Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China

Study Design and Participants

This retrospective, observational study was done at 3 centers (Main District, West Branch, and Tumor Center) of Union Hospital of Huazhong University of Science and Technology (Wuhan, China). These 3 centers are designated hospitals assigned by the government to treat patients with COVID-19. We retrospectively analyzed consecutive patients from January 16, 2020, to February 19, 2020, who had been diagnosed as having COVID-19, according to WHO interim guidance.⁸ A confirmed case of COVID-19 was defined as a positive result on high-throughput sequencing or real-time reverse-transcription polymerase chain reaction analysis of throat swab specimens. Throat swab samples were collected and placed into a collection tube containing preservation solution for the virus.⁹ A SARS-CoV-2 infection was confirmed by real-time reverse-transcription polymerase chain reaction assay using a SARS-CoV-2 nucleic acid detection kit according to the manufacturer’s protocol (Shanghai bio-germ Medical Technology Co). Radiologic assessments included chest and head CT, and all laboratory testing (a complete blood cell count, blood chemical analysis, coagulation testing, assessment of liver and renal function testing, C-reactive protein, creatine kinase, and lactate dehydrogenase) was performed according to the clinical care needs of the patient. Two hundred fourteen hospitalized patients with laboratory confirmation of SARS-CoV-2 were included in the analysis.⁹ Before enrollment, verbal consent was obtained from patients or an accompanying relative for patients who could not give consent. The study was performed in accordance with the principles of the Declaration of Helsinki. This study was approved and written informed consent was waived by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, on February 20, 2020, owing to the rapid emergence of the disease and the urgent need to collect data.

Data Collection

We reviewed electronic medical records, nursing records, laboratory findings, and radiologic examinations for all patients with laboratory-confirmed SARS-CoV-2 infection and collected data on age, sex, comorbidities (hypertension, diabetes, cardiac or cerebrovascular disease, malignancy, and chronic kidney disease), typical symptoms from onset to hospital admission (fever, cough, anorexia, diarrhea, throat pain, abdominal pain), nervous system symptoms, laboratory findings, and CT scan (chest and head if available). Subjective symptoms were provided by patients who were conscious, cognitively and mentally normal, and linguistically competent to respond to interview. Any missing or uncertain records were collected and clarified through direct communication with involved patients, health care clinicians, and their families. We defined the degree of severity of COVID-19 (severe vs nonsevere) at the time of admission using the American Thoracic Society guidelines for community-acquired pneumonia.¹⁰

All neurologic manifestations were reviewed and confirmed by 2 trained neurologists. Major disagreement between 2 reviewers was resolved by consultation with a third reviewer. Neurologic manifestations were categorized into 3 categories: central nervous system (CNS) manifestations (dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and seizure), peripheral nervous system (PNS) manifestations (taste impairment, smell impairment, vision impairment, and nerve pain), and skeletal muscular injury manifestations. Impaired consciousness includes the change of consciousness level (somnolence, stupor, and coma) and consciousness content (confusion and delirium). To avoid cross-infection during the outbreak, we had to minimize patients going out for examination. Therefore, the diagnosis of nervous system manifestations mainly depended on the subjective symptoms of patients and the examinations available. Acute cerebrovascular disease includes ischemic stroke and cerebral hemorrhage diagnosed by clinical symptoms and head CT. Seizure is based on the clinical symptoms at the time of presentation. Skeletal muscle injury was defined as when a patient had skeletal muscle pain and elevated serum creatine kinase level greater than 200 U/L (to convert to microkatals per liter, multiply by 0.0167).⁷

Statistical Analysis

For baseline data, mean and standard deviations (SD) were used for normally distributed data and median and range for data that were not normally distributed. Categorical variables were expressed as counts and percentages. Continuous variables were compared by using the Wilcoxon rank sum test. Proportions for categorical variables were compared using the χ² test. All statistical analyses were performed using R, version 3.3.0, software (the R Foundation). The significance threshold was set at a 2-sided P value less than .05.

