Dr. Benit is an experienced neurologist specialised in multiple sclerosis (MS). We discussed with her the challenges of diagnosing neurological disorders such as MS and Parkinson’s, and the potential role of miRNAs as diagnostic biomarkers. MS is difficult to diagnose due to many "MS mimic" diseases (such as neuromyelitis optica or encephalitis) and the lack of specific biomarkers. Dr. Benit emphasises that the miRADAR test would be especially useful in cases of doubt and that in MS it is important to treat the disease early.

She also mentions the various forms of MS and indicates that for the most common form of MS, relapsing remitting MS has the best treatment options. This helped to focus us on this form of MS, as diagnosis is only useful if it allows doctors like Dr. Benit to then treat the patients.

"MS is still very difficult to diagnose, mainly because of the many ’MS mimics’."

“You don’t have a biomarker that says, this is MS, so you really have to base it on the clinic (symptoms as described by the patient) and what the scan looks like.”

"With MS you have certain criteria, such as the McDonald’s criteria, where you have to exclude other diseases, which makes the diagnostic process complex."

"I think that in 70-90% of patients the results will be clear within four weeks [after initial specialist testing] whether it is MS, but in some cases this can take months."

“Treating MS early can really prevent damage, especially in the relapsing-remitting form.”

"If you had an additional test to better diagnose MS when in doubt, that would certainly be useful."

Dr. Kuijpers emphasises the versatility of symptoms and the uncertainties associated with the diagnosis, especially since no specific blood test is available. The McDonald’s criteria, which are based on MRI and lumbar puncture, remain the standard, but these have their limitations, mainly due to the overlap with other neurological conditions similar to MS, such as neuromyelitis optica. Dr. Kuijpers sees potential in developing new diagnostic tests, such as those based on miRNA, which may provide faster and more specific diagnoses. He emphasises the importance of high specificity, especially to distinguish between MS and other serious conditions. In addition, he points out the possible benefits of such tests, such as speeding up diagnosis and reducing uncertainty among patients.

“Patients with MS, can have many different neurological complaints. So basically any kind of neurological symptoms can be caused by MS. What is somewhat typical for MS is that it does not start very acutely.”

“There can be someone of whom you think, well this one has a course that fits very well with MS. But then they don’t have a specific number of abnormalities on the MRI, for example. As a result, you don’t come to a diagnosis. While your suspicion is very strong that that person has it.”

“And vice versa, some people have abnormalities on an MRI scan that make you think, well, they actually fit very well with MS. But they don’t have a story that fits very clearly. As a result, you don’t come to a certain diagnosis.”

“So you just have quite a few uncertainties in diagnosing MS at the moment, you work with a set of (McDonald) criteria and do not have a conclusive blood test.”

“The first criterion of diagnosing MS is make sure another cause is unlikely or excluded. And only then can you diagnose MS. And it is precisely that first step that is the tricky part.”

“You have a number of conditions. for example you have neuromyelitis Optica or anti-MOG diseases, other inflammatory diseases of the central nervous system that can be very similar both in terms of symptoms and in terms of MRI image.”

“I think being sure to make the diagnosis yourself and thus being able to tell the patient you have this disease can help a lot.”

“If a test can help to distinguish between MS itself and the diseases that are very similar, and I think that is perhaps even more important the other way around. It is the case with other diseases and especially neuromyelitis Optica. That is a very serious inflammation of the central nervous system, where you have to act very strongly and treat very hard, while that does not apply to MS in principle. Of course, those are treatments that also have a lot of unpleasant side effects, and also often affect someone’s immune system, so if you don’t have to do that, you don’t really want to do that. If you have a test with which you can distinguish early between that disease that you then have to treat very aggressively versus MS that you have to treat less aggressively, then that would be very valuable.”

“I think that in the medical world, everything that has an effect on the cost burden is valuable. So if you need less staff, you can automate it, it takes less time, then I think it also costs less money. I think that that always yields an advantage.”

“Yes, it can sometimes take a month to years before you can make the diagnosis. Whereas if you can do a blood test to see if it is MS, then of course you are done much faster. Then you have much less uncertainty, also for the patient of course.”

“I think that micro-RNAs are certainly more widely applicable for neurological diagnostics, and I think that also applies to those other conditions that it can shorten the diagnostic process a lot.”

