Abstract
Background
Neurological involvement associated with SARS‐CoV‐2 infection has been reported from different regions of the world. However, data from South East Asia are scarce. We described the neurological manifestations and their associated factors among the hospitalized COVID‐19 patients from an academic tertiary hospital in Malaysia.
Methods
A cross‐sectional observational study of hospitalized COVID‐19 patients was conducted. The neurological manifestations were divided into the self‐reported central nervous system (CNS) symptoms, stroke associated symptoms, symptoms of encephalitis or encephalopathy and specific neurological complications. Multiple logistic regression was performed using demographic and clinical variables to determine the factors associated with outcome.
Results
Of 156 hospitalized COVID‐19 patients with mean age of 55.88 ± 6.11 (SD) years, 23.7% developed neurological complications, which included stroke, encephalitis and encephalopathy. Patients with neurological complications were more likely to have diabetes mellitus (p = 0.033), symptoms of stroke [limb weakness (p < 0.001), slurred speech (p < 0.001)]; and encephalitis or encephalopathy [confusion (p < 0.001), forgetfulness (p = 0.006) and seizure (p = 0.019)]. Unvaccinated patients had a 4.25‐fold increased risk of having neurological complications (adjusted OR = 4.25; 95% CI: 1.02, 17.71, p = 0.047). Anosmia and dysgeusia were less associated with neurological complications (adjusted OR = 0.22; 95% CI: 0.05, 0.96, p = 0.044). The odds of neurological complications were increased by 18% in patients with leukocytosis (adjusted OR = 1.18, 95% CI: 1.003, p = 0.0460).
Conclusions
Stroke, encephalitis and encephalopathy were the common neurological complications from our study. Diabetes mellitus, presence of symptoms of stroke, symptoms of encephalitis or encephalopathy, leukocytosis, and being unvaccinated against COVID‐19 were the associated risk factors of developing neurological complications.
Keywords: encephalitis, encephalopathy, neurological manifestations, SARS‐CoV‐2, stroke
1. INTRODUCTION
The coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2) has spread from its origin in Wuhan, China, since December 2019. It was officially declared as a pandemic on 11 March 2020 by the World Health Organization (WHO).
Although the upper respiratory tract is the main target, extra‐pulmonary manifestations are not uncommon. Viral neuroinvasion by SARS‐CoV‐2 via systemic vascular dissemination or local entry across the cribriform plate of the ethmoid bone. The virus invades neural tissue through neurotropism where it binds and interacts with angiotensin‐converting enzyme 2 (ACE2) receptors in the capillary endothelium. 1 The neurological manifestations of SARS‐CoV‐2 infection are broadly classified into the central and peripheral nervous system disorders (PNS).
The diverse neurological features include self‐reported symptoms, such as anosmia and dysgeusia, 2 neuropathic pain, myalgia and dizziness. 3 The neurological syndromes reported encompass stroke, 2 , 3 , 4 , 5 seizures, 2 , 6 acute encephalopathy, 4 acute hemorrhagic necrotizing encephalopathy, 7 meningitis/encephalitis, 8 myelitis 9 and myopathies. 10 Evidence of PNS involvement was seen in Guillain‐Barré syndrome, 11 , 12 polycranialis neuritis and Miller Fisher syndrome. 13 Regional studies by Koh et al. demonstrated a similar range of neurological manifestations such as acute disseminated encephalomyelitis and encephalitis, cerebrovascular disorders, cerebral venous thrombosis and mono/polyneuropathies. 14
The neurological manifestations of COVID‐19 patients may be variable due to regional disparities. The substantial heterogeneity in both the prevalence and severity of neurological dysfunction hampers efforts for an accurate analysis of the data. There are limited studies in South East Asia to address this pertinent issue with objective clinical case definitions. Despite the heavy COVID‐19 burden in the region, the evaluation of the neurological complications is poorly represented in global research. The effects of neurological complications are profound, which can add burden to the healthcare system. To address these gaps, we conducted this study to determine the incidence of neurological abnormalities, and to analyze their associated factors among the hospitalized COVID‐19 patients from an academic tertiary hospital in Malaysia.
