|Ahead of print publication
Neurological manifestations and mortality in hospitalized coronavirus disease 2019 patients
Tugba Ozel1, Nazan Şimşek Erdem1, Ali Ünal1, Ata Nevzat Yalçın2, Dilara İnan2, Nevruz Ilhanli3, Hilmi Uysal1
1 Department of Neurology, Akdeniz University Faculty of Medicine, Antalya, Türkiye
2 Department of Infectious Diseases, Akdeniz University, Antalya, Türkiye
3 Department of Biostatistics, Akdeniz University, Antalya, Türkiye
|Date of Submission||14-Jun-2021|
|Date of Decision||30-Jul-2021|
|Date of Acceptance||07-Nov-2021|
|Date of Web Publication||11-Mar-2022|
Department of Neurology, Akdeniz Universitesi Faculty of Medicine, Pınarbaşı, Antalya 07070
Source of Support: None, Conflict of Interest: None
Purpose: The purpose of the study is to analyze the neurological manifestations and to determine the association between these symptoms and mortality in hospitalized patients with coronavirus disease 2019 (COVID-19). Materials and Methods: Five hundred and forty-seven hospitalized patients with positive reverse transcriptase-polymerase chain reaction tests for severe acute respiratory syndrome coronavirus in a nasopharyngeal swab were included in this study. The demographic features, laboratory data, and radiologic imaging, neurological symptoms of hospitalized patients with COVID-19 were collected. Results: Of 547 hospitalized COVID-19 patients, the median age was 61 (range 18–93), 61.4% were male. Three hundred and forty-seven (63.4%) patients had a severe infection and 200 (36.6%) patients had a mild infection. Eighty-eight patients (16.1%) died during hospitalization. One hundred and fifty-four (28.2%) patients had at least one neurological symptom. Thirty-five (6.4%) patients manifested with only neurological symptoms at hospital admission. The most frequent neurological symptoms were headache (15.2%), taste and smell disorders (9.1%), and myalgia (6.6%). The other initial neurological manifestations were acute cerebral ischemic stroke, impaired consciousness, epileptic seizure, and posterior reversible encephalopathy. The late-onset neurological complications were autoimmune encephalitis and Guillain-Barre syndrome. The neurological manifestation was linked to the severity of disease (P = 0.005) but not correlated with mortality (P = 0.137). Conclusion: Neurological symptoms were frequent in COVID-19 patients. The neurological symptoms can be the initial symptoms or can be late-onset complications of COVID-19.
Keywords: Autoimmune encephalitis, coronavirus disease 2019, late-onset complication, mortality, Neurologic manifestations, sensorineural hearing loss
|How to cite this URL:|
Ozel T, Erdem N&, Ünal A, Yalçın AN, İnan D, Ilhanli N, Uysal H. Neurological manifestations and mortality in hospitalized coronavirus disease 2019 patients. Neurol Sci Neurophysiol [Epub ahead of print] [cited 2022 May 16]. Available from: http://www.nsnjournal.org/preprintarticle.asp?id=339381
| Introduction|| |
Coronavirus disease 2019 (COVID-19), a severe acute respiratory syndrome (SARS) resulting from the SARS coronavirus (SARS-CoV-2) coronavirus, is the most serious pandemic since the 1918 influenza pandemic. SARS-CoV-2 is a beta-coronavirus with single-stranded positive-sense ribonucleic acid. Although SARS-CoV-2 mostly affects the lower respiratory tract, COVID-19 can cause multiorgan disease often involving the nervous system. First, the involvement of the central nervous system (CNS) by SARS-CoV-2 was reported in a patient with viral encephalitis at the beginning of the pandemic. Subsequently, the neurotropism and neuroinvasion properties of SARS-CoV-2 were identified in the literature. In addition, in the literature, various neurological symptoms, ranging from subjective neurological symptoms such as myalgia, taste and smell disorders, headache, and dizziness to more serious complications such as acute cerebrovascular events, encephalopathy, seizures, and Guillian-Barre syndrome (GBS) have been reported in COVID-19 patients. Neurological manifestations of COVID-19 are common, even a previous study has stated that more than 90% of individuals with COVID19 had at least one subjective neurological symptom. The most frequent neurological manifestations in COVID-19 patients are headache, taste and smell dysfunctions, confusion, and dizziness. Furthermore, a previous study has reported that neurological complications were the main reason for mortality in patients with COVID-19. A previous study has stated that impaired consciousness or acute ischemic stroke significantly increased the likelihood of in-hospital mortality separate from disease severity in COVID-19 patients. Conversely, it has been reported that taste and smell disorders and headaches were linked to a lower hospital mortality rate in COVID-19 patients. This study aimed to analyze the neurological manifestations and ascertain the relationship between these symptoms and mortality in COVID-19 patients hospitalized in a single center during a year.
