condition now did not meet the old criteria. For example, you had to have both optic neuritis and myelitis to make this diagnosis, and we recognize some patients with this condition have just recurrent myelitis or just recurrent optic neuritis; they wouldn\u2019t have satisfied the criteria. So those were the key reasons that drove developing new criteria.

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MSDF

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What are some of the new criteria?

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Dr. Weinshenker

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The first important point is that we\u2019ve eliminated distinction between neuromyelitis optica \u2013 that is, having optic neuritis and myelitis \u2013 and having some of these more limited forms or unusual forms of the disease with brain lesions. And we\u2019ve used the term neuromyelitis optica spectrum disorder to refer to all of them.

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Second aspect of the diagnostic criteria is that we\u2019ve stratified them based on whether or not you have this biomarker, the aquaporin-4 IgG. And we\u2019ve separately defined patients with that biomarker and those without, the largest group being those with the biomarker. So in the patients with this biomarker, we really require only one clinical syndrome. The clinical criteria are very, very liberal, and we don\u2019t even require, say, for myelitis, as we had before, we used to require having a long spinal cord lesion. We now recognize that about 10 to 20% of patients do not have those kind of long spinal cord lesions when they have a myelitis, so we no longer require it if you have that biomarker.

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But we\u2019ve left open a category that we call seronegative neuromyelitis optica spectrum disorder, because some patients who meet all of the various clinical criteria\u2019s, even the strictest clinical criteria, seem to be seronegative for this biomarker. We recognize that\u2019s a heterogeneous group of patients; some of them ultimately will become seropositive. In some of those patients, we\u2019re recognizing other antibodies that seem to be associated with a similar clinical syndrome, so I think, ultimately, we may create new silos based on those biomarkers, but when these criteria were developed, it was felt to be premature to include other antibodies as diagnostic biomarkers. So we\u2019ve grouped them into this group of seronegative NMO spectrum disorder.

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But we\u2019re much more strict in that category. We do require two clinical syndromes \u2013 two different clinical syndromes \u2013 and in some situations we do require additional MRI criteria in order to meet those criteria.

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MSDF

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Okay, because it was sounding like you were being so liberal about it people could lack this symptom and that symptom and antibody, but, in this case, if they\u2019re lacking antibody, they need other criteria to qualify.

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Dr. Weinshenker

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That\u2019s correct; both clinical and radiologic criteria. And we also have exclusionary \u2013 well, I shouldn\u2019t say exclusionary. There are no exclusionary criteria. We refer to them as red flags. If you have certain characteristics that would make it more likely that you have MS, which is the major competing diagnosis, or if you have certain comorbidities like, say, cancer or sarcoidosis \u2013 we know sarcoidosis can sometimes mimic neuromyelitis optica \u2013 we add that as a note of caution, but strictly, no criteria is considered exclusionary for a diagnosis of neuromyelitis optica spectrum disorder.

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MSDF

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Would other systemic autoimmune states also fall into the category of red flags: we\u2019re going to have to decide whether it really is NMO or not?

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Dr. Weinshenker

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Actually, that used to be excluded by some people that if patients had systemic lupus or Sj\xf6gren's disease they were excluded, but we recognize that patients with neuromyelitis optica spectrum disorder have an excess of those other autoimmune diseases. We very frequently detect comorbid disease, so we actually say that, say, a diagnosis of lupus or Sj\xf6gren's actually increases the chances that his patient has neuromyelitis optica spectrum disorder if they present, say, with optic neuritis or myelitis. The old literature was replete with patients who were described as having lupus myelitis. Actually the majority of those patients actually have comorbid neuromyelitis optica spectrum disorder. So it\u2019s no longer an exclusionary criterion.

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MSDF

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There used to be a requirement for bilateral optic nerve involvement? Is that right? Has that gone by the wayside?