2. MATERIALS AND METHODS
2.1. Study design, eligibility criteria
This cross‐sectional observational study was carried out at the Universiti Kebangsaan Malaysia Medical Centre from 1 July 2021 to 31 December 2021. Participants recruited were confirmed COVID‐19 patients referred for tertiary care either from the primary or private healthcare centers. Participants were diagnosed with COVID‐19 via qualitative reverse transcription polymerase chain reaction (RT‐PCR) from the nasopharyngeal and/or oropharyngeal swab, with a cycle threshold value below 45. Consent was obtained prior to clinical assessment by two neurologists independently.
Neurological manifestations elicited were divided into general symptoms of COVID‐19 (fever, running nose, cough, sore throat and shortness of breath), self‐reported central nervous system (CNS) symptoms (anosmia, dysgeusia, headache, blurring of vision and dizziness), stroke‐associated symptoms (limb weakness, numbness, speech problems), symptoms of encephalitis or encephalopathy (confusion, forgetfulness, seizures) and specific neurological complications (stroke, encephalitis, encephalopathy, cerebral venous thrombosis, critical illness polyneuropathy and status epilepticus). Stroke is a clinical syndrome encompassing a wider range of symptoms, which would also fall under the category of self‐reported stroke‐associated symptoms, for example, dizziness. The diagnosis of stroke was established with neuroimaging; and encephalitis with neuroimaging as well as lumbar puncture.
The association between the neurological manifestation observed and COVID‐19 infection was graded ‘probable’ or ‘possible’ using the case definitions by Ellul et al. 15 Probable is defined by (1) SARS‐CoV‐2 being detected in respiratory or other non‐CNS sample, or evidence of SARS‐CoV‐2‐specific antibody in serum indicating a acute infection; and (2) no other explanatory pathogen or cause found; whereas possible is defined if the patient meets the suspected case definition of COVID‐19 according to the national or WHO guidance on the basis of clinical symptoms and epidemiological risk factors, in the context of known community SARS‐CoV‐2 transmission, with supportive features including any of the following: new onset of cough, fever, muscle aches, loss of smell, or loss of taste and lymphopenia. The severity of patients with COVID‐19 was divided into five clinical categories according to our local guideline; 1‐asymptomatic, 2‐symptomatic, 3‐evidence of pneumonia, 4‐oxygen supplement requirement, and 5‐intubated and/or multiorgan failure. 16
Data on the demographics, clinical history, vaccination status and laboratory findings were subsequently collated. This study was approved by the Institutional Review Board of our hospital (JEP‐2021‐589).
2.2. Statistical analysis
Data were explored and analyzed using SPSS software version 21.0. Numerical variables were presented using the mean and standard deviation. Categorical variables were presented as frequency and percentage. Distributions of continuous variables between COVID‐19 infection with and without neurological complications were compared using Student's t tests; Pearson's chi‐square tests or Fisher's exact tests were used for distributions of categorical variables. Statistical significance was defined by a p value of less than 0.05. Simple logistic regression and multiple logistic regression were used to determine the risk factors associated with neurological complications among the COVID‐19 patients without or with adjustment of covariates. All odd ratios (ORs) were presented with 95% confidence interval (CI).
3. RESULTS
Of 156 COVID‐19 patients, who were admitted to our hospital during the study period, 23.7% (n = 37) of them had neurological complications. They comprised stroke 17.9% (28/156), encephalitis 3.8% (6/156), encephalopathy 3.2% (5/156), status epilepticus 2.6% (4/156), cerebral venous thrombosis 1.3% (2/156) and critical illness polyneuropathy 0.6% (1/156). The distribution of different stroke subtypes was as follows; total anterior circulation 3.6% (1/28), partial anterior circulation 7.1% (2/28), posterior circulation 28.6% (8/28) and lacunar syndrome 60.7% (17/28). The demographic characteristics of our patients with and without neurological complications are shown in Table 1. The mean time from the onset of COVID‐19 symptoms to hospital admission and mean length of hospitalization were 4.72 and 16.58 days, respectively. More than three‐quarters of the patients 78.8% (123) were discharged well with no neurological deficits, 7.1% (11) remained bedbound and 14.1% (22) died.
TABLE 1.
