The SARS-CoV-2 Pandemic represents a major global health challenge that we as movement disorders experts also have to face. Different efforts are trying to decipher the consequences that this impactful condition is having in our field. In this blog entry, two experts, Dr. Tiago Outeiro and Dr. Mariana HG Monje, addressed important open questions about the relationship of SARS-CoV-2 and movement disorders. We also had the privilege to include a final statement from Dr. Patrik Brundin outlining the key aspects about this enigmatic and impactful condition that will be studied in the history books of future generations.
Question 1: Could you please comment on the relationship between Movement Disorders and COVID-19?
Dr. Outeiro: This is indeed an important question that deserves close attention, given the global scale of the COVID-19 pandemic in a time when the human population is aging.
Fortunately, there is currently no evidence that patients with movement disorders are at increased risk for COVID-19, when compared to age-matched individuals. However, since COVID-19 is such as novel disease, it is still early to rule out the possibility that COVID-19 survivors may be at increased risk of movement disorders. Therefore, it is important that clinicals stay vigilant for a possible association, especially if we consider this possible connection from a molecular perspective. Movement disorders, of which Parkinson’s disease (PD) is one of the most common, are typically associated with the misfolding and accumulation of proteins in the brain. This process is known to be age-associated but is also known to be associated with the impairment of cellular pathways that are also used by viruses, such as SARS-CoV-2, during infection. Therefore, based on our current understanding of the molecular mechanisms underlying both movement disorders and COVID-19, it is wise to hypothesize that, perhaps, a relationship may emerge. This is still speculative at this point, and should not cause unwanted alarm and unsettlement, but it is a hypothesis that needs to be considered and investigated.
Dr. Monje: A broad spectrum of neurological syndromes has been progressively described associated with SARS-CoV-2 infection. Neurological manifestations vary from unspecific symptoms (i.e. headache and myalgias, present up 66% in those patients with neurological manifestations) to stroke and neuroinflammatory syndromes (Romero-Sánchez et al. 2020). In this scenario, even in the most extensive reported series, the appearance of movement disorders in SARS-CoV2 infection is scarce (Whittaker et al. 2020). So far, the few cases reported in the literature are hyperkinetic movement disorders, mainly severe generalized myoclonus/myoclonic tremor. The Movement Disorder Society repository of "COVID-19 and movement disorders observations" and the upcoming studies would hopefully give us a better description of the movement disorders associated with COVID-19.
Question 2: In your opinion are these phenomena immune mediated or a direct effect of COVID19 on the Central Nervous System?
Dr. Outeiro: To address this, we need to consider what we know about the pathological mechanisms involved. We know that SARS-CoV-2, the virus responsible for COVID-19, enters cells by strongly interacting with the ACE2 receptor (Yan et al. 2020). This receptor is expressed by cells in the respiratory system, and this explains why they may be particularly vulnerable. However, the ACE2 receptor is also expressed in several other tissues, including in the central nervous system, suggesting it may also directly affect neuronal cells in the brain. Indeed, recent studies have identified coronaviruses in the central nervous system, including in patients with neurodegenerative disorders (Gómez-Pinedo et al. 2020). This suggests there may be direct effects of SARS-CoV-2 in the brain.
When we consider the major risk factors for the severity of COVID-19, the common denominator is the immune system (Lippi et al. 2020). Aging and other conditions known to impact on the performance of the immune system significantly increase the risk for a worse prognosis of COVID-19. Although neuropathological examinations of COVID-19 brains are scarce, signs of neuroinflammation have been detected, supporting the idea that altered immune responses in the brain may be taking place. Therefore, given the established connection between neuroinflammantion and neurodegeneration, it is possible that the connection between COVID-19 and movement disorders may also result from altered immune responses in the brain.
Dr. Monje: There is some evidence about the neurotropism of coronaviruses, although studies elucidating molecular details of SARS-CoV2 infection and affection of the central nervous system (CNS) are still missing. But despite this, with the data we have so far, the movement disorders reported seems a postinfectious/immune-mediated phenomenon rather than a direct effect of COVID19 on the CNS. In those patients the severe myoclonus occurred after 10 days since the SARS-CoV2 infection onset in the so-called inflammatory phase, they recovered after treatment with steroids/immunotherapy and no other potential causes were found (Rábano-Suárez et al. 2020). These immune-mediated phenomena would be in line with the data supporting a post-infectious-immune mediated mechanism underlying other neurological manifestation described in COVID-19, such as neuroinflammatory disorders or peripheral nervous system affection (i.e. Guillain barre syndrome) (Paterson et al. 2020). On the other hand, admittedly, we have seen hospitalized patients referring mild myoclonus that could be explained by the severe hypoxia, metabolic disturbances or drugs.
