Incidence and characteristics of post-COVID-19 parkinsonism and dyskinesia related to COVID-19 vaccines.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an infectious disease mainly affecting the respiratory system; however, a significant prevalence of neurological symptoms has been noted. OBJECTIVES: To investigate the incidence and characteristics of post-COVID-19 parkinsonism and to study dyskinesia related to COVID-19 vaccines. MATERIAL AND METHODS: The MEDLINE, PubMed, Scopus, and Web of Science databases were searched for all manuscripts relevant to post-COVID-19 parkinsonism and dyskinesia related to COVID-19 vaccines. Subsequently, we extracted and analysed data from the manuscripts in a structured manner. RESULTS: We found 24 patients with post-COVID-19 parkinsonism, with a mean onset age of 58 years after a mean of 30 days from the COVID-19 onset. Akinetic-rigid (n = 11) and mixed (n = 6) subtypes were the most common. Asymmetry was present in 13/15 patients. Brain MRI was unremarkable in 11/19, whereas dopaminergic system imaging was abnormal in 8/8 patients. Responsiveness to dopaminergic treatment was observed in 12/15 patients. Four patients improved after immunomodulatory therapy. Comorbidities were present in 9/24, encephalopathy symptoms in 11/24, and loss of smell in 9/13 patients. Most patients (n = 14) suffered serious COVID-19- related complications and three were treated with haloperidol. Parkinsonism improved (n = 5) or resolved (n = 4) during the follow-up. Five patients, with a mean age of 52, developed dyskinesia at a mean of 25 hours after receiving the COVID-19 mRNA vaccines. One patient had a history of neuropsychiatric symptoms and developed functional dyskinesia of the tongue. Four patients had a previous history of Parkinson's Disease (PD) with a mean duration of 10 years and developed dyskinesia and dystonia, which resolved (n = 2) or improved (n = 2) during the follow-up. CONCLUSIONS: Post-COVID-19 parkinsonism is a very rare complication, and it is likely that this is an umbrella syndrome that includes many different etiologies. Dyskinesia due to COVID-19 vaccines is exceedingly rare and probably has the same pathophysiological basis as in other conditions with exacerbation of PD symptoms.

Clinical features and outcomes of hospitalised patients with COVID-19 and Parkinsonian disorders: a multicentre UK-based study (preprint)

Background: Parkinsons disease has been identified as a risk factor for severe Coronavirus disease 2019 (COVID-19) outcomes. However, whether the significant high risk of death from COVID-19 in people with Parkinsons disease is specific to the disease itself or driven by other concomitant and known risk factors such as comorbidities, age, and frailty remains unclear. Objective: To investigate clinical profiles and outcomes of people with Parkinsons disease and atypical parkinsonian syndromes who tested positive for COVID-19 in the hospital setting in a multicentre UK-based study. Methods: A retrospective cohort study of Parkinsons disease patients with a positive COVID-19 test admitted to hospital between February 2020 and July 2021. An online survey was used to collect data from clinical care records, recording patient, Parkinsons disease and COVID-19 characteristics. Associations with time-to-mortality and severe outcomes were analysed using either the Cox proportional hazards model or logistic regression models, as appropriate. Results: Data from 552 admissions were collected: 365 (66%) male; median (inter-quartile range) age 80 (74-85) years. The 34-day mortality rate was 38.4%; male sex, increased age and frailty, Parkinsons dementia syndrome, requirement for respiratory support and no vaccination were associated with increased mortality risk. Community-acquired COVID-19 and co-morbid chronic neurological disorder were associated with increased odds of requiring respiratory support. Hospital-acquired COVID-19 and delirium were associated with requiring an increase in care level post-discharge. Conclusions: This first, multicentre, UK-based study on people with Parkinsons disease or atypical parkinsonian syndromes, hospitalised with COVID-19, adds and expands previous findings on clinical profiles and outcomes in this population.

Satisfaction With Telemedicine Consultation as Follow-Up Visit in Patients with Parkinsonism and Essential Tremor in during the Covid-19 Pandemic.