Demographic characteristics of hospitalized COVID‐19 patients with and without neurological complications
| Without neurological complications | With neurological complications | p value | |||
|---|---|---|---|---|---|
| N = 119 | N = 37 | ||||
| Mean (SD) | n (%) | Mean (SD) | n (%) | ||
| Sociodemographics | |||||
| Age | 55.30 (16.52) | 57.73 (14.76) | 0.425 a | ||
| Gender | |||||
| Male | 63 (52.9) | 23 (62.2) | 0.325 b | ||
| Female | 56 (47.1) | 14 (37.8) | |||
| Race | |||||
| Malay | 76 (63.9) | 18 (48.6) | 0.197 b | ||
| Chinese | 28 (23.5) | 15 (40.5) | |||
| Indian | 8 (6.7) | 3 (8.1) | |||
| Others | 7 (5.9) | 1 (2.7) | |||
| Underlying medical illness | |||||
| No | 30 (25.2) | 8 (21.6) | 0.657 b | ||
| Yes | 89 (74.8) | 29 (78.4) | |||
| Vaccination status | |||||
| No | 33 (27.7) | 22 (59.5) | <0.001 b | ||
| Yes | 86 (72.3) | 15 (40.5) | |||
| Clinical parameters | |||||
| General symptoms at presentation | |||||
| No | 13 (10.9) | 11 (29.7) | 0.006 b | ||
| Yes | 106 (89.1) | 26 (70.3) | |||
| CNS symptoms at presentation | |||||
| No | 54 (45.4) | 25 (67.6) | 0.018 b | ||
| Yes | 65 (54.6) | 12 (32.4) | |||
| Stroke symptoms at presentation | |||||
| No | 114 (95.8) | 9 (24.3) | <0.001 b | ||
| Yes | 5 (4.2) | 28 (75.7) | |||
| Symptoms of encephalitis & encephalopathy at presentation | |||||
| No | 111 (93.3) | 23 (62.2) | <0.001 b | ||
| Yes | 8 (6.7) | 14 (37.8) | |||
| Severity of COVID‐19 infection | |||||
| Category 1 | 10 (8.4) | 4 (10.8) | 0.031 b | ||
| Category 2 | 18 (15.1) | 5 (13.5) | |||
| Category 3 | 30 (35.2) | 3 (8.1) | |||
| Category 4 | 48 (40.3) | 14 (37.8) | |||
| Category 5 | 13 (10.9) | 11 (29.7) | |||
| Laboratory investigations | |||||
| Hemoglobin | 12.91 (2.42) | 13.87 (2.51) | 0.039 a | ||
| White cell count | 8.23 (3.14) | 11.16 (5.23) | 0.002 a | ||
| ALC | 1.42 (0.78) | 1.71 (1.55) | 0.134 a | ||
| Sodium | 134.24 (5.13) | 136.54 (9.40) | 0.162 a | ||
| CRP | 15.95 (91.19) | 8.68 (8.79) | 0.630 a | ||
| ALT | 49.90 (76.45) | 35.86 (24.63) | 0.274 a | ||
| Creatinine | 143.22 (227.13) | 156.70 (119.57) | 0.730 a | ||
Abbreviations: ALC, absolute lymphocyte count; ALT, alanine transaminase; CRP, C‐reactive protein.
Student's t test.
Pearson's Chi‐Square test.
There was no significant difference in patients' age, gender, race and preexisting medical illness between groups with and without neurological complications. The mean age was 55.88 ± 6.11 (SD) years during admission, and more than 70% of the patients had comorbidities. Table 2 summarizes the comorbidities among our participants. In the group with neurological complications, there were more patients with diabetes mellitus at baseline compared to those without (p = 0.033). No significant statistical difference was observed in other medical illnesses between both groups. Unvaccinated patients (59.5%) developed more neurological complications compared to the vaccinated group (27.7%; p < 0.001).
TABLE 2.
