Vulnerability of Parkinson's Patients to COVID-19 and Its Consequences and Effects on Them: A Systematic Review

Introduction Parkinson's disease (PD) is the second most common neurological disorder. Patients with PD were affected by the COVID-19 pandemic in many different ways. This study's principal purpose is to assess PD patients' vulnerability to COVID-19 and its consequences. Method This systematic review was performed based on Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines. A thorough search was conducted in the Medline (through PubMed) and Scopus databases from inception to January 30, 2022. The Joanna Briggs Institute (JBI) critical appraisal checklist was used to evaluate the studies. Results Most of the studies (38%) had been conducted in Italy. Of the total number of studies, 17 (58%) were cross-sectional, seven (22%) were cohort, four (12%) were quasiexperimental, two (6%) were case-control, and one (3%) was a qualitative study. The PD duration in patients ranged from 3.26 to 13.40 years (IQR1: 5.7 yrs., median: 3.688 yrs., and IQR3: 8.815 yrs.). Meanwhile, the sample size ranged from 12 to 30872 participants (IQR1: 46, median: 96, and IQR3: 211). Despite worsening PD symptoms in the targeted population (persons with COVID-19 and Parkinson's disease), some studies found PD to be a risk factor for more severe COVID-19 disease. There are many adverse effects during the pandemic period in PD patients such as abnormalities of motor, nonmotor functioning, clinical outcomes, activities of daily living, and other outcomes. Conclusion This study confirmed the negative effect of the COVID-19 pandemic on health-related quality of life and its determinants in patients with PD and their caregivers. Thus, due to the worsening symptoms of PD patients in the current pandemic, these people should be given more care and supervision to minimize their coronavirus exposure.


Introduction
Parkinson's disease (PD) is the second most common neurological disorder. Patients with PD were afected by the COVID-19 pandemic in many diferent ways. Although the exact cause of PD is unknown, many researchers believe that factors such as genetics and environment lead to the gradual degeneration of neurons in sensitive areas of the brain and the development of PD [1]. PD afects 1 to 2 out of every 1,000 people in the population. Its prevalence increases with age and afects 1% of the population over the age of 60 [2]. From 1990 to 2019, the global and regional burden of Parkinson's disease increased. PD has had the most rapid growth in incidence and disability among neurological disorders in recent years, becoming one of the most signifcant causes of disability worldwide [3].
Te continuation of the COVID-19 pandemic has raised numerous concerns about the increasing vulnerability of people with chronic diseases, especially neurological diseases [4]. COVID-19 can afect patients with a pre-existing neurological disorder, whether acquired or inherited. Tis efect is one of the signifcant issues facing neurologists in recent months. Also, concerns have been raised in long-term care centers about the vulnerability of PD patients to . Tis is also true for most neurological diseases, which means that patients sufering from a debilitating neurological disorder are at greater risk of other diseases, especially COVID-19. But there is still not enough data to confrm this claim [5].
As a risk factor, PD can negatively afect the prognosis in cases of COVID-19. COVID-19 causes pharmacodynamic changes, such as the interaction between dopaminergic and renin-angiotensin systems in the striatum and systemic infammation responses in PD patients, leading to the worsening of PD and exacerbation of symptoms. Also, factors such as disease-related weakness and aging may make these patients weaker than others in society. Antonini and colleagues stated that patients with PD would have a higher mortality rate if they developed COVID-19 [6]. Stress, anxiety, depression, and social isolation can also have devastating efects on PD symptoms, leading to the worsening of the disease [7]. Symptoms of the exacerbated disease include impaired motor function, an increased need for daily doses of levodopa, fatigue, cognitive impairment, and sleep disturbances. Nevertheless, the evidence for the efect of COVID-19 outcomes in patients with PD is not yet conclusive, and currently, PD and additional motion disorders have not been recognized as risk factors for COVID-19 [7].
Given that PD is a common neurological disorder in developed and developing societies, preventing the exacerbation of symptoms and declining quality of life is one of the most critical actions that policymakers should consider. In the current context of the COVID-19 pandemic worldwide, some studies have suggested that the physical and cognitive symptoms of PD patients have worsened because the current pandemic has prevented them from continuing their rehabilitation programs as usual [8][9][10][11]. Some studies have also suggested that COVID-19 disease has a more devastating efect on PD patients, leading to the worsening of vital signs compared to other patients [4,[12][13][14]. All these statements have been stated in recent studies, but for a more detailed review and evaluation of its various dimensions, a comprehensive and more detailed review is needed. So, it needs to be clarifed precisely whether the COVID-19 pandemic has afected PD patients or not. By knowing the extent of COVID-19's impact and consequences, we can think of appropriate solutions to prevent such efects, reduce harm, and ultimately improve patients' health. Terefore, there is a need for a comprehensive systematic review to investigate the impact of the COVID-19 pandemic on PD patients. Tis systematic review endeavors to answer the following questions: RQ1: what are the symptoms and consequences of PD that may be exacerbated by COVID- 19? RQ2: what are the efects and consequences of the COVID-19 pandemic for PD patients?