Background: Telemedicine (TM) consultations have shown to be feasible for the management of neurological conditions including movement disorders. In contrast, satisfaction with such consultations have been less studied. Objective: To assess the satisfaction of persons with a movement disorder with a TM consultation in comparison to previous experiences in face-to-face visits. Subjects and Methods: A cross-sectional multicenter study was carried out. Persons with a diagnosis of a movement disorder underwent a TM consultation. After the consultation concluded, a satisfaction survey was sent for the subject to fill out anonymously. The survey included ease of use-related items, setup-related items, and quality-of-service-related items. Results: A total of 175 survey responses were received (response rate of 71.4%), all of which were included for analysis. A total of 102 subjects considered that the TM consultation involved much less time in comparison to their previous experience with face-to-face visits. Overall, 96% reported to be satisfied with the consultation. In addition, 92% were satisfied or very satisfied with the neurologist ability to communicate recommendations. Furthermore, 93.7% indicated that the consultation was valuable, and 90.9% considered that they would recommend teleconsultation to another patient. Conclusion: Patients with a diagnosis of a movement disorder consider TM as a convenient and potential tool for health services with a high level of satisfaction.

Covid-19 and Parkinson's disease: Acute clinical implications, long-COVID and post-COVID-19 parkinsonism.

The Coronavirus Disease 2019 (Covid-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has led to unprecedented challenges for the delivery of healthcare and has had a clear impact on people with chronic neurological conditions such as Parkinson's disease (PD). Acute worsening of motor and non-motor symptoms and long-term sequalae have been described during and after SARS-CoV-2 infections in people with Parkinson's (PwP), which are likely to be multifactorial in their origin. On the one hand, it is likely that worsening of symptoms has been related to the viral infection itself, whereas social restrictions imposed over the course of the Covid-19 pandemic might also have had such an effect. Twenty cases of post-Covid-19 para-infectious or post-infectious parkinsonism have been described so far where a variety of pathophysiological mechanisms seem to be involved; however, a Covid-19-induced wave of post-viral parkinsonism seems rather unlikely at the moment. Here, we describe the interaction between SARS-CoV-2 and PD in the short- and long-term and summarize the clinical features of post-Covid-19 cases of parkinsonism observed so far.

[Post COVID-19 disorders: is the epidemic of parkinsonism threatening the world?] / Postkovidnye narusheniya: grozit li miru epidemiya parkinsonizma?

During the pandemic caused by SARS-CoV-2, the ability of this virus to infect the structures of the peripheral and central nervous system becomes increasingly clear. Damage to the nervous system is noted in almost 85% of patients who have had COVID-19, both those who have had this disease in severe form, and in patients with mild or asymptomatic course. COVID-19 worsens symptoms in patients with Parkinson's disease (PD), which potentially increases the risk of death due to pneumonia and respiratory disorders in patients with severe stages of PD. There is a concern that the COVID-19 pandemic may lead to a sharp increase in the incidence of parkinsonism, while the ability of the SARS-CoV-2 virus to cause PD is assumed. The following ways of virus penetration, including the SARS-CoV-2 virus, into the structures of the central nervous system are considered - viremia and endothelial cell damage, as well as retrograde axonal transport. The direct penetration of the COVID-19 virus into the structures of the brain may be due to a disturbance of the blood-brain barrier due to a «cytokine storm¼ and activation of lymphocytes, which is due to the processes of neuroinflammation. According to some of its manifestations, the extrapyramidal syndrome observed in patients with COVID-19 resembles lethargic encephalitis von Economo. However, the question of the possibility of COVID-19 causing the development of PD is extremely complex and ambiguous. The latency period between viral encephalitis and the onset of parkinsonism can reach 5 years. It is possible that the basis for the development of neurological disorders, including parkinsonism, in this category of patients is an energy deficit that leads to disruption of the functioning of neural networks (human connectome) of the human brain. Based on the currently very limited data concerning the penetration of the COVID-19 virus into the structures of the central nervous system, there is no convincing evidence of this virus causing parkinsonism. The final clarity on this issue will be provided by the results of observations on the condition of patients who have undergone COVID-19.

Viruses, parkinsonism and Parkinson's disease: the past, present and future.

Parkinsonism secondary to viral infections is not an uncommon occurrence and has been brought under the spotlight with the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A variety of viruses have been described with a potential of inducing or contributing to the occurrence of parkinsonism and Parkinson's disease (PD), although the relationship between the two remains a matter of debate originating with the description of encephalitis lethargica in the aftermath of the Spanish flu in 1918. While some viral infections have been linked to an increased risk for the development of PD, others seem to have a causal link with the occurrence of parkinsonism. Here, we review the currently available evidence on viral-induced parkinsonism with a focus on potential pathophysiological mechanisms and clinical features. We also review the evidence on viral infections as a risk factor for developing PD and the link between SARS-CoV-2 and parkinsonism, which might have important implications for future research and treatments.

