Effects of COVID-19 Lockdown on Movement Disorders Patients With Deep Brain Stimulation: A Multicenter Survey

Background: The containment measures taken by Italian government authorities during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic caused the interruption of neurological activities of outpatient clinics. Vulnerable patients, as Parkinson's disease (PD) and dystonic patients with deep brain stimulation (DBS), may have an increased risk of chronic stress related to social restriction measures and may show a potential worsening of motor and psychiatric symptoms. Methods: This cross-sectional multicenter study was carried out during the SARS-CoV-2 pandemic and was based on a structured survey administered during a telephone call. The questionnaire was designed to gather motor and/or psychiatric effects of the lockdown and coronavirus disease 2019 (COVID-19) epidemiologic information in PD and dystonic patients with a functioning DBS implant. Results: One hundred four patients were included in the study, 90 affected by PD and 14 by dystonia. Forty-nine patients reported a subjective perception of worsening of global neurological symptoms (motor and/or psychiatric) related to the containment measures. In the multivariate analysis, having problems with the DBS device was the only independent predictor of motor worsening [odds ratio (OR) = 3.10 (1.22–7.91), p = 0.018]. Independent predictors of psychiatric worsening were instrumental activities of daily living (IADL) score [OR = 0.78 (0.64–0.95), p = 0.012] and problems with DBS [OR = 5.69 (1.95–16.62), p = 0.001]. Only one patient underwent nasopharyngeal swabs, both negative, and no patient received a diagnosis of COVID-19. Conclusions: Lockdown restriction measures were associated with subjective worsening of motor and psychiatric symptoms in PD and dystonic patients treated with DBS, and they may have exacerbated the burden of neurological disease and increased the chronic stress related to the DBS management.


Methods:
This cross-sectional multicenter study was carried out during the SARS-CoV-2 pandemic and was based on a structured survey administered during a telephone call. The questionnaire was designed to gather motor and/or psychiatric effects of the lockdown and coronavirus disease 2019 (COVID-19) epidemiologic information in PD and dystonic patients with a functioning DBS implant.
Results: One hundred four patients were included in the study, 90 affected by PD and 14 by dystonia. Forty-nine patients reported a subjective perception of worsening of global neurological symptoms (motor and/or psychiatric) related to the containment measures. In the multivariate analysis, having problems with the DBS device was the only independent predictor of motor worsening [odds ratio (OR) = 3.10 (1. 22-7.

INTRODUCTION
In early 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread worldwide, becoming a pandemic. Coronavirus disease 2019 (COVID-19) commonly presents with fever, cough, and dyspnea; the most severe complication of the infection is the acute respiratory distress syndrome (1). Many government authorities took emergency containment measures to reduce viral transmission (2). In Italy, according to Prime Minister Decree of March 11, 2020, the containment measures recommended a reduction of routine hospital activities: activities of outpatient clinics were stopped, and admittance of patients affected by neurological disorders was allowed only for emergency conditions. Elderly individuals with preexisting comorbidities, including movement disorders, are fragile patients due to their higher risk of infections and poor outcome of disease management (3). Deep brain stimulation (DBS) is a well-established second-level treatment for patients with severe Parkinson's disease (PD) and dystonia who show poor response to pharmacological treatment (4). These patients are routinely monitored with close follow-up, given the need for periodic adjustments of stimulation parameters to optimize motor control and for periodic checks of implantable pulse generator (IPG) functionality and battery status in order to reduce the risk of device-related complications (5,6). In addition, PD and dystonic patients treated with DBS often need a close follow-up of possible psychiatric symptoms (depression, anxiety, apathy, impulse control disorders, psychosis, disorders of sleep, and wakefulness) (7). For the aforementioned reasons, patients with movement disorders are exposed to an increased risk of chronic stress related to social restriction measures and may show a potential worsening of motor and psychiatric symptoms (8)(9)(10). Aim of the present study was to analyze the effects of the lockdown on this vulnerable category of patients affected by PD and dystonia treated with DBS and, secondarily, to investigate the prevalence of COVID-19 suggestive symptoms in this population.

PATIENTS AND METHODS
This cross-sectional multicenter study was carried out during the SARS-CoV-2 pandemic and was promoted by the Neurology Clinic of the Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome (Italy), in collaboration with other neurology clinics based in Lazio region with good expertise on the management of DBS for movement disorders.

Inclusion Criteria
PD and dystonic patients who received a DBS implant, which was functioning during the COVID-19 lockdown, and followed in the DBS centers of Lazio region were asked to participate in a telephone survey. Patients were included regardless of the DBS target, the hospital, and the year in which implantation of the neurostimulator was carried out.

Exclusion Criteria
Patients were excluded if they were unable to provide informed and valid consent at the time of the interview, if they show cognitive decline, and if they did not speak Italian fluently.

