|Year : 2022 | Volume
| Issue : 1 | Page : 12-22
Spectrum of de novo movement disorders in the setting of COVID-19 infection: Part 1: Pathogenesis and hypokinetic-rigid syndrome
Heli Shah1, Mitesh Chandarana2, Soaham Desai3
1 Department of Neurology, Sterling Hospital, Ahmedabad, Gujarat, India
2 Department of Neurology, Medisquare Hospital, Ahmedabad, Gujarat, India
3 Department of Neurology, Shree Krishna Hospital and Pramukhswami Medical College, Bhaikaka University, Karamsad, Anand, Gujarat, India
|Date of Submission||15-Oct-2021|
|Date of Decision||12-Jan-2022|
|Date of Acceptance||17-Jan-2022|
|Date of Web Publication||25-Apr-2022|
Dr. Soaham Desai
Consultant Neurologist and Head, Department of Neurology, Shree Krishna Hospital and Pramukhswami Medical College, Bhaikaka University, Karamsad, Anand, Gujarat
Source of Support: None, Conflict of Interest: None
The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with a myriad of potential neurological manifestations, with de novo movement disorders still being reported. There is growing concern about a possible new wave of neurological complications in the aftermath of the COVID-19 pandemic. The objective of our review is to summarize all available evidence documenting new-onset movement disorders associated with COVID-19, with focus on hypokinetic movement disorders and their pathogenesis. We identified 66 new-onset movement disorder cases from using the PubMed and Google Scholar databases. Myoclonus was the most frequently reported movement disorder associated with COVID-19 alone or in combination with ataxia and tremor, while parkinsonism was the most notable movement disorder associated with the pandemic. To date, only eight cases of de novo parkinsonism associated with COVID-19 have been reported in the literature. Their exact pathophysiology is not well-understood but can include viral neuroinvasion–neurodegeneration, central nervous system-specific immune activation, vascular damage, systemic inflammation, autoimmune mechanisms, hypoxia, or metabolic disturbances. Although it is difficult to point out the specific relationship between SARS-CoV-2 and movement disorders, in this brief review, we unfold various potential plausible mechanisms responsible for the pathogenesis of movement disorders, with focus on hypokinetic movement disorders. Clinicians should closely monitor patients who have recovered from COVID-19 for the possibility of new-onset COVID-19-associated movement disorders. Longitudinal follow-up studies are necessary to ascertain the long-term neurological and neuropsychological consequences of the disease and the associated evolution of movement disorders.
Keywords: COVID-19, hyperkinetic movement disorders, hypokinetic movement disorders, neuroimaging, Parkinson’s disease, SARS-CoV-2
|How to cite this article:|
Shah H, Chandarana M, Desai S. Spectrum of de novo movement disorders in the setting of COVID-19 infection: Part 1: Pathogenesis and hypokinetic-rigid syndrome. Ann Mov Disord 2022;5:12-22
|How to cite this URL:|
Shah H, Chandarana M, Desai S. Spectrum of de novo movement disorders in the setting of COVID-19 infection: Part 1: Pathogenesis and hypokinetic-rigid syndrome. Ann Mov Disord [serial online] 2022 [cited 2022 Aug 10];5:12-22. Available from: https://www.aomd.in/text.asp?2022/5/1/12/343845
| Introduction|| |
As the COVID-19 pandemic has rapidly progressed, its diverse presentations, with the involvement of different systems and organs has been increasingly recognized. The spectrum of different neurological disorders described with COVID-19 infection includes anosmia; headaches; myalgia/myositis; encephalopathy; stroke; meningitis/encephalitis; seizures; peripheral neuropathy; and postviral chronic neurological manifestations such as disseminated encephalomyelitis, necrotizing hemorrhagic encephalopathy, transverse myelitis, Guillain–Barré syndrome, multisystem inflammatory syndrome (Kawasaki’s disease), dysautonomia, and chronic fatigue syndrome.,,,,
In some patients, referred to as “long-haulers,” the symptoms (such as low-grade fever, clouding of mentation, sleep disturbances, and various other somatic symptoms) persist for months. Many case series and reports have described the different neurological disorders and neuropsychiatric manifestations occurring with COVID-19 infection. However, data on movement disorders preceded by SARS-CoV-2 are scarce. Infectious diseases of the nervous system are among the most common causes of neurological disability worldwide. It is important to note that the SARS-CoV-2 infection can affect any part of the neural axis from the central to the peripheral nervous systems. A series of movement disorders can develop in isolation (i.e., direct neurovirulence), with or without encephalopathy, or as part of a broader neurological dysfunction (i.e., indirect neurovirulence).
