Robin Huiras (00:01):

Hello. Welcome to today's installment of Diagnostics and Practice, where we discuss the latest diagnostic offerings from Mayo Clinic Laboratories. I'm Robin Huiras, a senior marketing specialist with Mayo Clinic Labs and strong believer in the ability of advanced testing to change patients' lives. I'm happy to be here today with two guests to talk about Mayo Clinic Laboratories' approach to precision epilepsy testing. This dynamic area of precision medicine enables a holistic diagnostic care experience that supports better outcomes for patients with epilepsy. Today I'm joined by Dr. Div Dubey, a neurologist and co-director of the Clinical Neuroimmunology Laboratory at Mayo Clinic, and Dr. Paul Jannetto, director of the Clinical and Forensic Toxicology, Clinical Mass Spectrometry and Metals Laboratories at Mayo Clinic. Welcome to you both. Thanks so much for being here.

Div Dubey (00:54):

Thank you Robin, and glad to be here.

Paul Jannetto:

Yeah, thanks, Robin. It's a pleasure to be here.

Robin Huiras (00:57):

Before we dig into today's discussion, I'm hoping you both can tell us a little bit about yourselves and your experience at Mayo Clinic and Mayo Clinic Laboratories. Dr. Jannetto?

Paul Jannetto (01:08):

Sure. I'm the vice chair of practice for clinical pathology in the Department of Laboratory Medicine and Pathology. I am also the co-director of three laboratories, the Clinical Mass Spectrometry Lab where I oversee the therapeutic drug monitoring, the Clinical and Forensic Toxicology Lab, where we do controlled substance monitoring, and the Metals Lab.

Robin Huiras (01:26):

Dr. Dubey?

Div Dubey (01:27):

I'm a professor of neurology and Lab Medicine and Pathology here at Mayo Clinic. I see patients with a wide range variety of autoimmune neurological disorders, including patients with autoimmune epilepsy, and also serve as co-director of the Neuroimmunology Lab and a consultant lead for Laboratory Services and Partnership Development, also known as LSPD. On the research side, my focus is on identification of novel biomarkers for autoimmunological disorders, including autoimmune seizures and epilepsy. And our lab has contributed to identification of many novel antibodies, some of which are being currently offered by Mayo Clinic as a clinical test for centers all across the world.

Robin Huiras (02:05):

Thanks both of you for sharing. Your experience really does underscore the expertise and insight that goes into test development at Mayo Clinic Laboratories. Now, let's get started. Epilepsy is one of the most common neurological diseases globally, affecting more than 50 million people around the world. It can be hard to diagnose and also difficult to treat. I'd like to set the stage for our discussion today by asking what exactly is precision epilepsy testing, and how can it be applied to help diagnose and care for patients? Dr. Jannetto, why don't you kick us off today?

Paul Jannetto (02:39):

I'm happy to. In the classic sense, precision epilepsy testing uses a combination of genetic and other tests to understand a person's specific genetic makeup and lead to optimized and personalized treatments. This approach moves beyond the one-size-fits-all to identify the root cause of epilepsy, allowing doctors to choose treatments that are most likely to be effective. Precision epilepsy testing at Mayo Clinic Laboratories typically involves using pharmacogenomic tests in tandem with therapeutic drug monitoring to first identify genetic variations a patient has that might affect how he or she responds to a particular treatment, and then monitor the treatment by serially measuring the active medicine concentrations in the blood to make sure the therapy remains effective and we minimize adverse drug effects.

Robin Huiras (03:31):

Thanks so much for that quick intro to precision epilepsy testing, Dr. Jannetto. Now. you mentioned using pharmacogenomic testing and therapeutic drug monitoring to maximize treatment effectiveness, but I'm wondering, what is the role of diagnostic neurology testing in the precision epilepsy paradigm? Dr. Dubey, do you want to answer this one?