Post-COVID-19 Parkinsonism and Parkinson's Disease Pathogenesis: The Exosomal Cargo Hypothesis.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease, globally. Dopaminergic neuron degeneration in substantia nigra pars compacta and aggregation of misfolded alpha-synuclein are the PD hallmarks, accompanied by motor and non-motor symptoms. Several viruses have been linked to the appearance of a post-infection parkinsonian phenotype. Coronavirus disease 2019 (COVID-19), caused by emerging severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, has evolved from a novel pneumonia to a multifaceted syndrome with multiple clinical manifestations, among which neurological sequalae appear insidious and potentially long-lasting. Exosomes are extracellular nanovesicles bearing a complex cargo of active biomolecules and playing crucial roles in intercellular communication under pathophysiological conditions. Exosomes constitute a reliable route for misfolded protein transmission, contributing to PD pathogenesis and diagnosis. Herein, we summarize recent evidence suggesting that SARS-CoV-2 infection shares numerous clinical manifestations and inflammatory and molecular pathways with PD. We carry on hypothesizing that these similarities may be reflected in exosomal cargo modulated by the virus in correlation with disease severity. Travelling from the periphery to the brain, SARS-CoV-2-related exosomal cargo contains SARS-CoV-2 RNA, viral proteins, inflammatory mediators, and modified host proteins that could operate as promoters of neurodegenerative and neuroinflammatory cascades, potentially leading to a future parkinsonism and PD development.

Parkinsonism associated with viral infection.

There are several known causes of secondary parkinsonism, the most common being head trauma, stroke, medications, or infections. A growing body of evidence suggests that viral agents may trigger parkinsonian symptoms, but the exact pathological mechanisms are still unknown. In some cases, lesions or inflammatory processes in the basal ganglia or substantia nigra have been found to cause reversible or permanent impairment of the dopaminergic pathway, leading to the occurrence of extrapyramidal symptoms. This chapter reviews current data regarding the viral agents commonly associated with parkinsonism, such as Epstein Barr virus (EBV), hepatitis viruses, human immunodeficiency virus (HIV), herpes viruses, influenza virus, coxsackie virus, and Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). We present possible risk factors, proposed pathophysiology mechanisms, published case reports, common associations, and prognosis in order to offer a concise overview of the viral spectrum involved in parkinsonism.

COVID-19 and Parkinsonism: A Critical Appraisal.

A few cases of parkinsonism linked to COVID-19 infection have been reported so far, raising the possibility of a post-viral parkinsonian syndrome. The objective of this review is to summarize the clinical, biological, and neuroimaging features of published cases describing COVID-19-related parkinsonism and to discuss the possible pathophysiological mechanisms. A comprehensive literature search was performed using NCBI's PubMed database and standardized search terms. Thirteen cases of COVID-19-related parkinsonism were included (7 males; mean age: 51 years ± 14.51, range 31-73). Patients were classified based on the possible mechanisms of post-COVID-19 parkinsonism: extensive inflammation or hypoxic brain injury within the context of encephalopathy (n = 5); unmasking of underlying still non-symptomatic Parkinson's Disease (PD) (n = 5), and structural and functional basal ganglia damage (n = 3). The various clinical scenarios show different outcomes and responses to dopaminergic treatment. Different mechanisms may play a role, including vascular damage, neuroinflammation, SARS-CoV-2 neuroinvasive potential, and the impact of SARS-CoV-2 on α-synuclein. Our results confirm that the appearance of parkinsonism during or immediately after COVID-19 infection represents a very rare event. Future long-term observational studies are needed to evaluate the possible role of SARS-CoV-2 infection as a trigger for the development of PD in the long term.

COVID-19: The cynosure of rise of Parkinson's disease.

Parkinson's disease (PD) is one of the most common age-related disorders globally. The pathophysiological mechanisms and precipitating factors underlying PD manifestations, including genetic and environmental parameters, inflammation/stress and ageing, remain elusive. Speculations about whether the Coronavirus Disease 2019 (Covid-19) pandemic could be a pivotal factor in affecting the prevalence and severity of PD or triggering a wave of new-onset parkinsonism in both the near and distant future have recently become very popular, with researchers wondering if there is a changing trend in current parkinsonism cases. Could the current understanding of the Covid-19 pathophysiology provide clues for an impending rise of parkinsonism cases in the future? Are there any lessons to learn from previous pandemics? Our aim was to look into these questions and available current literature in order to investigate if Covid-19 could constitute a cardinal event affecting the parkinsonism landscape.

