We used a five-grade scale derived from the Glasgow Outcome Scale (GOS) 12 to estimate the CNS viral infection outcomes 6–12 months after discharge by questioning the patients or their family members. To identify the prognostic factors for the CNS viral infections, the patients were assigned to a ‘favorable outcome’ category for patients with good recovery or mild or moderate disability (GOS grades I–III) or a ‘poor outcome’ category for patients with severe disability or those who died (GOS grades IV and V).
Venous blood was drawn from an antecubital vein after overnight fasting at about 6 a.m. on the day after admission and at the first follow-up visit within 1 month after hospital discharge. SUA levels were measured using a clinical analyzer (AU5831; Beckman Coulter Inc., Brea, California, USA). In our hospital, the normal SUA range is 208–428 mM for men and 155–357 mM for women.
All continuous variables are presented as mean±SD. All noncontinuous variables are presented as medians (with ranges). We used analysis of variance analysis of variance for three-group comparisons and Student’s t-test for between-group comparisons. To analyze nonparametric data, we used Fisher’s exact tests for qualitative variables and the Mann–Whitney U-test for quantitative variables. We compared the SUA levels of patients and HCs through covariance analysis with age as the covariant. SUA levels are sex dependent 13, and thus we explored the effect of sex by dividing the patients in each group into subgroups. We analyzed differences between same-patient SUA measurements at different timepoints using the Wilcoxon matched-pairs signed rank test. We used Spearman’s rank correlation to investigate associations between SUA levels and GOS scores, CSF pressure, white blood cell counts, and protein levels. We carried out all analyses in SPSS, version 21.0 (IBM Corp., Armonk, New York, USA). We defined statistical significance as a P value less than 0.05.
The SUA levels in the VM group were significantly lower than those in the HCs (P<0.001), and those in the VE group were in turn significantly lower than those in the VM group (P<0.001) (Table 3). The SUA levels in the female HCs were significantly higher than those in female VM and VE group patients (P<0.001 for both comparisons, Table 3). The same observation was made in men (P<0.001 for both comparisons, Table 3). Furthermore, we observed significantly lower SUA levels in patients who had neurological abnormalities (P=0.001), seizures (P=0.006), abnormal EEG results (P<0.001), abnormal MRI findings (P<0.001), or a need for ICU treatment (P<0.001) than in patients who did not have these conditions (Table 4).
Alterations in the different groups’ SUA levels across timepoints are shown in Table 5. The patients’ SUA levels were significantly increased after treatment (VM: P<0.001; VE: P=0.001). The patients’ SUA levels correlated negatively with their GOS scores (r=−0.399, P<0.001) (Fig. 1 and Table 6), but did not correlate with their CSF findings, such as CSF pressure (r=−0.136, P=0.089), white blood cell counts (r=−0.1, P=0.212), protein levels (r=−0.037, P=0.646), glucose levels (r=−0.125, P=0.12), or chloride levels (r=0.031, P=0.699) (Table 6).
The pathology of CNS infections can include infiltration of mononuclear cells and lymphocytes around the meninges and cerebral vessels, microglial proliferation, neuronal edema and damage, nerve demyelination, and degeneration and death of cerebral vascular endothelial cells. These pathological changes can sometimes cause severe brain damage 14, although the precise pathophysiological mechanisms of meningitis and meningoencephalitis are not fully understood. In addition to direct damage to nervous tissue caused by invasive viruses, abundant oxygen free radicals resulting from inflammation, ischemia, hypoxia, and abnormal metabolism are important factors that aggravate brain injury in VE and VM. NO and its toxic metabolite PN are critical mediators of neurological damage 15. PN is involved in the pathogenesis of CNS inflammatory diseases 9, and can cause DNA cleavage, lipid peroxidation, and oxidation and nitration of amino acid residues and guanine. This results in cytochrome C release and finally induces cytotoxicity or apoptosis 16. PN releases active matrix metalloproteinase from its proenzyme forms and metalloproteinase then splits the tight junctions between the BBB’s endothelial cells 17. PN is also an important modulator of cyclooxygenase, which is a key enzyme for the production of inflammatory mediators such as prostaglandins, which aggravate inflammation and induce a vicious cycle 18.
