|Year : 2023 | Volume
| Issue : 1 | Page : 7-15
Prevalence of neurological manifestations in coronavirus disease 2019 positive patients in Makkah city – Saudi Arabia
Eyad Altarazi1, Amal M AlKhotani2, Doaa Khalid Mohorjy3, Abdullah Almoabdi1, Rahaf Almatrafi4
1 Department of Neurology, King Abdulla Medical City, Makkah, Saudi Arabia
2 Department of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
3 Department of Science and Technology, Research Center, King Abdulla Medical City, Makkah, Saudi Arabia
4 Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
|Date of Submission||28-Nov-2022|
|Date of Acceptance||17-Jan-2023|
|Date of Web Publication||15-Mar-2023|
Source of Support: None, Conflict of Interest: None
Background: Coronaviruses are the important pathogens of humans and animals that can cause diseases ranging from the common cold to more severe or even fatal respiratory infections. Regarding nervous system complications, existing literature has revealed increasing reports of neurological manifestations in coronavirus disease 2019 (COVID-19)-positive patients ranging from mild-to-severe manifestations. Aim: In this study, we aimed to determine the prevalence of neurological manifestations in COVID-19-positive patients. Furthermore, we sought to ascertain the most common and most severe manifestations and to find the significant associations with laboratory or clinical findings. Setting and Design: This is a retrospective cross-sectional observational study that was conducted at two centers. Materials and Methods: Patient data were collected in periods from of March 1 to of July 30, 2020 labeled as the first wave, and from December 1, 2021 to January 30, 2022 labeled as the second wave in two tertiary care hospitals, Al-Noor Specialist Hospital and King Abdullah Medical City, situated in Makkah city, Saudi Arabia. The study included patients who were ≥ 18 years of age and were found to have any neurological manifestations and/or complications secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The study was conducted in different periods to assess the different waves of the COVID-19 pandemic and to allow the comparison between them. Results: From a total number of 4751 patients with confirmed SARS-CoV-2 infection eligible during the periods included in our study, we found neurological manifestations in 263 patients, particularly 229 from the first wave and 34 from the second wave. In the first wave patients, 102 (44.5%) were aged between 18 and 39 years of age. The prevalence of neurological manifestations was 6.4% in the first wave and 2.9% in the second wave. Conclusion: Our study showed a large variety of neurological manifestations in COVID-19-positive patients. The most common neurological manifestations were headache and impaired level of consciousness, whereas the most severe conditions were cerebrovascular events, seizure, encephalopathy, and brain death.
Keywords: Coronavirus disease 2019, infections, neurological manifestations, neurology, neuroscience, neurosurgery
|How to cite this article:|
Altarazi E, AlKhotani AM, Mohorjy DK, Almoabdi A, Almatrafi R. Prevalence of neurological manifestations in coronavirus disease 2019 positive patients in Makkah city – Saudi Arabia. Saudi J Health Sci 2023;12:7-15
|How to cite this URL:|
Altarazi E, AlKhotani AM, Mohorjy DK, Almoabdi A, Almatrafi R. Prevalence of neurological manifestations in coronavirus disease 2019 positive patients in Makkah city – Saudi Arabia. Saudi J Health Sci [serial online] 2023 [cited 2023 Mar 31];12:7-15. Available from: https://www.saudijhealthsci.org/text.asp?2023/12/1/7/371709
| Introduction|| |
Coronaviruses are the important pathogens of humans and animals that can cause diseases ranging from the common cold to more severe or even fatal respiratory infections. In the past two decades, two highly pathogenic human coronaviruses, the coronavirus responsible for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV) and the coronavirus responsible for the Middle East Respiratory Syndrome have emerged in two separate events. They induce lower respiratory tract infection as well as extrapulmonary manifestations, leading to hundreds or thousands of cases with high mortality rates, of up to 50% in certain populations. In December 2019, a new strain of coronavirus, officially named SARS-CoV-2, was first isolated from three patients with coronavirus disease 2019 (COVID-19) by the Chinese Center for Disease Control and Prevention. Thereafter, the World Health Organization (WHO) named the COVID-19 a global pandemic in March 2020.