Demographic and Clinical Characteristics

A total of 214 hospitalized patients with confirmed SARS-CoV-2 infection were included in the analysis. Their demographic and clinical characteristics were shown in Table 1. Their mean (SD) age was 52.7 (15.5) years, and 87 were men (40.7%). Of these patients, 83 (38.8%) had at least 1 of the following underlying disorders: hypertension (51 [23.8%]), diabetes (30 [14.0%]), cardiac or cerebrovascular disease (15 [7.0%]), and malignancy (13 [6.1%]). The most common symptoms at onset of illness were fever (132 [61.7%]), cough (107 [50.0%]), and anorexia (68 [31.8%]). Seventy-eight patients (36.4%) had nervous system manifestations: CNS (53 [24.8%]), PNS (19 [8.9%]), and skeletal muscle injury (23 [10.7%]). In patients with CNS manifestations, the most common reported symptoms were dizziness (36 [16.8%]) and headache (28 [13.1%]). In patients with PNS symptoms, the most common reported symptoms were taste impairment (12 [5.6%]) and smell impairment (11 [5.1%]).

According to the American Thoracic Society guidelines for community-acquired pneumonia,¹⁰ 88 patients (41.1%) had severe infection and 126 patients (58.9%) had nonsevere infection. The patients with severe infection were significantly older (mean [SD] age, 58.2 [15.0] years vs 48.9 [14.7] years; P < .001) and more likely to have other underlying disorders (42 [47.7%] vs 41 [32.5%]; P = .03), especially hypertension (32 [36.4%] vs 19 [15.1%]; P < .001), and had fewer typical symptoms of COVID-19 such as fever (40 [45.5%] vs 92 [73%]; P < .001) and dry cough (30 [34.1%] vs 77 [61.1%]; P < .001). Moreover, nervous system manifestations were significantly more common in severe infections compared with nonsevere infections (40 [45.5%] vs 38 [30.2%], P = .02). They included acute cerebrovascular disease (5 [5.7%]; 4 patients with ischemic stroke and 1 with cerebral hemorrhage who died later of respiratory failure; vs 1 [0.8%]; 1 patient with ischemic stroke; P = .03, Figure), impaired consciousness (13 [14.8%] vs 3 [2.4%]; P < .001), and skeletal muscle injury (17 [19.3%] vs 6 [4.8%]; P < .001). In the severe group, 1 patient had a seizure characterized by a sudden onset of limb twitching, foaming in the mouth, and loss of consciousness, which lasted for 3 minutes.

Apart from cerebrovascular disease and impaired consciousness, most neurologic manifestations occurred early in the illness (median time, 1-2 days). Of 6 patients with acute cerebrovascular disease, 2 arrived at the emergency department owing to sudden onset of hemiplegia but without any typical symptoms (fever, cough, anorexia, and diarrhea) of COVID-19. Their lung lesions were found by an emergent lung CT and were diagnosed as having COVID-19 by a positive SARS-CoV-2 nucleic acid detection in the later stage. Some patients with fever and headache were admitted to the neurology ward after initially being ruled out of COVID-19 by routine blood test results and a screening lung CT in the clinic. However, several days later, they had typical COVID-19 symptoms such as cough, throat pain, lower lymphocyte count, and ground-glass opacity appearance on lung CT. Their diagnosis of COVID-19 was confirmed by a positive nucleic acid test and then they were transferred to the isolation ward.

Laboratory Findings in Patients and With Severe and Nonsevere Infection

Table 2 showed the laboratory findings in severe and nonsevere subgroups. Patients with severe infection had more increased inflammatory response, including higher white blood cell counts, neutrophil counts, lower lymphocyte counts, and increased C-reactive protein levels compared with those patients with nonsevere infection (white blood cell count: median, 5.4 × 10⁹/L [range, 0.1-20.4] vs 4.5 × 10⁹/L [range, 1.8-14.0]; P < .001; neutrophil: median, 3.8 × 10⁹/L [range, 0.0-18.7] vs 2.6 × 10⁹/L [range, 0.7-11.8]; P < .001; lymphocyte count: median, 0.9 × 10⁹/L [range, 0.1-2.6] vs 1.3 × 10⁹/L [range, 0.4-2.6]; P < .001; C-reactive protein: median, 37.1 mg/L [range, 0.1-212.0] vs 9.4 mg/L [range, 0.2-126.0]; P < .001). The patients with severe infection had higher D-dimer levels than patients with nonsevere infection (median, 0.9 mg/L [range, 0.1-20.0] vs 0.4 mg/L [range, 0.2-8.7]; P < .001), which was indicative of consumptive coagulation system. In addition, patients with severe infection had multiple organ involvement, such as serious liver (increased lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase levels), kidney (increased blood urea nitrogen and creatinine levels), and skeletal muscle damage (increased creatinine kinase levels).