In this two-part review, we delineate the current understanding of COVID-19-associated movement disorders and review the pathogenesis of new-onset movement disorders in association with COVID-19 infection, such as hypokinetic movement disorders post-COVID-19 (in this article, Part 1) and hyperkinetic movement disorders post-COVID-19 (in Part 2 of this review).
| Search methodology|| |
We performed an electronic search using the PubMed and Google Scholar databases to include articles from August 1 2019 to August 31, 2021. We used the following keywords: “ Parkinsonism More Details” OR “Ataxia” OR “myoclonus” OR “tremor” OR “dystonia” OR “chorea” OR “movement disorders” AND “SARS-CoV-2” OR “COVID-19”. We included peer-reviewed studies, including cohort, case-control studies, and case reports describing COVID-19-associated movement disorders and studies reporting the management and outcome of these cases. In addition, cross-references, if found relevant, were included. The search yielded 468 results. After removing duplicates and irrelevant studies, 330 items remained. The titles and abstracts of these studies were screened for inclusion by three reviewers (HS, MC, SD). We excluded articles published in non-English languages and the ones with only abstracts or conference presentations without complete information. Furthermore, we excluded studies that lacked information on neurological manifestations of movement disorders, especially the management and treatment plan. Similarly, we excluded studies describing patients with an existing baseline movement disorder or with previous history of movement disorders that worsened post-COVID-19. This yielded 111 articles, whose full text was accessed and reviewed. After a detailed review of different articles in the selection, and after excluding articles with incomplete details or contentious or analogous descriptions, a total of 66 articles were finally included in our review ([Figure 1]).
|Figure 1: PRISMA flow-chart detailing the selection of publications for this systematic review of spectrum of de novo movement disorders in the setting of COVID-19 infection|
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| Pathogenesis of new-onset movement disorders post-COVID-19 infection|| |
The important mechanisms for the various neurological syndromes associated with COVID-19, either individually or in conjunction with, include direct viral-mediated neuronal injury; hyperinflammation syndrome; para and postinfectious inflammatory or immune-mediated disorders; or the various effects of a systemic disorder with the neurological consequences of hypoxia, sepsis, hypercoagulability, and critical illness. The multiple neurological manifestations, including de novo movement disorders, are postulated to occur due to different pathogenic mechanisms. This can occur as a direct injury to the nervous system, as parainfectious/postinfectious inflammation to the nervous system, as immune-mediated direct neuronal injury, as neurological complications of the systemic effects of COVID-19, or as a result of drug toxicity. Reasons for the pathophysiology of movement disorders in COVID-19 can yield several possible explanations. First, this includes, the neuroinvasion and neurovirulence potential of the SARS-CoV-2 virus., Second, many cases, especially those with myoclonus, could be ascribed to drugs, metabolic derangement, or severe hypoxia. Furthermore, a post or parainfectious immune-mediated mechanism related to the inflammatory phase of COVID-19 can trigger both hypokinetic and hyperkinetic movement disorders ([Figure 2]).
|Figure 2: Spectrum of phenomenology of de novo movement disorders in the setting of COVID-19 infection|
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The possibility of postencephalitic parkinsonism has been entertained since Von Economo recognized a mysterious increase in patients with Parkinson’s symptoms, a few years after the influenza pandemic. Moreover, conversion from prodromal to symptomatic Parkinson’s disease (PD), directly or indirectly related to COVID-19, in reported cases raises the possibility of postencephalitic parkinsonism in patients who recover from COVID-19, similar to patients encountered after the 1918 pandemic.