Although patients with SARS-CoV-2 infection primarily show respiratory symptoms, various systemic complications can also arise that impact several organ systems. These include skin, cardiovascular, nervous, and immune systems complications. Regarding nervous system complications, existing literature has revealed the increasing reports of headache as one of the most common neurological manifestations in COVID-19-positive patients. A recent retrospective study found that focal neurological deficit is the most prevalent neurological symptom (40.5%) in COVID-19-positive patients, followed by headache (27.7%). In addition, a systematic review on COVID-19-related neurological manifestations, which screened a total of 2441 articles, found headache, dizziness, taste and smell dysfunctions, and impaired consciousness to be the most commonly mentioned neurological symptoms.
Past studies have noted the increasing reports of delirium in COVID-19-positive patients, a symptom that may be associated with a more severe disease phenotype. According to a new retrospective case series from China, 22% of patients who died from COVID-19 had delirium as compared to only 1% who recovered. Similarly, in a small cohort, Helms et al. reported that 84% of COVID-19-positive patients had delirium or abnormal neurological examination, which was substantially linked with the duration of ventilation.
In a retrospective observational study carried out in Wuhan (Hubei province, China), the epicenter of COVID-19 outbreak, involving 221 COVID-19 positive patients, 11 (5%) had ischemic stroke, 1 (0.5%) had cerebral venous thrombosis, and 1 (0.5%) had brain hemorrhage. Patients who developed acute cerebrovascular events were significantly older than those who did not and were more likely to present a more severe COVID-19 phenotype (84.6% vs. 39.9%). These patients were also more likely to present cardiovascular risk factors, including hypertension (69.2% vs. 22.1%), diabetes (46.2% vs. 12.0%), and previous medical history of cardiocerebrovascular diseases (23.1% vs. 6.7%).
Considering this scenario, this study aimed to assess the frequency and severity of neurological manifestations as well as putative risk factors of COVID-19-positive patients in the city of Makkah, Saudi Arabia.
As viruses can innately mutate, new variants can emerge and either disappear or, conversely, persist. Specifically, SARS-CoV-2 variants originated multiple waves during the COVID-19 pandemic.
In Saudi Arabia, the first case was diagnosed in March 2, 2020. Accordingly, the first wave we analyzed was defined between March 2 and June 30, 2020. And As WHO classified a new variant, B.1.1.529, as a Variant of Concern and named it Omicron on November 26, 2021 and on November 30, 2021, the United States also classified it as a variant of concern.
Taking this into consideration, we also aimed to compare the neurological manifestations between different waves, choosing the first and one of the latest waves in December 2021.
| Materials And Methods|| |
Study design and patients
This retrospective cross-sectional observational study was conducted in periods from March 1 to July 30, 2020 labeled as the first wave from December 1, 2021 to January 30, 2022 labeled as second wave, in two tertiary care hospitals, Al-Noor Specialist Hospital and King Abdullah Medical City, situated in Makkah city, Saudi Arabia.
The study population included patients with 18 years of age and above, admitted to the hospital with positive polymerase chain reaction test for SARS-CoV-2 RNA on nasopharyngeal swab, regardless of clinical severity, hospital admission, the appearance of neurological symptoms or signs or clinical picture suggestive of COVID-19 (fever above 37.5°C, symptoms of respiratory system infection). Patients were excluded from the analysis if they were nonconfirmed COVID-19 status patients, pregnant patients or if there was insufficient clinical information.
Before data collection, we obtained Institutional Review Board approval from King Abdullah Medical City Research Ethics Committee in Makkah city, with number 21–851.
