Robin (00:01):

Hello. Welcome to today's installment of “Diagnostics in Practice.” I'm Robin Huiras, senior marketing specialist for Mayo Clinic Laboratories and strong believer in the power of advanced testing to change patients' lives.

I'm happy to be here today with two guests to discuss recent updates to the diagnostic criteria that guide how multiple sclerosis, or MS, is diagnosed. We'll focus on what these changes mean for clinical practice and how laboratory testing fits into the broader diagnostic evaluation of patients with suspected MS.

Today I am joined by Dr. Maria Alice Willrich, associate professor of lab medicine and pathology, and co-director of Mayo Clinic's Protein Immunology Laboratory, where MS testing is performed, and Dr. Samantha Banks, assistant professor of neurology and a Mayo Clinic neurologist whose practice focuses on treating patients with multiple sclerosis. Thank you both for being here today.

Dr. Banks (01:00):

Thanks for having me.

Dr. Willrich

Glad to be here.

Robin (01:03):

So before we begin, I am hoping you can both tell our listeners a little bit about your work around laboratory testing for MS and patient care here at Mayo Clinic. Dr. Willrich, you want to go first?

Willrich (01:15):

Hi. I am a clinical chemist in the Department of Laboratory Medicine and Pathology at Mayo Clinic, where I co-direct the Protein Immunology Laboratory. A large part of my work focuses on developing, validating, and interpreting CSF biomarkers used in the evaluation of inflammatory and immune-mediated neurologic diseases, such as multiple sclerosis. It's part of my role as well to ensure these tests are used appropriately and interpreted in the right clinical context.

Robin (01:46):

Thanks, Dr. Willrich. And Dr. Banks.

Banks (01:49):

I am a neurologist with specialty training in multiple sclerosis and autoimmune neurology. I work primarily in our MS Clinic, where I diagnose MS and care for patients longitudinally. I also care for patients with other autoimmune neurologic disorders that may mimic multiple sclerosis.

Robin (02:05):

Thank you both for sharing your experience. The insights you have in this space really does underscore the expertise that supports test development at Mayo Clinic Laboratories.

I wanted to start off our conversation today with a little bit of background for those listeners who might lack familiarity with how MS is diagnosed. Since its publication in 2001, the McDonald criteria has served as a guideline to establish a unified approach for MS diagnosis. The criteria are periodically updated by the International Advisory Committee on Clinical Trials in MS. With the most recent update happening in 2024 and its publication in October of 2025. For MS, which can be difficult to diagnose due to a wide range of symptoms and lack of a single diagnostic test, these criteria have helped to reduce time to diagnosis from four years in 2001 to one year, most recently. The most recent updates, which include using measurements of new biomarkers and evidence of CNS inflammation, could reduce the time to diagnosis even more, from months or years to weeks or even days. This is good news for anyone struggling with this complex condition. To set the stage for our discussion today, I wanted to ask why patients with MS are so challenging to diagnose. Dr. Banks, can you please get us started?

Banks (03:29):

Absolutely. When we meet a patient first presenting with symptoms or MRI findings suggestive of multiple sclerosis, we want to make an accurate diagnosis for them quickly. We have highly effective medications these days and we can change the course for these patients' lives if we start treatment early. But at the same time, avoiding wrong diagnosis is just as important, as we are committing our patients to many years of immunosuppressant treatment and we don't want to miss other mimics. MS can be challenging to diagnose as it can mimic many other conditions, and there's not one single biomarker that can easily make the diagnosis. To accurately make the diagnosis, this requires integration of clinical history, neurologic examination, MRI studies, and CSF testing.

Robin (04:11):

Thanks for sharing your insights on the complexities of MS diagnosis, Dr. Banks. Do you feel like the McDonald criteria greatly reduces the difficulties of pinpointing diagnosis in affected patients?

Banks (04:23):

Yes. So there's been kind of three major changes that have advanced the criteria to allow earlier initiation of disease-modifying therapy. First, the new criteria now includes optic neuritis. Previously, patients who first presented with optic neuritis were left without treatment until they developed further events. Further, the new criteria now includes radiologically isolated syndrome, allowing us the opportunity to treat and prevent symptomatic MS. And last, the new criteria have included kappa free light chain testing on CSF, which allows for more rapid diagnosis of MS.

Robin (04:58):

Thanks so much for sharing your experiences on how the diagnostic criteria work in practice Dr. Banks. I'd like to shift gears just a little bit and talk about the changes to the criteria. Dr. Willrich, this next question's for you. What are the primary changes, and how will they make MS diagnosis easier?