Project idea:
"The design of your new test is very promising. A simple and accurate test for the diagnosis of MS will be very helpful for neurologists."

Storage:
"The kit must have a long shelf life. Storage at room temperature or in the refrigerator."

RNA tools hospital:
"Hospital laboratories of major teaching hospitals are familiar with RNA analysis. Most of the RNA tests are provided as ready-to-use kits. Smaller hospital laboratories in the Netherlands have no possibilities to perform these tests, but are connected to one of the larger hospitals."

Full kit:
"An unambiguous package insert is needed with e.g. literature references of patient results.";
"All special disposable parts have to be provided in the kit package.";
"The kit must also contain a positive sample (liquid) to perform the QC-check to release the kit for patient sample tests.";
"The test must comply with the requirements of the IVDR (European in vitro diagnostic regulation)"

High accuracy:
"Using this test for selected patients with MS-abnormalities on the MRI-scan and anamnesis, the positive predictive value as well as the negative predictive value must be high (>95%).";
"Using this test for unselected patients in a population survey the number of false positive results should be nearly zero otherwise a lot of patients will be wrongly diagnosed as MS-patients.";
"Before the test can be used as a diagnostic test for patients’ samples, the specifications of the test should be determined in clinical trials."

Pablo Villoslada is researcher experienced in many fields he has over 20 years of experience in translational medicine and has experience in every step of the development of new technologies. From researching the underlying biology, to developing new drugs and medical devices in one of his many startups and he implements it as he continues to practise as neurologist. For these reasons we felt he was the perfect person to interview to get a full picture on the development of the miRADAR test. He explained the current methods of diagnosing MS, emphasising the use of clinical criteria, MRI, and cerebrospinal fluid (CSF) analysis. While these methods are effective, he noted the absence of a single definitive test for MS. He also addressed the hurdles in MS diagnosis, including access to MRI and specialists, particularly in less developed regions.
Dr. Villoslada highlighted the potential of a new diagnostic tool based on microRNA, and emphasised the importance of its accuracy. He suggested starting with a specialised application before considering a tool for broader, public screening. He also discussed the challenges of targeting specific age groups for early MS detection and stressed the need for precision in diagnostics due to the complexity of neurodegenerative diseases.

"MS is one of the diseases that we diagnose based on clinical criteria... meaning we don’t have a single test that is highly specific to MS."

"The ideal test would be something very easy and very cheap to do... eventually a blood test with high specificity and predictive positive value."

"The main hurdle is the MRI, although MRI now is very accessible in Europe... accessing an MS specialist is also critical."

"If you are able to diagnose MS before symptoms, during the prodrome, this would change everything."

"Having a test that tells you about all neurological conditions would be extremely nice... but it’s extremely difficult to succeed in that."

"You need to find microRNAs that tell you about an autoimmune process specific to MS... this is where the challenge lies."

"If the accuracy is not high enough to avoid the MRI and the CSF analysis, then it’s going to be just a nice test to have on the side."

During our interview with Marianne Vogels, a patient with multiple sclerosis (MS), she discusses in detail the challenges and experiences associated with living with this disease. Marianne Vogels has relapsing-remitting MS, a form of the disease characterised by periods of attacks alternate with stable periods. Despite the stability of her disease, confirmed by recent MRI scans, the impact on her life remains significant. She is taking Copaxone, an older MS drug, which she says has a less strong effect on the immune system than other, more recent medications, which she appreciates. Marianne Vogels talks about her difficult path to a diagnosis, which took years despite obvious symptoms such as loss of feeling. Only after a surgery caused a severe relapse, the diagnosis of MS was made, which raises questions about the diagnostic processes in healthcare. She also discussed the different forms of MS, such as primary and secondary progressive MS, and expresses her concerns about the lack of effective treatments for these progressive forms. She emphasises the importance of early diagnosis, but also recognises the ethical dilemmas involved, especially when effective treatments are still lacking. As a spokesperson for the MS Association, Marianne Vogels is committed to creating awareness about the disease. She explains how difficult it is to understand the impact of MS, given the varying symptoms and severity of the disease among patients. She illustrates this with personal experiences such as difficulty walking and having to constantly plan and budget for energy, which leads to social isolation and financial obstacles. She advocates more inclusivity in public spaces and for visually explaining energy loss, for example with the "spoon theory", to create more understanding of MS.
In the last part of the interview we discuss the miRADAR test. She expresses her hope that innovation in MS treatment and diagnosis can lead to more targeted therapies that place less burden on the immune system, given that current treatments are very invasive.
All in all, Marianne Vogels provides a compelling picture of the complex reality of life with MS. She emphasizes the importance of patient-centered innovation in medical technology and calls for more research and awareness to improve the quality of life for people with MS.

