Study Selection Results
The primary search yielded 6709 articles, with 41 articles remaining after removal of duplicates and screening titles, abstracts, and full texts. As a result of the rapid growth of the COVID-19 literature, a second search was conducted yielding another 23 articles. Forty-four articles were included in the final meta-analysis and 20 case reports were included in the qualitative descriptive review (Figure 1). Seventeen articles were available on the search databases but they were not yet published in their final form.
Demographics and Characteristics
Forty-four studies were included in the meta-analysis, 14 of which were available as pre-prints at the time of the search (Table 1). A total of 13480 patients were included in our analysis with a mean age of 50.3 (95% CI, 47.7 to 52.9) years, and 53% (95% CI, 50.2% to 55.7%) being males. Thirty-six (81.8%) studies were from China, two (4.5%) were from Italy, and the rest being one from each of Australia, France, Japan, Netherlands, Belgium and the UK. The study sample size ranged from 13 to 6606 patients per study.
The remaining 20 studies were included for the qualitative assessment of case reports (Table 2), three of them were available as pre-prints at the time of the search. These case reports included 57 patients with a mean age of 59.5 (± 20.2) years and 38 (67%) being males.
Risk of Bias Assessment Results
Of the 44 studies included in the meta-analysis, 39 were considered as case series and they were assessed for risk of bias using the NIH Quality Assessment Tool for Case Series Studies (16). The study quality was rated as good, fair, or poor if the number of “Yes” responses were ≥6, 3 to 5, or ≤2, respectively. Of the 39-case series, 33 received a “fair” rating and 6 studies received a “good” rating.
Two studies were considered cohort studies and three were considered cross-sectional studies. They were assessed using the NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies (15). The study quality was rated as good, fair, or poor if the number of “Yes” responses were ≥9, 4 to 8, or ≤3, respectively. All of the five included cohort and cross-sectional studies were given a “fair” rating.
Moreover, some questions of the previous quality assessment tools were not applicable to all studies. A more detailed illustration of the risk of bias assessment for each study is attached as a table in the supplementary appendix (Additional files 2 and 3).
Clinical features and laboratory findings
The frequency of NM in COVID-19 patients was as follows: Myalgia (22.2%, 95% CI, 17.2% to 28.1%), taste impairment (19.6%, 95% CI, 3.8% to 60.1%), smell impairment (18.3%, 95% CI, 15.4% to 76.2%), headache (12.1%, 95% CI, 9.1% to 15.8%), dizziness (11.3%, 95% CI, 8.5% to 15.0%), encephalopathy or cognitive dysfunction (9.4%, 95% CI, 2.8% to 26.6%), and ataxia or abnormal gait (2.1%, 95% CI, 0.2% to 23.7%). Nearly, 2.5% (95% CI, 1% to 6.1%) of COVID-19 patients had acute cerebrovascular diseases (CVD); which included ischemic stroke (IS), intracerebral hemorrhage (ICH), and cerebral venous sinus thrombosis (CVT) (Table 3, additional file 4).
About a third of COVID-19 patients were severely affected (31.1%, 95% CI, 21.9% to 42.2%) and 20.6% (95% CI, 14.1% to 29.0%) were admitted to intensive care units. About 37.4% (95% CI, 33.1% to 41.9%) had a pre-existing comorbidity, and 5.7% (95% CI, 3.3% to 9.7%) had a preexisting neurological disease. Detailed characteristics of the pre-existing comorbidities are presented in (Table 3, additional file 5).
Regarding laboratory abnormalities (Table 1, additional file 6), the mean values were as follows: CK: 85.57 U/L (Normal range; 40-200 U/L), LDH: 263.49 U/L (Normal range; 120–250 U/L). The mean lymphocyte, neutro0phil, and monocyte count were 1.08, 3.44, and 0.39 (*10^9/L), respectively.
No published data regarding COVID-19 treatment related neurological side effects and complications were found.