Willrich (05:15):

The McDonald criteria provide a standardized framework for diagnosing multiple sclerosis across several clinical presentations, including relapsing and progressive disease. Some of the key changes are, addition of imaging features, such as the involvement of the optic nerve, as Dr. Banks already alluded to, and the central vein sign. From a laboratory standpoint, the criteria now also recognize the kappa free light chain index as an alternative biomarker of intrathecal immunoglobulin synthesis. The kappa index is a combination of four tests that require paired samples of cerebrospinal fluid, or CSF, and serum samples to measure kappa free light chain concentrations in CSF., then kappa measured in serum, albumin in CSF, and albumin in serum. These biomarkers are not diagnostic tests on their own. They're intended to provide supportive evidence in specific clinical scenarios and must always be interpreted in conjunction with clinical findings and neuroimaging. The recent updates do not eliminate diagnostic complexity, but they do expand the tools available to support a diagnosis when clinical and imaging findings are suggestive of MS.

Robin (06:35):

Moving on a little bit. I'm curious, could you elaborate on what kappa free light chains are and why testing for them can be useful for diagnosis?

Willrich (06:44):

Yes. Kappa free light chains are small protein fragments produced during normal immunoglobulin synthesis by activated B cells and plasma cells. They're present at low concentrations in both blood and cerebrospinal fluid, and their levels can increase when there is immune activation within the central nervous system. In the context of multiple sclerosis, elevated kappa free light chains in CSF reflect intrathecal immunoglobulin synthesis, a hallmark of the disease. However, the findings are not entirely specific to MS, and it must be interpreted alongside clinical findings and MRI features, as I said earlier as well.

Robin (07:24):

Thanks for explaining what kappa free light chains are, Dr. Willrich, and why testing for them can be useful. Why is the addition of kappa light chain testing to the McDonald criteria important in your view?

Willrich (07:37):

Well, kappa free light chain testing provides a quantitative marker of intrathecal immunoglobulin synthesis in contrast to the more traditional biomarker, oligoclonal banding, which was only qualitative. Now, the McDonald Criteria update recognize that kappa free chain index is an alternative to the oligoclonal bands for establishing evidence of intrathecal immunoglobulin synthesis.

From a lab perspective, the kappa index is automated, quantitative, and can be implemented on a wide number of platforms, which lowers technical barriers for adoption across laboratories. As a result, it has the potential to improve access to this type of supportive biomarker, and in some practices, this may also help reduce delays in obtaining lab evidence relevant to MS diagnosis. Oligoclonal banding remains established test. It is still in the criteria, and it can provide complementary information in certain scenarios. At Mayo Clinic Laboratories, we continue to use both approaches as part of a reflexive, context-driven strategy. Oligoclonal banding is a diagnostic test in the 2024 McDonald criteria, but it's time-consuming, a manual assay that requires both CSF and serum samples and expert interpretation of the test results and, taken together, these features contribute to much longer turnaround times for results.

Robin (09:04):

Thanks for sharing your perspective on the importance of the addition of kappa free light chain testing to the diagnostic criteria, Dr. Willrich. I'm curious, does Mayo Clinic Labs’ kappa free light chain testing align with these new updates?

Willrich (09:17):

Yes, it does. Our current strategy aligns well with the McDonald criteria, and it was designed with the same principles in mind. Since 2020, Mayo Clinic Labs has offered a multiple sclerosis profile that we abbreviate MSP3. This test begins with measurement of kappa free light chain concentrations in CSF. Then, when results of the kappa test are borderline or elevated, the testing algorithm reflexes to oligoclonal banding for further evaluation. This reflex to the more traditional test, oligoclonal banding, gives physicians a lot of confidence in our testing. The performance of kappa CSF and oligoclonal banding has very similar sensitivity and specificity, according to several of our internal studies and meta-analysis published in the literature as well. Right now, we are one of the only labs in the world that offer this testing, especially in this reflexive approach.

Robin (10:14):

Wow, that's really interesting. Thanks so much for elaborating on how our MS cascade has really been on the leading edge of this approach. I'm curious about the oligoclonal banding testing aspect of the cascade. Dr. Willrich, is this a unique test, and why is this particular component of the cascade important?

Willrich (10:33):

Well, oligoclonal banding has been in place for decades. It's a very well-established test, a manual assay that looks for the presence of CSF-specific IgG band patterns, which reflect immune activity within the central nervous system. The results are always interpreted in conjunction with serum samples and then with clinical findings and imaging. Oligoclonal banding is not unique to Mayo Clinic Laboratories, but it's technically demanding, that requires paired samples and experienced interpretation. So very few labs, I think a few hundred of them, run this testing in North America. In our practice, incorporating oligoclonal banding as a reflexive step, after kappa concentration, allows us to use it selectively, when it adds the most value, rather than a universal first-line test. This approach helps balance efficiency with diagnostic rigor, ensuring that clinicians receive results that are both clinically meaningful, aligned with current diagnostic frameworks, and in the best possible turnaround time.

