Acute Neurological Manifestations of COVID-19 Patients From Three Tertiary Care Hospitals in Qatar

Introduction Worldwide, there are more than 424 million confirmed cases of COVID-19. Most of the hospitalized critical COVID-19 patients manifested neurological signs and symptoms and higher mortality. The majority of COVID-19 fatalities occurred mostly in patients with advanced age and underlying medical comorbidities. This is the first local retrospective study in Qatar, which reported neurologic manifestations (48.5%) of hospitalized COVID-19 patients. The primary objective of this study is to evaluate acute neurological manifestations in COVID-19 hospitalized patients in the country. Methods This is a retrospective, observational study of 413 hospitalized COVID-19 patients. They were admitted to three different COVID-19 designated hospitals (Hazm Mebaireek, Ras Laffan, and Cuban tertiary care Hospitals) under the Hamad Medical Corporation, Qatar from 1st January 2020, to 31 January 2021. We evaluated electronic medical records of these patients and data were collected while their neurological manifestations were confirmed by two trained neurologists. These neurologic manifestations were categorized into three major groups: central nervous system (CNS), peripheral nervous system (PNS), and neuromuscular system. Results Of 413 patients, 94% (389) were male and 6% (24) were female; the mean age was 52 years. Among all different nationalities of COVID-19 patients, 20.3% (84) were Indian, 12.5% (52) were Bangladeshi, 10.1% (42) were Qatari and 9.2% (38) were Nepali. The most common symptoms at the onset of COVID-19 illness were as follows: 77.5% (321) had a fever, 67.4% (279) experienced cough, 58.7% (243) experienced shortness of breath and 26.1% (108) developed a sore throat. Overall 48.5% (201) patients developed different neurologic manifestations. The most common neurologic symptoms were myalgia (28%; 116), headache (10.4%; 43), dizziness (5.8%; 24) and hemiparesis due to strokes (5.3%; 22). In this study, the most common risk factors were hypertension (47.6%), diabetes (46.9%), obesity (21%), chronic kidney disease (10%), ischemic heart disease (9.7%), and smoking (6.8%). About 45.2% (187) patients were admitted to MICU and 8.5% (35) died due to COVID-19 complications. Significant other extrapulmonary multiorgan system involvement were skeletal muscle injury (39.4%), kidney injury (36.7%), liver injury (27.5%), myocardial injury (23.9%), rhabdomyolysis (15.7%) heart failure (11.4%) and acute pancreatitis (11.1%). Discussion The most common neurologic signs and symptoms were myalgia, headache, dizziness, and strokes, mainly due to large vessel thrombosis, lacunar, and posterior circulation strokes. Conclusions Patients with COVID-19 are at high risk of developing neurological manifestations. The most common COVID-19-related acute neurological manifestations were myalgia, headache, dizziness, and acute ischemic stroke. Prompt recognition, early diagnosis, and appropriate management of these manifestations could potentially lead to better patient outcomes in COVID-19 patients.


Introduction
In late December 2019, several patients with viral pneumonia were diagnosed in Wuhan, Hubei Province of China. This virus rapidly involved several provinces of China and many countries in the world. WHO declared a pandemic in March 2020 due to this novel virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1].
The spectrum of symptomatic infection ranges from mild to critical. The global case fatality rate of COVID-19 is 2-3% and most of the fatalities occurred in patients with advanced age or underlying medical comorbidities. However, there is an estimated asymptomatic infection rate as high as 30 to 40% in the community [2].
Several studies have described typical COVID-19 clinical manifestations such as fever, cough, dyspnea, fatigue, and diarrhoea. There have been few studies describing neurological manifestations in COVID-19 patients. However, to our knowledge, this is the first large case series in the six Gulf Cooperation Council (GCC) countries (Qatar, KSA, UAE, Kuwait, Oman, and Bahrain) to report the characteristic neurological manifestations of COVID-19 infection in 48.5% (201) of 413 patients with a laboratory-confirmed diagnosis of COVID-19, treated at three tertiary care hospitals in Qatar.