According to Egger et.al (20), publication bias assessment is only reliable for 10 or more pooled studies. Therefore, we presented the results of publication bias for variables that were discussed in 10 or more studies (Additional file 7). Publication bias was observed in the following variables: fever (p < .001), headache (p < .001), serum LDH (p = .0015), Diabetes Mellitus (DM) (p = .0089), pre-existing neurological diseases (p = .0089), malignancy (p = .031), and chronic kidney disease (CKD) (p = .044).
A sensitivity analysis, in which the meta-analysis was serially repeated after the exclusion of each study, demonstrated that no individual study affected the overall prevalence for each variable except for the following: Taste impairment prevalence was reduced from 19.6% to 10.9% when the study by Spinato et.al was excluded(60); smell impairment prevalence was reduced from 18.3% to 7.5% when the study by Lechien et.al was excluded(53), and increased to 35.2% when the study by Mao et.al was removed (6). After excluding the study conducted by Guan et.al, the reported frequency of NC increased from 3% to 5.8% (2). More details can be found in additional file 8.
When comparing severe to non-severe COVID-19 patients, the severe group included older patients [mean age 60 vs 44.7 years-old, p < .001] and more males [60.3% vs 48.6%, p = .001] than the non-severe group. Myalgia [34.9% vs 4.1%, p = .045], acute CVD [34.9% vs 4.1%, p = .045], higher CK value [324.9 vs 121.2 U/L, p = .01] , and higher LDH value (247.6 vs 83.0 U/L, p = .012) were more likely in the severe group. While encephalopathy and cognitive dysfunction were more frequent in the severe group [16.9% vs 1.9%, p = .054], this was not statistically significant. There was no significant difference for the rest of the variables evaluated (Table 4). Heterogeneity was significant for all the variables and was not resolved by subgroup analysis.
Twenty case reports (57 patients) were identified and their details are summarized in Table 5. Six (10.5%) patients were diagnosed with GBS 5-10 days after the onset of respiratory symptoms (69,72). Their neurological symptoms included numbness, weakness, dysphagia, and facial weakness; four patients (7.0%) had facial weakness including one (1.8%) with facial diplegia. All of these patients had abnormal NCS/EMG findings consistent with an axonal variant in three patients and a demyelinating variant in two.
Besides the above-mentioned EMG/NCS abnormalities, ND findings included neuro-imaging, CSF, and EEG findings. Neuro-imaging utilized were head CT, brain MRI and spinal MRI. Six patients had significant neuroimaging findings, including two patients with cerebral hemorrhage (12,66), one patient with encephalitis/ventriculitis (11), two GBS patients with enhancement of the caudal nerve roots (72), and one GBS patient with bilateral enhancement of facial nerves (72). Besides, six (10.5%) patients had CSF changes; mainly increased protein in five (8,69,72), and only one with SARS-CoV-2 RNA detected in CSF using RT-PCR assay (11). Lastly, one patient had EEG changes consisting of bilateral and focal slowing in the left temporal region with left temporal sharp waves (8).
Twelve patients received neurology-related management including IVIG in eight patients, and four who used one or more of the following therapies: ceftriaxone, vancomycin, acyclovir, ganciclovir, steroids, levetiracetam, phenytoin, plasma exchange, or vitamin B12.
Of note, some NM and ND findings were reported by a few studies, out of the 44 studies, and were insufficient to be included in the meta-analysis. These included manifestations like visual impairment (6), nerve pain (6), and diffuse corticospinal tract signs with enhanced tendon reflexes, ankle clonus, and bilateral extensor plantar reflexes (52). CSF findings included positive oligoclonal bands with the same pattern in serum, elevated CSF IgG and CSF protein levels, and low albumin level (52). Head CT findings included ischemic stroke, cerebral hemorrhage, and cerebral venous sinus thrombosis (6,10). Brain MRI findings included leptomeningeal enhancement, bilateral frontotemporal hypoperfusion, and acute and subacute ischemic strokes (52). EEG findings included nonspecific changes and slowing consistent with encephalopathy (52).