"I had a loss of sensation and that was very typical (for MS) (...) And then I got an MRI and, well, nothing could be seen. And it went away again, that took more than a year, but then it was also gone again."

“Yes, that is common, yes. And that is something that always surprises me, how is it possible that I still had clear complaints, and it was not visible, and then suddenly it is visible.”

“And the bad thing about that progressive variant is that there is actually nothing that can be done about it.”

“If you have an early diagnosis, you can prevent a lot of damage by using medication.”

“I used to do ballet at a serious level, so I think dancing is not very difficult,. but then suddenly I couldn’t keep it up anymore. That I fell out of rhythm.”

“I was, let’s say, 37 when it started, and at 52 I was diagnosed. Suppose I had been on medication ten years earlier, then damage would have been prevented."

"I also think that MS is actually very likely not one disease, but indeed several diseases under one cover could be.”

“I think, besides the fact that I have it myself, it is also a very interesting disease. Because there are so many aspects to it, and the more I learn about it, the more realize I actually don’t know a lot.”

“And I also think that researchers who are working on it (with MS) have the same thing. It is very vague and hazy in everything we read. No one has a clear idea of what exactly happens.”

“I became a public information officer because I also really enjoy talking about it. And to make people understand that more.”

“The disease is quite invisible in people like me. I am not in a wheelchair, but how much impact it all has, on your energy level in particular, I think it is important that you make that more widely known”

Marianne Vogels expresses her opinion about the oversimplification of the symptoms of MS patients. She shares that the intensity of MS can vary from person to person, and over time. It is a spectrum, where most people have serious symptoms but are not always in a wheelchair. This makes a large proportion of MS patients less visible:
“I am older, it is frustrating to have little energy, and embarrassing to walk with a stroller. But I know a woman who is 27 that already needs a walker, while all her friends go out partying. Especially for patients of that age, MS is really impactful to their social life.”

A boy once said to me: ’When it was my birthday, I put a tent at my house, because I had to accommodate all those guests who came. Since I have MS, no one comes anymore.’ Because they know , he just gets tired quickly. Let alone that they still ask him, because he always says no.” His motto is: “Keep asking me, even though you know I will say no.”

There is also a big financial impact of MS:
“There is a spectrum of symptoms (1-10), with some people having more severe symptoms and some less. Half of the people with MS can still work, but might prefer to work three days a week. Is there financial support for these people? No, that’s just a shame”

“So it does indeed cost a lot of money. And everything just costs extra. There are many sides to it, except the complaints, which you never really see.”

“I have two glasses and one has a hundred sticks and the other has ten, that is the energy difference. You get a hundred sticks of energy every day, and I get ten. Then I get up and take a shower, then get dressed and then a stick comes out. You’re also going to have a bit of trouble. But you still have ninety-nine left, and I have nine.”

“That tiredness. Or that lack of energy. That is actually one of the things that you are most disappointed with.”

Question: You first go to the doctor and then you explain your complaints. At what point would you prefer to do such a test? Answer: “Yes, it seems to me, what I said earlier, if you have a fatal disease that is unavoidable, then I understand very well that you do not want to know that. But this could prevent damage. And then knowing early is actually very useful”

“So if it is a blood test to perform the diagnosis? Yes, then I would say just perform it directly when you see the doctor”

