Movement Disorders Associated with COVID-19

As neurological complications associated with COVID-19 keep unfolding, the number of cases with COVID-19-associated de novo movement disorders is rising. Although no clear pathomechanistic explanation is provided yet, the growing number of these cases is somewhat alarming. This review gathers information from 64 reports of de novo movement disorders developing after/during infection with SARS-CoV-2. Three new cases with myoclonus occurring shortly after a COVID-19 infection are also presented. Treatment resulted in partial to complete recovery in all three cases. Although the overall percentage of COVID-19 patients who develop movement disorders is marginal, explanations on a probable causal link have been suggested by numerous reports; most commonly involving immune-mediated and postinfectious and less frequently hypoxic-associated and ischemic-related pathways. The current body of evidence points myoclonus and ataxia out as the most frequent movement disorders occurring in COVID-19 patients. Some cases of tremor, chorea, and hypokinetic-rigid syndrome have also been observed in association with COVID-19. In particular, parkinsonism may be of dual concern in the setting of COVID-19; some have linked viral infections with Parkinson's disease (PD) based on results from cerebrospinal fluid analyses, and PD is speculated to impact the outcome of COVID-19 in patients negatively. In conclusion, the present paper reviewed the demographic, clinical, and treatment-associated information on de novo movement disorders in COVID-19 patients in detail; it also underlined the higher incidence of myoclonus and ataxia associated with COVID-19 than other movement disorders.


Introduction
Coronavirus disease 2019 (COVID-19), a lower respiratory infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with a wide range of neurological manifestations. Most frequent neurological symptoms are nonspecific and include headache, dizziness, disturbance of smell and taste, and myalgia [1,2]. Among the less common yet more severe complications are cerebrovascular diseases, encephalitis, encephalopathy, and inflammatory central and peripheral nervous systems (CNS and PNS) disorders [3]. Movement abnormalities such as ataxia and opsoclonusmyoclonus have also been observed in COVID-19 patients [4,5].
Hypothetically, there are multiple entry routes for the virus into the CNS (e.g., trans-synaptic, hematogenous, and lymphatic pathways) [6]. However, the expression of angiotensin-converting enzyme 2 (ACE2) in the human brain parenchyma and whether SARS-CoV-2 infects the CNS neuronal cells is not established yet [7]. Although low to very-low concentrations of viral RNA have been detected by reverse transcription-polymerase chain reaction (RT-PCR) in some autopsied brain samples-especially those from the olfactory bulb and medulla; lack of correlation with microglial activation and nodules in those specimens is against the speculated CNS tropism [8,9]. Nevertheless, direct neuronal invasion is not the only way SARS-CoV-2 may contribute to neurodegeneration and neuroinflammation. Meanwhile, several observations of movement abnormalities development or worsening in COVID-19 patients have been reported (reviewed later in this paper), which sounds alarming. We review all published reports on COVID-19-associated movement disorders and present three new patients with myoclonus after contracting COVID-19.

Literature Search Strategy and Inclusion Criteria
We conducted a comprehensive systematic literature search in PubMed and Scopus databases using the following terms: "coronavirus disease 2019," "COVID," "COVID-19," "SARS-CoV-2," "Neurologic," "Movement disorders," "Tremor," "Myoclonus," "Parkinsonism," "ataxia," "dystonia," and "chorea". e Mendeley application was used to detect, scan, and remove duplicates. e remaining studies were scanned for relevant titles/abstracts. All relevant articles that reported patients who developed a movement disorder during/after a SARS-CoV-2 infection were included. Reference lists of the obtained articles were searched for additional relevant results. Any movement disorders in COVID-19 patients were reviewed; demographic information and data on clinical characteristics, treatments applied, and the outcome of patients were extracted. We included case reports, case series, and observational studies published in peer-reviewed journals and preprints available in English. Articles without full texts and studies without laboratory confirmation (RT-PCR) of COVID-19 diagnoses were excluded.

Results
Our extensive search in the literature yielded a final number of 43 publications reporting movement disorders in 64 patients with SARS-CoV-2 infection (Table 1). Demographic information and data on their medical history, COVID-19 infection severity, movement disorders, treatment, and outcome are presented in Table 1. Furthermore, we added 3 cases of movement disorders in COVID-19 patients from our center to the literature, reported below.