Robin (11:41):

That really does make so much sense, Dr. Willrich. I want to take a step back for a second and return to the subject of the kappa index as recommended in the McDonald criteria. Does Mayo Clinic Labs have plans to begin offering the kappa index now that it's included in the criteria?

Willrich (11:58):

Oh, that's a great question. At present, we don't offer a single bundle test reported explicitly as kappa index, but we do offer all of the individual components needed to calculate it, including kappa free light chains in serum and albumin also in serum and CSF. Our current testing strategy was intentionally designed to support the same clinical question the index addresses, which is evidence of intrathecal immunoglobulin synthesis, while allowing for flexibility and reflexive testing based on the clinical scenario. As the criteria continues to be implemented in practice, we're actively evaluating how to best align our test offerings with clinical needs while maintaining appropriate use and interpretive clarity.

Robin (12:46):

Thanks for breaking that down for us, Dr. Willrich. It seems to me like our MS cascade provides a simplified, streamlined approach to diagnosis. Dr. Banks, I am curious, in your experience, does our MS cascade offer the confidence you need to definitively diagnose patients?

Banks (13:03):

Yes, absolutely. So in patients presenting with a typical phenotype of multiple sclerosis, we're not waiting on spinal fluid test results before we start treating them with acute treatments, such as steroids and plasma exchange, but this allows them rapid confidence in their diagnosis and potential for disease-modifying therapy counseling earlier. In our more atypical cases, patients presenting in the hospital, for example, with tumefactive multiple sclerosis, this fast turnaround time is essential when we're planning to decide if we should give them acute treatment for an MS relapse or not, and has a potential, in some cases, to avoid brain biopsy even. I really appreciate this test is offered as a reflex, so that once we have that positive kappa free light chain result, we do also get the oligoclonal band result, which is what we're all a bit more familiar with.

Robin (13:50):

You mentioned fast diagnosis, Dr. Banks. Why is it important for patients with multiple sclerosis to have a fast diagnosis?

Banks (13:58):

There's a few reasons. So when we're in the outpatient setting and we're meeting a patient for the first time, they're of course very anxious. The spinal fluid result can be what makes the diagnosis of multiple sclerosis for them or not. It can be what determines whether or not we will offer them disease-modifying therapy for the future, and many of our patients are highly motivated to start on these treatments to prevent future relapses. So in the outpatient setting, it's been very helpful to be able to counsel our patients and rapidly get them started on treatment. And also, in the hospital setting, if you're treating a patient for a first relapse, it's very helpful to be able to give them that ultimate diagnosis before they're discharged, so they don't leave the hospital feeling uncertain and without a final answer.

Robin (14:42):

I'm curious, how quickly can our kappa light chain testing deliver answers? Are we talking same day? Dr. Willrich?

Willrich (14:49):

Analytically, the kappa free light chain assay in CSF itself is performed on an automated platform and has a 20-minute instrument runtime, but in practice, testing is performed in daily scheduled runs, so turnaround time depends on when the specimen arrives in the laboratory. In many cases, results are available within one to two days after receipt, which can be meaningfully faster than more complex manual assays. While the result does not establish a diagnosis on its own, it does provide supportive evidence information that helps guide clinical decision-making while additional data is being gathered.

Robin (15:25):

Thanks, Dr. Willrich, this test does sound like it's really fast, and I'm wondering, is testing for kappa light chains a first-line test? Is this a test that would be performed as soon as there is suspicion of MS? Dr. Banks, do you want to take this one?

Banks (15:39):

Yeah, so in patients presenting with a first event suspicious for multiple sclerosis, they're typically undergoing lumbar puncture at the same time as their first visit, alongside their MRIs. For patients who have only had one clinical presentation, are presenting as clinically isolated syndrome, if they do have positive kappa free light chain on spinal fluid, and two areas involved in MRI, we can make the diagnosis at that time, which may mean months earlier of treatment.

Robin (16:04):

Thanks, Dr. Banks. And next question, what does earlier treatment mean for patients?

Banks (16:09):

When our patients are able to access disease-modifying therapy earlier, it has the potential to prevent irreversible disability. High-efficacy disease modifying therapies are extremely effective at preventing new lesions and new relapses, potentially preventing development of future disability, and offering our patients much hope and certainty in their futures.

Robin (16:27):

It's just so great to hear that our testing can not only help diagnose patients more quickly, but also lead them to treatment that will limit the impact of their condition. It sounds to me like incorporating kappa chain testing into the McDonald criteria will facilitate much faster diagnosis for patients. Dr. Willrich, do you agree?

Willrich (16:46):

Yes. When a patient has positive CSF testing, be it the kappa index and/or a positive oligoclonal banding test result at the onset of their symptoms, we don't need to wait for a second clinical event to make the final diagnosis. Lab evidence of intrathecal immunoglobulin synthesis can be used to demonstrate dissemination in time.