Laboratory Findings in Patients With and Without CNS Symptoms

Table 3 showed the laboratory findings of patients with and without CNS symptoms. We found that patients with CNS symptoms had lower lymphocyte levels, platelet counts, and higher blood urea nitrogen levels compared with those without CNS symptoms (lymphocyte count: median, 1.0 × 10⁹/L [range, 0.1-2.3] vs 1.2 × 10⁹/L [range, 0.2-2.6], P = .049; platelet count: median, 180.0 × 10⁹/L [range, 18.0-564.0] vs 227.0 × 10⁹/L [range, 42.0-583.0], P = .005; blood urea nitrogen: median, 4.5 mmol/L [range, 1.6-48.1] vs 4.1 mmol/L [range, 1.5-19.1], P = .04). For the severe subgroup, patients with CNS symptoms also had lower lymphocyte levels and platelet counts and higher blood urea nitrogen levels compared with those without CNS symptoms (lymphocyte count: median, 0.7 × 10⁹/L [range, 0.1-1.6] vs 0.9 × 10⁹/L [range, 0.2-2.6], P = .007; platelet count: median, 169.0 × 10⁹/L [range, 18.0-564.0] vs 220.0 × 10⁹/L [range, 109.0-576.0], P = .04; blood urea nitrogen: median, 5.0 mmol/L [range, 2.3-48.1] vs 4.4 mmol/L [range, 1.5-19.1], P = .04). For the nonsevere subgroup, there were no significant differences in laboratory findings of patients with and without CNS symptoms.

Laboratory Findings in Patients With and Without PNS Symptoms

Table 4 showed the laboratory findings of patients with and without PNS symptoms. We found that there were no significant differences in laboratory findings of patients with PNS and those without PNS. Similar results were also found in the severe subgroup and nonsevere subgroup, respectively.

Laboratory Findings in Patients With and Without Skeletal Muscle Injury

The eTable in the Supplement shows the laboratory findings of patients with and without skeletal muscle injury. Compared with the patients without muscle injury, patients with muscle injury had significantly higher levels of creatine kinase (median, 400.0 U/L [range 203.0-12216.0] vs median, 58.5 U/L [range 8.8-212.0]; P < .001), regardless of their severity. Meanwhile, patients with muscle injury had higher neutrophil counts, lower lymphocyte counts, higher C-reactive protein levels, and higher D-dimer levels. The abnormalities were manifestations of increased inflammatory response and blood coagulation function. In addition, we found that patients with muscle injury had multiorgan damage, including more serious liver (increased lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase levels) and kidney (increased blood urea nitrogen and creatinine levels) abnormalities.

For the severe group, patients with skeletal muscle injury had decreased lymphocyte counts and more serious liver injury (increased lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase levels) and kidney injury (increased creatinine levels).

Limitations

This study has several limitations. First, only 214 patients were studied, which could cause biases in clinical observation. It would be better to include more patients from Wuhan, other cities in China, and even other countries. Second, all data were abstracted from the electronic medical records; certain patients with neurologic symptoms might not be captured if their neurologic manifestations were too mild, such as with taste impairment and smell impairment. Third, because most patients were still hospitalized and information regarding clinical outcomes was unavailable at the time of analysis, it was difficult to assess the effect of these neurologic manifestations on their outcome, and continued observations of the natural history of disease are needed. Fourth, during the outbreak period of COVID-19, because of the influx of many patients infected with SARS-CoV-2, advanced neuroimaging, such as magnetic resonance imaging and diagnostic procedures such as lumbar puncture and electromyography/nerve conduction velocity, was purposefully avoided to reduce the risk of cross infection. Therefore, in our study, most of the symptoms were a patient’s subjective descriptions. We could not distinguish whether these neurologic manifestations are caused by the virus directly or by the pulmonary disease or other organ damage indirectly.