COVID-19 Infection Enhances Susceptibility to Oxidative Stress-Induced Parkinsonism.

BACKGROUND: Viral induction of neurological syndromes has been a concern since parkinsonian-like features were observed in patients diagnosed with encephalitis lethargica subsequent to the 1918 influenza pandemic. Given the similarities in the systemic responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with those observed after pandemic influenza, there is a question whether a similar syndrome of postencephalic parkinsonism could follow coronavirus disease 2019 infection. OBJECTIVE: The goal of this study was to determine whether prior infection with SARS-CoV-2 increased sensitivity to a mitochondrial toxin known to induce parkinsonism. METHODS: K18-hACE2 mice were infected with SARS-CoV-2 to induce mild-to-moderate disease. After 38 days of recovery, mice were administered a non-lesion-inducing dose of the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and euthanized 7 days later. Subsequent neuroinflammation and substantia nigra pars compacta (SNpc) dopaminergic (DA) neuron loss were determined and compared with SARS-CoV-2 or MPTP alone. RESULTS: K18-hACE2 mice infected with SARS-CoV-2 or MPTP showed no SNpc DA neuron loss after MPTP. In mice infected and recovered from SARS-CoV-2 infection, MPTP induced a 23% or 19% greater loss of SNpc DA neurons than SARS-CoV-2 or MPTP, respectively (P < 0.05). Examination of microglial activation showed a significant increase in the number of activated microglia in both the SNpc and striatum of the SARS-CoV-2 + MPTP group compared with SARS-CoV-2 or MPTP alone. CONCLUSIONS: Our observations have important implications for long-term public health, given the number of people who have survived SARS-CoV-2 infection, as well as for future public policy regarding infection mitigation. However, it will be critical to determine whether other agents known to increase risk for PD also have synergistic effects with SARS-CoV-2 and are abrogated by vaccination. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Molecular Imaging Findings on Acute and Long-Term Effects of COVID-19 on the Brain: A Systematic Review.

Molecular imaging techniques such as PET and SPECT have been used to shed light on how coronavirus disease 2019 (COVID-19) affects the human brain. We provide a systematic review that summarizes the current literature according to 5 predominant topics. First, a few case reports have suggested reversible cortical and subcortical metabolic alterations in rare cases with concomitant para- or postinfectious encephalitis. Second, imaging findings in single patients with the first manifestations of parkinsonism in the context of COVID-19 resemble those in neurodegenerative parkinsonism (loss of nigrostriatal integrity), but scarceness of data and a lack of follow-up preclude further etiologic conclusions (e.g., unmasking/hastening of neurodegeneration vs. infectious or parainfectious parkinsonism). Third, several case reports and a few systematic studies have addressed focal symptoms and lesions, most notably hyposmia. The results have been variable, although some studies found regional hypometabolism of regions related to olfaction (e.g., orbitofrontal and mesiotemporal). Fourth, a case series and systematic studies in inpatients with COVID-19-related encephalopathy (acute to subacute stage) consistently found a frontoparietal-dominant neocortical dysfunction (on imaging and clinically) that proved to be grossly reversible in most cases until 6 mo. Fifth, studies on post-COVID-19 syndrome have provided controversial results. In patients with a high level of self-reported complaints (e.g., fatigue, memory impairment, hyposmia, and dyspnea), some authors found extensive areas of limbic and subcortical hypometabolism, whereas others found no metabolic alterations on PET and only minor cognitive impairments (if any) on neuropsychologic assessment. Furthermore, we provide a critical appraisal of studies with regard to frequent methodologic issues and current pathophysiologic concepts. Finally, we devised possible applications of PET and SPECT in the clinical work-up of diagnostic questions related to COVID-19.