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Dr. Weinshenker

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Yes, this is before there were actually formal criteria, but yes, that was considered to be, say, a red flag that you might be dealing with neuromyelitis optica compared to standard MS. We recognize that that applies to a relatively small percentage of patients, so it doesn\u2019t really appear in these current diagnostic criteria, but certainly it would not exclude it. And I would say that it does add to the suspicion that someone has neuromyelitis optica spectrum disorder compared to MS.

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MSDF

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What about pediatric neuromyelitis optica spectrum disorder?

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Dr. Weinshenker

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We did have several people, who were pediatrics experts, on our international panel and, in general, it was felt that the same criteria that we\u2019ve applied to adults can be applied to children. We do recognize that certain brain syndromes are relatively more common in children, and there is one caveat, that is, in pediatric multiple sclerosis, sometimes patients will have long spinal cord lesions, and that\u2019s one of the criteria that adds to the suspicion that somebody has NMO spectrum disorder as to MS. It may be somewhat less reliable in children.

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MSDF

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Is there any confounding or concern about ADEM in children?

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Dr. Weinshenker

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Well, neuromyelitis optica spectrum disorder can be associated with brain lesions that can be interpreted as ADEM. They can be large, tumefactive, extensive. Brain biopsy, which is not part of the criteria that we use for neuromyelitis optica spectrum disorder, can sometimes differentiate ADEM \u2013 standard ADEM \u2013 from the ADEM-like lesions that occur in neuromyelitis optica spectrum disorder, so yes, it can be a diagnostic problem. But generally speaking, if one relies on the other criteria \u2013 the presence of optic neuritis and myelitis, which can occur in both ADEM and neuromyelitis optica spectrum disorder \u2013 usually one can come to a clinical diagnosis. But there are some situations that can be confusing and occasionally additional tools, even brain biopsy, can be necessary to make a definitive diagnosis.

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MSDF

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If serologic testing is not available, do you still require the two other criteria to make the diagnosis?

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Dr. Weinshenker

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We propose that, for now, if serologic testing is not available \u2013 and there aren\u2019t many places in the world where it\u2019s strictly unavailable; it is offered worldwide \u2013 that you rely on the criteria for the seronegative and satisfy those criteria of seronegative NMO spectrum disorder.

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MSDF

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Are the criteria fairly straightforward that any neurologist up-to-speed can interpret them and use them clinically?

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Dr. Weinshenker

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Yes. We have designed these so that they can be used by neurologists in standard practice. Obviously, they don\u2019t cover every single possibility, and there are complex patients where consultation will be necessary, but these are designed to be as good any diagnostic criteria can be. I think one has to realize that diagnostic criteria are for typical patients with conditions, and there are rare situations in difficult-to-interpret situations where one does need this kind of consultation.

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MSDF

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What about other historical terminology, and what kind of recommendations have you made vis-\xe0-vis that?

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Dr. Weinshenker

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This has been a confusing element of the literature. For example, one term used in Asia, where it was recognized that you can have a relapsing condition that primarily targets the optic nerves and spinal cord was often referred to as Asian or Japanese opticospinal MS. And historically, this has been a very important contribution. I think our colleagues in Asia were the first to recognize that this relapsing condition was distinct from MS and may be something different, but the terminology was confusing. It was called opticospinal MS. Was this MS or something distinct from MS? And was it the same as neuromyelitis optica?

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And the panel felt that this term is no longer useful in clinical practice, and it doesn\u2019t distinguish from multiple sclerosis. So it was felt all of those patients could be probably put into either the NMO spectrum disorder category or multiple sclerosis category, proposed that, for clinical practice, that terminology be eliminated.

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MSDF

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This is a good way to make the diagnoses, but it leads into the question of then what do you do? And next week\u2019s podcast will focus on new clinical approaches to looking at NMO.

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Thank you for listening to Episode Seventy of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF\u2019s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

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Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

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We\u2019re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

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For Multiple Sclerosis Discovery, I\u2019m Dan Keller.

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