Previously, establishing dissemination in time often required either longitudinal imaging or a second clinical event. By allowing the CSF biomarkers to serve this role, the criteria make it possible to reach a diagnosis earlier in the disease course for some patients, when clinical and imaging are supportive. This does not mean the diagnosis is based on lab testing alone. The results are always seen or interpreted alongside patients’ symptoms and MRI findings as part of a comprehensive diagnostic evaluation.

Robin (17:40):

Thanks, Dr. Willrich. So I'm wondering, besides our MS cascade, what other testing might be useful to help diagnose challenging cases? Maybe Dr. Banks, can you share your thoughts on what other Mayo Clinical Labs tests you've used to help pinpoint diagnosis for atypical or challenging cases?

Banks (17:58):

In cases that mimic multiple sclerosis with brain lesions, spinal cord lesions, or optic neuritis, I'm frequently testing for other antibody-mediated demyelinating diseases, such as MOG IgG, and aquaporin-4 IgG by live cell-based assay on serum, with either the CDS1, NMOFS, or MOGFS. It's important to remember that MOG can be false positive at low titers, so reviewing the 2023 MOGAD criteria is always helpful when it does return positive. In cases of myelopathy, without classical features of MS or with concern for paraneoplastic syndromes, such as a tractopathy, I'm usually checking the autoimmune myelopathy panels on serum and CSF. These are called the MAS1 and MAC1. This will include paraneoplastic antibodies as well as testing for GFAP antibody. It's very helpful to have all these tests available from one lab through the Mayo Clinic Labs.

Robin (18:51):

I totally agree. We really are a one-stop solution for advanced diagnostic testing for MS and many other conditions. We've talked a lot about the advantages of our testing, but I'm curious, specifically for the MS cascade, are there limitations to our testing approach? Dr. Willrich, can you take this one?

Willrich (19:10):

Yes. That's an important question, Robin, because no single lab test is perfect in every clinical scenario, right? One limitation of relying on kappa free light chain CSF concentrations alone is that they can be influenced by factors unrelated to MS, such as systemic immune activation, immunosuppression, the use of anti-CD20 immunosuppressive therapies, for example, or underlying plasma cell disorders such as multiple myeloma. In those situations, interpreting the CSF results in isolation can be challenging. This is where approaches like the kappa free light chain index, the four-test combination, or oligoclonal banding can really add value. The index would help account for serum contributions and blood-brain barrier dysfunction, while oligoclonal banding can provide complementary qualitative information when clinical suspicion remains high, and differentiating a monoclonal protein from that oligoclonal banding pattern that we are used to seeing in MS. For that reason, at Mayo Clinic Labs, we intentionally maintain multiple testing options and a reflexive strategy so clinicians can select or add testing based on the clinical context rather than relying on a single test result.

Robin (20:30):

Thanks so much for providing that context on scenarios where a different testing approach is needed to pinpoint diagnosis, Dr. Willrich. It sounds like we really have thought of everything at Mayo Clinic Labs when it comes to defining diagnosis for patients with MS, and also patients with similar conditions that require different management. As we wrap things up for today, I'm wondering if either of you have any final thoughts on our MS testing and how it fits into the diagnostic criteria. Dr. Willrich?

Willrich (20:58):

Well, I feel like we've been pioneers in understanding the role of kappa free light chains in CSF as a biomarker for MS. We've been studying kappa and CSF for almost a decade, and during this time we've learned a great deal about where this biomarker adds value and where careful interpretation is especially important. It's been rewarding to see this body of work reflected in the updated MacDonald criteria published last October. Our goal has always been to build a testing approach that supports timely and confident diagnosis without oversimplifying a complex disease. We also view lab testing as a partnership. Our lab directors and clinical consultants are available to work directly with providers, review results, help interpret findings in challenging cases. We truly value being a part of the care team and supporting clinicians as they care for patients with suspected or confirmed MS.

Robin (21:53):

Thanks so much, Dr. Willrich. Dr. Banks, do you have anything to add?

Banks (21:57):

Yeah. I'm very grateful for the expertise of leaders in this area, such as Dr. Willrich, and for the experience we've already had for a number of years ordering this test clinically, seeing the faster turnaround time, and the confidence we have in the diagnosis. It's been very helpful for our patients and improved patient satisfaction.

Robin (22:16):

And providing faster, better testing and answers for patients is always our priority here at Mayo Clinic Labs. It is just so great to hear that such strides are being made in expediting diagnosis for patients with this debilitating condition.

Thank you both so much for sharing your time and insights with us today. I've learned a lot, and I hope our listeners have as well. And to our listeners today, thanks for tuning in. We hope you enjoy today's discussion and will join us again for the next installment of “Diagnostics in Practice.”