Collection of Articles on COVID-19 and Movement Disorders

Background: The Parkinson's disease (PD) patient population, with an already reduced life expectancy, is rendered particularly vulnerable by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).  

Objectives: We determined the risk factors that increase the risk of death in patients with Parkinson's disease who are infected by SARS-CoV-2.  

Methods: Patients with a diagnosis of PD admitted to Montefiore Hospital (Bronx, New York) and tested for SARS-CoV-2 were identified. Retrospective review of electronic medical records confirmed the diagnosis; patients were classified by severity of PD. PD severity, demographic, socioeconomic factors, and co-morbidities were correlated with mortality rates in patients with SARS-CoV-2.  

Results: We identified 162 patients meeting criteria; chart review confirmed a diagnosis of PD in 70 patients. Of the 70 patients, 53 were positive for SARS-CoV-2 and 17 were negative. PD patients with SARS-CoV-2 infection had a higher mortality rate (35.8%) compared to PD patients without the infection (5.9%, P = 0.028). PD patients older than 70 years of age, those with advanced Parkinson's disease, those with reductions in their medications, and non-Hispanics (largely comprised of Black/African- Americans) had a statistically significant higher mortality rate, if infected.  

Conclusions: PD did not increase mortality rates from SARS-CoV-2 infection when age was controlled. However, certain unalterable factors (advanced disease and age greater than 70 years) and alterable ones (reductions in PD medications) placed PD patients at increased risk for mortality. Also several socioeconomic factors contributed to mortality, for example, non-Hispanic patients with SARS-CoV-2 infection fared worse, likely driven by poorer outcomes in the Black/African-American cohort.

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The authors provide a systematic review and meta-analysis to review the impact of PD on the prognosis of Covid-19 patients, including 13 papers. They found a pooled prevalence rate of Covid-19 of 2.12% (95%CI: 0.75-5.98). Fever, cough, fatigue and anorexia were the most common symptoms with a rate of 72.72% (95% CI: 57.3 - 92.29), 66.99% (95% CI: 49.08-91.42), 61.58% (95% CI: 46.69-81.21) and 52.55% (95% CI: 35.09-78.68), respectively. The pooled rates were 39.89% (95% CI: 27.09-58.73) for hospitalisation, 4.7% (95% CI: 1.56-14.16) for ICU admission and 25.1% (95%CI: 16.37-38.49) for mortality. Overall, there were no significant differences in hospitalisation and mortality rates among Covid-19 patients with and without PD. The authors conclude that the prevalence and prognosis of Covid-19 patients seem comparable in patients with PD and those without it.
 

The authors review the state of the art about the relationship between Covid-19 and Parkinson's disease, focusing on five points: 1) Covid-19's impact on Parkinson's disease (PD) based on their health and their risk of developing severe Covid-19; 2) the consequences of lockdown and restrictive measures on mental and cognitive health on both patients and caregivers; 3) patients' care and management; 4) the importance of continuity of exercise; and 5) potential causative links in that COVID may trigger parkinsonism.
 

A standardized investigatation of the consequences of the first COVID-19 lockdown (mid-March - mid-April 2020) on motor and non-motor symptoms (NMS) including psycho-social aspects in a cohort of French people with Parkinson's disease (PwP).

2653 PD patients were included, enrolled through a patient community or as part of a hospital based PD Expert Center. The authors report that physiotherapy was interrupted among 88.6% of the patients. 40.9% referred a clinical modification of their symptoms. Pain (9.3%), rigidity (9.1%) and tremor (8.5%) were the most frequently new or worsened reported symptoms. The authors conclude that the COVID-19 lockdown had a negative impact on motor and NMS of PwP and that efforts should be allocated to avoid interruption of care, including physiotherapy and physical activities and implementation of telemedicine.
 

An investigation of sensor-derived physical activity measured over 7 days using the Actigraph GT3x accelerometer and perceived health of people with PD during the first wave of the COVID-19 pandemic, as well as the factors associated with these outcomes in 89 participants.

Overall, this Swedish patient cohort was relatively physically active. However, women were less active at moderate-vigorous levels and were at greater risk of deterioration in perceived health during this time. To elaborate: The majority (67%, women more than men) reported a pandemic-related reduction in exercise habits. A pandemic-induced deterioration in health was reported by 42%, women being 5 times more likely than men to do so.
 

A review to explore the risk of COVID-19 in PD based on the susceptibility to severe disease, its impact on PD disease severity, potential long-term sequelae, and difficulties of PD management during this outbreak, where neurologists face various challenges on how to maintain effective care for PD patients without exposing them, or physicians, to the risk of infection.
 

A study to explore the effects of prolongation of lockdown in a sample of 100 PD patients. The authors found that patients faced a significantly increased number of problems due to this pandemic, specifically, the inability to access health care and difficulty procuring medication. Patients also reported worsening of motor symptoms.
 

Increasing evidence suggests an involvement of oxidative stress and contribution of NFκB in the development of both COVID-19 and PD. Although it is early to identify if SARS-CoV-2 led infection enhances PD complications, it is likely that oxidative stress may exacerbate PD progression in COVID-19 affected individuals and/or vice versa.