Question 3: Do you think that we will see delayed phenomena such as post-encephalitic Parkinsonism after the current COVID-19 pandemic?
Dr. Outeiro: Here, one can only speculate. In previous studies, it was not possible to associate viral infections, such as influenza, with post-encephalitic Parkinsonism. This is a rare condition, and I do not think we should be alarmed. However, we should be vigilant, and ready to act in case such an association emerges. Given the increased affinity of SARS-CoV-2 to the ACE2 receptor, when compared to that of SARS-CoV, one might expect effects that were not previously observed. It is possible that some of these effects will appear with delay after the disease has manifested and subsided. However, this is merely speculative, and we will need additional data and patient observations in order to address this directly.
Dr. Monje: This is a controversial question which is excellent for a constructive scientific debate. The warning assumption that a parkinsonism epidemic could follow the current COVID 19 pandemic is justified based on two main facts. First, patients with SARS-CoV-2 infection can present with hyposmia, like Parkinson’s disease (PD) patients. This could suggest an invasion through the olfactory bulb and potential progression to the nigrostriatal circuit as proposed for PD. Secondly, the 1920s encephalitis lethargica epidemic, resulting in thousands of patients suffering from parkinsonism in its chronic stage, was historically considered related to the 1918 Influenza (H1N1) pandemic. Although the etiology of encephalitis lethargica and its related parkinsonism is still unknown.
On the other hand, we know that inflammation might have a role as part of the pathophysiology of PD (i.e. viral infections has been suggested as a trigger); furthermore, in this context, PD patients had been shown higher titles of coronavirus antibodies in the cerebral spinal fluid (Fazzini et al. 1992). Therefore, there are some arguments for concern, but the present evidence regarding SARSCoV-2 neurotropism and its potential to produce delayed neurological effects is limited.
Dr Outeiro and Dr Monje have done an outstanding job at reviewing the rapidly evolving picture of the effects of SARS-CoV-2 on the central nervous system. Despite the short history since COVID-19 emerged, it is clear that it is not only a respiratory disease but that it affects multiple organs and tissues. The nervous system is sadly among them, and this is not directly correlated to the severity of the respiratory disease (Paterson et al. 2020). The COVID-19 research field is developing at a breakneck pace and almost every week there are new reports of preliminary observations of the acute effects on the brain. From these reports, one thing is certain, namely that COVID-19 is associated with many neurological symptoms and deficits, some of which, as discussed above, appear to be directly related to the immune response to the virus and others that are secondary to the complex vascular disease that appears in some of the afflicted patients. Obviously, we all hope that new treatments can reduce the acute damage to the brain. Top research priorities need be to understand which patients are most likely to develop brain lesions and what the underlying pathogenetic mechanisms are. Hopefully, as we gain more knowledge in these areas, it will be possible to limit brain damage, even in a situation where there are no effective antiviral medications.