Research Problems and
Objectives. According to our overview, several studies have examined the efects of the COVID-19 pandemic on PD patients. In most cases, studies have shown that the COVID-19 pandemic either directly through the individual's illness or indirectly through lifestyle changes and quarantine problems has caused various problems for PD patients. Nevertheless, the efects of COVID-19 on PD patients have not yet been defnitively examined in any comprehensive study. Te COVID-19 pandemic has disrupted PD-related care, including medical care, exercise, and social activities. Some medical centers, even Parkinson's clinics, have closed their services due to the pandemic. Impaired medical care can lead to irregular hospital visits and more problems with PD medications because they require a prescription, which may force PD patients to reduce or discontinue their medications. It can also worsen the symptoms of PD, which increases the mortality rate of PD patients. It also has more devastating efects on their condition if they are infected with COVID-19. Te principal purpose of this study is to assess the vulnerability of PD patients to the COVID-19 pandemic and its consequences. Te purpose of this study is to (1) consider the extent of change in signs and symptoms of PD due to COVID-19 (direct impact of COVID-19); (2) examine the various consequences of COVID-19 lockdown on patients with PD (the indirect efect of COVID-19).

Methods
Te current study is a systematic review. Te study protocol was written together with the research team. In this protocol, the study method was designed in six steps. Te frst step was to determine the inclusion and exclusion criteria. Te second step was designing the search strategy. Te third step was to select the studies that ft the purpose of the research, and the next step was to collect and extract the relevant data from the included studies. Te assessment of the studies and the synthesis of the results were the two fnal steps, which are all explained in detail in the following. Also, this systematic review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) proposed by Zhang et al. [15].

Eligibility Criteria
PICO is a useful tool for conducting qualitative reviews and asking focused clinical questions. A reliable and comprehensive query should have four components that recognize the patient problem or population (P), the intervention (I), the comparison (C), and the outcome (O). According to the PICO tool, the inclusion criteria in this systematic review include the following:

Study Selection.
Te selection process was performed in two stages. In the frst stage, two reviewers (SR and MR) independently fltered the titles and abstracts of the retrieved citations. At this stage, articles that did not meet the inclusion criteria were removed. In the second stage, the full text of the articles was retrieved and reviewed and two reviewers confrmed their relevance. In the event of disagreement, the third and fourth reviewers (LS and MN) were consulted to solve the problem through a consensus method. In Figure 1, the screening process is depicted by the 2020 PRISMA checklist.

Data Collection Process and Data
Items. Two reviewers (SR and MR) collected the required information from the chosen examinations. Te accuracy of the accumulated information was verifed by a reviewer (LS). In the last phase, a third reviewer (MN) assessed and solved any conficts. Te main features of the included papers that were mined and synthesized were entered into a structured form in Excel. In Figure 2, the characteristics of chosen articles are depicted.

