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[00:00:44] Dr. Eduardo De Pablo-Fernández: Thank you very much for the invitation. A pleasure to here.
[00:00:46] Dr. Sara Schaefer: So let's dive into some of the background here. Can you talk a little bit about why there is diagnostic difficulty with multiple system atrophy?
[00:00:58] Dr. Eduardo De Pablo-Fernández: So multiple system atrophy [00:01:00] is one of the most challenging conditions to diagnose, I would say.
So it's multiple clinical pathological series is the most common condition misdiagnosed as Parkinson's disease. And due to this variable clinical presentation symptoms overlap with other conditions. With neurodegenerative parkinsonian disorders, but also with cerebellar ataxia.
So it is one of the conditions that can mimic multiple other neurodegenerative disorders. So it's well documented that it's very challenging to diagnose correctly in life for clinicians and multiple pathological series have shown that unfortunately the global accuracy of the diagnosis had been poor really with figures around 60 to 70% in the more recent series.
[00:01:45] Dr. Sara Schaefer: So you mentioned in your paper that in 2022, the MDS published an updated version of the criteria for the diagnosis of multiple system atrophy. There were previous versions in 1999, [00:02:00] and then a second version in 2008. And actually call back to one of our previous episodes, number 72, where Eduardo himself is on the interviewer side of things, talking to the authors of this updated MSA criteria.
So if you haven't listened to that episode, that would be a good episode to listen to either before or after you listen to this one. So can you tell us in brief how the MSA criteria was changed between the different versions and how the release of this criteria kind of led to the idea for this study?
[00:02:37] Dr. Eduardo De Pablo-Fernández: So as you said, this was discussed in the previous podcast by Dr. Wen and Dr. Stankovich. But in summary there has been, since 2008 where the previous version of any clinical diagnostic criteria was published. There has been a lot of advances in the understanding of the pathogenesis and the clinical presentation of multiple system atrophy.
And as I said before, the diagnostic accuracy [00:03:00] in clinical practice was poor. So the aim of the MDS Clinical diagnostic criteria was trying to incorporate some of these advances into criteria to improve the diagnosis in clinical practice and also in research. So essentially the categories change slightly compared to the second consensus diagnostic criteria.
Now we have clinically established MSA which aims to maximize the specificity, so with a purpose of trying to ensure the diagnosis at earlier stages and recruit participants with a very highly likely diagnosis of MSA into clinical trials and research. And we have also the clinically probable MSA, which aims for a balance between sensitivity and a specificity, which is more or less what clinicians, we aim to do in our consultations in order to reach a diagnosis. So the main changes they have incorporated, for example the MRI abnormalities clinically established criteria to improve the specificity.
They have changed, for [00:04:00] example, the urinary criteria in order to incorporate in urinary retention as one of the features of a clinical criteria for established MSA. But also on the other hand, for the clinically probable MSA, they have sort of relaxed some of the criteria in order to improve the sensitivity, which was relatively low in the previous clinical criteria.
So, for example, they have included delayed orthostatic hypotension or have reduced the drop of blood pressure to meet the criteria for orthostatic hypotension. And then they have incorporated a lot of other clinical features as additional criteria. So that's the brief summary. But yeah, I would refer the listeners to the previous episode of the podcast for further details.
[00:04:44] Dr. Sara Schaefer: And ,where did the idea for your study come from and can you explain how the study was performed?
[00:04:51] Dr. Eduardo De Pablo-Fernández: So we are lucky at the Queen Square Brain Bank that it's one of the oldest brain banks specializing in parkinsonian conditions. So [00:05:00] thanks to the generous donation of the patients, we have one of the largest collection of patients with multiple system atrophy, but also other sorts of other conditions included in the differential diagnosis of multiple system atrophy.
So when the diagnostic criteria were published, we were already working on the similar project, trying to evaluate the clinical diagnostic accuracy in Parkinson's disease, and other parkinsonian conditions. So we were really in a very good position to evaluate with a pathological validation, evaluated the diagnostic properties of the new released MDS criteria for MSA.