Comorbidities among COVID‐19 patients
| Without neurological complications | With neurological complications | p value | |
|---|---|---|---|
| N = 119 (%) | N = 37 (%) | ||
| Diabetes mellitus | |||
| No | 72 (60.5) | 15 (40.5) | 0.033 a |
| Yes | 47 (39.5) | 22 (59.5) | |
| Hypertension | |||
| No | 61 (51.3) | 15 (40.5) | 0.255 a |
| Yes | 58 (48.7) | 22 (59.5) | |
| Ischemic heart disease | |||
| No | 97 (81.5) | 30 (81.1) | 0.953 a |
| Yes | 22 (18.5) | 7 (18.9) | |
| Heart failure | |||
| No | 117 (98.3) | 36 (97.3) | 0.559 b |
| Yes | 2 (1.7) | 1 (2.7) | |
| Dyslipidemia | |||
| No | 98 (82.4) | 29 (78.4) | 0.587 a |
| Yes | 21 (17.6) | 8 (21.6) | |
| Stroke | |||
| No | 111 (93.3) | 31 (83.8) | 0.099 b |
| Yes | 8 (6.7) | 6 (16.2) | |
| Chronic kidney disease | |||
| No | 106 (89.1) | 31 (83.8) | 0.396 b |
| Yes | 13 (10.9) | 6 (16.2) | |
| Pulmonary tuberculosis | |||
| No | 114 (95.8) | 37 (100.0) | 0.593 b |
| Yes | 5 (4.2) | 0 (0) | |
| Hyperthyroidism | |||
| No | 116 (97.5) | 36 (97.3) | >0.999 b |
| Yes | 3 (2.5) | 1 (2.7) | |
| Atrial fibrillation | |||
| No | 115 (96.6) | 35 (94.6) | 0.628 b |
| Yes | 4 (3.4) | 2 (5.4) | |
| Chronic obstructive pulmonary disease | |||
| No | 116 (97.5) | 37 (100.0) | >0.999 b |
| Yes | 3 (2.5) | 0 (0) | |
| Bronchial asthma | |||
| No | 109 (91.6) | 37 (100.0) | 0.118 b |
| Yes | 10 (8.4) | 0 (0) | |
Pearson's Chi‐Square test.
Fisher's Exact test.
In terms of symptoms at presentation, most patients without neurological complications presented with general symptoms of COVID‐19 (fever, running nose, cough, sore throat and shortness of breath), and self‐reported CNS symptoms (anosmia, dysgeusia, headache, blurred vision and dizziness) compared to those with neurological complications, p = 0.006 and p = 0.018, respectively. In the group with neurological complications, more patients had symptoms of stroke (75%) and encephalitis or encephalopathy (37.8%) at presentation compared to the group with non‐neurological complications, 4.2% and 6.7%, respectively (p < 0.001). Regarding the severity of COVID‐19 infection, patients classified with category 5 had higher incidences of neurological complications (p = 0.031).
Patients with neurological complications had higher hemoglobin level and white cell count compared with those without (p = 0.039 and p = 0.002, respectively). Other clinical parameters such as absolute lymphocyte count (ALC), sodium, C‐reactive protein (CRP), alanine transaminase (ALT) and serum creatinine (Cr) were statistically non‐significant between these two groups.
Self‐reported CNS symptoms included anosmia 36.5% (n = 57), dysgeusia 33.3% (n = 52), headache 25.6% (n = 40), blurring of vision 9% (n = 14) and dizziness 9.6% (n = 15). The stroke symptoms were limb weakness 19.9% (n = 31), numbness 1.9% (n = 3) and speech problems 5.8% (n = 9). The stroke subtypes included total anterior circulation, partial anterior circulation, posterior circulation, and lacunar syndrome. The symptoms of encephalitis and encephalopathy consisted of confusion 15.4% (n = 24), forgetfulness 5.8% (n = 9) and seizures 5.1% (n = 8).
A subgroup analysis was performed to explore the characteristics of stroke symptoms, symptoms of encephalitis or encephalopathy and self‐reported CNS symptoms among COVID‐19 patients as shown in Table 3. In terms of stroke‐associated symptoms, the most common symptoms in patients with neurological complications were limb weakness (p < 0.001) and slurred speech (p < 0.001). Patients with neurological complications presented more with symptoms of encephalitis or encephalopathy, such as confusion (p < 0.001), forgetfulness (p = 0.006) and seizure (p = 0.019) compared with those without. Anosmia (p = 0.011) and dysgeusia (p = 0.011) were less observed in patients with neurological complications. Symptoms such as headache, blurred vision and dizziness were not specific symptoms for patients with neurological complications.
TABLE 3.