In relation to PD, it is notable that COVID-19 and prodromal PD both often are associated with hyposmia. Of course, as mentioned by Dr Monje, this does not necessarily mean that they share any underlying mechanisms and that hyposmia in COVID-19 will translate to an increased risk for PD or a related neurodegenerative disease. Indeed, reports suggest that the hyposmia in COVID-19 is reversible in a majority of cases (Moein et al. 2020), and that it might be due to damage of the olfactory epithelium (Kirschenbaum et al. 2020), although more centrally located olfactory structures have not been extensively studied. Clearly, more studies are needed to clarify this. That said, it has been suggested that viral and bacterial infections might gain entry to the central nervous system via the olfactory route and possibly via inflammatory mechanisms that involve upregulation of the aggregation prone protein alpha-synuclein they would trigger e.g. PD, dementia with Lewy bodies (Rey et al. 2018). In animal studies of other viruses (e.g. the mosquito-borne single-stranded RNA flavivirus West Nile Virus), the infection has been shown to upregulate alpha-synuclein. In those settings, alpha-synuclein appears to restrict the viral infection because mice that are null mutants of alpha-synuclein are more prone to develop encephalitis than wild type control mice (Beatman et al. 2015). Overall, there is a growing body of evidence that alpha-synuclein has a role in the immune system, and that infections could be a risk factor for PD and other synucleinopathies (Tulisiak et al. 2019). Another notable link between PD and the inflammation that occurs in COVID19 is that in both conditions IL-6 and the kynurenine pathway are affected. Thus, a recent report states that IL-6 is upregulated and kynurenine pathway metabolites are altered in COVID19 (Thomas et al. 2020). Similarly, IL-6 has been shown to be increased in serum of PD patients (Lindqvist et al. 2012) and a recent paper in Movement Disorders indicates that in PD the changes in kynurenine pathway metabolites (e.g. elevated quinolinic acid levels) occur in PD and are associated with symptom severity (Heilman et al. 2020). Thus, overlapping inflammatory pathways might be active in COVID19 and PD, raising the question if COVID19 can trigger PD pathogenetic mechanisms in the brain. Finally, a recent study performed in cultures of different cell types derived from human pluripotent stem cells suggests that dopamine neurons might be particularly susceptible (e.g. compared to cortical neurons and microglia) to SARS-CoV-2 infection, possibly related to them expressing high levels of the ACE receptor (Yang et al. 2020). If this is the case also in patients who have survived COVID19, one can speculate that patients infected with SARS-CoV-2 will lose a subset of nigral dopamine neurons and be more susceptible to develop full blown PD later in life.
Taken together, as stated by Dr Outeiro and Dr Monje, it is too early to say if COVID19 infections will lead to an increase in movement disorders. However, the early evidence suggests that this might be the case, and the clinical and research communities need to be vigilant and closely monitor this rapidly emerging area. By understanding the underlying mechanisms it might be possible to rapidly develop therapeutic strategies that reduce the neurological consequences of COVID19.
Beatman, E., Massey, A., Shives, K., Burrack, K., Chamanian, M., Morrison, T., Beckham, J. (2015). Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain. Journal of virology 90(6), 2767-82. https://dx.doi.org/10.1128/jvi.02949-15
Fazzini E, Fleming J, Fahn S. 1992. Cerebrospinal fluid antibodies to coronavirus in patients with Parkinson’s disease. Mov Disord. 7:153–158.
Gomez‐Pinedo U, Matias‐Guiu J, Sanclemente‐Alaman I, Moreno‐Jimenez L, Montero‐Escribano P, Matias‐Guiu JA. Is the brain a reservoir organ for SARS2‐CoV2? J Med Virol. 2020 May 21;jmv.26046.
Heilman, P., Wang, E., Lewis, M., Krzyzanowski, S., Capan, C., Burmeister, A., Du, G., Galvis, M., Brundin, P., Huang, X., Brundin, L. (2020). Tryptophan Metabolites Are Associated With Symptoms and Nigral Pathology in Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society https://dx.doi.org/10.1002/mds.28202
Kirschenbaum, D., Imbach, L., Ulrich, S., Rushing, E., Keller, E., Reimann, R., Frauenknecht, K., Lichtblau, M., Witt, M., Hummel, T., Steiger, P., Aguzzi, A., Frontzek, K. (2020). Inflammatory olfactory neuropathy in two patients with COVID-19. Lancet (London, England) 396(10245), 166. https://dx.doi.org/10.1016/s0140-6736(20)31525-7
Lindqvist, D., Kaufman, E., Brundin, L., Hall, S., Surova, Y., Hansson, O. (2012). Non-Motor Symptoms in Patients with Parkinson’s Disease – Correlations with Inflammatory Cytokines in Serum PLoS ONE 7(10), e47387. https://dx.doi.org/10.1371/journal.pone.0047387
Lippi A, Domingues R, Setz C, Outeiro TF, Krisko A. SARS‐CoV‐2: At the Crossroad Between Aging and Neurodegeneration. Mov Disord. 2020 May 24;35(5):716–20.