Div Dubey (03:51):

Absolutely. Epilepsy affects about 1 to 2% of people worldwide, and figuring out the cause can be tough because there are so many different possibilities: autoimmune conditions, strokes, infections, metabolic issues, genetic changes, structural malformations, cancer, or trauma. Even with all those known causes, about 30 - 40% of patients, we still don't know why the seizures are happening. These are what we call cryptogenic cases. And here's what's interesting - on more comprehensive evaluations, that is precision testing or precision diagnostics at centers like ours, about 15-20% of those turn out to have a genetic basis, and a smaller proportion, I would say 7-10%, have an autoimmune etiology. And that's why precision testing matters. Instead of just treating seizures, what we are really going after is the root cause or targeting the root cause, which is causing the seizures to happen. This approach is especially important at tertiary care centers, where we see more complex cases, more cryptogenic cases.

For clinicians, it means better treatment decisions. For patients and families, it often means peace of mind, because they finally have an answer why they're having seizures, and the goal changes from just managing seizures to treating the underlying disease process.

Robin Huiras (05:04):

Thanks, Dr. Dubey. That really does make a lot of sense. It seems like a precision medicine approach can really put the pieces together to create a full picture of what might be going on with a particular patient and how best to treat them. Do you think the precision epilepsy testing approach that you described is common among physicians treating epilepsy patients?

Div Dubey (05:24):

This approach isn't standard everywhere, but it's gaining traction. There are a few reasons why it's not a common practice outside of places like Mayo Clinic. First, it takes specialized infrastructure and expertise. Precision epilepsy testing involves advanced antibody panels, genetic testing, drug monitoring, all of which require not just technology, but patient care team trained to interpret these complex results. The good news is Mayo Clinic Laboratories is already providing this testing to multiple sites outside of Mayo. We are not just keeping these Mayo developed tests in-house. We are building partnership and sharing expertise so more patients can benefit from precision diagnostics. Secondly, at Mayo, we see a higher proportion of challenging cryptogenic cases referred from other centers. So precision testing makes a huge difference. In a smaller or community setting, those cases are less frequent, so the investment doesn't always feel as urgent. And yes, the cost and insurance coverage can be hurdles too.

That said, I think more and more centers are adopting these tools as evidence continues to show better outcomes with precision testing. Mayo is actively working to expand access and share our expertise so that patients everywhere can benefit.

Robin Huiras (06:36):

Thanks, Dr. Dubey. And Dr. Jannetto, I'm curious, has this been your experience as well?

Paul Jannetto (06:41):

Yes. Not all clinicians have access to a comprehensive genomic and/or therapeutic drug monitoring test menu, where they can get clinically relevant turnaround times to use the data in a meaningful way.

Robin Huiras (06:53):

Thanks. I really appreciate both of your insights on what you've noticed outside of Mayo Clinic. Given the benefit of a precision approach, I'm wondering, isn't it advantageous for all patients affected by epilepsy?

Div Dubey (07:06):

Great question. Yes, a precision approach can benefit all patients with epilepsy because treatment never is one-size-fits-all, but some patients stand to gain even more, especially those with an immune-mediated cause of their epilepsy, also known as autoimmune epilepsy. These autoimmune epilepsy patients often do not respond to standard anti-seizure medications, especially if not used in conjunction with immunotherapy or immunosuppressive medications. Those drugs might reduce seizures temporarily, the anti-seizure medications, but the underlying autoimmune process driving the disease persists. What really is needed as a treatment here is targeting the immune system through medications like steroids, IVIG, plasma exchange, rituximab, or tocilizumab, alongside anti-seizure medications. And then we need to monitor these treatments carefully so they are not causing side effects and that we are using them optimally. That's where precision medicine makes a huge difference. It helps us diagnose things correctly, choose the right therapy, track how well the patient is doing, and how well these drugs are working.