Characteristics of stroke symptoms, symptoms of encephalitis & encephalopathy and self‐reported CNS symptoms
| Without neurological complications | With neurological complications | p value | |
|---|---|---|---|
| N = 119 (%) | N = 37 (%) | ||
| Stroke symptoms | |||
| Limb weakness | |||
| No | 116 (97.5) | 9 (24.3) | <0.001 a |
| Yes | 3 (2.5) | 28 (75.7) | |
| Numbness | |||
| No | 116 (97.5) | 37 (100.0) | >0.999 b |
| Yes | 3 (2.5) | 0 (0) | |
| Speech problem | |||
| No | 118 (99.2) | 29 (78.4) | <0.001 a |
| Yes | 1 (0.8) | 8 (21.6) | |
| Symptoms of encephalitis & encephalopathy | |||
| Confusion | |||
| No | 117 (98.3) | 25 (67.6) | <0.001 b |
| Yes | 2 (1.7) | 12 (32.4) | |
| Forgetfulness | |||
| No | 116 (97.5) | 31 (83.8) | 0.006 b |
| Yes | 3 (2.5) | 6 (16.2) | |
| Seizure | |||
| No | 116 (97.5) | 32 (86.5) | 0.019 b |
| Yes | 3 (2.5) | 5 (13.5) | |
| Self‐reported CNS symptoms | |||
| Anosmia | |||
| No | 69 (58.0) | 30 (81.1) | 0.011 a |
| Yes | 50 (42.0) | 7 (8.9) | |
| Dysgeusia | |||
| No | 73 (61.3) | 31 (83.8) | 0.011 a |
| Yes | 46 (38.7) | 6 (16.2) | |
| Headache | |||
| No | 86 (72.3) | 30 (81.1) | 0.284 a |
| Yes | 33 (27.7) | 7 (18.9) | |
| Blurred vision | |||
| No | 107 (89.9) | 35 (94.6) | 0.521 b |
| Yes | 12 (10.1) | 2 (5.4) | |
| Dizziness | |||
| No | 108 (90.8) | 33 (89.2) | 0.755 b |
| Yes | 11 (9.2) | 4 (10.8) | |
Pearson's Chi‐Square test.
Fisher's Exact test.
Table 4 summarizes the associated factors of neurological complications among our subjects. These factors were analyzed using simple logistic regression with no adjustment for other covariates. There were several factors that might be associated with or predict neurological complications among the COVID‐19 patients. These factors were diabetes mellitus at baseline, vaccination status, clinical parameters such as hemoglobin and white cell counts, and symptoms at presentation including general symptoms, self‐reported CNS symptoms, stroke symptoms and symptoms of encephalitis or encephalopathy, p < 0.05. Patients with encephalitis associated with SARS‐CoV‐2 confirmed in CSF are described in Table 5.
TABLE 4.
Associated risk factors of neurological complications among COVID‐19 patients
| Variables | Simple logistic regression | Multiple logistic regression a | ||||
|---|---|---|---|---|---|---|
| b | Crude OR (95% CI) | p | b | Adjusted OR (95% CI) | p | |
| Age | 0.01 | 1.01 (0.99, 1.03) | 0.423 | |||
| Gender | ||||||
| Male | 0 | 1 | ||||
| Female | −0.38 | 0.69 (0.32, 1.46) | 0.326 | |||
| Race | ||||||
| Malay | 0 | 1 | ||||
| Chinese | 0.82 | 2.26 (1.01, 5.09) | 0.048 | |||
| Indian | 0.46 | 1.58 (0.38, 6.57) | 0.527 | |||
| Others | −0.51 | 0.60 (0.07, 5.22) | 0.646 | |||
| Diabetes mellitus | ||||||
| No | 0 | 1 | ||||
| Yes | 0.81 | 2.25 (1.06, 4.77) | 0.035 | |||
| Vaccination status | ||||||
| Yes | 0 | 1 | 0 | 1 | ||
| No | 1.34 | 3.82 (1.77, 8.25) | 0.001 | 1.45 | 4.25 (1.02, 17.71) | 0.047 |
| General symptoms at presentation | ||||||
| No | 0 | 1 | ||||
| Yes | −1.24 | 0.29 (0.12, 0.72) | 0.008 | |||
| Self‐reported CNS symptoms at presentation | ||||||
| No | 0 | 1 | 0 | 1 | ||
| Yes | −0.92 | 0.40 (0.18, 0.87) | 0.020 | −1.52 | 0.22 (0.05, 0.96) | 0.044 |
| Stroke symptoms at presentation | ||||||
| No | 0 | 1 | 0 | 1 | ||
| Yes | 4.26 | 70.93 (22.04, 228.27) | <0.001 | 4.88 | 131.09 (26.84, 640.37) | <0.001 |
| Symptoms of encephalitis & encephalopathy at presentation | ||||||
| No | 0 | 1 | 0 | 1 | ||
