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Jurnal Bells Palsy

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  RESEARCH ARTICLE Open Access Corticosteroid and antiviral therapy for Bell ’ spalsy: A network meta-analysis Pawin Numthavaj 1 , Ammarin Thakkinstian 1* , Charungthai Dejthevaporn 2 , John Attia 3 Abstract Background:  Previous meta-analyses of treatments for Bell ’ s palsy are still inconclusive due to differentcomparators, insufficient data, and lack of power. We therefore conducted a network meta-analysis combiningdirect and indirect comparisons for assessing efficacy of steroids and antiviral treatment (AVT) at 3 and 6 months. Methods:  We searched Medline and EMBASE until September 2010 using PubMed and Elsviere search engines.A network meta-analysis was performed to assess disease recovery using a mixed effects hierarchical model.Goodness of fit of the model was assessed, and the pooled odds ratio (OR) and 95% confidence interval (CI) wereestimated. Results:  Six studies (total n = 1805)were eligible and contributed to the network meta-analysis. The pooled ORs forresolution at 3 months were 1.24 (95% CI: 0.79 - 1.94) for Acyclovir plus Prednisolone and 1.02 (95% CI: 0.73 - 1.42)for Valacyclovir plus Prednisolone, versus Prednisolone alone. Either Acyclovir or Valacyclovir singly had significantlylower efficacy than Prednisolone alone, i.e., ORs were 0·44 (95% CI: 0·28 - 0·68) and 0·60 (95% CI: 0·42 - 0·87),respectively. Neither of the antiviral agents was significantly different compared with placebo, with a pooled OR of 1·25 (95% CI: 0·78 - 1·98) for Acyclovir and 0·91 (95% CI: 0·63 - 1·31) for Valacyclovir. Overall, Prednisolone-basedtreatment increased the chance of recovery 2-fold (95% CI: 1·55 - 2·42) compared to non-Prednisolone-basedtreatment. To gain 1 extra recovery, 6 and 26 patients need to be treated with Acyclovir and prednisolonecompared to placebo and prednisolone alone, respectively. Conclusions:  Our evidence suggests that the current practice of treating Bell ’ s palsy with AVT plus corticosteroidmay lead to slightly higher recovery rates compared to treating with prednisone alone but this does not quitereach statistical significance; prednisone remains the best evidence-based treatment. Background Bell ’ s palsy is a condition characterized by an acuteonset of facial nerve palsy with no known cause. Theincidence is about 20/year/100,000 population [1], andleads to a considerable disturbance in social activitiesamong patients[2].Although the actual cause of Bell ’ s palsy is unknown,the widely accepted mechanism is inflammation of thefacial nerve during its course through the bony labyr-inthine part of the facial canal, which leads to compres-sion and demyelination of the axons, and disruption of blood supply to the nerve itself[3]. Previous studies havesuggested viral infection as the etiology of the diseasebased on serological evidence;[4,5] for example, positive serology for Herpes Simplex virus (HSV) has beenreported in 20-79% of patients.Treatment of Bell ’ s palsy varies, and no clear consensusexists. Most physicians prescribe corticosteroids as a pri-mary treatment due to its potential to reduce swellingand inflammation. The addition of antiviral treatment(AVT) such as Acyclovir or Valacyclovir is aimed at era-dication of HSV infection. Acyclovir, a nucleoside analog,inhibits HSV replication through inhibition of viral DNApolymerase. It is absorbed slowly from the gastrointest-inal tract, necessitating the use of a five-times daily regi-men. Valacyclovir, a Valine derivative of Acyclovir, isclaimed to lead to higher drug levels through conversionto Acyclovir by intestinal and hepatic esterase enzymes,leading to less intensive regimens. Its distribution, * Correspondence: raatk@mahidol.ac.th 1 Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine,Ramathibodi Hospital, Mahidol University, Bangkok, ThailandFull list of author information is available at the end of the article Numthavaj  et al  .  BMC Neurology   2011,  11 :1http://www.biomedcentral.com/1471-2377/11/1 © 2011 Numthavaj et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the srcinal work is properly cited.  