And here's the exciting part. For many autoimmune epilepsy patients, treatment might not be lifelong. If we address the root cause, the autoimmune disease, we can actually cure the epilepsy rather than just managing the seizure. A great example is a patient I saw a few weeks ago with pilomotor seizures, a rare form of seizures that presents with goosebumps. Through Mayo's EPC2 and EPS2 panels, we identified the patient was positive for LGI1 antibodies, confirming an autoimmune basis that finding completely changed the treatment plan. The patient was started on immunotherapy, specifically steroids and rituximab, and seizures and the cognitive changes he was having resolved. I've had many other similar cases with other antibodies like CASPER2 antibody, who have become seizure-free once a diagnosis of autoimmune epilepsy is made and they've been started on appropriate immunotherapies.

Robin Huiras (09:00):

That's a great example, Dr. Dubey. Thanks so much for sharing. Curious, do you have any examples that might touch on how this approach would be helpful for individuals with a hereditary cause of epilepsy?

Div Dubey (09:12):

Yes, for sure. Precision testing can be especially valuable for patients with hereditary causes as well. Often in the pediatric cases, many children have genetic drivers of their seizures, and identifying those early can completely change the treatment plan. For example, our pediatric team recently cared for a 4-year-old who had been followed for most of his life. As an infant, he experienced long repeated convulsions whenever he had fever. These seizures often affected just one side of his body, and after they ended, he was weak on that side. Over time, the ongoing seizure activity impacted his development and he wasn't meeting his milestones. The presentation was suggestive of a genetic etiology called a Dravet syndrome. So our pediatric neurologist ordered the genetic epilepsy panel, EPPAN panel, which confirmed the pathogenic SCN1A gene variant. It allowed him to get started on Dravet-specific medications and even enroll in a clinical trial for a genetic therapy that targets underlying defect by modification of the gene expression at the RNA level.

The hope is that with this therapy, not only there's reduction or elimination of seizures, but he helps catch up developmentally. That's the power of precision medicine: moving from symptom management to truly addressing the root cause.

Robin Huiras (10:33):

That's an amazing case, Dr. Dubey. Thanks so much for sharing. It really is a powerful example of the benefit of a precision testing approach. I'd like to turn this question now over to Dr. Jannetto. From your perspective, is there a certain type of epilepsy patient who might benefit more than others from precision testing?

Paul Jannetto (10:53):

Yes. There are certainly some patients who might get more of a benefit from a precision testing approach. For instance, numerous patients. that are either referred to Mayo Clinic or whose specimen comes through Mayo Clinic Laboratories. are individuals who have not responded to several treatment modalities and medications. These patients tend to be taking much higher doses and/or combinations of medicines with the concentrations in their blood are outside the traditional therapeutic ranges. But for that patient, that is their therapeutic value. Even though their medication concentration might be high or critical for other patients. So having those serial measurements that we do with therapeutic drug monitoring is crucial to make sure that we're maintaining those levels, because normal changes throughout a patient's lifetime, such as kidney, liver changes, or pregnancy, can affect the medication concentrations and the dose needs to be constantly adjusted so they can maintain those therapeutic concentrations and be seizure-free.

Furthermore, many of these patients often need to start taking additional medications for seizures or other conditions, and drug monitoring can help identify potential drug-drug interactions. Those results can help inform the patient's provider on any dose adjustments needed to maintain the therapeutic target, or if an alternate therapy might be needed.

Robin Huiras (12:20):

Thanks, Dr. Jannetto. The example you provided here is related to patients who may be refractory to therapy, so I really wanted to dig into that subject a little bit more. Why is a precision medicine approach so important for these patients with drug-resistant epilepsy? Dr. Jannetto, you want to take this one as well?

Paul Jannetto (12:38):

Absolutely. Patients with drug resistance or refractory epilepsy, which is about one-third of epilepsy patients, require an objective means to really understand how well a treatment works for them. A lot of testing is subjective, like asking patients how many seizures they might be having or if they've been taking all of their medications as prescribed. It relies on honesty, awareness, and an accurate memory. Objective lab tests that measure the actual concentration of the medication in their blood removes any guesswork. Drug monitoring can also help physicians understand prescription compliance, which is the number one reason why a medication doesn't work. What does this mean? It can mean a patient didn't take the medication at all. It can mean the patient took some of the dosages. Remember, some of these medications are taken two, three, four times a day, and that can be very challenging. Anytime a dose is skipped, it can change the steady state concentrations you're trying to achieve, and it may be the reason why the medication's not working.