| Yes | 2.13 | 8.45 (3.18, 22.46) | <0.001 | 2.32 | 10.22 (1.94, 53.85) | 0.006 |
| Severity of COVID‐19 infection | ||||||
| Category 1 | 0 | 1 | ||||
| Category 2 | −0.37 | 0.69 (0.15, 3.19) | 0.639 | |||
| Category 3 | −1.39 | 0.25 (0.05, 1.31) | 0.102 | |||
| Category 4 | −0.32 | 0.73 (0.20, 2.69) | 0.635 | |||
| Category 5 | 0.75 | 2.12 (0.52, 8.67) | 0.298 | |||
| Laboratory investigations | ||||||
| Hemoglobin | 0.17 | 1.18 (1.01, 1.39) | 0.042 | |||
| Total white cell | 0.19 | 1.21 (1.09, 1.34) | <0.001 | 0.16 | 1.18 (1.003, 1.38) | 0.046 |
| ALC | 0.25 | 1.28 (0.91, 1.80) | 0.164 | |||
| Sodium | 0.06 | 1.06 (0.99, 1.12) | 0.076 | |||
| Creatinine | 0.0003 | 1.00 (0.999, 1.002) | 0.729 | |||
| CRP | −0.002 | 0.998 (0.988, 1.008) | 0.686 | |||
| ALT | −0.005 | 0.995 (0.985, 1.005) | 0.302 | |||
Note: Hosmer‐Lemshow test (p = 0.433), classification table (overall correctly classified percentage = 92.9%) and Nagelkerke R 2 (0.749) were applied to check the model fitness.
General symptoms of COVID‐19: Fever, running nose, cough, sore throat, shortness of breath.
Abbreviations: ALC, absolute lymphocyte count; ALT, alanine transaminase; CRP, C‐reactive protein.
Multiple Logistic Regression with Forward LR method was applied.
TABLE 5.
Characteristics of patients with encephalitis associated with SARS‐CoV‐2 detected in their CSF
| Patient | 1 | 2 | 3 | 4 | 5 | 6 |
|---|---|---|---|---|---|---|
| Age | 44‐year‐old | 28‐year‐old | 72‐year‐old | 48‐year‐old | 16‐year‐old | 54‐year‐old |
| Gender | Female | Male | Male | Male | Female | Male |
| Comorbidities | Subclinical hyperthyroidism | Nil | Diabetes Mellitus | Diabetes Mellitus | Nil | Diabetes Mellitus, Hypertension |
| Clinical presentation | Confusion | Seizure | Confusion | Confusion, Headache | Headache | Fever, Sore throat, Confusion |
| SARS‐CoV‐2 de in CSF | Positive | Positive | Positive | Positive | Positive | Positive |
| Outcome | Discharged well with no neurological deficits on day 13 of hospitalization | Discharged well with no neurological deficits on day 9 of hospitalization | Discharged well with no neurological deficits on day 28 of hospitalization | Discharged well with no neurological deficits on day 28 of hospitalization | Discharged well with no neurological deficits on day 26 of hospitalization | Discharged well with no neurological deficits on day 12 of hospitalization |
Multiple logistic regression was performed to address the confounders and identify factors independently related to the neurological complications of COVID‐19. After adjusting all the covariates, we found that unvaccinated patients were 4.25 times more likely to have neurological complications after COVID‐19 compared to vaccinated patients (adjusted OR = 4.25; 95% CI: 1.02, 17.71, p = 0.047). Patients presenting with stroke symptoms had a high risk of developing neurological complications (adjusted OR = 131.09; 95% CI: 26.84, 640.37, p < 0.001). In addition, symptoms of encephalitis at presentation were 10 times more likely to be associated with neurological complications (adjusted OR = 10.22; 95% CI: 1.94, 53.85, p = 0.06). Presenting CNS symptoms such as anosmia and dysgeusia were less likely to be associated with neurological complications (adjusted OR = 0.22; 95% CI: 0.05, 0.96, p = 0.044). The last factor which was associated with neurological complications was white cell count. Each increment in WCC by one unit increased the likelihood of developing neurological complications by 18% (adjusted OR = 1.18, 95% CI: 1.003, 1.38, p = 0.046).