cellular kinetics, mechanism, and excretion are otherwiseidentical to Acyclovir[6].Efficacy of AVT in Bell ’ s palsy is still not established,and the question exists whether adding AVT to anothertreatment such as corticosteroid can lead to better andfaster recovery compared with corticosteroids alone orwithout treatment. The srcinal Cochrane systematicreview of this topic[7] included 3 studies; these wereheterogeneous however and could not be pooled. Sincethat date, there have been at least 3 more large indivi-dual studies[8-13] and 3 more recent meta-analyses [14-16] published, although the comparator groups vary  considerably and make traditional direct meta-analysisdifficult. The meta-analsis by de Almeida et al. appliedlogistic regression analysis to assess interation effectsbetween corticosteroids and AVT, however this doesnot account for heterogeneity and did not estimate theindividual effect of AVT(Acyclovir or Valacyclovir).Furthermore, the review combined adult and paediatricstudies (6 studies), in which dosages and effects of treat-ments may be different. The most recent update of theCochrane systematic review included 6 studies [17], butdid not look at the effects of AVTs alone. We thereforeconducted a systematic review and network meta-analysis with the aim of comparing complete recovery rates at 3 and 6 months for corticosteroids, AVT(Acyclovir or Valacyclovir), or the combination of bothfor treatment of adult Bell ’ s palsy. Performing a networkmeta-analysis by borrowing information from indirectcomparisons integrates information about relative treat-ment efficacy[18-20]. This technique has been applied in systematic reviews of other clinical topics such aschronic insomnia[21], polymer-based drug-eluting stents[22], and highly-active AVT[23]. Methods Search strategy One author (NP) located studies in MEDLINE (from1966 to August 2010) and EMBASE (from 1950 to Sep-tember 2010) using PubMed and Ovid search engines.Search terms used were as follows: (Bell ’ s palsy or idio-pathic facial palsy) and (antiviral agents or acyclovir or valacyclovir), limited to randomized controlled trials.Search strategies for both databases are described in theadditional file 1. Selection of study and inclusion/exclusion criteria Abstracts and/or full papers of identified studies werereviewed by one author (NP) and checked by anotherauthor (TA). Studies were included if they were RCTs,and studied subjects aged 18 years or older with suffi-cient data. Non-English papers were excluded from thereview. Where eligible papers had insufficient informa-tion, corresponding authors were contacted by e-mailfor additional information. The reference lists of theretrieved papers were also reviewed to identify relevantpublications. Where there were multiple publicationsfrom the same study group, the most complete andrecent results were used. Data extraction & Quality assessment (QA) Data extraction was independently performed in dupli-cate by PN and AT using a standardized data extractionform, which included study design, sample size, patientcharacteristics (i.e., age, gender), type of interventionand comparator, outcomes, and follow-up time. Any dis-agreement was resolved by discussion.Quality of studies was also independently assessed by PN and AT based on a modified Jadad score whichtakes into account randomization technique, allocationconcealment, blinding, intention to treat, and patientattrition[24]. Each item was graded 2, 1, or 0 for appro-priately, partially, and inappropriately described meth-ods. Any disagreement between the two reviewers wasdiscussed and resolved by consensus. Outcome Complete recovery was defined as a score  ≤ 2 on theHouse-Brackman Facial Recovery scale[12,13,25],  ≥  8 onthe Facial Palsy Recovery Index[8], > 36 points ontheYanagihara score[10], or 100 on the Sunnybrookscale[9]. Statistical analysis For direct meta-analysis, the odds ratio (OR) and var-iance of each study were estimated and pooled. Hetero-geneity of ORs was assessed using Cochran ’ s Q test andI 2 . If heterogeneity was present, ORs were pooled usingthe random effects model, i.e. Der-Simonian and Lairdmethod. Meta-regression was applied to assess whetherage, gender, and QA were sources of heterogeneity, if these data were available. Contour enhanced funnelplots were used to detect publication bias due to smallstudy effects [26-29]. Trim and fill meta-analysis was applied to impute the number of missing studies [30].For network meta-analysis, treatment groups wereconsidered in a mixed effects hierarchical model withlogit link function using the xtmelogit command inSTATA[31]. The treatments were included in the modelas fixed effects whereas the study was included as a ran-dom effect. Likelihood estimates were used for estima-tion of parameters in the model. Goodness of fit of themodel was assessed using the Hosmer-Lemeshow Chi-square test. The pooled ORs and 95% confidence inter- vals (CI) were estimated by exponential coefficients of treatments. Discrepancy of treatment effects betweendirect and indirect meta-results was then assessed usingthe standardized normal method (Z), i.e. by dividing the Numthavaj  et al  .  