Study Risk of Bias Assessment. Te Joanna Briggs
Institute (JBI) critical appraisal checklist can be used for assessing all types of studies' methodological conduct or reporting. Tis tool has eight questions, which can be answered with four choices: 1: yes; 2: no; 3: unclear; and 4: not applicable. Each "yes" answer obtains one score, and if 70% of the questions are responded with "yes" in research, the risk of bias is considered "low." Also, if 50% to 69% of them are answered yes, the risk of bias is "moderate," and fnally, if less than 50% of the questions responded "yes," the risk of bias is considered as "high" [16]. Two authors (SR and MR) completed this checklist, and in the event of a controversy between the two authors, the disagreement was resolved via discussion with the third and fourth referees (LS and MN).
2.6. Synthesis of Results. Meta-analysis was not used in this systematic review, as the methods and methodology of reporting results in chosen papers were heterogeneous.

Results of the Search.
A total of 1117 articles were found in the initial search, and after removing duplicates, 736 papers were left. Authors mined the title, abstract, and keywords of selected articles, so 96 articles were identifed for further review. After viewing the full text of these articles and focusing on our objectives, 31 papers were included in this review. Given that the purpose of this systematic review was to examine the vulnerability of PD patients to COVID-19, the key results and characteristics are presented in three Tables (Tables 2-4). In Table 2, the study group consisted of PD patients who sufered from various injuries. In Table 3, the study group is PD patients who have COVID-19, and the consequences of the disease for them have been studied. In Table 4, the target group is both PD patients (without COVID-19) and PD patients with COVID-19 in a combined form.

Quality Assessment of the Included Papers.
Various studies with diferent designs were entered into this systematic review, and they were evaluated with an appropriate scale. Te Joanna Briggs Institute Critical Appraisal (JBI) checklists were used for assessing cross-sectional, casecontrol, cohort, quasiexperimental, and qualitative studies. As we can see in Figure 3, twenty-one studies were considered to have a low risk of bias and ten were considered to have a moderate risk of bias.

Distribution of Papers by Published Year/Month and by
Teir Conducted Countries. Te fnal distribution of papers indicates that 31 academic citations met the inclusion criteria. As can be seen in Figure 4, the largest number of studies was published in 2021. Most of the papers (38.70%) were conducted in Italy ( Figure 5).

Distribution of Academic Papers by Journals, Quartile
Scores, Impact Factors (IF), and Publisher. Reviewed scientifc papers (n � 31) were retrieved from 18 journals. Te impact factor (IF) and quartile scores of the journals are presented in Table 5. It is worth noting that seven of the eighteen journals (38.88%) are ranked in the frst quarter. As our analysis showed, Springer had the frst rank (28.57%) among the publishers.

General Characteristics of the Included Papers.
Of the total number of studies, 17 (58%) were cross-sectional, seven (22%) were cohort, four (12%) were quasiexperimental, two (6%) were case-control, and one (3%) was qualitative. In eighteen studies (58%), the study population was PD patients who had been afected by pandemic conditions (PD patients without . Furthermore, in eleven papers, PD patients infected with COVID-19 were the study population. In two papers, PD patients with and without COVID-19 were the study population (both study

