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Exacerbation of neurological symptoms and COVID-19 severity in patients with preexisting neurological disorders and COVID-19: A systematic review

Highlights • COVID-19 effects were studied in patients with comorbid neurological disorder.• This review included 26 reports of comorbid neurological disorder and COVID-19.• Papers were identified from the MEDLINE (PubMed) and medRxiv databases.• Overall, 22.0 % of patients had severe COVID-19 course.• Notably, 31.9 % of patients experienced an exacerbation of preexisting neurological symptoms.


Introduction
Coronavirus disease (COVID- 19) was first reported in China in December 2019 and has rapidly spread around the world. COVID-19 is one of the leading causes of critical pneumonia and death worldwide. Typically, 14-15 % of patients with COVID-19 develop severe pneumonia and 1.5-2.3 % die [1,2]. Risk factors for severe COVID-19 include cardiovascular disease, diabetes mellitus, hypertension, and old age [3].
As for patients with chronic neurological disorder, a few cohort studies have reported that patients with preexisting neurological disorders who contracted COVID-19 developed more severe clinical symptoms and worse outcomes, compared to the general population [4,5]. In addition, some patients with neurological disorders such as Parkinson's disease and dementia who developed COVID-19 had a worsening of preexisting neurological symptoms [6,7].
However, the overall severity of COVID-19 and the changes in neurological symptoms in patients with preexisting neurological disorders and COVID-19 are unknown due to limited reports (few case reports or small cohort studies). Therefore, we conducted a systematic review to evaluate the exacerbation of neurological symptoms and the severity of COVID-19 in patients with preexisting neurological disorders and COVID-19.

Material and methods
A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [8]. This review protocol was not formally registered. The MEDLINE (accessed from PubMed) and medRxiv databases were searched systematically on May 22, 2020. In PubMed, the following key words (in the title/abstract) were used: ("COVID-19 ′′ OR "Coronavirus" OR "SARS-CoV-2 ′′ OR "2019-nCoV") AND ("Neurology" OR "Neurologic" OR "Neurological" OR "Neuropathy" OR "Brain" OR "Spine" OR "Stroke" OR "Nerve" OR "Epilepsy" OR "Parkinson's disease" OR "Dementia" OR "Brain tumor" OR "Multiple Sclerosis" OR "Movement disorder" OR "Headache" OR "Tremor" OR "Amyotrophic lateral sclerosis" OR "Dystonia")". In medRxiv, the number of search terms that can be used is limited; therefore, the following key words were used: ("COVID 19 ′′ OR "SARS CoV 2 ′′ ) AND ("Neurologic" OR "Stroke" OR "Epilepsy" OR "Parkinson" OR "Dementia" OR "Multiple sclerosis"). The aforementioned neurological diseases were selected from among the chronic neurological diseases with a high prevalence [9,10].
We included studies based on the following criteria: (1) those reporting patients who had preexisting neurological disorders and COVID-19; (2) those that documented the severity of COVID-19 and/or changes in preexisting neurological symptoms; and (3) original reports such as case reports, letters, case series, or cohort studies. Case reports were included because so few large population-based studies of patients with preexisting neurological disorders and COVID-19 are available. We defined a severe case as a patient with severe/critical pneumonia or who had been admitted to the intensive care unit. We defined exacerbation as exacerbation of preexisting neurological disease-related symptoms. We excluded studies written in languages other than English. We also excluded studies that only included patients who were critically ill or deceased.
Two reviewers (TK and NK) independently screened the titles and abstracts. After screening, a reviewer (TK) assessed the full texts of the selected articles and included those that met the inclusion criteria. Any disagreements were resolved by discussions between the reviewers (TK and NK).

Results
A total of 1702 studies were retrieved (866 papers from MEDLINE and 836 papers from medRxiv) on May 22, 2020. After title and abstract screening and duplicate removal, 313 studies were identified. The fulltext screening of these studies led to the exclusion of 286 that did not meet the inclusion criteria. The remaining 26 studies were identified as eligible to be reviewed [6,7,. Fig. 1 outlines the selection process. Table 1 lists the characteristics of the included articles. A total of 2278 patients with preexisting neurological disorder and COVID-19 were included. The neurological disorders included cerebrovascular disease, Parkinson's disease, multiple sclerosis and related disorders, aquaporin-4 (AQP-4)-positive neuromyelitis optica spectrum disorder (NMOSD), dementia and cognitive disorder, epilepsy, spinal cord injury, systemic atrophy, myelopathy, intracranial mass, and unspecified neurological disorders. Since the selected articles did not always report both the exacerbation of neurological symptoms and severity of COVID-19, the patients were divided into two groups: 232 patients with preexisting neurological disorders and COVID-19 for whom the exacerbation of neurological symptoms was reported, and 2168 patients with preexisting neurological disorder and COVID-19 for whom the severe COVID-19 course was reported. Of the 232 patients in the first group, 74 (31.9 %) showed an exacerbation of preexisting neurological symptoms, including patients with dementia (55/92; 59.5 %), Parkinson's disease   Table 3.