BMC Neurology   2011,  11 :1http://www.biomedcentral.com/1471-2377/11/1Page 2 of 10  difference by its standard error[20,32]. Number needed to treat/harm (NNT/NNH) was estimated using prob-ability of complete recovery and ORs derived from themixed effects hierarchical model, where the ORs wereconverted to risk ratios following the method of Zhang et al[33]. All analyses were performed usingSTATA version 11.0. P values < 0·05 were considered asstatistically significant except for the heterogeneity testwhere <0·10 was used. Results A flow diagram of study selection is shown in Figure 1.Fourteen and twenty-five studies were identified fromMEDLINE and EMBASE databases, respectively. Amongthese 39 studies, 1 studies were duplicates, 13 studieswere ineligible, leaving 12 studies to review. Six studieswere excluded; two were in Spanish, one was in German,and 3 were subsets or duplicated reports, leaving six stu-dies[8-10,12,13,25] with a total of 1805 patients for analy- sis. Characteristics of the 6 included studies are describedin table 1. Five studies[8-10,12,13] compared recovery  rates of AVT plus corticosteroid with corticosteroidalone or placebo; the remaining study directly comparedthe recovery rate of AVT against corticosteroid[25]. Twostudies were based on factorial design[9,12] and the others were parallel randomized control trials. The AVTsused were Acyclovir for 4 studies[8,12,13,25] and Valacy- clovir for the other 2 studies[9,10]. Prednisolone was the major corticosteroid used. Mean age of participants inthese studies ranged from 40 to 50 years, and percentageof male participants ranged from 45% to 59%. Medianquality assessment score was 8 (range = 2-12). 14 articles identified from MEDLINE14 excluded:-6 duplicates -5 duplicated reports/or commentaries-2 systematic reviews -1 narrative review14 eligible for review6 included in the review14 articles identified from EMBASE8 excluded:-2 Spanish papers -6 subsets or duplicated reports Figure 1  Diagram of selection of studies . Numthavaj  et al  .  BMC Neurology   2011,  11 :1http://www.biomedcentral.com/1471-2377/11/1Page 3 of 10  Direct comparisons Among 6 studies, 3 studies[8,12,13] compared recovery  rates within 3 months between Acyclovir plus Prednisolone versus Prednisolone alone (table 2). Pooled treatmenteffects were heterogeneous (Chi-sqaure = 6·30 (d.f. = 2)p = 0·043; I 2 = 68.3%). Using the random effects model gavea pooled OR of 1·39 (95% CI: = 0·52 - 3·75), i.e. patientswho received Acyclovir plus Prednisolone were about 40%more likely to recover within 3 month than patients whoreceived Prednisolone alone, although this did not reachstatistical significance. Only 2 studies[9,10] compared recovery rates between Valacyclovir plus Prednisolone andPrednisolone. They were homogeneous and the pooled ORwith fixed effect model was 1·17 (95% CI: 0·75 - 1·81).Combining 5 studies[8-10,12,13] to assess the effect of  AVT (Acyclovir/Valacyclovir) plus Prednisolone versusPrednisolone found moderate heterogeneity (Chi-sqaure =7.78 (d.f. = 4) p = 0.100; I 2 = 48.6%). The pooled OR with Table 1 Baseline characteristics of included studies Author(Year)N Meanage% MaleParticipantsMeandiseaseseverityscoreType of treatment Outcomes FU time(month)QAscoreIntervention (dosage) Control Adouret al.(1996) [8]99 43 50 3 (FPRP) Acyclovir 2,000 mg/day × 10 daysPrednisolone 30 mg/kg/day × 5 days,10 mg/day × next 5 daysPrednisolonewith the samedosageFPRI  ≥  8 4 7De Diegoet al.(1998)[25]101 - - - Acyclovir 2,400 mg/day ×10 days Prednisolone 1mg/kg/day ×10 days, taperover next 6daysHB grade  ≤  II,FPRI score ≥  83 3Hato et al.(2007)[10]221 50 53 15(Yanagihara)Valacyclovir 1,000 mg/day × 5 daysPrednisolone 60 mg/day for 5 days,taper with Mecobalamin 1·5 mg/day ×6 monthsPlacebo Yanagihara score> 36 points, nofacial contractureor synkinesis6 9Sullivan etal. (2007)[12]551 44 51 3.6 (HB) Acyclovir 2000 mg/day × 10 daysPrednisolone 50 mg/day × 10 daysPlacebo HB grade I 3, 9 12Yeo et al.(2008)[13]91 41 45 3.7 (HB) Acyclovir 2,400 mg/day × 5 daysPrednisolone 1 mg/kg/day × 4 dayswith maximum of 80 mg/day, 60 mg/ day × 5-6 day, 40 mg/day × 7-8 day,20 mg/day × 9-10 dayPlacebo HB grade  ≤  II 2, 6 2Engstromet al.(2008) [9]829 40 59 4 by HB Valacyclovir 3,000 mg/day × 7 daysPrednisolone 60 mg/day × 5 days, 10mg/day until 10 daysPlacebo Sunnybrook 100/ 100, HB  ≤  II1, 2, 3,6, 1212 Table 2 Describe numbers of recovery according to treatment groups for each included study Author Treatment groups Recovery at 3 months Total N Recovery after 3 months Total N Adour et al. [8] Acy+Pred 34 38 49 53Pred 20 29 35 46De Diego[25] Acy 42 54 - -Pred 44 47 - -Engstorm et al. [9] Val+Pred 134 206 149 206Val 113 207 120 207Pred 137 210 150 210Plac 111 206 127 206Hato et al. [10] Val+Pred 94 114 110 114Pred 80 107 96 107Sullivan et al. [12] Acy+Pred 99 124 115 124Acy 76 123 96 123Pred 109 127 122 127Plac 79 122 104 122Yeo et al. [13] Acy + Pred 36 44 41 44Pred 35 47 40 47 Numthavaj  et al  .  BMC Neurology   2011,  11 :1http://www.biomedcentral.com/1471-2377/11/1Page 4 of 10
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