Using bioinformatics analysis, the authors investigate whether NFκB-associated inflammatory pathways following oxidative stress in SARS-CoV-2 and PD patients are correlated by searching for similarities of SARS-CoV-2 proteins against human proteome. In addition, a human cell model of PD was created in 6-hydroxydopamine (6OHDA)-induced differentiated dopamine-containing neurons (dDCNs) obtained from an immortalized human neural progenitor cell line derived from the ventral mesencephalon region of the brain (ReNVM). The authors find that SARS-CoV-2 infection and 6OHDA-induced toxicity triggered stimulation of caspases-2, -3 and -8 via the NFκB pathway, resulting in the death of dDCNs. Specific inhibitors for NFκB and certain caspases reduced the death of stressed dDCNs. Selective inhibition of caspases and NFκB activation may contribute to the development of potential therapeutic approaches for the treatment of COVID-19 and PD.
 

The description of the possible cellular and molecular mechanisms underlying the development of acute parkinsonism following coronavirus disease 2019 (COVID-19) and whether COVID-19 might be associated with elevated long-term risk of PD are discussed.
 

An early viewpoint discussing insights from basic science and clinical perspectives of brain COVID-19. The authors interpret neuropathology studies and discuss the role of ACE2 expression in healthy and infected brains.
 

A review article discussing the neurotropic potential of SARS-CoV-2 and its possible involvement in the pathogenesis of PD. Specifically, the involvement of the toll-like receptor 4 (TLR4) signaling pathway and the possible interaction between SARS-CoV-2 and α-SYN are explored.
 

The authors discuss how far COVID-19 may accelerate neurodegeneration in patients with neurodegenerative disease.
 

Given the clinical overlap between COVID-19 and PD (e.g. hyposmia), the authors highlight the importance of monitoring convalescent individuals for potential long-term implications that may include neurodegenerative sequelae such as viral-associated parkinsonism. They call for a strategized health policy to ensure healthcare systems all over the world are prepared for a third wave of the virus in the form of parkinsonism.
 

The authors discuss neurotropic properties and longevity of coronaviruses, with some selectively targeting the basal ganglia. The authors discuss that coronavirus is detected in brain autopsies and in CSF of affected patients and the role of marked inflammatory responses.
 

A systematic search on previous viral epidemics regarding cognitive difficulties following the infection. The authors discuss how coronavirus infections may increase the probability of post-infection memory impairment, and acceleration of neurodegenerative disorders such as Alzheimer's disease.
 

An investigation of the links between neurodegeneration and COVID-19. Primary health records of 13,338 UK individuals tested for COVID-19 between March and July 2020 were analyzed. While a pre-existing diagnosis of Alzheimer's disease predicted the highest risk of COVID-19 and mortality among elderly individuals, Parkinson's disease was also associated with a higher risk of SARS-CoV-2 infection but not mortality from COVID-19. The authors conclude that there are disease-specific differences in COVID-19 susceptibility among patients affected by neurodegenerative disorders.
 

The authors surveyed PD patients with self-reported COVID-19 for COVID-19 symptoms, general clinical outcomes and changes in motor and non-motor PD symptoms. In this cohort of 46, PD with COVID-19 manifestations of COVID-19 were similar to the general population, ranging from asymptomatic carriers (1/46) to death (6/46). The most common COVID-19 symptoms were fever/chills, fatigue, cough, weight loss, and muscle pain. Participants reported worsening and new onset of motor and non-motor PD symptoms during COVID-19 illness, including dyskinesia, rigidity, balance disturbances, anxiety, depression and insomnia.
 

This study investigated the genetic impact or mechanisms that may induce Parkinsonism in COVID-19 patients or after COVID-19 by looking for commonly dysregulated genes, transcriptional regulators, and pathways between PD and COVID-19. The authors integrated genome-wide transcriptomic datasets from peripheral blood mononuclear cells (PBMC) samples from COVID-19 and PD and associated pathways. They found 81 upregulated and 48 downregulated differentially expressed genes (DEGs) shared between PD and COVID-19, which were involved in key pathways "mitochondrion structure organization," "cell activation in immune response," and "signaling by interleukins." Specifically, RELA, TP53 and SP1 TFs were identified that may regulate the upregulated DEGs.
 

The authors report clinical findings in a cohort of 117 community-dwelling PD patients with COVID-19 followed in 21 tertiary centers in Italy, Iran, Spain and the UK. Overall mortality was 19.7%, with a significant effect of co-occurrence of dementia, hypertension and PD duration.
 

Multicenter case series to assess risk factors for and outcomes after myoclonus in a cohort of eight patients with coronavirus disease in 2019 from Massachusetts, Georgia, and Virginia.