. Discussion
Te main goal of our systematic review was to describe and examine the vulnerability of PD patients to COVID-19 and its consequences and efects on them. To our knowledge, this study primarily focuses on identifying the symptoms and consequences of PD that may be exacerbated by COVID-19 and also the critical efects and consequences of the COVID-19 pandemic on PD patients. In total, 31 studies from the PubMed and Scopus databases were included in the review.
In some studies, the target groups were PD patients with COVID-19, among whom the acute symptoms and consequences of COVID-19 were evaluated [14,[17][18][19][20][21][22][23][24][25][26]. In some other studies, the target groups were PD patients afected by the COVID-19 pandemic, whose symptoms had been worsened [5,[8][9][10][27][28][29][30][31][32][33][34][35][36][37][38][39]. However, in only two studies, the target groups were both PD patients with and without COVID-19 [11,40].  Some studies have shown that COVID-19 is more common in people with Parkinson's than in people who do not have Parkinson's. Tey also showed that people over the age of 65 or those with severe Parkinson's disease have been afected rapidly by the new coronavirus [4,9,41]. Researchers also found that people with Parkinson's were more likely to be afected by high-risk illnesses if they get infected with COVID-19. People with Parkinson's disease may be at an increased risk for severe COVID-19 because of their weakness. Te risk increases with age and the development of advanced Parkinson's disease. Lung function may be impaired due to Parkinson's disease and respiratory muscle weakness [5,7]. Hence, recently published studies have shown that 31.9% of patients with pre-existing neurological disorders, including Parkinson's disease, have experienced the exacerbation of neurological symptoms during COVID-19 infection, regardless of age and duration of illness [42].
In the current pandemic situation, PD patients experience rigidity, fatigue, tremors, and a high level of pain. Te subjective increase in tremor and rigidity is in line with previous studies that show these symptoms are susceptible to stress [20,32,34]. Increased pain may similarly result from increased anxiety but could also be caused by rigidity. Fatigue is a well-known consequence of psychological distress in PD [43][44][45].
Studies have shown that the COVID-19 quarantine and pandemic have altered the structure of health care and reduced patient access to the care they need, especially the trilogy treatments, and this has worsened the symptoms of PD patients [33]. Restrictions on access to hospital and outpatient services and interruptions in nonmedical treatments such as motor and cognitive rehabilitation and psychological support were signifcantly experienced by PD patients during the pandemic [45,46]. Te main problem for these patients was the lack of regular medical advice, which had a negative efect on their quality of life [31]. Also, the feeling of not having access to required services was much greater than the actual experience of not having access to these services [14,28]. During quarantine, follow-up of medical services became problematic, and PD patients were reluctant to attend virtual therapy sessions [47,48]. As it turned out, one of the biggest problems of PD patients during the prevention and control period was that they could not get regular advice from a physician [38]. Most of the PD patients decided to go to the hospital with their family members or relatives, and some others used social media software to contact their physicians [49,50]. However, not all patients are able to use social media on their smartphones.
PD patients sometimes need to modify their medication regimen, which is often delayed during quarantine, causing concern for patients and their families [51,52]. Changing medication routines, having difculty accessing medications, and getting medication on time were also challenges that made PD patients anxious. Furthermore, these patients had difculty obtaining diagnostic and therapeutic medical equipment [53][54][55].
A review of studies showed that the COVID-19 pandemic and quarantine created challenges in accessing a variety of health services and drugs, causing anxiety and concern in PD patients [56][57][58]. In general, the COVID-19 pandemic has had a negative impact on the quality of life of PD patients, caregivers, and families. Parkinson's patients need special attention from medical systems on how to receive medical services and psychosocial support [52,59,60].
Most studies have shown that the fear of getting infected by COVID-19, being confned to a limited space, and being banned from outdoor activities have reduced the physical activity of PD patients in addition to worsening their symptoms [33,61]. In PD patients, experiencing fear can be associated with a greater risk of COVID-19 due to chronic comorbidity and is often attributed to anxiety [16,37,38]. During the pandemic, fear increases anxiety in healthy individuals and exacerbates the symptoms of individuals with previous psychiatric disorders [48,62,63]. Movement and lack of movement in patients also afect their physical, cognitive, and psychosocial health [56]. Some studies have suggested that a lack of physical activity is the main cause of loss in residual motor skills, especially the inability to perform high-level daily activities [13]. Decreased physical activity causes pain, headache, fatigue, worsening of walking patterns, reduced daily activities, sleep disorders, and insomnia [58]. Like the general population, the most common symptoms of COVID-19 in PD patients include fever or chills, cough, weight loss, and muscle aches. Tese people may have a fever with nonrespiratory symptoms, such as delirium or a distinct functional decline without any apparent physical symptoms [64,65]. PD patients have also reported frequent motor symptoms such as bradykinesia, stifness, and balance disorders, as well as nonmotor symptoms such as lack of motivation [66,67].
By reducing physical activity, the time spent watching TV and using a mobile phone increase in patients with Parkinson's disease [68,69]. Social distancing, loneliness, the inability to perform physical, recreational, family, and group activities, the elimination of therapeutic activities, changes in daily routine, and not continuing physiotherapy sessions or other training-motor training activities lead to physical problems, stress, depression, frustration, anxiety, decreased cognitive functions (attention, concentration, and memory), dissatisfaction with life, and even suicidal thoughts [5,40]. Studies have shown that reducing physical activity, not continuing rehabilitation sessions, and aggravating the disease's motor symptoms also cause and exacerbate cognitive and psychological symptoms and afect the quality of life of patients and their families [70,71].