Moein, S., Hashemian, S., Tabarsi, P., Doty, R. (2020). Prevalence and Reversibility of Smell Dysfunction Measured Psychophysically in a Cohort of COVID‐19 patients International Forum of Allergy & Rhinology https://dx.doi.org/10.1002/alr.22680
Paterson RW, Brown RL, Benjamin L, Nortley R, Wiethoff S, Bharucha T, Jayaseelan DL, Kumar G, Raftopoulos RE, Zambreanu L, Vivekanandam V, Khoo A, Geraldes R, Chinthapalli K, Boyd E, Tuzlali H, Price G, Christofi G, Morrow J, McNamara P, McLoughlin B, Lim ST, Mehta PR, Levee V, Keddie S, Yong W, Trip SA, Foulkes AJM, Hotton G, Miller TD, Everitt AD, Carswell C, Davies NWS, Yoong M, Attwell D, Sreedharan J, Silber E, Schott JM, Chandratheva A, Perry RJ, Simister R, Checkley A, Longley N, Farmer SF, Carletti F, Houlihan C, Thom M, Lunn MP, Spillane J, Howard R, Vincent A, Werring DJ, Hoskote C, Jäger HR, Manji H, Zandi MS, UCL Queen Square National Hospital for Neurology and Neurosurgery COVID-19 Study Group. 2020. The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain. 2–37.
Rábano-Suárez P, Bermejo-Guerrero L, Méndez-Guerrero A, Parra-Serrano J, Toledo-Alfocea D, Sánchez-Tejerina D, Santos-Fernández T, Folgueira-López MD, Gutiérrez-Gutiérrez J, Ayuso-García B, González de la Aleja J, Benito-León J. 2020. Generalized myoclonus in COVID-19. Neurology. 10.1212/WNL.0000000000009829.
Rey, N., Wesson, D., Brundin, P. (2018). The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases Neurobiology of Disease 109(Pt B), 226-248. https://dx.doi.org/10.1016/j.nbd.2016.12.013
Romero-Sánchez CM, Díaz-Maroto I, Fernández-Díaz E, Sánchez-Larsen Á, Layos-Romero A, García-García J, González E, Redondo-Peñas I, Perona-Moratalla AB, Del Valle-Pérez JA, Gracia-Gil J, Rojas-Bartolomé L, Feria-Vilar I, Monteagudo M, Palao M, Palazón-García E, Alcahut-Rodríguez C, Sopelana-Garay D, Moreno Y, Ahmad J, Segura T. 2020. Neurologic manifestations in hospitalized patients with COVID-19: The ALBACOVID registry. Neurology. 10.1212/WNL.0000000000009937.
Thomas, T., Stefanoni, D., Reisz, J., Nemkov, T., Bertolone, L., Francis, R., Hudson, K., Zimring, J., Hansen, K., Hod, E., Spitalnik, S., D’Alessandro, A. (2020). COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status JCI Insight 5(14)https://dx.doi.org/10.1172/jci.insight.140327
Tulisiak, C., Mercado, G., Peelaerts, W., Brundin, L., Brundin, P. (2019). Can infections trigger alpha-synucleinopathies? Progress in molecular biology and translational science 168(), 299-322. https://dx.doi.org/10.1016/bs.pmbts.2019.06.002
Whittaker A, Anson M, Harky A. 2020. Neurological Manifestations of COVID-19: A systematic review and current update. Acta Neurol Scand. 142:14–22.
Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020 Mar 27;367(6485):1444–8.
Yang, L., Han, Y., Nilsson-Payant, B., Gupta, V., Wang, P., Duan, X., Tang, X., Zhu, J., Zhao, Z., Jaffré, F., Zhang, T., Kim, T., Harschnitz, O., Redmond, D., Houghton, S., Liu, C., Naji, A., Ciceri, G., Guttikonda, S., Bram, Y., Nguyen, D., Cioffi, M., Chandar, V., Hoagland, D., Huang, Y., Xiang, J., Wang, H., Lyden, D., Borczuk, A., Chen, H., Studer, L., Pan, F., Ho, D., tenOever, B., Evans, T., Schwartz, R., Chen, S. (2020). A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids. Cell stem cell 27(1), 125-136.e7. https://dx.doi.org/10.1016/j.stem.2020.06.01