Materials And Methods
This is a retrospective, observational cross-sectional study, conducted at three COVID-19 designated government hospitals (Hazm Mebaireek, Ras Laffan, and Cuban) of the Hamad Medical Corporation (HMC), Doha, Qatar. The data of 413 consecutive COVID-19 patients, confirmed by reverse transcriptionpolymerase chain reaction (RT-PCR), admitted during the first wave from 1st January 2020, to 31 January 2021 were retrospectively analyzed.
Electronic medical records including laboratory and radiologic findings of all patients with confirmed SARS-CoV-2 infection were evaluated and data were collected on age, gender, nationality, symptoms (fever, cough, SOB, myalgia, headache), comorbidities (hypertension, diabetes, obesity, ischemic heart disease, chronic kidney disease, and smoking). We defined the degree of severity of COVID-19 (mild vs severe) at the time of admission using the American Thoracic Society guidelines for community-acquired pneumonia.
Neurologic manifestations were categorized into three major groups: central nervous system (CNS) manifestations (included dizziness, headache, impaired consciousness/encephalopathy, acute cerebrovascular disease, and seizure), peripheral nervous system (PNS) manifestations (included anosmia, dysgeusia, Guillain-Barre syndrome (GBS) and nerve injury), and neuromuscular system manifestations (including skeletal muscular injury). All neurological manifestations were checked by two trained neurologists.
The study was performed according to the principles of the Declaration of Helsinki. This study was approved and written informed consent was waived by the Medical Research Center of HMC, Doha, Qatar, in August 2020 due to the COVID-19 pandemic and urgent need to collect and analyze new data to identify gaps in practice and improve patient outcomes.
The primary objective of this study was to determine the prevalence of acute neurological manifestations and the secondary objective was to determine other extrapulmonary multiorgan system involvement in COVID-19 patients from three tertiary care hospitals of Qatar.