COVID-19 infection enhances susceptibility to oxidative-stress induced parkinsonism (preprint)

Background: Viral induction of neurological syndromes has been a concern since parkinsonian-like features were observed in patients diagnosed with encephalitis lethargica subsequent to the 1918 influenza pandemic. Given the similarities in the systemic responses following SARS-CoV-2 infection with those observed after pandemic influenza, there is a question if a similar syndrome of post-encephalic parkinsonism could follow COVID-19 infection. Objectives: To determine if prior infection with SARS-CoV-2 increased sensitivity to a mitochondrial toxin known to induce parkinsonism. Methods: hACE2 mice were infected with SARS-CoV-2 to induce mild to moderate disease. After 31 days recovery, mice were administered a non-lesion inducing dose of the parkinsonian toxin MPTP. Subsequent neuroinflammation and SNpc dopaminergic neuron loss was determined and compared to SARS-CoV-2 or MPTP alone. Results: hACE2 mice infected with SARS-CoV-2 or MPTP showed no SNpc DA neuron loss following MPTP. In mice infected and recovered from SARS-CoV-2 infection, MPTP induced a 23% or 19% greater loss of SNpc dopaminergic neurons than SARS-CoV-2 or MPTP, respectively (p < 0.05). Examination of microglial activation showed a significant increase in the number of activated microglia in the SARS-CoV-2 + MPTP group compared to SARS-CoV-2 or MPTP alone. Conclusions: Our observations have important implications for long-term public health, given the number of people that have survived SARS-CoV-2 infection as well as for future public policy regarding infection mitigation. However, it will be critical to determine if other agents known to increase risk of PD also have synergistic effects with SARS-CoV-2 and if are abrogated by vaccination.

Parkinsonism in viral, paraneoplastic, and autoimmune diseases.

Secondary parkinsonism, namely parkinsonism due to causes other than idiopathic neurodegeneration, may have multiple etiologies. Common secondary etiologies of parkinsonism such as drug-induced or vascular etiologies are well documented. Other secondary causes of parkinsonism such as infectious (mainly viral and prion-like diseases), autoimmune (systemic/drug-induced) and paraneoplastic etiologies are rare but are a topic of increasing interest. Older examples from the existing literature demonstrate the intricacies of viral infection from the last pandemic of the 20th century on the development of hypokinetic symptoms experienced in post-encephalitic patients. Viral and prion-like infections are only part of a complex interplay between the body's immune response and aberrant cell cycle perturbations leading to malignancy. In addition to the classic systemic autoimmune diseases (mainly systemic lupus erythematosus - SLE, and Sjögren syndrome), there have been new developments in the context of the current COVID-19 pandemic as well as more prominent use of immunotherapies such as immune checkpoint inhibitors in the treatment of solid tumors. Both of these developments have deepened our understanding of the underlying pathophysiologic process. Increased awareness and understanding of these rarer etiologies of parkinsonism is crucial to the modern diagnostic evaluation of a patient with parkinsonian symptoms as the potential treatment options may differ from the conventional levodopa-based therapeutic regimen of idiopathic Parkinson's disease. This review article aims to give an up-to-date review of the current literature on parkinsonian symptoms, their pathogenesis, diagnostic methods, and available treatment options. Many potential future directions in the field of parkinsonian conditions remain to be explored. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna.

Exercise Management Using a Mobile App in Patients With Parkinsonism: Prospective, Open-Label, Single-Arm Pilot Study.

BACKGROUND: Patients with parkinsonism have higher inactivity levels than the general population, and this results in increased comorbidities. Although exercise has benefits for motor function and quality of life (QOL) in patients with parkinsonism, these patients face many barriers to exercise participation, such as lack of motivation, fatigue, depression, and time constraints. Recently, the use of mobile apps has been highlighted as a remote exercise management strategy for patients with chronic diseases. OBJECTIVE: This study aimed to evaluate the effects of home-based exercise management with a customized mobile app on the exercise amount, physical activity, and QOL of patients with parkinsonism. METHODS: This was a prospective, open-label, single-arm pilot study. The therapist installed the app in the smartphones of the participants and educated them on how to use the app. The therapist developed an individualized multimodal exercise program that consisted of stretching, strengthening, aerobic, balance and coordination, and oral-motor and vocal exercises. Participants were encouraged to engage in an 8-week home-based exercise program delivered through a customized app. The alarm notifications of the app provided reminders to exercise regularly at home. The primary outcome was the exercise amount. The secondary outcomes were assessed using the International Physical Activity Questionnaire (IPAQ), Parkinson's Disease Questionnaire-39 (PDQ-39), and Geriatric Depression Scale (GDS). The usability of the customized app was assessed using a self-report questionnaire. RESULTS: A total of 21 participants with parkinsonism completed the intervention and assessment between September and December 2020 (mean age: 72 years; women: 17/21, 81%; men: 4/21, 19%). The participants reported a significant increase in the total amount of exercise (baseline: mean 343.33, SD 206.70 min/week; 8-week follow-up: mean 693.10, SD 373.45 min/week; P<.001) and in the amount of each exercise component, including stretching, strengthening, balance and coordination, and oral-motor and vocal exercise after 8 weeks. Analysis of the secondary outcomes revealed significant improvements in the IPAQ (P=.006), PDQ-39 (P=.02), and GDS (P=.04) scores. The usability of the program with the mobile app was verified based on the positive responses such as "intention to use" and "role expectation for rehabilitation." CONCLUSIONS: Exercise management with a customized mobile app may be beneficial for improving exercise adherence, physical activity levels, depression management, and QOL in patients with parkinsonism. This remotely supervised technology-based, reinforcing, and multimodal exercise management strategy is recommended for use in patients with parkinsonism. In addition, this program proved useful as an alternative exercise management strategy during the COVID-19 pandemic when patients with Parkinson disease were less physically active than before and showed aggravation of symptoms. However, additional clinical trials are needed to evaluate the efficacy of this exercise program in a large population and to confirm its disease-modifying effects.