Clinical and laboratory data were extracted from the electronic hospital records. The clinical information details collected were: age, biological sex, nationality, history of comorbid diseases (hypertension, diabetes, chronic kidney disease (CKD), congestive heart failure [CHF], thyroid disease, pneumonia, stroke, dementia, respiratory disease, human immunodeficiency virus, sickle cell disease, rheumatoid arthritis, heart disease, malignancy), clinical symptoms (fever, dyspnea, cough, fatigue, sore throat, diarrhea, and anorexia), admission to intensive care unit, neurology wards, COVID-19 wards or outpatient department, and neurological symptoms (headache, psychomotor agitation, ataxia, seizures, meningeal signs, anosmia, ageusia, dysphagia, encephalopathy, myalgia, dizziness, and sleep disorders), radiological abnormality, patients mortality. The laboratory parameters collected were lymphopenia, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), lactate dehydrogenase, D-dimer, liver enzymes, serum creatinine, coagulation profile, platelet count, fibrinogen, ferritin, electroencephalogram, and cerebrospinal fluid analysis.
Neurological manifestations were divided based on the severity as follows:
- Mild manifestations, including headache and myalgia
- Moderate manifestations, including loss of smell and taste, facial palsy, visual symptoms, peripheral neuropathy, dizziness, myopathy, and radiculopathy
- Severe manifestations, including encephalopathy, stroke, seizure, ataxia, psychomotor agitation, and brain death.
The Statistical Package for the Social Sciences (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp) software was used for data analysis. Discrete variables were reported by using counts and percentages, whereas continuous variables used the mean and standard deviation. Comparative analysis was performed using than Mann–Whitney U-test used for the continuous variables and the Chi-square test or Fisher exact test for the categorical variables.
| Results|| |
From a total number of 4751 patients with confirmed SARS-CoV-2 infection eligible during the periods included in our study, we found neurological manifestations in 263 patients, particularly 229 from the first wave and 34 from the second wave [Figure 1] and [Figure 2]. In the first wave patients, 102 (44.5%) were aged between 18 and 39 years of age, 131 (57.2%) were male, 143 (62.4%) were non-Saudi, 117 (51.1%) presented no comorbidities, 185 (80.8%) are still alive, and 134 (58.5%) were from KAMC. In the second wave patients, the majority of participants (14, 41.2%) were aged between 60 and 90 years of age, 18 (52.9%) were female, 20 (58.8%) were Saudi, 27 (79.4%) presented comorbidities, 28 (85.3%) are alive, and 18 (52.9%) were from Al-Noor Specialist Hospital [Table 1].
|Table 1: Sociodemographic and general characteristics of the study population|
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We observed that known comorbidities were significantly associated with some diseases [Table 2]. Comparing first with second waves, examples of these associations include: pneumonia (P = 0.050), hypertension (P = 0.000), and ischemic heart disease (IHD) (P = 0.044) which were significantly altered. Comparison of the comorbidities between waves also revealed that the following variables were also significantly associated: Chronic renal failure (CRF) (P = 0.009), cerebrovascular accident (CVA) (P = 0.000), dementia (P = 0.000), malignancy (P = 0.000), CKD (P = 0.000), CHF (P = 0.000), and others (P = 0.008).
We then evaluated the frequency of neurological symptoms in the COVID-19-positive patients of our study [Table 3]. Our neurophysiological and radiological findings show that symptoms such as impaired consciousness, encephalopathy, myalgia, and dizziness significantly differ among the first and second waves, with a P < 0.05.
Regarding the laboratory findings [Table 4], we found that all analyzed parameters, except the variable D-dimer (P = 0.490), namely CRP, ESR, and ferritin were statistically significant (P < 0.050).
