Special Series: Differential diagnosis of myoclonus

He worked as a consultant at the Charité in Berlin before he moved to the excellent Toronto Western Hospital team in Canada. In the MDS, he was the [00:01:00] founding chair of both the MDS tic disorder and Tourette syndrome task force and study group. His main topic is tic disorder, spanning from clinical characterization to studies on pathophysiology and novel treatment developments inevitably connected with jerky hyperkinetic movements.

One of his amazing and most downloaded paper is a video atlas of the spectrum of involuntary vocalizations in humans in movement disorders in 2019. Christos, thank you so much for joining me today. And I would say, let's get started.

Dr. Christos Ganos: Thank you, Marina, for the beautiful introduction and it's nice to do this together.

Prof. Marina de Koning-Tijssen: Yes, absolutely. We're gonna do it together. So to start with Christos what do you consider the most relevant differential diagnosis in myoclonus?

Dr. Christos Ganos: This is a very nice question and it's actually a very nice opportunity to have to discuss this. So there are many ways to go about this, and we know that myoclonus is one of the big [00:02:00] jerky, hyperkinetic movement disorders. So you can think of the differential in general terms, but I don't think this is particularly helpful.

It might be more helpful if we consider of the differential diagnosis based on somatotopy and where do we see actually jerks or jerky movements occurring. And this will guide also our differentials and the difficulties we have in clinic in everyday life. Of course, when we speak about myoclonus, we have to consider and keep in our back of my minds epileptic disorders. So we're not gonna deal with them. We are movement disorders, neurologists. But of course when we see a jerky movements that fit in the myoclonus umbrella and the myclonus rubric, then we have to consider epilepsy. And we have to consider also syndromes like Jeavons syndrome and sunflower syndrome for eyelid myoclonia et cetera.

But if we go to proper movement disorder, so to say one and look by so somatotopy, let's focus first on the neck region. And cervical jerks. So the most common differential diagnosis we'll have there will be dystonic jerks. [00:03:00] And we know that they also co-occur, like in myoclonus dystonic syndromes, for example, myoclonus dystonia.

And we know that those myoclonic jerks are subcortical. So the distinction between a jerky, dystonic movement and a myoclonic movement will be difficult and will be faced with the same question again and again. Particularly, for example, in the onset of cervical dystonia, when people might have like subtle jerks of the neck before it starts to develop more and more in some cases and also in full blown syndrome.

So we'll have jerky movements there. So when we think of the neck, I think the most clear question would be, is it myoclonus or is it dystonia? Now we can move upwards, for example, and go to the face. And we have observed in literature the difficulties between myoclonic jerks of the face and their distinction from choreic jerks, for example.

And we know the ABCY5 story that if the original family was classified as having chorea of the face too, and then it came out that neurophysiologically, it fulfilled criteria for [00:04:00] myoclonus. And we have many different such examples. I think one I would like to highlight is the subtle smile.

That we ask our patients sometimes to do, to unmask myoclonic jerks on the face around the cheeks. And these can also look like tremulousness as well. So tremor and myoclonus will be also another differential we will have for the facial muscles. For the tongue muscles. So it is like a difficult differential in these cases, and we'll speak about clues later on.

Another one, when we think about facial jerks, we, of course, we have to think of tics. Tics are usually easier to distinguish because of their surpressability and their urge. Now moving down to the arms, I think when we look at jerks at the arms, again, we have to consider chorea, but looking particularly at distal jerks.

Then we come back to the question of, could this be rapid myoclonic jerks, for example, that we would see at cortical myoclonic tremor syndromes, or is this actual [00:05:00] tremor, and this is another differential that is difficult on clinical ground sometimes it's really difficult. And looking at jerks that occur in occasions during action and particular intention.

And if we think of the Lancet Adams paper, the syndrome of action and intention myoclonus in post hypoxic cases. I think intention myoclonus is something that's often missed and misunderstood or mislabeled as ataxia. And this can co-occur, but this is also important to keep in mind. Now we have two body parts that's left and excuse me, for the long answer.

The legs myoclonus of the legs. It's often mistaken as functional symptoms, like people stand and they jerk and they can't keep on standing because they jerk. And these are often older people and. This can be mistaken as a phobic component, anxiety or weakness. But this can be myoclonus, so it shouldn't be missed.

And of course, myoclonus of the legs and standing can be also mistaken for orthostatic tremor. And the final [00:06:00] category is the trunk. This entity of propriospinal myoclonus that you worked a lot on, we know that the majority of these cases will have functional jerky movements that will not be myoclonus.