Case 1.
A previously healthy 42-year-old man presented with difficulty speaking, cognitive deficits, ataxia, and progressive disabling jerks in upper and lower limbs, leading to falls (see Supplementary video-1). Neurological examination demonstrated spontaneous, action-induced, and tactilesensitive myoclonus on the face, upper extremities, and lower extremities. He had dysmetria and dysdiadochokinesia with superimposed action-induced myoclonus in the upper and lower extremities. Myoclonus prevented him from standing independently, and he had a wide-based gait. e rest of the neurological examination was normal. Laboratory tests including renal function, liver function, ammonium, urea, and CO2 were normal, except for the nasopharyngeal RT-PCR test for SARS-CoV-2, which was positive. Computed tomography (CT) of the head and brain magnetic resonance imaging (MRI) were normal. Electroencephalogram (EEG) and electromyography (EMG) were performed but did not reveal any abnormalities. Given these findings and the positive SARS-CoV-2 PCR, myoclonus was considered postinfectious. No other symptoms such as fever, myalgia, cough, fatigue, hyposmia, or hypogeusia were present. Cerebrospinal fluid (CSF) analysis was unremarkable, RT-PCR test for SARS-CoV-2 and autoantibodies were negative. He was treated with methylprednisolone 1000 mg IV daily for five days, bringing about a partial resolution of myoclonus. Complete recovery was observed on a follow-up session one month later.

Case 2.
A previously healthy 52-year-old man presented with progressive imbalance and generalized jerks (see Supplementary video-2). A week before, he had experienced myalgia and tested positive for SARS-CoV-2. Upon admission, he had generalized stimulus-sensitive myoclonus affecting his face, hands, and legs, confining him to a wheelchair. Other neurological findings, including eye movements, muscle tone, and deep tendon reflexes, were normal. He did not have any coughing, fever, dyspnea, and O2 saturation was more than 97% without nasal O2. Ground-glass opacities suggestive of SARS-CoV-2 infection were detected on chest CT. Laboratory studies showed no increase in inflammatory markers in peripheral blood; CRP and white blood cell count were normal. Brain CT and MRI were normal. Results from CSF evaluations, including autoantibody investigations, were unremarkable. e cerebellar syndrome improved after high-dose IV methylprednisolone (1 gr/day for five days); on a follow-up session after three weeks, the patient could walk independently.

Case 3.
A 38-year-old man was referred to our clinic with generalized jerks in his hands (see Supplementary video-3). A week before, he had been discharged from the hospital after four days of hospitalization due to a positive nasopharyngeal RT-PCR test and evident involvement of his lungs. Four days after discharge, he developed fine jerks in his hands and could not write; three days later, he was referred to our clinic with progression and generalization of jerks. He had generalized myoclonus in upper and lower limbs and bizarre abnormal movements that diminished with distraction; he was also restless and seemed anxious. e rest of the neurological examinations were normal. Lab tests were unremarkable. Laboratory investigations and brain MRI scans were normal. CSF analyses, including cell count, protein, and autoimmune panel, were normal. Clonazepam (2 mg/day), levetiracetam (1000 mg/ day), and IV methylprednisolone for 5 days (1 g/day) were started, resulting in partial improvement. After two weeks, myoclonus was resolved; functional movements improved with some residual deficits, but he was still suffering from anxiety.

Discussion
Our understanding of COVID-19-associated neurological manifestations is evolving. With about 200 million confirmed cases of COVID-19, a relatively limited, yet    concerning, number of cases of post-/parainfectious movement disorders-most common of which were myoclonus and cerebellar ataxia-have been reported. e overall frequency of abnormal movements in hospitalized COVID-19 patients may not exceed one percent; it was reported as 0.7% (6/841) [51]. All six had hyperkinetic movements (mostly myoclonic tremor; the mean interval between COVID-19 onset and abnormal movements, 3-8 days). Further, we identified numerous cases of movement abnormalities occurring during or after a COVID-19 infection in the literature (reviewed in Table 1). In most cases, the underlying pathomechanisms were assumed to involve immune-mediated and postinfectious processes by the reporting authors. On the other hand, few cases were reportedly caused by hypoxia (case no. 27 [20]) or ischemic strokes (cases no. 46 [35] and 65 [50]); thus, in some instances, patients required different therapeutic approaches. We added three more cases of myoclonus development after COVID-19 infection, furthering our understanding of the neurological manifestations associated with SARS-CoV-2 infection.

Myoclonus and COVID-19.
Infection-associated myoclonus can often be encountered among patients with severe viral, bacterial, or parasitic infections and is characterized by abrupt, brief, and sometimes repetitive contractions of the trunk, limbs, or face muscles [16,25]. Myoclonus is reportedly the most common movement disorder in hospitalized COVID-19 patients [52]. Given the numerous cases of myoclonus in patients without a remarkable history of abnormal movements (see Table 1) and the close temporal association of myoclonus with COVID-19 symptoms, one could suspect a causal link between the two conditions. Some have also advised monitoring COVID-19 survivors for probable, unfortunate posthypoxic myoclonus as a long-term COVID-19 complication [20]. Mechanistically, SARS-CoV-2 infection is speculated to cause myoclonus through one or any combination of the following: (I) hypoxia and systemic (e.g., metabolic) disturbances and (II) direct invasion of the CNS cells and (III) immune-mediated pathways, such as molecular mimicry with the host's CNS tissue [24].