Discussion
In this systematic review, our findings suggest that COVID-19 may increases the risk of a worsening of neurological symptoms in patients with preexisting neurological disorders. In addition, our results indicate that patients with preexisting neurological disorders and COVID-19 may likely develop severe COVID-19. To our knowledge, this is the first systematic review to demonstrate the exacerbation of neurological symptoms and the severity of COVID-19 in patients with preexisting COVID-19 and neurological disorders.
We found that 31.9 % of patients with preexisting neurological disorders and COVID-19 experienced a worsening of neurological symptoms. In particular, approximately 60 % of patients with Parkinson's disease or dementia had an exacerbation of preexisting neurological symptoms. In general, the most common cause of symptom exacerbation in patients with Parkinson's disease was infection (25.6 %), followed by anxiety (18.6 %), medication errors (13.9 %), and poor adherence to the treatment regimen (13.9 %) [35]. Moreover, symptoms of COVID-19 and changes in the environment, such as hospitalization, may interrupt the scheduled intake of medication, resulting in the deterioration of symptoms. In addition, an infection induces the production of systemic and central nervous system cytokines and prostaglandins that cause acute cognitive declines and delirium in patients with dementia [36]. The presence of cytokines and monokines in the brain has been reported in patients with severe acute respiratory syndrome coronavirus [37]. Consequently, COVID-19 may trigger a cognitive decline or delirium in patients with dementia. Although the number of patients with epilepsy is small, they exhibited an exacerbation in symptoms. The association between seizures and COVID-19 has not been clearly determined; however, infection is a common precipitating factor for the development of seizures in patients with epilepsy [38][39][40]. Thus, COVID-19 may worsen seizure control in patients with epilepsy. In contrast, patients with multiple sclerosis and related diseases did not exhibit neurological symptom exacerbations in our study. On the other hand, a previous cohort study reported that viral infections were associated with temporal exacerbations in the symptoms of approximately 9% of patients with multiple sclerosis [41]. Our systematic review may not have detected symptom exacerbations in such patients due to the small sample size.
We found that 22.0 % of patients with preexisting neurological disorders and COVID-19 developed severe COVID-19. The frequency of severe COVID-19 among these patients was greater than that of patients in general population studies (22.0 % vs 14.2-15.7 %) [1,2]. Among patients with cerebrovascular disease or dementia, who comprised the majority of patients, 19.3 % and 22.2 %, respectively, developed severe COVID-19. This may be because such patients have risk factors for severe COVID-19, including old age, diabetes mellitus, and hypertension [3]. In patients with multiple sclerosis, the percentage of patients in whom COVID-19 severity increased was as high as 39.4 %. Comorbidities, obesity, age, and progressive forms of multiple sclerosis have been reported as risk factors for severe COVID-19 in patients with preexisting multiple sclerosis [42]. Although the patients with multiple sclerosis in our study were relatively young (23-59 years), they may have had other comorbidities and progressive forms of the disorder. The severity of COVID-19 also increased in 71.4 % of patients with spinal cord injury, although this population was small. Difficulty with spontaneous breathing and clearing respiratory secretions may worsen pneumonia in patients with spinal cord injury. In contrast, the frequency of patients with Parkinson's disease who experienced increased COVID-19 severity was low, compared to the general population (11.7 % vs 14.2-15.7 %) [1,2]. This low percentage was inconsistent with the frequencies in patients with other predominantly elderly neurological diseases, such as dementia and stroke. In patients with epilepsy, the percentage of patients with severe COVID-19 was low (10.2 %). Although the mean age of these patients is unknown, the studies may have included pediatric patients with epilepsy.
Our study had several limitations. First, most of the included studies were case reports or small cohort studies. Consequently, there may be   AQP-4: Aquaporin-4. NMOSD: neuromyelitis optica spectrum disorder.
large differences in the clinical settings between these reports. Second, the studies included in the systematic review may have been subject to selection and presentation bias. For example, severe or complicated cases may have been more likely to be published. Third, mild exacerbation of preexisting neurological symptoms might have been missed and unreported. Fourth, patients with unspecified neurological disorders were reported. Finally, the criterion of severity varied slightly across studies. Therefore, the criteria in our study may not have been completely accurate and uniform.
In conclusion, our results suggest that patients with preexisting neurological disorders and COVID-19 may experience a worsening of neurological symptoms and may likely develop severe COVID-19. Clinicians should be aware of the risks of an exacerbation of neurological symptoms and an increase in COVID-19 severity in patients with preexisting neurological diseases, and should focus on the prevention and early care of COVID-19. Further detailed retrospective and prospective large-cohort studies are needed to confirm the risk of an exacerbation of neurological symptoms and the clinical outcomes in patients with COVID-19 and preexisting neurological disorders.