Discussion
In late December 2019, several patients with viral pneumonia were diagnosed in Wuhan, Hubei Province of China. This viral infection was epidemiologically associated with a seafood market where a number of nonaquatic animals such as birds and rabbits were also on sale before the outbreak [1,3]. This rapidly involved several provinces of China and many countries in the world and hence WHO declared a pandemic in March 2020 due to a novel single-stranded RNA coronavirus, named SARS-CoV-2 [1].
As of February 2022, there are more than 424 million confirmed COVID-19 cases, including more than five million deaths worldwide [1]. Acute respiratory distress syndrome is a major complication in patients with severe COVID-19 infection [3]. COVID-19 has a 2-3% case-fatality rate globally [2] and most of the fatalities occurred in patients with advanced age or underlying medical comorbidities [4][5][6]. COVID-19 case-fatality rate in the country of Qatar is quite low at 0.255% as compared to the rest of the world. Several variants of SARS-CoV-2 have emerged notably because of the potential for increased transmissibility [7] and hence more complications. There have been few studies describing neurological manifestations in COVID-19 patients.
This is the first detailed retrospective, observational study of acute neurological manifestations in hospitalized COVID-19 patients in Qatar, and to our knowledge, this is the first study in the GCC countries to describe these findings in COVID-19 patients. Our population is relatively younger, and the majority were male (94%), mostly expatriates largely from underdeveloped countries. Around 28 nationalities were included in our study as people from over a hundred different nationalities are living in Qatar.
Neurological manifestations were observed in 36.4% of hospitalized patients which were more common in patients with severe infection and had higher mortality rates [9]. In our study, there were overall 48.5% (201/413) of patients with various neurologic manifestations including CNS, PNS and neuromuscular systems involvement. The most common neurological manifestations of the neuromuscular system were skeletal muscle injury, myalgia and rhabdomyolysis, while in CNS the most common manifestations were headaches, dizziness, strokes, CVST and seizures and in PNS the manifestations were ICU acquired weakness (ICU-AW), anosmia and dysgeusia in order of descending frequency.
Neurologic complications in COVID-19 patients may be due to multifactorial mechanisms that may arise from direct as well systemic responses to the virus [10]. In addition to traditional vascular mechanisms in COVID-19 patients, dysfunction of the renin-angiotensin system (RAS) due to virus binding to angiotensinconverting enzyme -2 (ACE2), hypercoagulability, severe inflammation, and cardiac dysfunction may lead to secondary cardiovascular and cerebrovascular effects [11][12][13]. Critically ill COVID-19 patients may develop hyperinflammation, endothelialitis, cytokine storm, thrombophilia, and complement activation [14,15] leading to thromboembolic disease. SARS-CoV-2 may invade the brain through the olfactory epithelium and neural-mucosal interface. In addition to potential direct SARS-CoV-2 viral myositis, cytokines storm could also lead to pathological changes in skeletal muscle tissue.
Toxic-metabolic encephalopathy and strokes are common acute neurological manifestations in critically ill COVID-19 patients with other rare case reports of Guillain-Barre syndrome (GBS), acute disseminated encephalomyelitis (ADEM), meningoencephalitis, generalized myoclonus, and posterior reversible encephalopathy syndrome (PRES). In a study of 509 hospitalized COVID-19 patients, 31.8% had encephalopathy [16]. A spectrum of neuroimaging abnormalities has been described in patients with COVID-19, the most common being acute ischemic stroke, cortical FLAIR signal abnormality, cerebral microbleeds, leptomeningeal enhancement, cytotoxic lesions in the splenium of the corpus callosum, and other manifestations of encephalitis [17].
We had 10.4% of patients with headaches in our study which is comparable to another study that reported 13% [9]. US CDC data recorded headache in 34% of patients [8] while they had only 14% hospitalized patients. The incidence of ischemic and hemorrhagic strokes in COVID-19 hospitalized patients have ranged from 0.4 to 2.8% and 0.2 to 0.9% respectively [9,18,19] while our study showed 4.6% ischemic and 0.7% hemorrhagic strokes. In our study, the rate of ischemic stroke is high which is likely due to an overall higher number of patients with known underlying vascular risk factors and severe COVID-19 illness leading to thromboembolic complications [13].
Around 3.1% (13) patients developed intensive care unit-acquired weakness (ICUAW) which comprises critical illness myopathy (CIM), critical illness polyneuropathy (CIP), and a combination of both (CIMP). Three patients had CIM and seven patients had a combination of both critical illness myopathy and critical illness polyneuropathy (CIMP) clinically supported by electrophysiological studies, while three patients were diagnosed clinically as ICUAW after excluding brain and spinal cord pathology as NCS/EMG studies were not possible. None of the patients' samples were sent for biopsy. Among MICU admitted patients, ICUAW developed in 7% of our patients. We do not know the exact incidence of ICUAW in critically ill COVID-19 patients, but one study has shown that 9.9% of the patients developed ICUAW [20].
Anosmia and dysgeusia have been reported in more than 80% of the patients as early symptoms in mild to moderate COVID-19 illness [21,22]. Loss of smell or taste was recorded in 8% of patients in a study by CDC [8]. Similar to our study they reported a loss of taste and smell in 5.6% and 5.1% of patients respectively while our study showed 2.9% of the patients with anosmia and 1.4% had dysgeusia. Most of our patients had severe COVID-19 disease with the majority needing MICU care and probable physicians' unawareness about these symptoms could potentially limit accurate data collection for anosmia and dysgeusia.
Our study showed 28% of patients had myalgia at the onset of their illness. Myalgia has been reported in 36% of the patients in which the majority were managed as outpatients due to mild to moderate disease [8].
Skeletal muscle injury has been reported in 10.7% hospitalized COVID-19 patients [9] while our study showed 39.4% of the patients had evidence of skeletal muscle injury (high serum creatine kinase >300U/L) and 15.7% of the patients had evidence of rhabdomyolysis (high serum creatine kinase >1000 U/L).
The skeletal muscle injury rate in our study is far higher than previously reported. Perhaps the more likely explanations are a higher number of patients with underlying comorbidities, especially obesity and chronic kidney disease, longer MICU care, and stay with higher rates of invasive and non-invasive ventilation due to underlying critical COVID-19 disease, multiorgan involvement, and on top of that, all our patients had CK level checked as a part of the initial protocol.
In addition to respiratory and neurological systems, other multi-organ system involvement in COVID-19 patients were kidney injury, liver injury, myocardial injury, heart failure, acute pancreatitis, and uncontrolled blood glucose in our study. The rates of such multi-organ system involvement were higher in our study compared to other studies [9,23] but similar to another study with critically ill patients [5]. The likely explanations are more sick patients, with a significant number admitted to MICU needing invasive and non-invasive ventilatory support and underlying medical co-morbidities.
This study has several limitations. First, it is a retrospective study that could cause bias in clinical observation. Second, certain patients with milder neurological manifestations as well as lack of physician's knowledge about COVID-19-related neurological manifestations like loss of taste and smell might not be captured as all data were retrieved from the electronic medical records. Third, several patients had critical diseases with multi-organ failure which limit assessing and eliciting neurological signs in such patients. Fourth, during COVID-19 peak and high admissions rate, neuroimaging like magnetic resonance imaging (MRI) and other diagnostic procedures such as electromyography/nerve conduction velocity were limited due to infection control precautions. In our study, therefore, most of the symptoms were a patient's subjective descriptions.

Conclusions
Patients with COVID-19 infection are at higher risk of developing neurological manifestations. The most common COVID-19 related acute neurological manifestations were myalgia, headache, dizziness, and acute ischemic stroke. Prompt recognition, early diagnosis and appropriate management of these manifestations could potentially lead to better patient outcomes in COVID-19 patients. We need prospective randomized control trials to understand and capture all neurological manifestations in COVID-19 patients.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Medical Research Center of Hamad Medical Corporation, Doha issued approval 01-20-437. IRB Protocol ID-MRC-01-20-437 entitled "Acute Neurological Manifestations of COVID-19 Positive Patients in Tertiary Care Hospitals, Qatar" has been approved by MRC. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.