And there is also where our phenomenology classifications a little bit fail us. We still don't know whether to label these jerks as functional myoclonus or functional jerky movements, but yes, I think functionality theology would be relevant there. And finally the hyperplastic syndromes are startling.

I think startling is also something that is sometimes difficult to distinguish. Is it on clinical grounds? Is it the pathological startling reaction or is it actually increased anxiety and there are clues as variability help us perhaps.

Prof. Marina de Koning-Tijssen: Thank you so much for this very extensive, I like this way of classifying it by area. And can I ask you a few things about this? Because you're mentioning this issue of myoclonic dystonia and dystonia with jerks. Do you think age of onset can [00:07:00] help us there about what of these subcategories you're thinking of?

Because clonic dystonia, it's usually like in puberty, right? That it starts, which is usually not the case with dystonic jerks in the neck. That usually come at a later age, or do you disagree?

Dr. Christos Ganos: No, I agree with whether we are looking with myoclonic dystonia as epsilon sarcoglycan, for example. And thank you for highlighting this. However, when I'm faced in the clinic with somebody who's in their mid forties and they have cervical jerks on top of cervical dystonia, then I sometimes wonder and thinking away from the etiology of a genetic etiology, perhaps I was unclear before.

Then I wonder, are these really rapid jerks there? Are they dystonia or are they subcortical myoclonus? Then when we try to approach them with neurophysiology, we don't get the helpful answer because they might have 300 milliseconds latency, and then you're like or 350 or 400, and then what is it at latency?

Duration. Tricky.

Prof. Marina de Koning-Tijssen: And another [00:08:00] question I would like to pose to you is you're mentioning in the propriospinal, and I discussed that with Mark Edward in the next episode. Won't you agree that in every area where you have jerks, you should consider that it could be functional jerks?

Dr. Christos Ganos: Absolutely. And we see them a lot. They're usually labeled in different terms. I see in my clinics a lot of cases with jerky movements that are functional, labeled as functional tics or tic like disorder. They don't come as functional myoclonus, but yes, we any kind of jerk of course can have a functional etiology.

Absolutely.

Prof. Marina de Koning-Tijssen: Okay. You gave this lovely overview of clinical differentiation between different movement disorders. Do you use a lot of additional investigations in your clinic to discriminate between the different types of movement disorders?

Dr. Christos Ganos: I'm a bit spoiled because at Toronto Western there is a lab of Dr. Chen and what they do there is fantastic. With a five page [00:09:00] report on the neurophysiology. Yes. Really. So it's it's a lot and it's really beautiful and helpful. So neurophysiology, I think in this case is where we are not sure if it's a cortical tremor versus cortical myoclonic tremor versus a tremor syndrome where we still debate could it still be myoclonus or dystonia?

Could it be a functional jerky movement disorder? Or could it be myoclonus? Neurophysiology is very helpful, and there we have really surface myography that might help. But we also can look at cortical potentials, et cetera. I think neurophysiology is the key examination here when we are clinically uncertain.

One caveat there though, it really is in the hands of the neurophysiologist who performs the examination. Then the recording to provide you with useful results. If the neurophysiologist is also uncertain about, or cannot tease out the characteristics that you want to be teased out and studied, then unfortunately also the neurophysiology investigation will [00:10:00] not be helpful, so we have to keep this in mind.

Prof. Marina de Koning-Tijssen: Yeah, at the end, the clinical picture is the main one, right? It's supported by electrophysiology, but as you said, you are spoiled, so you get a whole package. But many people are not so spoiled, so they have to make choices. What would be your main investigation? And it can be different for different differential diagnosis, but what would be your main, tests that you would like to perform if you're doubting.

Dr. Christos Ganos: Yes. So let's stay a little bit on the clinical examination because I think this is very helpful. And one thing I do is just putting, I'm asking the patient for permission of course, and then putting my hands on the affected area. And just using essentially my hands as the myography try to feel the jerks.

And this sometimes tells you a lot, this can be enough actually. And when you have this touch with your patient, you can also see, for example, these specific postures modulate the jerks, if destructibility, you know, we [00:11:00] are also reliant on our visual perception. But if I'm doing a task with a patient on one hand and I'm holding the other arm, for example, I can feel what's happening there.

So I think this is very helpful already. 

Prof. Marina de Koning-Tijssen: Can you tell us what you feel, for example, if there is cortical myoclonus or subcortical myoclonus, can you tell what you feel then in that arm?