Survey Design and Testing
The study was based on a structured survey administered during a telephone call carried out as part of the close follow-up scheduled for the included patients. Surveys started on April 28, 2020, and ended on May 12, 2020. A questionnaire was employed, aimed at gathering the following data: -demographic and clinical data related to PD  For patients who complained one or both "difficulties in the management of the DBS device" and "feeling of insecurity about the DBS device, " the cumulative variable "problems with the DBS device" was considered.
The variables related to the effects of the lockdown were assessed to detect emergent symptoms and/or changes of preexisting symptoms after March 11, 2020.

Statistical Analysis
All statistical analyses were carried out using the Statistical Package for Social Science (SPSS) program, version 25.0 (IBM Co., Armonk, NY). Data were analyzed for normality of distribution using the Kolmogorov-Smirnov test of normality and were expressed as mean [±standard deviation (SD)] for continuous variables or as frequencies (n, %) for categorical variables according to a neurological diagnosis. The Mann-Whitney rank sum test was used to compare continuous variables between diagnostic subgroups (PD and dystonia) and between patients with or without subjective perception of worsening of neurological symptoms. The χ 2 test or Fisher's exact test was used for categorical variables. Phi coefficients were calculated to estimate correlation strengths between motor/psychiatric worsening and the other binomial variables evaluating the effects of the lockdown. Finally, multivariate binary logistic analysis was performed to evaluate the relationship between the worsening of motor or psychiatric symptoms and clinical findings. The coefficients obtained from the logistic regression were expressed in terms of odds ratio (OR) with 95% confidence intervals. All statistical tests were two-tailed; statistical significance was defined as p value < 0.05, and the effect size was also reported.

Standard Protocol Approvals, Registration, and Patient Consent
The study and the survey questions were reviewed and approved by local ethical committee. Because of the biological risks related to the pandemic, after receiving a copy of written informed consent by mail or fax, patients were asked to carefully read, sign, and send it by mail or fax to the referral hospital.

Data Availability
Anonymized data will be shared with qualified external researchers after approval of their requests.

RESULTS
One hundred four patients treated with DBS were asked to participate in the survey. Since all agreed to participate, met the inclusion criteria, and no one had exclusion criteria, all 104 patients were included in the study. Ninety patients were affected by PD and 14 patients by dystonia (including 10 patients with idiopathic dystonia and four patients with secondary dystonia). In the total sample, the male/female ratio was 64/40, the mean age was 61 years (SD ±12), and the mean disease duration was 19 years (SD ±8). All dystonic patients underwent globus pallidus internus (GPi) DBS, while the DBS target was different among PD patients: 85 patients were implanted in the subthalamic nucleus (STN), three patients in the GPi, and two patients in the thalamic ventral intermediate nucleus (Vim).

Coronavirus Disease 2019-Related Questions
Distribution of symptoms suggestive of COVID-19 in the last 4 months, epidemiologic data, and medications potentially interfering with the SARS-CoV-2 infection are reported in Table 2. Twenty-six patients reported one or more symptoms suggestive of COVID-19, while only five of them referred three or more of these symptoms. The most frequent symptom was cough, reported by 17 patients. Only one patient underwent (twice) nasopharyngeal swabs, both negative, and no patient received a diagnosis of COVID-19. In our sample, there was no correlation between symptoms suggestive of SARS-CoV-2 infection and assumption of angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), or immunosuppressant therapy. No significant differences were found between the two diagnostic subgroups (PD and dystonia) as to COVID-19suggestive symptoms or additional information related to SARS-CoV-2 pandemic.

Effects of the Lockdown on Disease Burden
Information related to the impact of the lockdown on disease burden is reported in Table 3. Forty-nine patients out of 104 (47%) reported a subjective perception of worsening of global neurological symptoms related to the containment measures: 20 patients (19%) reported a worsening of motor symptoms; five patients (5%), a worsening of psychiatric symptoms; 24 patients   (23%), a worsening of both motor and psychiatric symptoms. The overall worsening of the health status was also confirmed by the mean score on the CGI Improvement scale (4.6 ± 1.3  proportion of patients on treatment with dopamine agonists was not significantly higher in the subgroup with worsening of impulsive-compulsive behaviors than in the other subgroup of patients (48 vs. 39%, respectively, p = 0.6). No significant differences were found between the two diagnostic subgroups (PD vs. dystonic patients) as to the effects of the lockdown.
Considering the subgroup of 26 patients reporting one or more symptoms suggestive of COVID-19 and comparing this one with the subgroup of patients without symptoms suggestive of COVID-19, no significant differences were found in worsening of motor or psychiatric symptoms.
No difference was found on disability scales between the subgroups of patients with and without worsening of motor symptoms. By contrast, the subgroup with worsening of psychiatric symptoms, as compared to the subgroup without psychiatric worsening, presented significantly lower scores on IADL (3.7 ± 3.0 vs. 5.2 ± 2.9, p = 0.0436, effect size = 0.50small) and higher scores on CGI Severity scale (4.5 ± 1.0 vs. 3.7 ± 1.4, p = 0.0081, effect size = 0.71-medium).
In the reduced models of multivariate logistic regression analysis, having problems with the DBS device (difficulties in the management of the DBS device or feeling of insecurity about the DBS device) was the only independent predictor of motor worsening [OR Other variables included in the models were age, sex, diagnosis (PD or dystonia), and disease duration ( Table 4).