Finally, the severity of neurological symptoms associated in the COVID-19-positive patients was assessed [Table 5]. More than half of the patients (134, 51%) had mild neurological manifestations. In contrast, we observed lower percentages of patients with severe (107, 40.7%) or moderate (46, 17.5%) neurological manifestations. COVID-19-positive patients with moderate neurological manifestations showed a significant level (P = 0.003). Importantly, the severity of neurological symptoms among COVID-19-positive patients per analyzed wave is illustrated in [Figure 3].
|Table 5: Severity of neurological symptoms in coronavirus disease 2019 patients|
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| Discussion|| |
Coronaviruses are the members of the beta-coronaviridae family. They are spherical or oval viral particles with an average diameter of 100 nm. Structurally, they are made by large spikes of viral membrane glycoproteins on the surface that, when observed by electron microscopy, show a typical crown-like shape. They are enveloped, nonsegmented viruses with single-stranded, positive-sense RNA genome. The pathogen of the now on-going novel pneumonia outbreak (COVID-19) is the coronavirus SARS-CoV-2.
The mechanisms underlying COVID-19-related neurological conditions are unclear, but recent evidence sheds light on some aspects related with direct damage to specific receptors, cytokine-related tokine-related injury, secondary hypoxia, and retrograde travel along nerve fibers.
Similar to lung epithelial cells, the expression of angiotensin-converting enzyme 2 on brain − blood barrier endothelial cells may allow viral binding to these important sites, which can facilitate viral entry into the central nervous system through the vasculature.
The binding of SARS-CoV-2 viral particles to pulmonary epithelial cells also generates a global systemic inflammatory response (SIRS), promoting increased levels of interleukin (IL)-6, IL-12, IL-15, and tumor necrosis factor alpha, activating glial cells and, ultimately, inducing a massive pro-inflammatory central nervous system state. In particular, IL-6 levels have been correlated with increased disease severity in COVID-19 patients.
Holy Makkah is one of the largest cities in Saudi Arabia. According to national registry, it recorded around 768,648 confirmed cases and 9149 deaths. NSH and KAMC are considered two of the largest hospitals in Makkah city, being approved as COVID-19 isolation and treating centers and part of the Advanced Multicenter Clinical Study for the Treatment of COVID-19 conducted by the Ministry of Health (MOH) of Saudi Arabia.
From a total number of 4751 cases of confirmed COVID-19 in Makkah city during periods included in our study, 263 patients had neurological manifestations, particularly 229 in the first wave and 34 in the second wave. Specifically, the prevalence of neurological manifestations was 6.4% in the first wave and 2.86% in the second wave, percentages lower than previously reported. Indeed, previous studies from China reported a 36.4% prevalence of neurological manifestations in COVID-19-positive patients. Moreover, a higher prevalence of neurological manifestations (57.4%) was previously reported in Europe. The lower prevalence rate of the first wave in our study is likely explained by the mass screening performed by the Saudi Arabia MOH in the beginning of the COVID-19 pandemic, which led to the identification of asymptomatic positive patients. Conversely, the lower prevalence rate of neurological manifestations in the second wave of our study may be explained by the global immunization program done after, which drastically reduced the number of SARS-CoV-2-infected individuals. Unfortunately, in our study, complete data regarding the immunization state of patients was not found on their medical records.
We did not find any statistical significance between genders in terms of the development of neurological manifestations in our study group.
Of the total number of participants of our study, around 41% patients had systemic comorbidities that were statistically significant in the first (48%) and second (79%) waves. In the first wave patients, comorbidities such as pneumonia, hypertension, and IHD were significantly associated with neurological manifestations. Other significant comorbidities included CRF, history of stroke, dementia, underlying malignancy, and CHF. These findings go in line with previous reports showing significance of different comorbidities.
Regarding the assessment of neurological manifestations in our study, these were divided into mild, moderate and severe. Mild manifestations were the most common (51%) in the entire population of the present study, with 52.8% of the population in the first wave and 38.2%in the second wave. These were followed by severe manifestations in 40.7% of the patients, an effect that was more pronounced during the second wave, as detailed in [Table 5]. Moderate manifestations had the lowest incidence (17.5%) when considering all patients of this study.