Hanneke Kool emphasises the importance of an early diagnosis to prevent serious damage. She shares her experience that many MS patients had to wait a long time for a diagnosis, especially before MRI technology was widely available. She also talks about her involvement in the MS patient association and her work as a spokesperson, in which she tries to increase the importance of awareness about MS.
She also speaks about the advances in treatment options for MS and how the disease has affected her personal life, both positively and negatively. Although medication has helped her slow the progression of MS, she acknowledges that the disease still has a major impact on her life, especially with regard to fatigue and cognitive problems.
She further reflects on the advantages and disadvantages of knowing the diagnosis early. While she emphasises that knowing her diagnosis early has benefits, such as the ability to initiate treatments in a timely manner, she also sees that living without the knowledge of her diagnosis has allowed her to do certain things that become more difficult once you are diagnosed. For instance, a chronic illnes can affect your mortgage or life insurance application. without to settle problems.
Hanneke Kool also discusses the challenges associated with the unpredictability of MS and how the disease can lead to isolation, job loss and economic hardship. She emphasizes the importance of work as a source of social connections and appreciation, and how early diagnosis can help preserve these aspects of life for as long as possible.
The interview also discusses the possible development of a new diagnostic blood test for MS. Hanneke Kool believes this is a valuable addition to current diagnostic methods, especially because a blood test is less stressful than, for example, a lumbar puncture. However, she emphasizes that a test must be very accurate (95-100%) to be useful and to avoid unnecessary panic.

“I was initially diagnosed and it said I was primarily progressive. (...) Despite what I said, I have had a kind of relapse (recurrence of MS complaints) from my MS several times over the past twenty years. And well, they wouldn’t accept that. So they had no medication for me. So the first two years were very intense.”

“At that time (early this century) there were still very limited inhibitors for MS. And you also had to have authorization from the health insurer to use them. So he (the neurologist) had to change the diagnosis from primary progressive to relapsing remitting. I am forever grateful to him for that, because I was allowed to inject inhibitor medication. I was also given a high dose of prednisone once a month. And from that moment on, peace slowly came into my body.”

“I thought when I was working in neurology... that I knew just about everything about MS. But that is not the case. It wasn’t until I got MS... started having symptoms that I had never heard of... then I really learned what MS is.”

“That tiredness won’t go away. And especially that cognitive aspect, you continue to have problems with that.”

“There are many MS patients who have to wait years for a diagnosis”

“So much research has been done that people now realize that the sooner you treat it, the more you can prevent damage. Because once there is damage, you cannot repair it.”

Question: “Would you say that an early diagnosis of MS is very essential for proper treatment?”
Answer: “It is certainly very essential, because the sooner you treat, the faster you can stop the progression of MS.”

“Yes, there is now medication, also for primary progressive, which never was there before. To administer, to slow down a bit.”

When we asked if people would like an early diagnosis:
“Some do, some don’t. You know, when I look at myself for a moment, I was very disappointed that it was only after more than twenty years that I was told that I was not crazy, that my complaints were indeed caused by MS. On the other hand, I felt like, how would I have reacted twenty years ago if I had been diagnosed, knowing that there was so little available for it.”

“For many young people, because MS often starts in young people, it can indeed be a huge intrusion on life, because you indeed mainly have the loss of energy, but also the complaints that can arise, which can lead to a lot of isolation , but also loss of work and economically it is very difficult”

“MS is a debilitating disease. He (MS) can surprise you, he can also leave you alone for a while. Not knowing when it will come is a great uncertainty. It means that it is also difficult to plan for your future.”

“People need to realize that MS is more than what they see. And we always show the iceberg, that tip. Where you see someone walking unsteadily or sitting in a wheelchair. But then you see that iceberg under water and then you see all the other complaints, the spasms, the fatigue, the cognition problems, the sensory disorders, the pain complaints.”

Question: “It would indeed be a blood test that could therefore already tell whether someone has MS. Do you see this as something possible and do you see this as something useful?”
Answer: “I think it’s certainly very useful. Because look, a blood test is the least burdensome research method. It makes a big difference with a lumbar puncture.”

"From the moment I was given medication, my body slowly calmed down. That activity, all those scales that rolled over each other, were muted."

Question: “And where do you think would be most convenient for this test to be administered? At the doctor’s office, for example, or in a hospital?"
Answer: “No, no, not at the doctor’s office. I just think in a hospital.”

Question: “What would you say, how accurate would a test have to be for it to be really useful?”
Answer: “I would still like to go for 95-100%. And then I’ll give you an example. When I worked in neurology there was a young woman who had all the symptoms: paralysis on one side, speech problems and it possibly matched an image of a scale. A CT scan was done and it showed something and she was diagnosed with MS. Later she got it again and it eventually turned out that she had a small infarction as a result of the pill she was taking. That was a side effect of the pill. But in those months before there was already panic at home and the house had already been half renovated and it was already completely planned out for when she came in the wheelchair and who knows what.”