Chorea Associated with COVID-19.
e most recognized chorea associated with infections is Sydenham's chorea, characterized by autoimmunity against the basal ganglia after a streptococcal infection [55]. We identified only one case of chorea in a COVID-19 patient [10], a 14-year-old girl with previously diagnosed Sydenham chorea when she was 11. She reported no disease activity during the past two years, yet she developed chorea on the third day after e authors could not conclude whether this was a recurrence of her previously silent disease or an immune-mediated newly developed chorea with a causal link to COVID-19 [10]. However, we assume the latter was less likely, with the very short interval between COVID-19 onset and chorea manifestation (3 days) arguing against an autoimmune scenario.  e acute hypokinetic-rigid syndrome has been reported in two cases (cases no. 5 [11] and 13 [15]); both developed a severe course of infection and required intensive care and mechanical ventilation.

Hypokinesia and Parkinsonism: Considerations in
Parkinson's disease (PD) is a neurodegenerative disease caused by the destruction of dopaminergic neurons in substantia nigra pars compacta (SNpc). Evidence of viral infections associated with PD exists; thus, vigilant monitoring and investigation of probable links between SARS-CoV-2 infection and parkinsonism may be necessary [7,56]. On this matter, the presence of antibodies targeting coronaviruses in cerebrospinal fluid of PD patients was more frequently observed when compared to individuals without PD. Further, the proposed ability of coronaviruses in breaching into the CNS via nasal cavity and nasal neuroepithelium can give us more reasons to be concerned [57,58]. Interestingly, it has been speculated that PD-associated α-synuclein retrograde spreading and aggregation from the olfactory bulb to the midbrain and deeper CNS structures-leading to cellular death of the affected tissue-could offer some protection against SARS-CoV-2 breaching into the CNS via the olfactory route [59]. However, the aforementioned neuropathological data from autopsy studies call this hypothesis into question [8,9]. Regardless of such hypothesized protective effects, PD patients are nevertheless more vulnerable to complications following respiratory infections, and odds for their hospitalization or development of other comorbidities are higher than the general population [60]. Furthermore, parkinsonian symptoms after viral respiratory infections may hint us toward the less-known sides of the disease etiology and pathogenesis [61].
A community-based case-control study on 12 PD patients who contracted COVID-19 documented a substantial risk of motor and nonmotor symptoms worsening associated with mild to moderate degrees of COVID-19, regardless of the patients' age and disease duration [7].
Lo Monaco and colleagues reported a patient with an 8year history of PD who developed severe generalized dystonia shortly after contracting COVID-19. Improvement was achieved after an increase in her daily dose of levodopa and clozapine [62].
Inversely, PD and its associated disabilities may negatively impact the outcome of COVID-19 illness, along with other known risk factors such as age and hypertension. Indeed, Fasano et al. reported a higher COVID-19 mortality rate in community-dwelling PD patients (i.e., not living in nursing homes) than the general population [63], and Salari et al. showed PD patients have a higher proportion of COVID-19 mortality in comparison with other patients hospitalized for COVID-19 [64].
Some limitations apply to the present review article, such as the keywords selection; some studies that have not used the keywords incorporated in our search strategy, e.g., those that only mentioned "neurological manifestations" without further specification, might have been missed. e literature search has not thoroughly adhered to the standards of a systematic review, albeit being as exhaustive and comprehensive as possible. Furthermore, cross-reference checking for some reviewed articles may have been incomplete. Review papers bear the limitation of their reviewed articles; as discussed earlier, myoclonus may stem from metabolic comorbidities in some cases.
us, the attribution of myoclonus to COVID-19 by some case studies is a potential limitation of such reports applying to the present review as well. Another limitation was that electrophysiological data were not obtained from two of our cases (i.e., Cases 2 and 3).

Conclusion
is review highlighted the higher incidence of myoclonus and ataxia after COVID-19 infection. Other movement disorders were not common after COVID-19, implying that SARS-CoV-2 mainly affects the brain through immunemediated pathways rather than a direct invasion of the CNS. Nonetheless, the COVID-19 pandemic can affect the outcome of patients with established movement disorders.

Data Availability
All relevant data are provided in the manuscript and the supplemental files; there are no additional data to be presented.

Conflicts of Interest
e authors declare that there are no conflicts of interest relevant to this work.

Supplementary Materials
A direct link to video files of the three patients reported are included as supplementary data of this manuscript. (Supplementary Materials)