| Materials and Methods|| |
The Health Ministry and the Akdeniz University Ethics Committee (KAEK-841) approved this study. Consecutive patients who had been diagnosed with COVID-19 according to the World Health Organization interim guidance were retrospectively analyzed from March 2020 to March 2021. In this study, we included hospitalized patients with a positive reverse transcriptase-polymerase chain reaction (PCR) test for SARS-CoV-2 in a nasopharyngeal swab. The patients with insufficient medical electronic doctor's records, the patients with age <18 years old, the patients who were transferred to another hospital were excluded from the study. The demographic characteristics included age, gender, and presence of a history of comorbid diseases such as neurological disorders, hypertension, cardiac disease, diabetes, malignancy, chronic kidney disease, and pulmonary disorders of hospitalized patients with COVID-19 were collected from electronic medical records. Radiologic imaging included chest computed tomography (CT), and laboratory data (hemogram, C-reactive protein (CRP), D-dimer, alanine aminotransferase (ALT), and aspartate aminotransferase) were analyzed. The degree of severity of COVID-19 (mild-severe) during hospital admission was determined in accordance with the American Thoracic Society guidelines for community-acquired pneumonia. The patients with severe infection had either one major criterion including septic shock with a need for vasopressors or respiratory failure requiring mechanical ventilation or three or more minor criteria including respiratory rate >30 breaths/min, PaO2/FIO2 ratio <250, multilobar infiltrates, confusion/disorientation, uremia, leukopenia, thrombocytopenia, hypothermia, and hypotension requiring aggressive fluid resuscitation.
Neurological manifestations were categorized into two subclasses: CNS manifestations (headache, impaired consciousness, acute cerebrovascular disease, ataxia, encephalopathy, and seizure) and peripheral nervous system (PNS) manifestations (taste and smell disorders, acute peripheral polyneuropathy, muscle pain, and sensorineural hearing loss). Acute cerebrovascular disease including cerebral hemorrhage and ischemic stroke was determined by clinical symptoms and cranial CT or magnetic resonance imaging (MRI). Acute peripheral polyneuropathy was confirmed by nerve electromyography, clinical neurological examination findings, and the patients' symptoms. Electroencephalography was performed in patients who were suspected of an epileptic seizure.
Data were analyzed using IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY, USA: IBM Corp. Qualitative variables were represented by number and percentage, quantitative variables were represented by median (minimum-maximum). The Shapiro–Wilk normality test was used to examine the normal distribution of the data. Mann–Whitney U-test was used to compare the data between two independent groups. The Chi-square test was used to evaluate the differences between categorical variables. Univariate and multivariate logistic regression was performed to evaluate risk factors for neurological manifestations, disease severity, and mortality. A P < 0.05 was used to evaluate the significance for all statistical analyses.