| Hyperinflammation and cytotoxin-mediated neuronal loss, vascular damage, and hypoxia|| |
The phenomenology of transient or permanent parkinsonism following a viral infection is well known. However, parkinsonism related to SARS-CoV-2 appears to be an intriguing manifestation. Brundin et al. hypothesized that parkinsonism occurs as a manifestation of COVID-19, either alone or in combination, through the following mechanisms: vascular insult to the nigrostriatal system along with a hypercoagulable state; neuroinflammation triggered by systemic inflammation via the novel SARS-CoV-2 leading to the demise of midbrain dopaminergic neurons via microglial activation and cytotoxic T-cell infiltration; and neuroinvasion and direct neuronal damage by the virus gaining access to the brain via the olfactory nerve or gastrointestinal/respiratory tract via the vagus nerve. In parkinsonism associated with viral infections, neuropathological involvement could be variable, ranging from direct acute infection to postinfectious neuroinflammation, with both eventually culminating in dopaminergic cell loss.,
Viruses can cause parkinsonism directly or indirectly. The direct manifestations occur with the development of virus tropism, replication, and subsequent neuronal lysis for the basal ganglia. On the other hand, microglia activation, the release of proinflammatory factors and T- cell response, hypercytokinemia with vascular damage, and brain hypoxia are possible indirect pathophysiological mechanisms.
Some novel possible mechanisms are postulated to cause COVID-19-associated hypokinetic and mixed movement disorders including the following complications:
Acute structural or functional damage of the basal ganglia, predominantly the substantia nigra pars compacta and nigrostriatal dopaminergic neurons
Extensive hypoxia or inflammatory brain injury with coexistent encephalopathy
Unmasking of underlying asymptomatic previously unknown parkinsonism
Viral infection-mediated cascade of events causing permanent damage to the basal ganglia that may trigger parkinsonism, especially in patients with high genetic susceptibility
| Neuroinvasion, neuronal cell death, and neurotransmitter imbalance|| |
In addition to viral or autoimmune encephalitis, other possible mechanisms that may predispose COVID-19 patients to the development of subsequent parkinsonism include hypoxia or vascular damage to the basal ganglia. Recent findings have revealed that coronaviruses are neurotropic. The SARS-CoV-2 could infect neurons in the central nervous system through retrograde axonal transport or hematogenic routes via its neurotropism. The angiotensin-converting enzyme 2 (ACE-2) receptors are highly expressed by striatal dopaminergic neurons, microglia, and astrocytes of the basal ganglia, which are also the receptors for SARS-CoV-2; therefore, they play an important role, in creating an entryway for the virus. ACE-2 is the co-receptor of virus spike proteins that play an important role in the pathogenesis of COVID-19. Once the viral spike protein binds to the ACE-2 receptor in the target cell, it leads to fusion of the viral envelope with the cell membrane and transfers the viral genomic material to the target cell. In addition, ACE-2 has is abundantly found in the substantia nigra, middle temporal gyrus, posterior cingulate cortex, and olfactory bulb., Recently, both ACE-2 and transmembrane serine protease 2 are expressed in the human corneal epithelium, suggesting that ocular surface cells could be a potential viral entry point. SARS-CoV-2 could invade the central nervous system through vascular or retrograde axonal pathways and infect the striatal neurons in the central nervous system ([Figure 3]). In addition to these, there could be different mechanisms through which the virus may cause movement disorders that manifest in a myriad of ways ([Figure 2]). Important mechanisms to note are the downregulation of the ACE-2 receptors, which could culminate in an imbalance of neurotransmitter levels, predominantly dopamine and norepinephrine ([Figure 3]), leading to dopamine deficiency and hypokinetic movement disorders. Finally, the virus could cause neuronal cell death, demyelination, and gliosis, leading to encephalitis along with associated mixed movement disorders.
|Figure 3: Neurotropism and pathogenesis of new-onset (de novo) movement disorders associated with COVID-19|
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| α-Synuclein aggregation-mediated neurodegeneration|| |
Recent studies have indicated that α-synuclein may participate in the innate immune response to any viral infection. The process of neurodegeneration in PD is suggested to start in the olfactory system or the enteric nerves, which may propagate along the nigrostriatal pathways to additional brain regions. It is noteworthy that constipation and hyposmia are common features of prodromal PD, and α-synuclein aggregates may contribute to their pathophysiology. Notably, hyposmia (and ageusia) are common features observed with SARS-CoV-2 infection. In addition, SARS-CoV-2 can infect the gastrointestinal tract, suggesting that the virus gains direct access to regions of the brain relevant to PD via these different routes. Furthermore, the respiratory tract is innervated by the vagus nerve, which may be another potential portal for viral entry into brain. The midbrain dopamine neurons express high levels of the ACE-2 receptor, which is essential for viral entry and replication, making these cells vulnerable to SARS-CoV-2-mediated cell damage. Another noteworthy possibility is that neuroinvasion by the SARS-CoV-2 can lead to upregulation of neuronal α-synuclein. Neuroinflammation can ultimately trigger α-synuclein aggregation, misfolding, and propagation through the nigrostriatal pathways. α-Synuclein aggregation may activate microglia, favoring the proinflammatory response and cell damage signals, leading to neuronal cell death. Therefore, in SARS-CoV-2 infection, sustained elevated levels of intraneuronal α-synuclein may lead to the formation of aggregates or upregulation, misfolding, and propagation of α-synuclein proteins, which is reminiscent of features in parkinsonian brains, possibly followed by neuronal death and neuronal lysis, particularly of the midbrain dopaminergic neurons, as well as those involving the substantia nigra pars compacta in the basal ganglia.