The impact of SARS-COV2 infection on people in residential care with Parkinson Disease or parkinsonisms: Clinical case series study.

On March 2019 the World Health Organization declared Coronavirus disease (COVID-19) pandemic. Several recent reports disclose that the outcome of the infection is related to age, sex and can be influenced by underlying clinical conditions. Parkinson's disease (PD) and other parkinsonisms are the most common chronic disease which can cause, directly or indirectly, the patient to be more exposed to other diseases, mostly respiratory system's ones. Our primary outcome is to evaluate if PD patients are more susceptible than non-PD to take COVID-19 infection. Second, to detect if the infection course is worse in PD-COVID+ patients versus non-PD. This is a retrospective observational study on a cohort of 18 patients (13 PD- 5 non-PD), hospitalized in a Rehabilitative Unit during the occurrence of SARS-CoV2 epidemic outbreak. All patients performed laboratory tests, lung Computed Tomography (CT) and have been tested for COVID-19 thorough pharyngeal swab. PD and non-PD groups were comparable for age, gender and Hoehn and Yahr stage. Seventy-seven (77)% of PD and 60% of non-PD resulted positive for COVID-19. PD-COVID+ and PD-COVID- did not differ for age, disease duration and L-dopa daily dose. PD COVID-19+ subjects were mainly asymptomatic (50%) while non-PD ones were all symptomatic, mostly with respiratory difficulties. PD doesn't seem to be a risk factor to take SARS-COV2 infection, even if our study is related to a limited sample size. Our results, together with those of other recent studies, highlight the need to evaluate the actual susceptibility of patients with Parkinson's disease to develop COVID-19 disease, and how the infection may influence the risk of clinical worsening and increase of mortality.

SARS-CoV-2-related encephalitis with prominent parkinsonism: clinical and FDG-PET correlates in two patients.

Considering the similarities with other pandemics due to respiratory virus infections and subsequent development of neurological disorders (e.g. encephalitis lethargica after the 1918 influenza), there is growing concern about a possible new wave of neurological complications following the worldwide spread of SARS-CoV-2. However, data on COVID-19-related encephalitis and movement disorders are still limited. Herein, we describe the clinical and neuroimaging (FDG-PET/CT, MRI and DaT-SPECT) findings of two patients with COVID-19-related encephalopathy who developed prominent parkinsonism. None of the patients had previous history of parkinsonian signs/symptoms, and none had prodromal features of Parkinson's disease (hyposmia or RBD). Both developed a rapidly progressive form of atypical parkinsonism along with distinctive features suggestive of encephalitis. A possible immune-mediated etiology was suggested in Patient 2 by the presence of CSF-restricted oligoclonal bands, but none of the patients responded favorably to immunotherapy. Interestingly, FDG-PET/CT findings were similar in both cases and reminiscent of those observed in post-encephalitic parkinsonism, with cortical hypo-metabolism associated with hyper-metabolism in the brainstem, mesial temporal lobes, and basal ganglia. Patient's FDG-PET/CT findings were validated by performing a Statistical Parametric Mapping analysis and comparing the results with a cohort of healthy controls (n = 48). Cerebrum cortical thickness map was obtained in Patient 1 from MRI examinations to evaluate the structural correlates of the metabolic alterations detected with FDG-PET/CT. Hypermetabolic areas correlated with brain regions showing increased cortical thickness, suggesting their involvement during the inflammatory process. Overall, these observations suggest that SARS-CoV-2 infection may trigger an encephalitis with prominent parkinsonism and distinctive brain metabolic alterations.