| Results|| |
Of 547 hospitalized patients, the median age was 61 (range 18–93), 61.4% were male. Four hundred and ten (75%) patients had a history of comorbid diseases. Neurological comorbidities were recorded in 33 (6.1%) patients, cerebrovascular events in 17 patients, dementia in 10 patients, Parkinson's disease in two patients, epilepsy in nine patients, and neuromuscular disorders in two patients. Three hundred and forty-seven (63.4%) patients had a severe infection and 200 (36.6%) patients had a mild infection according to the American Thoracic Society guidelines for community-acquired pneumonia. Eighty-eight patients (16.1%) died during hospitalization. All deaths were in the intensive care unit. Twenty patients of these patients were followed up in the intensive care unit at concomitant of diagnosis of COVID-19. Sixty-eight patients died after transferring to the intensive care unit from the clinical service. Independent risk factors for the severe infection were age (odds ratio [OR]: 1.032, 95% confidence interval [CI]: 1.020–1.043; P < 0.001), the presence of comorbid disease (OR: 1.696, 95% CI: 1.144–2.515; P = 0.009), the presence of neurological symptom (OR: 1.793, 95% CI: 1.192–2.696; P = 0.005), and high level of CRP (OR: 1.075, 95% CI: 1.043–1.108; P < 0.001). Independent risk factors for the mortality were age (OR: 1.061, 95% CI: 1.041–1.081; P < 0.001), the presence of comorbid disease (OR: 2.984, 95% CI: 1.498–5.945; P = 0.002), CRP (OR: 1.144, 95% CI: 1.104–1.185; P < 0.001), high level of leukocytes (OR: 1.106, 95% CI: 1.060–1.155; P < 0.001), reduced level of lymphocytes (OR: 0.551, 95% CI: 0.382–0.794; P = 0.001), and high level of D-Dimer (OR: 1.098 (1.051–1.146; P < 0.001). Univariate and multivariate analyses of the effects of clinical characteristics and laboratory variables on the severity of disease and death in COVID-19 patients are shown in [Table 1].
|Table 1: Univariate and multivariate analyses of the effects of clinical characteristics and laboratory data on the severity of disease and death in coronavirus disease 2019 patients|
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The most common nonneurological symptoms were pulmonary symptoms including cough or dyspnea (59.6%), fever (32.1%), and anorexia, and fatigue (13.5%). Thirty-five (6.4%) patients manifested with only neurological symptoms at hospital admission. One hundred and fifty-four (28.2%) patients had at least one neurological symptom; CNS symptoms in 94 (17.2%), PNS symptoms in 76 (14%) patients. The presence of at least one neurological symptom was more common in the female gender and the patients with the comorbid disease (P = 0.014, P = 0.039, respectively). [Table 2] shows the demographic characteristics and laboratory data of all patients with and without neurological symptoms.
|Table 2: The clinical demographic features and laboratory data of all patients|
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The most frequent neurological symptom at hospital admission was headache (15.2%). Headache was more common in females than males (P = 0.007). The second common neurological symptom was taste and smell disorders (9.1%). Thirty-six (6.6%) patients had myalgia. There was no significant difference among genders for taste and smell disorders and myalgia. Myalgia and taste and smell disorders were associated with severity of disease (P = 0.027, P = 0.025 respectively), but there was no significant difference between headache and severity of disease (P = 0.186). Age and laboratory data were not correlated with headache, myalgia, and taste and smell disorders (all were P > 0.05).
The other neurological manifestations were acute cerebral ischemic stroke, subdural hemorrhage, impaired consciousness, epileptic seizure, posterior reversible encephalopathy (PRES), autoimmune encephalitis, GBS, and sensorineural hearing loss. [Table 3] summarizes the neurological manifestations of hospitalized COVID-19 patients.
|Table 3: The neurological manifestations of hospitalized coronavirus disease 2019 patients|
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Acute ischemic stroke proven with radiological imaging was observed in 6 (1.1%) patients. The mean age of patients with acute ischemic stroke was 75.1 ± 9.1. Acute ischemic stroke in these patients was concurrent with the detection of COVID-19. One of six patients with severe ischemic stroke was treated with thrombolytic therapy at the emergency department and he had no complications of thrombolytic therapy. Acute cerebral ischemic stroke was frequent in the vertebrobasilar territory (five of six patients). Two of six patients died in the hospital. The characteristics of COVID-19 patients with severe ischemic stroke are summarized in [Table 4]. Subdural hemorrhage was recorded in one patient 5 days after being diagnosed with COVID-19.
|Table 4: The characteristics of coronavirus disease 2019 patients with acute ischemic stroke|
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The initial symptom of COVID-19 was impaired consciousness in two patients. The recurrent epileptic seizure was the initial symptom of COVID-19 in an 81-year-old female patient with a normal cranial CT.