| Immune-mediated and infection-related mechanisms|| |
Parainfectious or immune mechanisms affecting the neural function of different midbrain structures may be considered after COVID-19-associated parkinsonism. Infection-related movement disorders may sometimes be the result of an immune-mediated active process affecting the neural substrates through molecular mimicry and host susceptibility., This often results in the development of targeted antibodies against cell-surface dopaminergic receptors in the basal ganglia. Simultaneously, antineuronal antibodies directed against the cerebellar fastigial nucleus and omnipause neurons located in the brainstem may give rise to opsoclonus–myoclonus syndrome, as reported in several studies., An immune-mediated mechanism has been accepted in opsoclonus–myoclonus–ataxia syndrome, with the most convincing evidence arising from its response to immunotherapies, such as corticosteroids and immunoglobulins, although robust evidence remains lacking. In addition to hypoxia-mediated neuronal damage resulting from COVID-19 infection, which may be a substrate for new-onset movement disorders, other mechanisms such as cytokine-mediated neuroinflammation, microglial activation, vascular endothelial dysfunction, and megakaryocyte-mediated hemodynamic changes may have the potential to cause movement disorders. It is postulated that parainfectious mechanisms (inflammatory processes alone or in combination) affecting the cerebellum, brainstem, and striatum could contribute to myoclonus or ataxia associated with COVID-19 infection. SARS-CoV-2 infection is associated with increased levels of proinflammatory cytokines and systemic inflammation, including cytokine storm or cytokine release syndrome, which is considered to underpin the mechanism of multiple organ failure. Some cases of myoclonus, ataxia, and myoclonus with ataxia had increased serum or cerebrospinal fluid levels of interleukin-6, a key proinflammatory marker that partially or completely responds to interleukin-6-blocking agents. The positive effect of immunotherapy in many such patients indicates the important pathogenetic mechanisms for the development of movement disorders following SARS-CoV-2 infection may be mediated by deranged aberrant immune-mediated injury.
Finally, in postinfective myoclonus associated with COVID-19 infection, an autoimmune process against the cerebellar or brainstem neurons may change neuronal excitability and trigger mechanisms that could generate myoclonic jerks. This may occur by increasing the cerebellar excitatory output to the primary motor cortex through a di-synaptic excitatory connection via the thalamus, leading to hyperactivation of the corticospinal tract neurons or by abnormal activation of the brainstem nuclei or via cerebellar–brainstem projections; this, in turn, causes activity in the descending pathways from the brainstem, such as the reticulospinal or rubrospinal tract. Therefore, dysfunction in saccade circuits, cerebellar circuits, and motor circuits, as a result of brainstem hyperexcitability, may be responsible for generating opsoclonus, ataxia, and myoclonus, respectively.,
| Discussion on the currently available reports on de novo parkinsonism post-COVID-19|| |
There is scarcity of substantial evidence to quantify the substantially increased risk of developing parkinsonism as a result of COVID-19 infection. The high prevalence of anosmia combined with the suspicion about a link between an encephalitis lethargica-type association and a historic influenza pandemic leads us to question whether history could be repeating itself. However, there has been no evidence of this, despite the pandemic that has been ongoing for >18 months.