So what we did with our cases is we focused on the last 10 years of cases from our archives that presented the essential criteria in the diagnostic criteria for MSA. So it's basically adult onset progressive neurological disorders with either Parkinsonism or cerebellar ataxia.
And we included all those cases, which is over 300 in total, [00:06:00] including both the Parkinsonian and cerebellar presentations. This included patients with a pathological diagnosis of multiple system atrophy and also different conditions that could mimic the differential diagnosis. And we applied retrospectively.
We have a very detailed clinical information for each case. So we applied retrospectively. MDS criteria for MSA but also because we focus on the most recent cases. We wanted also to evaluate how they compared, not only with the previous clinical criteria, but also with the diagnosis in clinical practice.
So we compare the parameters of diagnostic accuracies of sensitivity and specificity predictive values and global accuracy for each of the criteria and also for the clinical diagnosis and clinical practice.
[00:06:50] Dr. Sara Schaefer: And what do you view as the take home points of what you discovered about the diagnostic performance of the new criteria, as compared to the old criteria. And how [00:07:00] did this change in the early stage? So less than three years from the onset of disease versus the late stage, or greater than three years from onset analysis?
[00:07:09] Dr. Eduardo De Pablo-Fernández: It was a pleasant surprise to see that the new clinical criteria had an excellent performance.
It's important to note that the diagnostic criteria should be evaluated in the context that what they were created for. So, for example the clinically established category has a poor sensitivity, but that's not the aim of those clinical criteria. The aim is to achieve a very high specificity, even at earlier stages.
And for example in our cohort, the clinically established criteria reach a 100 % of specificity even at the earliest stage. And similar, the clinically probable MSA category was aiming to reach a balance between sensitivity and specificity. And that was also accomplished with sensitivity and specificity and global accuracy over 94%, [00:08:00] which significantly outperformed the previous diagnostic criteria.
But also even the diagnosis in clinical practice that sometimes is regarded as they call the standard in life diagnostic by movement disorder experts. So the MDS diagnostic criteria for MSA showed better performance in terms of sensitivity and specificity.
[00:08:20] Dr. Sara Schaefer: So the take home point here would be that these criteria are an improvement over the last criteria in terms of diagnostic accuracy.
And the other thing that I took away from this is that if somebody meets the criteria for clinically established MSA, given the 100% specificity that you had in your cohort, that a clinician could be pretty confident that that does mean that the person has MSA and not another pathological condition.
Is that correct?
[00:08:50] Dr. Eduardo De Pablo-Fernández: That's correct. The 100% is the results that we obtain in our cohorts, obviously. So when you generalize these results to slightly different population the figures may be [00:09:00] slightly different, but as you said someone meeting their criteria for clinically established, we can be pretty certain that patient has MSA and no other neurodegenerative disorder.
[00:09:12] Dr. Sara Schaefer: Now, of course, and you mentioned this before, with any diagnostic criteria, there's going to be a careful balance of sensitivity and specificity. You want to capture as many patients as possible, but not over-diagnose and reduce the specificity of your diagnosis. Do you think based on your results, that a good balance has been made here with these criteria?
[00:09:36] Dr. Eduardo De Pablo-Fernández: Certainly for the category of clinically probable MSA. There is a good balance between sensitivity and specificity with no relevant difference between these parameters. And as I said the figures that they show is like over 94%. So I think in that way definitely that the new criteria were successful in achieving this purpose.
[00:09:58] Dr. Sara Schaefer: How do you think your findings [00:10:00] may help clinicians who are seeing and counseling these patients about MSA and how might your findings also help on the research front?
[00:10:09] Dr. Eduardo De Pablo-Fernández: So, another point that we found with the results is that comparing to previous clinical pathological series, the diagnostic accuracy of the clinicians didn't improve significantly despite the advances in the disease and the understanding of the clinical presentation of MSA.