Dr. Christos Ganos: Yes. I don't think I can, the superpower that I can distinguish between cortical and subcortical myoclonus...

Prof. Marina de Koning-Tijssen: No. But just give us a sense. Yeah.

Dr. Christos Ganos: Essentially you can, first of all, you feel the presence or absence of any jerkiness. You feel the rapidity of any kind of muscle twitch that will occur. You can feel if this is really a regular twitch occurring, so if you're going close to tremulousness, or if there is co contraction, for example, if the entire arm is stiff, you can feel these things very well.

And you particularly on tests, contralateral arm or other body parts, ballistic movements, you can see if there is a pause or you can feel if there is a pause of [00:12:00] activity in the body part you are touching. So essentially you're looking at silence of activity, et cetera. But in a very simple and crude way, but it's very helpful, essentially.

I think people should start using it more. Clinical examination tools, for example, when people are uncertain, if it's intention myoclonus, for example versus ataxia, then you look at other movements. You look at the gait and if it is intention myclonus, you will have these big myoclonic jerks at the end of the movement.

If it is ataxia then, and it's so severe that it would lead to this jerkiness at the end of the movement as part of intention tremor or ataxia, then you would see it also at gait. So you're searching for discrepancies. So essentially, and you can look at proximal muscles too. In intentional myoclonus, you will have the pectoralis also jerking. In ataxia, I don't think you will see this jerkiness there. So if it's the distinction of tics, of course, clinically you ask for suppression. If it's chorea, you look for the flowing character. And if you are not sure about it, just keep observing. You don't have to make up your mind in one minute.

This is the beauty of clinical [00:13:00] interaction and examination.

Prof. Marina de Koning-Tijssen: Is that something that you teach to your residents and fellows? Take your time to look carefully because that tells you a lot.

Dr. Christos Ganos: First of all, I learned it from you, from Kailash. Now learning from Tony. From Susan. Like many people you can learn from them and then pass it on. Exactly. So. Really take time and observe, and if you don't understand what or if you're confused, then see it a second time. This is really important.

Like we all make mistakes and we'll keep on making mistakes. It's part of being human and it's also nice because we can learn from them as long as we don't harm just one category, Marina that I forgot perhaps, is the eye movements and because we don't apply the terminology. We don't speak of myoclonus in rapid eye movements, but I have observed, and I keep observing a lot of errors in the diagnostic labeling of different eye movements. Abnormal eye movements. So I think although it doesn't fit the topic, it's a category that people should [00:14:00] also focus a little bit of efforts in distinguishing what is obsoclonus what is flatter, et cetera. So I think it's just important. So people keep the eye movements also in their rich neurological vocabulary.

In movement disorders. They're often neglected.

Prof. Marina de Koning-Tijssen: And do they help you in differentiating between types of movement disorders? 

movement 

Dr. Christos Ganos: Absolutely. Absolutely. Of course, we always look for gaze restriction, et cetera, in congregate gaze. But of course, we are looking for cerebellar signs. We're looking for psychotic intrusions. We are looking for many different signs. We look for vestibular ocular reflex. Actually, I'm surprised most people on a day-to-day basis don't examine the vestibular ocular reflex.

So I have always to ask as a principal, how is the vestibular ocular reflex? 

Prof. Marina de Koning-Tijssen: Can I ask you another question? Because you mentioned about this difficulty between ataxia and myoclonus. Can you tell us a bit about negative myoclonus? How can that interfere with difficulties in your differential diagnosis? Because I've noticed that's usually that people are not so [00:15:00] much aware of that.

That can be really a big problem. For patients in daily life.

Dr. Christos Ganos: This is a great point back to being in touch with your patient. So really if it's about myoclonus and standing. You just put your hand on the patient's leg with permission and then you feel the lapse. You feel it, you don't need a myography, you just feel it. And the same with the arms.

So I think negative myoclonus is a very helpful clue. And then there is a debate, and perhaps you can help us in the examination of a cortical myclonus, essentially one when we look for negative myoclonus. So there is a big issue, with investigating cortical myoclonus in general, let me just deviate a little bit, whether we do it completely addressed or on activation during posture.

So where would you touch the fingertips when the hand is resting or where it's active? I think there is a big debate. What would you say?

Prof. Marina de Koning-Tijssen: Yes. I'm in favor of holding the hand and that hand drop at rest. So I'm holding the the hand and [00:16:00] then the hands hanging down, and then I tip the fingers so they are at rest. But yeah it's really helpful for me to see these delayed jerky movements once you touch the finger.