A 28-year-old 33-week pregnant woman with a diagnosis of COVID-19 in her husband was admitted to the hospital with complaints of cough, fatigue, diarrhea, headache, blurred vision, and diplopia. Her cerebral MRI showed T2-flair hyperintensity in the bilateral parietal, occipital lobe [Figure 1]. She had SARS-COV-2-PCR positivity and a normal blood pressure range. She developed a generalized tonic-clonic epileptic seizure and underwent a cesarean section (C/S). Her control magnetic resonance (MR) imaging 2 weeks after the follow-up was normal. She was diagnosed with PRES associated with COVID-19.
|Figure 1: (a) Her first magnetic resonance showed T2-flair hyperintensity in the bilateral parietal, occipital lobe. (b) Her control magnetic resonance 2 weeks after diagnosis was normal|
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Autoimmune encephalitis associated with COVID-19 was recorded in two patients. The first case was a 35-year-old male patient with a COVID-19 diagnosis 3 months before admission to the emergency department with convulsive status epilepticus. His cranial MR showed hyperintensity in the right parietal and left frontal lobe on T2 fluid-attenuated inversion recovery images and diffusion-weighted images without contrast enhancement [Figure 2]. His cerebrospinal fluid (CSF) protein was high with 73 mg/dl. There were 64 mg/dL of CSF glucose and 102 mg/dL of simultaneous blood glucose level. CSF analysis revealed no polymorphonuclear leukocytes and lymphocytes. His seizures could be controlled and his control MR imaging [Figure 2] was normal after high-dose steroid and intravenous immunoglobulin treatment.
|Figure 2: (a) His first magnetic resonance imaging showed hyperintensity in the right parietal and left frontal lobe on T2 fluid-attenuated inversion recovery images (b) Control magnetic resonance imaging after treatment showed no abnormality|
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The second patient – a 65-year-old male – who had been diagnosed with COVID-19 a month ago presented to the hospital with a headache and confusion. T2-flair hyperintensity without contrast enhancement in bilateral temporal-parietal and occipital lobe was detected [Figure 3]. His CSF protein was high (118 mg/dl) and CSF glucose level was 67 mg/dl (simultaneous serum glucose level: 103 mg/dl). There were no polymorphonuclear leukocytes and lymphocytes in CSF. After high-dose methylprednisolone treatment for 5 days, his neurological symptoms showed partial improvement. In both patients, neuroimmunology tests were negative in serum and CSF for LGi1 and Caspr 2, anti-CV2 (CRMP-5), NMDA receptor antibodies, anti-Ri, anti-Hu, anti-Yo, anti-Ma-1, anti-Ma-2, anti-amphiphysin, anti-GABA B, an-ti-Tr, and anti-GAD. The culture of CSF was sterile and viral markers were negative in both patients.
|Figure 3: T2-flair imaging showed hyperintensity in bilateral temporal-parietal and occipital lobe|
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A diagnosis of GBS supported by clinical and electroneuromyography was recorded in three patients. All patients with GBS were treated with IVIG at a dose of 0.4 g/kg for 5 days. One of them died after 3 weeks of hospitalization. One patient developed GBS 1 month after the initial symptom of COVID-19, while two patients had GBS during the parainfectious process.
Sensorineural hearing loss was recorded in a 68-year-old male patient without any comorbid disease. Four days after diagnosis of COVID-19 infection, he developed suddenly bilateral hearing loss. His brainstem auditory evoked potential showed the prolonged latencies of the bilateral I, III, and V waves. He was treated with methylprednisolone at 1000 mg dose for 5 days. However, he did not show any improvement.
| Discussion|| |
SARS-CoV-2 enters the host cell through the angiotensin-converting enzyme (ACE) II receptor. ACE II is highly expressed in the alveolar epithelial cells of the lungs and epithelial cells of the gastrointestinal system. ACE II receptors are also expressed in endothelium and vascular smooth muscle cells in the brain. SARS-CoV-2 can damage the blood–brain barrier by the vascular endothelial cell pathway and the immune cell pathway. In addition, SARS-CoV-2 can enter the brain by retrograde axonal transport through the respiratory, olfactory, and enteric nervous systems. When the virus reaches its target, it rapidly replicates and causes cell death or functional impairment. Rapid viral replication, direct cell damage, and activation of the immune system including cytokine storm and hypoxic brain damage are the potential mechanisms of neurological acute and long-term problems caused by the SARS-CoV-2 infection.,
In our series, neurological symptoms were the most frequent disorders associated with COVID-19 after fever and dyspnea. Moreover, 6.4% of patients were diagnosed with COVID-19 with only neurological manifestations. We found that the presence of at least one neurological symptom was more common in the female gender and patients with the comorbid disease. Neurological manifestations were correlated with the severity of the disease but not hospital mortality. Age, presence of comorbidity, high levels of D-dimer, CRP, and leukocytes, and decreased levels of lymphocytes were found to be linked to increased hospital mortality in COVID-19 patients.
