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MDS 2021 | Movement disorders in patients with COVID-19 – What are the mechanisms?

A spectrum of neurological manifestations of COVID-19 have been described, affecting both the central and the peripheral nervous system, including movement disorders. Hadi Manji, MA, MB Bchir, MD, FRCP, National Hospital for Neurology, UCLH Foundation Trust, London, UK, shares the latest understanding of the possible mechanisms behind movement disorder presentation in COVID-19 cases. Firstly, strokes, caused by blood vessel inflammation and hypercoagulation of the blood, could lead to movement disorder presentation when occurring in certain regions of the brain. Dr Manji also discusses inflammation and autoimmune-mediated encephalitis as potential causes. It is not yet clear whether there is direct neurovirulence caused by SARS-CoV-2, but studies to date do not suggest viral damage that could cause movement disorders. Dr Manji emphasizes the importance of long-term monitoring for neurodegenerative and other post-infectious complications, such as encephalitis lethargica. This interview took place during the 2021 International Congress of Parkinson’s Disease and Movement Disorders.

Transcript (edited for clarity)

I suppose the first question one would ask is, well, “Is there a substrate by which COVID-19 affects the brain presents with movement disorders? Are there possible mechanisms which could present with movement disorders?” And the answer is yes. And if we look at the underlying mechanisms of the neurological diseases we’re seeing with COVID, the first is stroke, as I’ve indicated...

I suppose the first question one would ask is, well, “Is there a substrate by which COVID-19 affects the brain presents with movement disorders? Are there possible mechanisms which could present with movement disorders?” And the answer is yes. And if we look at the underlying mechanisms of the neurological diseases we’re seeing with COVID, the first is stroke, as I’ve indicated. Certainly strokes in certain parts of the basal ganglia could present with movement disorders. If you’ve had multiple strokes, lots of small vessel strokes, that can present with parkinsonism. We know that Parkinson’s can be due to small vessel disease. So that’s one category of possible mechanism. The second, as I’ve indicated to you, is this inflammatory process which can, again, affect parts of the brain, which may give you myoclonus, may give you movement disorders, depending on which part of the brain is affected. The third possibility, and again this is more theoretical than proven at the moment, is that certainly after certain virus infections, such as herpes simplex encephalitis, one third of patients may go on to develop an autoimmune mediated encephalitis, such as with NMDA antibodies. And these patients present with their own types of movement disorders.

The other question, big question, is, “Does the virus, itself, cause damage to the brain? And could that be a cause of movement disorders?” And we’ve got a precedent for this in, for example, Japanese B encephalitis, or West Nile virus, or even the HIV virus, which itself, was affecting the basal ganglia. The studies to date do not suggest that there is viral damage. And the evidence for this is that the CSF examinations, I think, one or two cases have shown evidence of the virus in the spinal fluid. There was one post-mortem study from Germany, where they looked at 34 patients. The first author was Matschke. And they found evidence of SARS-CoV-2 in about 53%, and the virus seemed to be around the brainstem and lower cranial nerves. But there was a disconnect between where they found traces of the virus and where the inflammatory changes were taking place. They were not in the same place. Then the question was, “Is there virus actually doing anything there?” So the jury is out on as to whether the virus enters the brain and causes damage but the evidence, to date, is not strong. And so those are sort of the mechanisms.

There are possible mechanisms of how movement disorders can be presented in COVID-19. So far, all the literature is very anecdotal. There is one paper in the journal Tremor by Francisco Cardoso, who looked at a review of all the case reports in the literature. And the conclusion of his group was that movement disorders are relatively rare in COVID-19. The most common movement disorder that was describe was myoclonus. And we’ve certainly described that as well in some of our papers. It was usually in the context of an encephalopathy. So these are patients who are quite severely ill, maybe with low levels of oxygen or infections. But myoclonus is the most commonly described movement disorder to date. There are a few case reports of parkinsonism in COVID-19, and that’s caused a lot of interests, a lot of debate, a lot of editorials in various journals about, “Is this going to be something we’re going to see more of?” The few cases so far have been not typical for Parkinson’s disease. They’ve been relatively acute onset. Although they’ve had positive DaTscan, which implies there is striatonigral dopaminergic cell loss, they haven’t really responded much to treatment as such.
And certainly, there’s a very interesting editorial by Marcelo, Bhatia, and Obeso where they discussed the possible mechanisms of what may be going on here. And one possibility is, okay, the virus or somebody with very serious illness gets ill, develops parkinsonism. Was it because they had the predisposition already? They had subclinical Parkinson’s and the virus infection triggered off parkinsonism. Is it that patients who are very ill develop parkinsonism due to the whole inflammatory process that’s going on? And this Parkinson’s syndrome may be just temporary or it could be long-term? And then there’s the possibility of whether a virus infection, like COVID-19, comes and goes, but then one’s left with an ongoing low grade inflammatory process, viral persistence, and that in five, 10, 15 years, these patients will develop parkinsonism or Parkinson’s disease. And so, the question then comes to whether the whole question of encephalitis lethargica is relevant to the current situation.

As you’re aware, after the 1918 flu pandemic, there were cases of encephalitis lethargica, which then—you may have seen the film “Awakenings” with Robin Williams and Robert De Niro—which illustrated this whole picture. So, the jury is out as to what the cause of encephalitis lethargica was because there were cases reported before the 1918 pandemic. They managed to get brains of patients who died of encephalitis lethargica, and they didn’t find any evidence of the flu virus in the brains. And subsequently, various reviews and studies have suggested possibly encephalitis lethargica was a post-infectious immune mediated process, which then presented a good time later on. So, I think the importance of that whole story is that we are going to need to follow up all our patients here, monitoring them for various long-term complications, including parkinsonism or any other neurodegenerative process, because only time will tell.

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