To date, only eight published cases have documented new-onset parkinsonism post-COVID-19 infection ([Table 1]). None of the reported cases provided evidence of COVID-19 positivity in cerebrospinal fluid while testing for COVID-19 infection using polymerase chain reaction. Furthermore, no cases revealed any structural lesions on brain imaging after the infection.
|Table 1: List of published cases of hypokinetic-rigid syndrome occurring after COVID-19 infection|
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At least eight such published case reports have indicated that patients with COVID-19 had developed clinical parkinsonism, either in isolation or with other neurological deficits such as myoclonus. All eight studies revealed a temporal relationship between acute COVID-19 infection and new-onset parkinsonism with intervals ranging from 2–7 weeks.,,,,,, Most patients were aged >50 years, and three patients were aged 35, 45, and 46 years. Six patients had moderate to severe respiratory infection requiring hospitalization.,,,, Two of the eight patients responded with reduced severity of parkinsonian symptoms upon administration of traditional dopaminergic medication,, and one patient had excellent recovery with complete resolution of symptoms over a mean period of 25 days. In all cases, neuroimaging revealed reduced function of the nigrostriatal dopamine system, similar to PD.,,,,,, None of the patients had family history of PD or history with signs of prodromal PD; one patient underwent genetic testing but did not carry any PD risk variants.
Méndez-Guerrero et al. reported the case of a 58-year-old man with an asymmetric hypokinetic-rigid syndrome combined with opsoclonus–myoclonus complex showed asymmetrically decreased presynaptic dopamine uptake in the putamen on dopamine transporter–single-photon emission computed tomography. The patient showed striking but incomplete symptomatic improvement over a period of 3 weeks even without specific dopaminergic treatment. Some animal models have proposed cellular dysfunction of the nigrostriatal neurons, as a result of a viral infection. Whether this mechanism, a cytolytic effect, on neurons, or both processes are involved in this clinical case is debatable. Cohen et al. described a case, where 45-year-old man showed mild improvement in symptoms of parkinsonism after therapy with steroids and pramipexole.
A 35-year-old previously healthy woman presented with anosmia and hypogeusia, asymmetric bradykinesia (right worse than left) and cogwheel rigidity, stooped posture, gait with reduced arm swing, en-bloc turning, and decreased stride length after 10 days of developing COVID-19 infection. It was evident that the patient had akinetic-rigid parkinsonism. Her abnormal dopamine transporter scan and levodopa responsiveness further confirmed the presynaptic nature of the parkinsonian syndrome. Faber et al. concluded that the patient may have had a direct dysfunction of the nigro-striatal system as a result of SARS-COV-2 in addition to acute infection/post-infectious neuroinflammation, both resulting in dopaminergic neuronal cell loss.
Morassi et al. reported the findings of two patients from Italy with COVID-19-related encephalopathy who developed prominent parkinsonism. Both patients developed a rapidly progressive form of atypical parkinsonism along with distinctive features of encephalitis. A possible immune-mediated etiology was suggested in one patient because of the presence of cerebrospinal fluid oligoclonal bands, but no patient responded favorably to immunotherapy to prove the exact etiopathogenesis. Notably, fluorodeoxyglucose–positron emission tomography findings were similar in both patients and almost similar to those observed in postencephalitic parkinsonism, with cortical hypo-metabolism associated with hyper-metabolism in the brainstem, mesial temporal lobes, and basal ganglia.
Taken together, these observations suggest that SARS-CoV-2 infection could trigger immune-mediated encephalitis with prominent parkinsonism and distinctive altered metabolic neuronal pathways as one of the alternative mechanisms of the infection. The rapid onset of severe motor symptoms in close temporal proximity to the viral infection could be suggestive of a possible causal link. An alternative possibility is that SARS-CoV-2 infection causes hastening of preclinical neurodegenerative diseases, as was suggested in a 64-year-old woman who showed symptoms suggestive of new-onset PD 5 days after infection with COVID-19; she had previous history of premotor symptoms (constipation for 10 years). Makhoul et al. concluded that PD, in this case, was a direct consequence of COVID-19 infection due to its acute onset within days of COVID-19-related symptoms. It was suggested that similar to other COVID-19-related cases of parkinsonism, this patient had prodromal parkinsonism that became symptomatic as a result of COVID-19. This hypothesis is further supported by the presence of decreased dopamine transporter scan uptake, which is unlikely to occur within such a short period of time (days or weeks).