In this study, headache was the most frequently observed neurological symptom as indicated in a previous study. We also observed that headache was more common in women than men with COVID-19 patients as indicated in a previous study. On the other hand, another study has reported that COVID-19 related headaches were more frequent in male patients. No association was observed between headache and disease severity and mortality, although a previous study stated that headaches had a negative correlation with severity and mortality.
In this study, the second neurological disorder was taste and smell dysfunction. In the literature, the frequency of smell dysfunction has been reported as high in COVID-19 patients. In the literature, previous studies have reported that smell and taste disorders were linked to a lower likelihood of severe disease and hospital mortality., However, in this study, taste and smell disorders were not associated with hospital mortality. This result may be related to the low number of cases with taste and smell disorders.
In the present study, acute ischemic stroke was the most common serious neurological complication. The incidence (1.1%) of ischemic stroke in our series was similar to the rate (approximately 1%–3%) reported in previous studies., A previous study has shown that mortality and cryptogenic stroke were high in stroke patients with a concurrent diagnosis of COVID-19. On the other hand, a recent study has reported that the rate of cryptogenic stroke did not increase in stroke patients with COVID-19. The pathogenesis of ischemic stroke linked to COVID-19 remains unclear, but cytokine storm-triggered coagulopathy and endotheliopathy may be responsible for pathophysiological mechanisms. The hemorrhagic stroke in our series was a subdural hemorrhage in one patient. Previous studies have also reported a low prevalence of intracerebral hemorrhage (ICH) associated with COVID-19., Furthermore, a systematic review has also shown that the most (71%) of COVID-19 patients with ICH were treated with anticoagulation at the time of ICH.
A new-onset seizure was seen in four patients; it was the initial symptom in one patient, it developed after diagnosis of COVID-19 in the others. In the literature, the rate of seizure associated with COVID-19 has been reported at 0.08% in a previous study. Another study found that the rate of seizures was about 13.2% and the presence of seizures was associated with a high mortality rate in COVID-19 patients. The direct viral invasion of CNS severe electrolyte or metabolic imbalances, hypoxia, multiorgan failure, and inflammatory processes are possible causes of seizures in COVID-19 patients.
In the present study, late-onset neurological complications that presented at least 1 month after diagnosis of COVID-19 were observed; autoimmune encephalitis in two patients and GBS in one patient. In the literature, most case reports with meningitis/encephalitis were concomitant to COVID-19 infection. However, in the literature, we could only find one case report on post-COVID autoimmune encephalitis like our cases. Therefore, we concluded that COVID-19 patients should be followed up closely for at least 6 months for late-onset neurological complications.
Irreversible sensorineural hearing loss in our series was a very rare complication of COVID-19. In the literature, few case reports with sensorineural hearing loss due to COVID-19 infection have been reported., The direct invasion of the virus into the cochlea, inflammatory response, and an increase in cytokines may cause sensorineural hearing loss in COVID-19 patients.
There were several limitations to this retrospective study. The long-term neurological sequelae related to COVID-19 could not be determined since the patients could not be followed up after discharge from the hospital. In addition, we could not evaluate the association between mortality and severe neurological disorders such as acute cerebral ischemic stroke, seizures, impaired consciousness, and encephalopathy because of the small number of COVID-19 patients with these neurological complications. However, we observed that most common neurological symptoms including headaches, taste and smell disorders, and myalgia were not correlated with hospital mortality.
| Conclusion|| |
At least one neurological symptom was observed in about one in three patients with COVID-19. Headache was the most frequent subjective neurological symptom, while acute ischemic stroke was the most frequent serious neurological complication in COVID-19 patients. The initial manifestations of COVID-19 can be an acute ischemic stroke, seizures, impaired consciousness, PRES. Furthermore, COVID-19 may cause serious late-onset neurological complications including such as GBS, autoimmune encephalitis.
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Conflicts of interest
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]