Compliance data shows that patients who only have to take one pill a day are only about 80% compliant. And if you have to take a medication four times a day, that rate drops down to about 50%. The compliance piece is important from the standpoint of therapeutic drug monitoring because we need to make sure the patient is taking the medication as prescribed. Therefore, for drug-resistant patients, medication monitoring is critical to understanding the reasons why a treatment might not be working, and if the patient is truly refractory to a particular medication.

Robin Huiras (14:18):

Thanks so much for breaking that down, Dr. Jannetto. It's great to hear how our testing can benefit treatment-refractory patients. I'm wondering, which or our therapeutic tests do you think would be most useful for refractory patients? Are there specific pharmacogenomic tests or treatment monitoring tests or maybe test combinations that you think are valuable, and why?

Paul Jannetto (14:41):

Sure. I want to first point out that our pharmacogenomic tests and therapeutic drug monitoring tests provide complementary information for clinicians. For example, carbamazepine is a commonly used medication that is FDA-approved for the treatment of epilepsy. However, a minority of carbamazepine-treated patients can have a cutaneous adverse reaction that varies in prevalence and severity, with some forms associated with substantial morbidity and mortality. As a result, the FDA-approved label for carbamazepine states that screening of patients with ancestry in genetically at-risk populations, like patients of Asian descent, for the presence of the HLAB*-15:02 allele should be carried out prior to initiating treatment with carbamazepine. If the test is positive, carbamazepine therapy should be avoided. In refractory patients, I find that serial determination of serum drug concentrations can help identify an individual's therapeutic range. Remember, refractory patients often require higher dosages and therefore have higher serum concentrations that fall above the regularly cited therapeutic ranges.

However, for that individual, those higher concentrations are therapeutic and not toxic. And so dosages shouldn't be decreased, but rather maintained so that they can maintain a seizure-free life.

Robin Huiras (16:09):

Yeah, I see that makes so much sense. And thanks for clarifying how some of our tests can work together, Dr. Jannetto. Now, Dr. Dubey, I'm wondering, can you share your experience treating patients with drug-resistant epilepsy and explain how precision testing might help identify why their treatments aren't working?

Div Dubey (16:30):

Sure. Drug resistance is something we often see in clinic, especially among patients being referred for autoimmune etiology. It can mean the patients aren't responding to anti-seizure medications or even the immunosuppressive treatments are losing effectiveness. A good example is patients with GAD65 antibody-associated epilepsy. They often come to us years into their disease when immunotherapies aren't working anymore. You can think of GAD65 autoimmune epilepsy a bit like type 1 diabetes. In diabetes, the immune system damages the insulin-producing cells, and by the time the diagnosis is made, those cells are gone. So we treat with insulin and not with immunosuppression. With GAD65 epilepsy, the immune system has injured the brain. The damage is done. So the focus shifts from controlling seizures with immunotherapy to starting patients on optimal anti-seizure medications. These patients are usually on two to six seizure medications, so therapeutic drug monitoring becomes critical. We always try to optimize one drug before adding another, and monitoring helps us do that.

More broadly, drug monitoring is helpful anytime treatment resistance occurs. If the patient's seizures were controlled to start with, but then are coming back now, we ask: Is the medication level too low? Is the disease progressing? Or is there another underlying cause, maybe a genetic or autoimmune cause that wasn't considered before and needs to be considered now and potentially treated? Sometimes these results guide big decisions, like moving from medical management to surgery or vagal nerve stimulators. Ultimately, precision testing feeds clinical decision-making, helps us escalate treatment appropriately, especially for complex cases we see at Mayo Clinic.