Limitations and Strengths of Tis Study. Tis study has several strengths, including
(1) Performing a comprehensive search strategy to identify a large number of studies (2) Reviewing and evaluating studies to extract data by three authors independently (3) Using a comprehensive tool (JBI) for evaluating the quality of selected studies We have also encountered some limitations in this study. Our limitations and challenges were the difculties of comparing studies due to the heterogeneity of the results and the exclusion of published studies because of their non-English language.

Conclusion
Tis systematic review examined the vulnerability of PD patients to COVID-19 and determined the consequences and efects of the COVID-19 pandemic on PD patients. By applying a systematic approach, the authors provided an exhaustive overview of the efects of COVID-19 on PD patients' symptoms. During the SARS-CoV-2 infection, patients with Parkinson's disease experienced worsening of both motor and nonmotor symptoms. Tese symptoms include the categories of abnormalities of motor and nonmotor functioning, clinical outcomes, activities of daily living, and other outcomes. In conclusion, this study confrms the negative impact of the COVID-19 pandemic on the quality of life and its determinants in PD patients and their caregivers. Tus, due to the worsening symptoms of PD patients in the current pandemic, these people should be given more care and supervision to minimize their exposure to coronavirus. Te use of modern technologies such as telemedicine is one of the solutions that can be used for many of these problems. Parkinson's disease questionnaire PDMSS: PD motor symptom scale PSS-10: Perceived stress scale PALQ: Physical activity levels questionnaire UPDRS: Te modifed Hoehn and Yahr scale and unifed PD rating scale DASS-21: Depression anxiety stress scale-21 item AES-S, AES-I: Apathy evaluation scale LSNS-R: Lubben social network scale-revised PDQ-39: Parkinson's disease questionnaire PDQ-39-SI: With summary index FES-I: Falls efcacy scale international ABCs-I: Te activity-specifc balance confdence scale IRI: Empathic attitude: interpersonal reactivity index CBI: Caregivers' burden caregiver burden inventory H and Y stage: Hoehn and Yahr stage NPI: Neuropsychiatric inventory PASE: Physical activity scale for the elderly HADS-A; HADS-D: Hospital anxiety and depression scale FI: Fox insight NMSQ: Nonmotor symptoms questionnaire PAM-13: Patient activation measure PCS: Physical component summary MCS: Mental component summary (SF)-8: Scores of the short form IPAQ-SF: International physical activity questionnaires-short form PWBM: Parkinson's well-being map BDI: Beck depression index NMSS: 12-item Zarit burden inventory nonmotor symptom scale CISI-PD: Clinical impression of severity index for Parkinson's disease PD-MCI: Parkinson's disease with mild cognitive impairment MCInoPD: Mild cognitive impairment not associated with Parkinson's disease PD: Parkinson disease PD-NC: Parkinson's disease with normal cognition CG: Control group EG: Experimental group AgeM: Age median PEC: Parkinson expert center SMT: Standard medical treatment APD: Advanced Parkinson's disease.

Data Availability
All data generated or analyzed during this study are included within the article.

Conflicts of Interest
Te authors declare that they have no conficts of interest.