4. DISCUSSION
4.1. Prevalence of neurological manifestations among COVID‐19 patients
In the South East Asia region, Koh et al. 14 only recorded 0.08% patients with neurological complications out of 47,572 COVID‐19 patients using the standardized definition by Elul et al. Our work comprised a hospital‐based cohort of COVID‐19 patients with a higher proportion of neurological complications; 23.7% (37 out of 156) with the similar criteria. The discrepancy of the reported rates can be attributed to the case definition criteria used as some studies included self‐reported neurological symptoms as well as definite complications in the same pool.
4.2. Diabetes mellitus and COVID‐19
The prevalence of diabetic mellitus in COVID‐19 patients ranged from 7.4% in China 17 to 8.9% in Italy. 18 In our study, 44% (69/156) patients had diabetes mellitus. Among all the comorbidities, only diabetes mellitus was found to be significantly higher in the group with neurological complications in the univariate analysis. This observed phenomenon could be due to a high prevalence of diabetes mellitus affecting 20.8% of the Malaysian population. 19 Hyperglycemia further facilitates viral replication in the lungs and impairs immunity. 20 The underlying mechanisms are attributable to reduction of interleukins in response to infections, decreased chemotactic and phagocytic activity; and immobilization of leukocytes. On the other hand, COVID‐19 infection leads to further inflammation contributing to hyperglycemia, which worsens the prognosis and subsequently increases the mortality risk. 21
4.3. Self‐reported CNS symptoms
The most common reported symptoms were dizziness (16.8%), headache (13.1%), taste impairment (5.6%) and smell impairment (5.1%). 2 Comparatively, a multicenter European study using the short version of the Questionnaire of Olfactory Disorders‐Negative Statements (sQOD‐NS), 22 found a higher prevalence of olfactory dysfunction in 85.6% and gustatory dysfunction in 88% of mild‐to‐moderate COVID‐19 cases. 23 However, the incidence of self‐reported symptoms of anosmia (36.5%) and dysgeusia (33.3%) were much lower in our study. The variable rates may be attributed to the differences in the study methodology and different methods used to detect smell and taste impairment. Another important finding from our study was that patients with anosmia and dysgeusia were less likely associated with neurological complications. This could be due to a different pathway of viral neuroinvasion, such as a local entry across the cribriform plate of the ethmoid bone, which was considered less systemic, and thus less serious. A meta‐analysis demonstrated that severely ill or hospitalized COVID‐19 patients have a lesser chance of experiencing loss of smell compared to non‐severely ill or non‐hospitalized COVID‐19 patients, (odds ratio = 0.527 [95% CI: 0.373–0.744; p < 0.001] and 0.283 [95% CI: 0.173–0.462; p < 0.001], respectively). 24 Understanding the nature of symptoms and close observation of patients without anosmia in early disease may assist in the expectant management.
Headache was another common symptom in a quarter (25.6%) of patients and dizziness in 9.6% of our cohort. The reported prevalence of headache ranged from 3.5% to 34% among the COVID‐19 patients. 3 The proposed mechanisms for headache could stem from direct effects from the viral invasion or indirect mechanisms including systemic inflammation, hypoxia, dehydration or metabolic derangement. 25
4.4. Cerebrovascular disease
Our study reported a higher incidence of ischemic stroke (17.9%) in our cohort, which included total anterior circulation, partial anterior circulation, posterior circulation and lacunar syndromes. No hemorrhagic stroke was reported in our cohort. Cerebral venous sinus thrombosis occurred in 1.3% of our patients. The World Stroke Organization had reported that the risk of ischemic stroke in COVID‐19 was around 5% (95% confidence interval [CI]: 2.8%–8.7%). 26 Our data was comparable to the reported findings of 21.1% of acute ischemic stroke in Singapore. 14
The occurrence of stroke may be secondary to the underlying risk factors or complications of COVID‐19 pathology. The main causative factors include hypercoagulability, vasculitis and cardiomyopathy. 27 The binding of SARS‐CoV‐2 to ACE2 receptors in the cerebral vasculature leads to damage and vessel wall rupture. The massive cytokine storm that ensues may lead to hemorrhagic stroke. Concomitant antiphospholipid antibodies with elevated prothrombin time, activated partial thromboplastin time, fibrinogen, D‐dimer and C‐reactive protein have been documented in COVID‐19 patients with hemispheric infarcts. 28 Vasculitis occurs from the inflammatory response following the affinity of the SARS‐ CoV‐2 to the ACE2 receptors in the vascular endothelium.