UA, which is an oxidative metabolite of purine, is an important neuroprotective antioxidant in humans. UA exerts its neuroprotective effects not only by eliminating PN’s oxidative toxicity but also by effectively scavenging downstream radicals of PN – that is, CO3 •− and NO2 •, which are produced following the rapid reaction of PN with CO2 19. Hooper et al. 9 found that UA not only reduced BBB disruption but also alleviated inflammatory responses and tissue injury in a myelin basic protein-induced experimental allergic encephalomyelitis model. The same group later observed that UA inhibited the onset of symptoms in Borna disease virus-infected adult rats and prevented elevated BBB permeability and CNS inflammation 20. This suggests that CNS inflammation because of neurotropic virus infections may be dependent on PN activity at the BBB. A 2-year follow-up study showed that the ability to repair tissue damage induced by PN and other free radicals was impaired in patients with relapsing-remitting MS and low SUA levels. Therefore, SUA may be a biomarker for relapse risk, disability progression, and cognitive function in MS 21. Liu et al. 22 observed recently that patients with different CNS infection types, including VM or meningoencephalitis, cerebral cysticercosis, tuberculous meningitis or meningoencephalitis, cryptococcal meningitis or meningoencephalitis, and bacterial meningitis or meningoencephalitis, had lower SUA levels than HCs. Effective therapy increased SUA levels in these patients. UA may thus be used to evaluate clinical treatments in patients with CNS infections.
SUA levels are naturally lower in healthy females of child-bearing age than males. This difference is not limited to individuals with diseases. We observed that patients with VM or VE showed obviously depressed SUA levels compared with HCs after eliminating the influence of age and sex. This finding is consistent with the results of a previous study of patients with VM by Liu et al. 22. Peng et al. 23 also found that SUA levels in patients with MS and those with VM or VE were obviously lower than those in HCs. Previous studies 12,23 have shown that female patients with MS or other neurological diseases have lower SUA levels than male patients. We found that SUA levels were clearly lower in patients with VM or VE than in HCs irrespective of sex and that there were no significant sex-related differences in SUA levels in patients with VM or VE. However, SUA levels were significantly decreased in patients with nervous functional disorders, seizures, ICU stays, EEG abnormalities, and MRI abnormalities, which implies that SUA levels are associated closely with disease severity. Kutzing et al. 24 analyzed the possible causes for decreased SUA levels and found that inflammation induces the consumption of UA, which is used to scavenge excess free radicals. This is turn reduces SUA levels. SUA levels were also correlated with CNS injury, especially BBB disruption. SUA protects the BBB’s integrity and reduces its permeability. It also reduces inflammatory cell infiltration and thereby relieves brain inflammation.
This study was designed to follow up the patients and determine their prognoses with the GOS. The GOS scores of patients correlated negatively with SUA levels and SUA levels in patients with poor prognoses were lower than those in patients with favorable prognoses. These results suggest that SUA might be a useful biomarker for assessing prognoses in patients with CNS infections. In addition, SUA levels were clearly increased in patients with VM or VE after antiviral treatment. This is consistent with the findings of Collazos et al. 25, who reported that hypouricemia is common in patients with AIDS and CNS infections, but that the patients’ SUA levels were increased after successful treatment of the CNS infections. This suggests that UA may be a predictive biomarker for evaluating therapeutic outcomes.
SUA levels were evidently decreased in patients with viral CNS infections, but effective treatments restored them. More importantly, lower SUA levels may be related to several phenomena indicative of disease severity, including neurological abnormalities, seizures, abnormal EEG results, abnormal MRI findings, and a need for ICU treatment. Furthermore, lower SUA levels were correlated closely with poor prognoses. Therefore, SUA levels may be a useful biomarker of acute CNS viral infections with inflammatory components and may be useful indicators for prognoses and treatment outcomes.
This study was supported by the Wenzhou Municipal Sci-Tech Bureau Program (grant no. Y20140278).
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2017 Wolters Kluwer Health | Lippincott Williams & Wilkins
outcome; oxidative stress; uric acid; viral encephalitis; viral meningitis