Ataxia Series: The ataxia exam - Phenomenology, classification, and a practical diagnostic roadmap

Today we are discussing the topic, the ataxia exam, phenomenology, classification, and practical diagnostic roadmap. But thank you for joining us.

Dr. Bart van de Warrenburg: Hi Orlando, thank you for having me. It's a real pleasure to contribute to this podcast [00:01:00] series on ataxias.

Dr. Orlando Barsottini: Bart, as we have different forms of ataxias including, for example, cerebellar ataxias, sensory ataxias, and sometimes a combination of both. Could you tell us about your clinical approach with emphasis on the gait examination and phenomenology, please.

Dr. Bart van de Warrenburg: Sure. Many patients with cerebellar disease will notice gait difficulties as the very first manifestation. If you see a patient with a gait ataxia, indeed, we first have to establish that this is actually of cerebellar cerebellar origin a nd I think people often think of cerebellar ataxic gait as being broad based.

But this is actually a compensatory element that kicks in later in the disease. And interesting thing is that the phenomenology of gait ataxia [00:02:00] that changes during disease progression. So in the very early stages patients might only have an abnormal tandem gait performance and perhaps a slightly hesitant first step after return.

And what happens next is actually not the broad based element, but variability. Variability as the keyword and variability in step length and step width. Patient starts to deviate from the straight line to both sides. And some of them will have a relatively high gait speed. And this is something interesting.

You can also play with the gait. Ask patients if you see this to slow down a bit or perform the tandem gait a bit slower, perhaps. And then later you will see the broad based gait kicking And the gaits slowing down. And sometimes it is stiffening of the knees again as a compensatory element.

So you see the dynamics of gait ataxia as disease progresses and it's [00:03:00] intertwined with these changing compensatory efforts. And in the next stage the patients will need to use supportive devices, otherwise they will fall 'cause of their severe balance difficulties. And I think as you mentioned, that we have to rule out other neuro anatomical sources of ataxia, sensory causes for which we will do the full sensory examination and see what happens a with the gate upon eye closure. You want to rule out a frontal type of ataxia or a more modern term, higher level gait disorder in which you will expect disproportionate balance difficulties often also with cognitive changes. And lastly I think a vestibular origin in which patients next to having complaints like dizziness, et cetera, will have gait deviation typically to one side consistently.

And then we will need to look for additional cerebellar signs in the rest of the exam. And I think many of us as [00:04:00] movement disorders experts put a lot of time and effort into the examination of the eye movements and the cerebellar disease. You will expect, for example, to find fixation instability, square wave jerks, jerky pursuit, gaze-evoked or downbeat nystagmus, and hypermetric saccades.

You can perhaps hear cerebellar dysarthria, scanning speech, and find upper limb detection in the form of dysmetria and intention tremor.

Dr. Orlando Barsottini: Bert the topic of classification of ataxias sometimes it is not so clear, especially for no experts. Could you discuss a little bit more about the classification of ataxias, please?

Dr. Bart van de Warrenburg: There are hundreds of conditions that can lead to ataxia and I think there have been many attempts to classify ataxia from a practical or research perspective. This turns out to be very complex and easily outdated as [00:05:00] well. I myself use a very simple framework that guides me through my thinking and practical workup.

So I separate three main groups of ataxias. So we have acquired ataxias, we have genetic ataxias, and we have non-genetic degenerative ataxias. For example, the cerebellar type multiple system atrophy. That said, I think for the genetic ataxias the MDS study group on the genetic nomenclature of movement disorders has done a very good job in listing the confirmed ataxia genes.

But still many of us still use the old terms, for example, SCA for the dominant ataxias. I think that's what it is, but again, I want to refer to my very simple framework as a way to provide guidance in what we think and do when confronted with an ataxia patient.

Dr. Orlando Barsottini: Bert like you said we have different forms of ataxia including acquired genetic and non-genetic. I have [00:06:00] two questions now, what is the diagnostic roadmap you suggest for these different forms of ataxia and what would be the importance of complementary exams such as brain MRI, CSF, and PET scan, all the classification and identification of different forms of ataxia?

Dr. Bart van de Warrenburg: Yes. Orlando, that's yeah.

To start with your second part, perhaps, I think all the investigations should serve a purpose and in this scenario, trying to reach a diagnosis for a patient. So I'm not serving classification purposes unless it's for a research effort. In line with other movement disorders.

I think history is really key and elements of the history will guide our differential tremendously. So things like onset age or rate of progression, [00:07:00] the family, medical history, current drugs, et cetera, are of utmost importance. In general, I think we need to keep in mind that acquired causes of ataxia are the most common ones.

And what I use of these elements in the history most is perhaps the type of progression, the rate of progression. So if this is acute or subacute, the cause will most likely be acquired and you will do the MRI. You will rule out drugs, metabolic causes, check for perineal neoplastic, or other immune mediated diseases, consider prion et cetera.