Among all the neurological symptoms, headache was the most prevalent (47.9%) in COVID-19-positive patients of our study, followed by impaired consciousness (18.3%) and acute stroke (15.2%). Our findings indicate a higher prevalence of headache in comparison to previously reported data., The rest of our findings regarding other neurological symptoms are in agreement with previously reported data.,
The pattern of neurological manifestations was significantly different between the two waves analyzed. Myalgia was more common in the first wave (11.4%–0%), whereas impaired consciousness (15.7%–35.3%, P = 0.006), encephalopathy (0.9%–8.8%, P = 0.002), and dizziness (2.2%–23.5%, P = 0.00) were more common in the second wave in comparison to the first one. This pattern change is likely reflected by the higher number of diagnosed asymptomatic patients in the first phases of the COVID-19 pandemic. In fact, in the second wave, only symptomatic patients were properly diagnosed, and patients who were admitted to the hospital likely had either a more severe disease phenotype than those treated as outpatients or more comorbidities in comparison to first wave patients.
In our study, patients from both waves with neurological manifestations were found to have abnormal CRP, ESR and ferritin levels. Although these are nonspecific findings, they are indicative of severe acute SIRS. Similar findings have been reported, establishing the relationship between acute-phase reactants and the development of neurological manifestations.,
Our study presents several limitations. First, it was conducted in two different centers, each with its own procedures in terms of documentation and recording. Second, missing data related to the retrospective nature of the study could be possible since our data were collected from the reports in patient files from some patients. Third, some patients were referred to other hospitals due to a shortage of beds and information regarding their clinical outcomes was missing. Finally, most importantly, our data lacked the vaccination status of confirmed cases, particularly regarding patients belonging to the second wave.
We recommend long-term prospective research to be carried out in different geographical locations in to collect more reliable results.
| Conclusion|| |
Our study showed a large variety of neurological manifestations in patients infected with SARS-CoV-2 coronavirus, with the most prevalent being headache and impaired level of consciousness. The most severe conditions observed were cerebrovascular events, seizures, encephalopathy, and brain death.
We found a significant relationship between comorbidities and developing neurological manifestations as well as the presence of systemic inflammatory markers in the observed population. Further studies are required to confirm a causal relationship.
There were clear differences between the two different waves selected in our study, particularly in terms of the numbers of cases with neurological manifestations and in terms of severity and manifestation types.
This is to inform you that the research approved by KAMC IRB registered at the National Biomedical Ethics Committee, King Abdulaziz City for Science and Technology on 14-07-1433 (Registration no. H-02-K-001) and is following the GCP-ICH regulations.
IRB number: 21-851 at 27-Dec-2021.
I would like to express my foremost gratitude to my god almighty Allah for letting me though all the difficulties in writing this article.
I would also like to express my deep appreciation to my team in writing this research paper, especially Dr. Amal Khotani, the research supervisor, for her great support.
I would like to extend my sincere thanks to the Laboratory Department in King Abdullah Medical City for their assistance, especially Dr. Najwa Altaweel, Esraa hazem, Eyas Almalibari, Hind Alhadrami, Rayed Algowaihili, Muna Ghazzawi, Bayan Alzain, Shahad Alsharif, Abeer Alzhrani, Norhanifah Alug, Mohammed Bagasi, Eyad Emrani and Fares Althaqafi.
I would also like to thank my research center, especially Mr. Maher, Miss Rania Flimban, Halah Nawab and Wedian for their valuable help. I must also thank Mr. Mashhoor Alotibi from the statistical department in Al-Noor Specialist Hospital. I'd like to acknowledge the effort of Dr. lama Allehaibi, Najla Kabli, Ghadeer Alamri, Kiran Waqar and Renad Sarhan. I would also like to extend many thanks to Dr. Musleh Algarni our residency program director for his advice and support throughout.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]