Robin Huiras (18:19):

These examples are really helpful, Dr. Dubey. One thing I'd like to talk a little bit about is integrated care, which I think is key to a precision medicine approach. Integration and collaboration is bedrock to how Mayo Clinic and Mayo Clinic Labs provide care. And it's really a great segue to my next question, which is, why is Mayo Clinic Labs so well-suited to offer precision epilepsy testing to patients and their physicians? Dr. Jannetto, this question's for you.

Paul Jannetto (18:48):

Honestly, we probably have one of the most world-renowned adult and pediatric epilepsy clinics at Mayo Clinic, with patients traveling from around the globe to get care. Similarly, complex patients from around the world are sending samples to Mayo Clinic Laboratories for testing in our state-of-the-art laboratories. These are patients who need high-quality, accurate test results the same day or the next day, if they're MCL clients, so their physicians can make a diagnosis or dosage adjustment. Because our clinicians, like Dr. Dubey, routinely treat these complex patients, they have a higher level of experience and confidence with complicated cases. This is especially important for patients who are on higher doses and combinations of medications whose drug concentrations may be outside of traditional therapeutic reference ranges, but we're able to interpret these results in the context of that individual patient. In the end, we offer a comprehensive therapeutic drug monitoring menu that uses modern technologies, like liquid chromatography tandem mass spectrometry, to test for the latest generation of medications as well as established medications.

Our assays also have large dynamic ranges to account for high medication concentrations, which enable us to provide timely results back to the ordering provider to improve patient management. For most of our MCL testing, we can get results back to clinicians within 24 hours, and that is meaningful because those results inform dosage adjustments and medication changes. And lastly, for patients who are brand new to Mayo Clinic or MCL, we can provide pharmacogenomic and genomic testing to help guide them and get started with their appropriate medication and dose with more certainty.

Robin Huiras (20:33):

Thanks so much for sharing your thoughts on what sets us apart, Dr. Jannetto. Dr. Dubey, same question to you. In your opinion, what is it about Mayo Clinic Labs’ neurologic epilepsy testing that plays well into the precision epilepsy testing paradigm?

Div Dubey (20:48):

I think what really sets Mayo Clinic Labs apart is the breadth and depth of our test menu. When it comes to the diagnosis, we cover all major causes of epilepsy. From autoimmune epilepsy, where we have our EPC and EPS2 panels, which include about 20 antibodies, and our lab is constantly updating them with new antibodies as they're discovered and validated. For infectious causes, we are offering meningitis, encephalitis PCRs and serologies, even metagenomic sequencing for hard-to-detect infections. And on genetic side, we can do targeted testing and go as far as whole exome or whole genome sequencing to identify the genetic drivers of epilepsy. What this means is that through precision testing, we can often give patients the answers to what is driving their seizures. That's huge, not just for treatment planning, but for peace of mind. It helps patients understand what the next few years might look like.

And most importantly, it allows us to treat the underlying disease, not just the symptoms. People come to Mayo for extra layers of information, and it's incredibly rewarding to be able to provide that clarity and direction.

Robin Huiras (22:01):

Yeah. And the more information we can provide to patients and their providers, the better equipped they will be to make decisions that positively impact their health. Before we wrap things up today, I'm wondering, do either of you have anything to add about the value of our precision epilepsy testing for patients and their doctors?

Div Dubey (22:20):

I would add that what makes Mayo Clinic's approach to complex neurological diseases unique is the level of collaboration. Epileptologists, neuroimmunologists, neuroradiologists, geneticists, and lab scientists, all working together to perform and interpret results in real time. The degree of collaboration is invaluable for the care of these patients and is ultimately what allows us to deliver care that is both precise and deeply personalized. For many patients and families, that kind of diagnostic clarity is truly life-changing.

Robin Huiras (22:53):

Thank you. I really couldn't agree more. I appreciate both of your time talking to us today. I really learned a lot and hope our listeners did as well. And to our listeners, thanks for tuning in. We hope you enjoyed today's conversation and will join us again for the next installment of Diagnostics in Practice.