The second interesting presentation progression-wise is if the ataxia is purely episodic. Because if this is the case, then the number of differential diagnostic groups to consider is very limited because generally this will either be something autoimmune, for example, an anti-GAD or anti-CASPR2 antibodies. Or be genetic, [00:08:00] like SCA27B or 1A and others.

I think the most challenging category is the slowly progressive ataxia. And there, if you have a family history, this will be very helpful and then you can jump to your genetics, I guess immediately. But if not, you are left with this sporadic, slowly progressive ataxia. And then you still have this large differential covering all the three groups we just discussed.

And I think in that scenario, we will also start with requesting for the MRI scan, ruling out acquired diseases and searching for clues pointing to a specific rare condition perhaps. We will do some minimal blood tests to rule out acquired causes like anti-GAD and the vitamins, et cetera. And then we will also do genetics in this group of sporadic, slowly progressive ataxias.

And here we want to make sure that we have access to testing the genes with repeat expansions as the mutational mechanism. These are the most common ones, [00:09:00] and I think most labs are still doing this as separate tests. So what you request, make sure that the lab tests for these repeat expansions.

This will change if we all have access to long read sequencing in the future. If repeats are negative, you can also look for the other non-repeat ataxia genes if you have access to next generation sequencing platforms. And if the genes are negative, I think the next step is to consider whether your patient with the slowly progressive, sporadic ataxia could perhaps have a cerebellar subtype of MSA. And I think that 2022 MDS criteria are very helpful to have a look at because I think these criteria will guide you through the workup to see whether your patient actually has clinically established or probable MSA. And if not, then your final interim diagnosis will be the sporadic adult onset ataxia or the older term, idiopathic late onset ataxia, ILOCA.

And I think you have to follow up those patients follow up because, new [00:10:00] genes will come out and it might be useful to retest your patients. And I think the relatively recent discovery of SCA27B is in a good example because this now explains many of the patients that we previously labeled as being ILOCA. And I think you should be aware that patients can still convert to MSAC and there's also a reason to keep them in followup.

Dr. Orlando Barsottini: Okay, Bart now I have one of the most difficult question for you. In the new era of technology and AI with genetic testing become more available, do you think that clinical skills, will have a place in the evaluation of patients with 

Dr. Bart van de Warrenburg: Yes, indeed. A difficult question, Orlando, and but my answer is clear. This is a yes. I know there are people who promote a genotype first strategy. I'm myself not an [00:11:00] advocate of that. I strongly believe that you need a good, robust and certain phenotype to enter genetics. And the reason is that genetic testing often leads also to a variant of unknown significance.

And if you have an uncertain phenotype to begin with and vast from your genetics. Then you are in trouble. So I think a good phenotype to begin with is key. And the other aspect I want to mention is what we have been calling reverse phenotyping. So if you get a genetic test result back, you want to be sure this can be matched to the patient's phenotype.

Clinically and or radiologically. And for this, you really need to have done the full examination because many of the ataxia conditions will present with relevant non-ataxia features. Think about ataxia plus neuropathy or spasticity or dystonia. And these non-ataxia features [00:12:00] can actually be quite discriminating and help you in this reverse phenotyping process.

On the other hand I think machine learning AI will be our new right hand in our work, clinical work and scientific work. And as an example, we are seeing machine learning based analysis of gait and speech disturbances that can objectively quantify and track disease status and disease progression.

And this we can deploy in clinical trials that are emerging. So there's certainly a place for AI machine learning in our ataxia approach in the clinics, in the research setting, what it'll be next to and together with doctors and scientists.

Dr. Orlando Barsottini: Okay. Particularly, I am very happy with your answer. We are nearing the end of our interview. And now what are the take home message to our [00:13:00] listeners?

Dr. Bart van de Warrenburg: The take home message for me is that, keep the clinical skills. Do the full neurological examination in the patient and invest, particularly in trying to pin down the cerebellar origin of the movement disorder you are confronted with. Play with the gait. Be mindful that gait ataxia is a dynamic feature and play with the compensatory elements.

For example, in modifying the speed of the gait task you are asking the patient to do. And what the nice thing is, Orlando, I'm still learning myself as well. So, I've been tweaking my neurological history taking and examination along the ride. And as an example, couple of years ago, the gene for the CANVAS syndrome, so cerebral ataxia neuropathy and vestibular areflexia syndrome, was discovered expansions in RFC1. And based on those phenotypic descriptions, I had been adding a question on chronic cough to my history and adding, I had [00:14:00] impulse tests to my examination.

So second message is don't stop learning.

Dr. Orlando Barsottini: Perfect. Thank you, Bart for sharing these insights and thank you to our listeners for joining us. We hope this episode helps you approach ataxia patients with greater confidence and procedure.