The authors found that the outcomes in patients with myoclonus were variable. One patient died. Five were cognitively intact and without focal neurologic deficits. In five cases, the myoclonus completely resolved within 2 days of onset. In three cases, it persisted for 10 days or longer. Significant metabolic derangements, hypoxemia, or exposure to sedating medications that may have contributed to the development of myoclonus was observed in seven patients. One patient developed encephalopathy with prolonged myoclonus in the absence of clear systemic provoking factors. Thus, myoclonus may be observed in severe acute respiratory syndrome coronavirus 2 infected patients, even in the absence of hypoxia.

 

The relationship between perceived levels of stress, changes in physical activity levels and PD motor symptoms (i.e. self-reported changes in PD motor symptoms and physical activity duration and intensity) during lockdown compared to before was assessed in 49 PD patients in New Zealand. Perceived stress was higher in PD than controls, and in those reporting a worsening of tremor, balance/gait, dyskinesia and bradykinesia compared to those indicating no change during the COVID-19 lockdown. Physical activity did not have a beneficial effect.

The authors recommend reducing stressors s important adjunct treatment strategy to improve motor function in PD.
 

The authors evaluated the motor, cognitive, and behavioral changes in Italian PD patients with and without mild cognitive impairment (PD-MCI and PD-NC) and in patients with MCI not associated with PD (MCInoPD) during the COVID-19 lockdown.

In total, 34 patients with PD-NC, 31 PD-MCI, and 31 MCInoPD and their caregivers were interviewed 10 weeks after the COVID-19 lockdown in Italy, using the Neuropsychiatric Inventory (NPI) and MDS-UPDRS, parts I and II, to detect changes in cognitive, behavioral, and motor symptoms. The authors found that all groups showed worsening of cognitive (39.6%), pre-existing (37.5%), and new (26%) behavioral symptoms, and motor symptoms (35.4%) during the lockdown, resulting in an increased caregiver burden in 26% of cases. Compared to PD-NC, PD-MCI was significantly and positively associated with the IADL lost during quarantine. PD-MCI, compared to MCInoPD, had significant worsening of motor symptoms. PD-MCI showed a significantly higher frequency of cognitive impairment, fatigue, and speech than PD-NC. On the contrary, PD-MCI showed significantly higher frequencies in several MDS-UPDRS items compared to MCInoPD.

A review on the direct and indirect associations between COVID-19 and PD patient care.

The authors discuss potential direct effects of COVID-19 including possible neurodegeneration, concerns of symptom self-management with over-the-counter (OTC) products and ICU challenges that can arise in PD patients. The social distancing measures and disruptions in health care systems and PD clinical trials have an indirect effects resulting in negative decreased mental wellbeing of PD patients.

On a more positive note, telemedical care is quickly emerging as a primary communication tool for virtual patient care.

Due to the pandemic elective procedures and non-urgent clinic visits have been postponed in many hospitals. This poses a challenge for DBS patients. This includes the case of the battery reaching end of life with the risk of interruption of therapy which is associated with rare but potentially life-threatening complications known as DBS-withdrawal syndrome. This may clinically manifest with status dystonicus in patients with generalized dystonia, patients with obsessive compulsive disorder can become suicidal, and epilepsy patients can experience potentially life-threatening worsening of seizures. Likewise, DBS system infection can require urgent, and rarely emergent surgery.

The authors recommend that elective interventions including new implantations and initial programming should be postponed. However, for patients with existing DBS systems, the battery status and electrical integrity interrogation can now be performed using patient programmers, and employed through telemedicine visits or by phone consultations. The decision for replacement of the implantable pulse generator to prevent interruption of DBS therapy should be made on a case-by-case basis taking into consideration battery status and a patient's tolerance to potential therapy disruption.
 

A study to assess the feasibility of smartphone remote patient monitoring in a real-life cohort including 54 PD patients during the Italian COVID-19 lockdown.

All patients used a smartphone application capable of providing indicators of gait, tapping, tremor, memory and executive functions, measured at least twice per week (i.e., full compliance). Non-motor symptoms and quality of life were assessed by phone using standardised questionnaires.

The authors found that forty-five patients (83.3%) ran the app at least once; Twenty-nine (53.7%) subjects were half-compliant, while 16 (29.6%) were fully compliant and satisfied by the provided monitoring program. Compliance was reduced by technical issues or digital illiteracy (38.7%), demotivation (24%) and health-related issues (7.4%). Ten patients (18.5%) had therapy changes for their PD medication.

The authors implemented a single cohort study of a coaching intervention grounded in self-determination theory and adapted to telehealth delivery, (called Engage-PD) conducted at Columbia University Parkinson's Foundation Center of Excellence in New York City, NY (USA), the early epicenter of the COVID-19 pandemic in the United States. The aim was to address an immediate need for support and guidance in the home environment, including people with early-mid-stage PD, delivered via a telehealth platform. Participants completed baseline and follow-up (3 months) assessments and participated in up to 4 coaching sessions. The intervention incorporated 1:1 coaching, goal-setting, physical activity monitoring, and use of a disease-specific workbook to promote and support safe exercise uptake.

27 individuals with PD enrolled in the first 2 months of the pandemic for a recruitment rate of 52%, with the program ongoing. The recruitment rate was larger than expected.