DISCUSSION
The study, based on a telephone survey administered by neurologists of the DBS movement disorders network in Lazio region, attempted to investigate the consequences of the COVID-19 lockdown on the perception of neurological status (motor and psychiatric symptoms) in patients affected by PD and dystonia treated with DBS.
The demographic and clinical characteristics between the two diagnostic subgroups differed significantly: as compared to PD patients, dystonic patients showed an earlier age at onset, a longer disease duration, and a milder disability.
Although patients with neurological disorders, especially in late disease stages, might be particularly at risk for COVID-19 complications (16)(17)(18), in our sample, only ¼ of patients reported symptoms suggestive of SARS-CoV-2 infection. One patient underwent nasopharyngeal swabs, and none received a diagnosis of COVID-19. No patient with symptoms suggestive of COVID-19 needed specific treatments, hospitalization, or respiratory assistance.
Half of the patients in our sample reported a subjective perception of global neurological worsening, which required urgent outpatient neurological visit in 18 cases. A mean CGI Improvement score >4 after the lockdown period confirmed these data. In most patients, worsening of health status seemed to result from discontinuation of neurological visits and physiotherapy, as reported for patients with chronic neurological diseases (19,20). A significant number of patients presented a worsening of sleep quality, mood, and behavioral disturbances, including onset or worsening of impulsive-compulsive behaviors. As well as worsening of impulsive-compulsive behaviors was not related to treatment with dopamine agonists, it may be a consequence of restriction measures more than an adverse effect induced by dopamine agonists. Indeed, 13 patients reported visual hallucinations during the weeks of social isolation probably induced by a home "hospitalization" phenomenon (21) and exacerbated by sleep disturbances (22). No significant differences were found between the two diagnostic subgroups (PD vs. dystonic patients) as to the effects of the lockdown. Furthermore, in the multivariate analysis, the specific neurological disease was not an independent predictor of motor or psychiatric worsening during the lockdown.
No significant differences were found in worsening of motor or psychiatric symptoms comparing the subgroup of patients with and without symptoms suggestive of COVID-19.
Significant correlations were found between the subjective perception of motor worsening and discontinuation of physiotherapy treatment, although with a small effect size, and between worsening of psychiatric symptoms and chronic intake of benzodiazepines, with a medium effect size. These findings point out the beneficial effects of physiotherapy in patients with movement disorders and the importance of strategies focused on remote rehabilitation treatment (23). Indeed, a closer psychiatric follow-up would be recommended for patients with chronic use of benzodiazepines, who have an increased risk of developing depressive symptoms (24). In our study, problems with the DBS device (difficulties in the management of the DBS device and feeling of insecurity about the DBS device) were independent predictors of motor and psychiatric worsening. Such difficulties may be chronic stressful factors that induce depression, anxiety, and insomnia (25). Therefore, DBS played an important role in impairing motor and psychiatric symptoms during the lockdown, independently from the underlying neurological disease. Greater disability (lower IADL score) due to the chronic neurological disease was another independent predictor of psychiatric worsening. On the other hand, demographic factors, disease duration, and neurological diagnosis (PD or dystonia) did not contribute to the global worsening during the lockdown.
These findings suggest that the effects of social restriction measures seriously impact on patients with chronic neurological disease and, in particular, in carriers of a DBS stimulator with greater disability. They also highlight the importance of management programs in the post-epidemic phase with the implementation of telemedicine, remote rehabilitation treatment, and technologies for remote DBS monitoring and programming (9,26,27).

Limitations
This study has several limits. First, since data collection was carried out by means of telephone contacts and not by a face-to-face assessment, the results of the survey might have been influenced by uncontrolled biases. Second, the effects of the lockdown were only assessed by subjective perception and not by validated scales for motor and psychiatric symptoms because of the lack of specific evaluation just before the lockdown. Furthermore, subjective perception of motor and/or psychiatric worsening may be influenced by depressive mood, which had a high prevalence in our sample and is typical of the pandemic situation. In fact, there is a positive correlation between depression and subjective perception of motor and/or psychiatric worsening, thus the patients might have overestimated the real worsening during the pandemic. Another limitation of the study is the small sample size for dystonic patients. Finally, although the multivariate analysis showed that DBS played an independent role in motor and psychiatric worsening, future comparative studies between carriers and noncarriers of DBS should be made.

CONCLUSIONS
Our findings suggest that lockdown restriction measures were associated with subjective worsening of motor and psychiatric symptoms in PD and dystonic patients treated with DBS, and that such measures may have exacerbated the burden of neurological disease and increased the chronic stress related to the DBS management.