4.5. Encephalopathy and encephalitis
Encephalopathy results from postictal state, metabolic or hypoxic changes triggered by cytokine storm and acute respiratory distress syndrome. From a meta‐analysis, 3 the overall pooled prevalence of disturbance in consciousness was 3.8% (95% CIs: 0.16–12.04). Similar results were obtained from our data showing that 3.2% of patients had encephalopathy.
Encephalitis results from SARS‐CoV‐2 invasion into the brain using the angiotensin converting enzyme 2 (ACE‐2) as a receptor for entry through the olfactory nerve. 29 Encephalitis accounted for the second highest neurological complication in our cohort after stroke. All patients had SARS‐CoV‐2 detected in their CSF and their neuroimaging showed cerebral infarcts in half of the cases. The reported average incidence of encephalitis as a complication of COVID‐19 was 0.215% (95% CI = 0.056%–0.441%). 30 We did not have any patients with acute demyelinating encephalomyelitis or acute necrotizing encephalitis in our study.
4.6. Vaccination status
Vaccination has been the mainstay of protective immunity against SARS‐CoV‐2 infection. Although there have been adverse events associated with vaccination in case reports and in clinical trials, there has been no definitive evidence to support the causality. Our study concluded that neurological complications were more significant in patients without being vaccinated. Unvaccinated patients had 4.25 times higher risk of having neurological complications compared to those vaccinated. Our findings supported the use of vaccination to confer protection against SARS‐CoV‐2 infection, especially the neurological complications. This study was conducted when vaccination was still in the early phase. The majority received at least one dose of vaccine, which could either be from the Pfizer, Sinovac or AstraZeneca. However, a subgroup analysis could not be performed as data on the type of vaccines were not collated.
4.7. Leukocytosis in COVID‐19 infection
Laboratory parameters are crucial in monitoring of the COVID‐19 patients as they may aid in the diagnosis, as well as prognostication of the disease. Patients with COVID‐19 infection had significantly lower leukocyte, neutrophil and thrombocyte levels compared to non‐COVID‐19 patients. 31 A meta‐analysis revealed that leukocytosis was associated with a poor prognosis of COVID‐19 infection. 32 Comparatively, our study showed that patients with neurological complications had higher white cell counts compared to those without complications (13.87 vs. 12.91, p = 0.039). There was no significant difference in other parameters. Each unit increment in white cell count had 1.18 times higher risk to be associated with neurological complications. The presence of leukocytosis in severe COVID‐19 patients was postulated to be as a consequence of secondary infection and cytokine storm. Heightened inflammatory responses to SARS‐CoV‐2 virus led to excessive cytokine responses and subsequent multiorgan dysfunction.
4.8. Limitations
There are some limitations in this study. Firstly, we only recruited hospitalized patients. Self‐reported symptoms such as anosmia, dysgeusia, headache, blurring of vision and dizziness could be under‐represented as home quarantined patients were not captured in our study. Secondly, olfactory and gustatory dysfunctions were determined by self‐ reported symptoms without any objective assessment by any otorhinolaryngologist. There were incomplete data to analyze the cerebrospinal fluid and neuroimaging as not all patients had the aforementioned procedures done. As this study was performed at a single tertiary center, the spectrum of neurological complications might not be fully represented.
CONFLICT OF INTEREST
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest for this paper.
Tan HJ, Goh CH, Khoo CS, et al. Neurological manifestations in SARS‐CoV‐2 infection: A single‐center cross‐sectional study in Malaysia. Neurol Clin Neurosci. 2023;11:17‐26. doi: 10.1111/ncn3.12677
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