Parkinson's Disease and COVID‐19: Do We Need to Be More Patient?

Since its emergence, there has been significant interest in the neurological manifestations of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. Lippi and colleagues were among the first to suggest that SARS‐CoV‐2 may have long‐term neurodegenerative implications and that incidence of postinfectious parkinsonism may rise (mirroring encephalitis lethargica following the “Spanish” flu). ¹ The authors argue that SARS‐CoV‐2 and H1N1 viruses share common pathophysiological mechanisms (mitochondrial dysfunction, proteostasis, lipid metabolism, and stress responses), which have also been implicated in Parkinson's disease (PD) pathophysiology. Many authors have followed suit, leading to significant concern that a postpandemic rise in PD is likely, in the absence of convincing empirical evidence.

In recent months, 3 cases of parkinsonism have been reported after SARS‐CoV‐2 infection. ² , ³ , ⁴ These cases have been cited as evidence that SARS‐CoV‐2 could demonstrate tropism for the basal ganglia and has led to a resurgence of the above theory. However, drawing parallels with encephalitis lethargica should be undertaken with caution because, notwithstanding the coincidence in time, the causal role of H1N1 on the former is debated. ⁵ Based on estimates of PD incidence and global burden of SARS‐CoV‐2, one might expect approximately 10,000 newly diagnosed PD cases among infected individuals.

Cohen et al and Faber et al described a 45‐year‐old man and 35‐year‐old woman both developing new‐onset asymmetric parkinsonism without atypical features during SARS‐CoV‐2 infection. ² , ³ Both cases showed imaging evidence of presynaptic nigrostriatal dopamine disturbance, and both responded rapidly to dopamine replacement therapy. Neither of these cases had documented examinations prior to presentation. It is therefore possible that they had prodromal PD, which was unmasked by the stress of SARS‐CoV2 infection. Zigmond et al showed that behaviorally normal rats with large dopamine‐depleting brain lesions became akinetic only when exposed to acute external stressors. ⁶ This suggests that the acute emergence of parkinsonism during stress may reflect preexistent damage to the nigrostriatal pathway, concealed in a preclinical phase via compensatory mechanisms. Hence, the significance of the cases reported by Cohen et al and Faber et al should be interpreted with considerable caution and, despite age and absence of clear monogenic risk, may simply represent unmasking of subclinical PD. It is possible that young age may play a role in the effective compensatory mechanisms that prevented them from being symptomatic. Young onset Parkin patients often have severe presynaptic nigrostriatal dopamine abnormalities when they present, which may suggest preclinical compensation.

Nevertheless, Méndez‐Guerrero et al reported a 58‐year‐old man developing asymmetric tremor, rigidity, and bradykinesia following SARS‐CoV‐2 infection with spontaneous improvement after 14 days, which is more suggestive of a postviral cause and which occurred in the setting of encephalopathy with other atypical features such as myoclonus and oculomotor abnormalities. ⁴

The rapidity with which SARS‐CoV‐2 has swept across the globe has promoted the rapid dissemination of ad hoc poorly designed studies from which conclusions are drawn. Although a postpandemic rise in PD incidence is possible, the long‐term consequences of SARS‐CoV‐2 infection and the impact, if any, that the pandemic will have on the burden of PD remains unknown and will require careful extended epidemiological study.

Author Roles

1) Research project: A. Conception, B. Organization, C. Execution;

2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique;

3) Manuscript: A. Writing of the first draft, B. Review and Critique.

P.G.L.: 1B, 1C, 3A.

C.F.: 1B, 1C, 3A.

A.F.: 1A, 3B.

A.E.L.: 1A, 3B.

Financial Disclosures (Preceding 12 Months)

P.G.L., C.L., and A.F. report no disclosures. A.E.L. has intellectual property rights with AbbVie, Acorda, AFFiRis, Biogen, Denali, Janssen, Intracellular, Kallyope, Lundbeck, Paladin, Retrophin, Roche, Sun Pharma, Theravance, and Corticobasal Degeneration Solutions; is a consultant for Jazz Pharma, PhotoPharmics, and Sunovion; is on the advisory boards of Sun Pharma, AbbVie, and Sunovion; is employed by Brain Canada, Canadian Institutes of Health Research, Corticobasal Degeneration Solutions, Edmond J Safra Philanthropic Foundation, Michael J. Fox Foundation, the Ontario Brain Institute, Parkinson Foundation, Parkinson Canada, and W. Garfield Weston Foundation; has received honoraria from the University Health Network and University of Toronto; and has received grants from Elsevier, Saunders, Wiley‐Blackwell, Johns Hopkins Press, and Cambridge University Press..