Yeah. It's not for negative myoclonus because for negative myoclonus you have to stretch out and hold the hand palm straight and then see if there are lapses there, right?

Dr. Christos Ganos: You need the activation.

Prof. Marina de Koning-Tijssen: Yeah. Are you, do you agree or I'm happy to hear that you disagree that you should do it in action.

Dr. Christos Ganos: So this might, yes, I agree. And Dr. Lang agrees that it should be addressed. Of course, with a negative myoclonus, there should be activation. I always wondered whether also for the positive myoclonus in cortical myoclonus. Having a pre activated state essentially facilitates its presence, and I don't know if this has been studied, so I just wonder just.

Prof. Marina de Koning-Tijssen: Okay. Putting it together. Christos, I understand from you that you mainly base your differential [00:17:00] diagnosis on the clinical picture and then different differential diagnosis based on where the myoclonus is, and that you in general would advise to do it mainly on clinical grounds. But if you're doubting that, then electrophysiology might help.

Dr. Christos Ganos: Yes, absolutely. Particularly in the tremulousness case you summarized it very well and perhaps in the excitement of speaking with you and about this topic. Of course, we're looking always for after we made up our mind, what is the, is this myoclonus or is this chorea? Or whatever it is. But let's stick with myoclonus.

Then we already have this fast track associations that myoclonus has. So myoclonus ataxia syndromes, myoclonus dystonia syndromes. We think of myoclonus plus syndromes, and then we try to piece this together to see is this going that direction? Is this going that direction? Is there deafness other signs?

So to try to come slowly with a more definite diagnostic spectrum or [00:18:00] range. Yeah.

Prof. Marina de Koning-Tijssen: Yeah. Yeah, I agree. That's very fascinating, isn't it? That the cortical myoclonus comes with ataxia and the sub cortical comes with dystonia. That can really guide you also in the differential diagnosis. 

Yeah.

Just one, one final answer because you're saying it's all mainly on clinical grounds.

And I fully agree with you, and as you said, that you can find support in electrophysiology. Do you think there is additional help here that we could have from machine learning in a way that we use videos for machine learning or we use EMG or accelerometry. Do you think that will help the clinicians at the end?

Do you have an idea about that?

Dr. Christos Ganos: Definitely. I think the more accurate we capture data, the more we will be able to also tease out subcategories of myoclonus syndromes. That our eyes and our crude measures now fail to see also patterns that we're not able to [00:19:00] recognize. I really believe that we'll start to understand specific networks that relate to specific somatotopic symptoms and types of symptoms, duration of myoclonus, et cetera.

So I think any kind of large data approach, even this is from a single person that will generate single case, that will generate large data, will advance our understanding. There is this caveat there more power, more resistance, more data, more errors. So we have to al also be mindful of that, but I think it's, it'll be useful and it'll also advance our understanding in ways that we have not been able to do in the last decades, for example.

Yes, definitely. And you're working actively on that.

Prof. Marina de Koning-Tijssen: Yeah. So you don't dare to say it's not useful, right?

Dr. Christos Ganos: I believe so, but it is definitely useful. It will become useful.

Prof. Marina de Koning-Tijssen: Yeah, I think, but I think you make a very important point there, similar to databases, rubbish in is rubbish out, right? So I think it's very important that if you do that, that you [00:20:00] start with the gold standard of clinical examination, right? What does this patient have that I put in with a certain label?

So I think that's a lot of work to do there, but it might in the future, like you said. Help us to get more insight and it might also help for less experienced neurologists as we heading towards a period with perhaps less neurologists than what we hope we will have, that they might be able to already discriminate between certain movement disorders and that they not all have to come to an expertise center.

Dr. Christos Ganos: The beautiful part, Marina, now that I think about it it's, it'll provide us dynamic measure. So let's imagine a single case that has hypoxic myoclonus. Then let's imagine a continuous EEG and EMG monitoring over days or months that would not be really bothersome for the patient to have on their bodies.

And then it'll provide us with data that we can see actually the evolution of cortical dynamics next [00:21:00] to muscle activity essentially. And this might help us understand what's exactly happening there in ways that we were not able before.

Prof. Marina de Koning-Tijssen: Yeah. 

Thank you so much, Christos. I think we had a lovely conversation on the differential diagnosis of myoclonus and thank you so much for sharing your thoughts with me in this podcast.

Dr. Christos Ganos: Thank you. Thank you, Marina, and the Movement Disorder Society. Thank you.