However, these cases do not prove a definite causal relationship between SARS-CoV-2 infection and the development of parkinsonism. We believe that these patients may have already been on the verge of developing PD, i.e., in the process of losing a number of nigral dopamine neurons adequate for the emergence of motor symptoms. Furthermore, the viral infection only accelerated and triggered an ongoing neurodegenerative process or unmasked the underlying neurodegenerative process around a critical timepoint—a double hit hypothesis. Finally, Fearon et al. descried the case of a 46-year-old man who developed severe hypoxia, acute respiratory distress syndrome necessitating intubation and ventilation, and disseminated intravascular coagulation. On extubation, he showed marked hypokinetic dysarthria and asymmetric parkinsonism but was unresponsive to levodopa (450 mg/day). This case highlights an important alternative cause of COVID-19-associated parkinsonism, distinct from discovering underlying PD or a form of unproven postinfectious/postinflammatory parkinsonism. Owing to respiratory compromise and “silent hypoxia,” which can accompany SARS-CoV-2, as well as virus-specific endothelial damage and vasculitis, this case may represent an equally important cause of parkinsonism that requires further vigilant documentation.
Despite the promising findings, our review has some limitations. Our review is based on a small number of available cases, even after an extensive search of the available literature; this may be due to the underreporting of cases. The examination of hospitalized patients may not have been conducted adequately (by not wearing masks, insufficient videoconferencing, etc.); this may explain the limited description of these cohorts. Some of the available reports do not describe the timeline of events in an organized manner, making interpretation difficult. In addition, laboratory, electroencephalography, and neuroimaging features have not been descried in detail in some cases. Furthermore, there is considerable heterogeneity in the available data that may be considered a hindrance in detailed analysis. Moreover, we have not included non-English articles. Despite these shortcomings, we hope that our review will act as a preliminary guide for clinicians when dealing with movement disorders that appear in the setting of COVID-19 infection. Although robust evidence to prove or refute the exact causal association of SARS-CoV-2 infection with the development of PD remains lacking, the potential neurological sequelae of this novel coronavirus should not be underestimated. Therefore, it is important to carefully observe large cohorts of patients affected by COVID-19 and monitor them for possible future manifestations of PD. If patients with the novel coronavirus infection are at an increased risk for PD and other related neurodegenerative disorders, it will be an important step to identify early treatment strategies that may help mitigate an elevated future risk. However, further in-depth research is needed to establish the exact association between COVID-19 infection and parkinsonism.
Cases of de novo movement disorders associated with COVID-19 are lacking worldwide. Underreporting of available cases, late presentation of cases, or insufficient data regarding the direct link between SARS-CoV-2 and movement disorders could be the reasons behind this paucity. In addition, it is well observed that among cases of neurological complications associated with COVID-19 infection, the neural substrates for movement disorders are often spared as evidenced by different neuroimaging studies,,,,, which could be responsible for the scarce data. It is likely that immune system derangements caused by the novel corona virus infection may lead to neurodegeneration, and potential movement disorders may manifest after a latent period. Furthermore, movement disorders following an infectious or autoimmune process typically develop after a period of weeks to months. It is possible that expected parenchymal changes in the brain need to reach a threshold level to manifest as delayed movement disorders.,,
Therefore, there is a need to develop long-term monitoring strategies for individuals in recovery, including those with neurodegenerative sequelae such as in virus-associated parkinsonism. Our review has definite future implications, since it will help clinicians to better understand the pathogenesis and be vigilant about the probable phenomenology of movement disorders in long-term COVID-19 survivors. The field of movement disorders is dynamic, with remarkable therapeutic implications and numerous strategies for better patient management.
| Conclusion|| |
To date, there are only few publications on the symptoms of parkinsonism associated with COVID-19 infection. Additional studies are needed to confirm or refute the effect of SARS-CoV-2 on neuroinflammatory and neurodegenerative processes leading to the development of parkinsonian symptoms. Exploring the potential relationship of SARS-CoV-2 and parkinsonism is essential because of the epidemiological implications, as well as to gain a better understanding of the pathophysiological aspects of these disorders.
- Research project: A. Conception, B. Organization, C. Execution;
- Statistical Analysis: A. Design, B. Execution, C. Review and Critique;
- Manuscript Preparation: A. Writing of the first draft, B. Review and Critique;
HS: 1A, 1B, 1C, 2A, 2B, 3A.
MC: 1A, 1B, 2A, 2B, 3B.
SD: 1A, 1B, 2A, 2C, 3B.
Ethical compliance statement
The authors confirm that neither informed patient consent nor the approval of an institutional review board was necessary for this work. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Dr Soaham Desai would act as the guarantor and corresponding author of this article.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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