So one thing that probably will help from this criteria will help the clinicians in the diagnosis. I think even if the criteria are not probably applicable in clinical practice when you have a basic clinic and probably you are not familiar with the criteria initially and so on.
But I think with time, probably some of the features will be incorporated in clinical practice. And I hope that will help the clinicians to improve the diagnostic accuracy in the day-to-day. Research-wise, one of the main objectives of MDS criteria was to improve the specificity [00:11:00] in the diagnosis of people taking part in research, particularly clinical trials, and particularly at the earliest stages when potential disease modifying treatments will be evaluated.
So I think that will definitely improve the selection of the participants for clinical trials and other research investigations.
[00:11:21] Dr. Sara Schaefer: So just to clarify, when you talk about the clinical accuracy, do you mean kind of the overall gestalt of the clinician, that based on what this person looks like, they probably have MSA, and maybe that's the ICD-10 code that they put into the computer or what they put in the assessment for the patient, but that they weren't necessarily applying strict criteria to make that diagnosis?
[00:11:48] Dr. Eduardo De Pablo-Fernández: So exactly, the diagnosis that we assessed in clinical practices, what the clinician at that time, at the earliest stages or at the finaler stages, thought that it was the most [00:12:00] likely diagnosis. We have access to all the clinical correspondence and clinical records of this patient. So we didn't use any coding system, so we had access to all the clinical information. So we were able to Enter with confidence what the clinician thought the most likely diagnosis would be. And as I said, it seems like there has not been any significant improvement with previous clinical pathological series from the literature. So, maybe at this stage probably the clinical skills have reached a ceiling.
And it'll be difficult unless there is any advances in other investigations. It'll be difficult to improve their diagnostic accuracy in clinical practice.
[00:12:39] Dr. Sara Schaefer: Well, I, for one, have put the MSA criteria, the 2022 MSA criteria as a dot phrase in Epic. For any of you who use Epic you'll know what that means, but I find that it's very useful to have that there so I can refer to it when I'm looking at patients who have some of the criteria and for whom I'm not sure.[00:13:00]
And I would encourage others to do that. I've certainly found it useful in my own practice.
[00:13:05] Dr. Eduardo De Pablo-Fernández: One of the points of this criteria when they were developed and that we discussed as well in the previous episode of the podcast is that they were trying to make them simple and easy to apply in clinical practice.
And as part of the methods and the process of developing this criteria, that was one of the aims to make them easy to apply in clinical practice as well. I have to say that I haven't been involved in the development of the criteria, so. But I think, definitely, our results show that they perform really well.
[00:13:34] Dr. Sara Schaefer: Yes. In your study also. And me as a clinician, I will use it as ammunition for my conversations with patients when I'm able to tell them they meet this criteria or that criteria for clinically probable or clinically established and what that actually means in terms of the likelihood of pathological diagnosis.
So thank you for that. You do mention the future, and this might be a [00:14:00] little bit of a cheeky question, but do you think this is the last iteration of the MSA criteria that we will expect to see? I imagine not, but what do you envision might be included in future iterations, potentially different types of biomarkers or other aspects of the criteria that you think might change in the future?
[00:14:19] Dr. Eduardo De Pablo-Fernández: Well, I hope it is the last. The last set of criteria really. As discussed in the diagnostic criteria. There is a lot of different investigations that probably at this stage, they are in early days of achieving results to be applicable in clinical practice. But there is very promising results, particularly with seeding studies of alpha synuclein in different samples and, biological fluids that hopefully will be able to give a sort of a biological definition of the disease rather than a clinical definition of the disease. So I hope this is the last set of clinical criteria and in the future, we will be able to be more categorical about the [00:15:00] diagnosis with biomarkers in clinical practice.
[00:15:02] Dr. Sara Schaefer: Excellent. Well, thank you for sharing your research with us today. I appreciate your time. And any parting words?
[00:15:11] Dr. Eduardo De Pablo-Fernández: No, it was a pleasure to share the results of our study.