Our network meta-analysis indicates that treatment with AVT alone or placebo is significantly inferior to Prednisolone alone; the effect of AVT alone and placebo are similar to each other. Current practice of adding AVT (either Acyclovir or Valacyclovir) in the regimen with Prednisolone may increase disease recovery rates compared with Prednisolone alone, but at this point this difference is not statistically significant. Prednisolone remains the strongest evidence-based treatment, whether compared to placebo or AVT monotherapy.
The possible explanations for the lack of any incremental effect of AVT when added to corticosteroids might include:
• corticosteroids reduces the inflammatory process in Bell's palsy and this facilitates remyelination of facial nerve.
• Bell's palsy is a post-infectious immune mediated facial neuropathy rather than direct viral infection
• There may be a small incremental increase in efficacy but there is not sufficient power, even with all the trials to date, to demonstrate this. Large RCTs are needed to specifically compare corticosteroid and corticosteroid plus AVT.
This meta-analysis demonstrates well the advantage of the network approach. Assessing the efficacy of treatments for Bell's palsy based on results of individual RCTs and direct meta-analysis is difficult due to the fact that there are various treatment regimens, and too few studies performing the same treatment comparisons for pooling. For instance, 6 treatment regimens are possible in clinical practice (i.e., Acyclovir, Valacyclovir, Prednisolone, Placebo, combination of Acyclovir + Prednisolone, and Valacyclovir + Prednisolone) resulting in 15 possible treatment-pair comparisons. Previous reviews have had problems with this multiplicity of comparisons:
• a previous systematic review of AVT versus corticosteroid[7
] included only 3 studies with 246 patients, and these could not be pooled since each study had a different combination of treatments;
• one systematic review[34
] included 3 studies with 117 patients and demonstrated no benefit of using corticosteroid compared with placebo/vitamin with relative risk of 0·86 (95% CI: 0·47 - 1·59).
• Another review[15
] included 5 studies with 709 samples and reported no benefit of AVT (OR = 1·03; 95% CI: 0·74 - 1·42) when compared with Prednisolone.
The small numbers in these previous meta-analyses clearly led to lack of power. Two more complete reviews[14
] were recently published. One accessed unpublished and non-English papers and thus included more studies than other previous meta-analyses. Point estimates of treatment effects for our results were similar to theirs, although confidence intervals varied. For instance, the effect of corticosteroid versus placebo at longer than 3 months was 0.54 in our study versus 0.69 for the recent meta but our study was slightly less precise (95% CIs were 0.40 - 0.74 versus 0.55 - 0.87, respectively). Effect of AVT plus corticosteroid versus AVT alone was also similar, i.e. the odds ratios for recovery were 0.49 (95% CI: 0.36 - 0.66) versus 0.48 (95% CI: 0.29 - 0.79). Our results are also consistent with the updated Cochrane review [17
] which found a possibility of benefit of AVT plus corticosteroid versus corticosteroid which did not reach statistical significance, with the pooled point estimate of 1.41, and with the de Almeida et al. review which also found borderline evidence for a synergistic effect of steroids and AVT[14
We have applied a mixed model for network meta-analysis[19
]. The mixed model gains power by integrating both direct and indirect comparisons[15
]. For instance, only two studies performed direct comparisons of Acyclovir plus Prednisolone versus Prednisolone alone, a total sample size of 409 (Table ). The network method "borrowed" information on the Prednisolone group from three other studies and increased the total sample size to 773. Although our pooled estimates were quite heterogeneous, the mixed model with random intercept takes into account variation at the study level. In addition, goodness of fit assessment suggested that our model fit well with the data. Overall, our results are quite robust since discrepancies between the direct and the network analyses are small.
Quality of included studies varied; quality assessment scores ranged from 2-12. Meta-regression of direct meta-analysis indicated that this might be a source of heterogeneity in pooling effects of AVT. However, we could not adjust for the effects of quality assessment score and other co-variables in the mixed effect model since this requires individual patient data. An individual patient data meta-analysis could be attempted, although individual level raw data are often difficult and more time consuming to access. However, with this method, covariables in both study (e.g., quality assessment) and individual levels (e.g., age, disease severity) can be assessed using a multi-level analysis approach.