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Antiviral treatment for Bell's palsy (idiopathic facial paralysis)
(Review)
Gagyor I, Madhok VB, Daly F, Somasundara D, Sullivan M, Gammie F, Sullivan F
Gagyor I, Madhok VB, Daly F, Somasundara D, Sullivan M, Gammie F, Sullivan F.

Antiviral treatment for Bell's palsy (idiopathic facial paralysis).
Cochrane Database of Systematic Reviews 2015, Issue 11. Art. No.: CD001869.
DOI: 10.1002/14651858.CD001869.pub8.
www.cochranelibrary.com

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 4
BACKGROUND.............................................................................................................................................................................................. 6
OBJECTIVES.................................................................................................................................................................................................. 6
METHODS..................................................................................................................................................................................................... 6
RESULTS........................................................................................................................................................................................................ 8
Figure 1.................................................................................................................................................................................................. 9
Figure 2.................................................................................................................................................................................................. 14
Figure 3.................................................................................................................................................................................................. 16
Figure 4.................................................................................................................................................................................................. 16
Figure 5.................................................................................................................................................................................................. 17
Figure 6.................................................................................................................................................................................................. 17
DISCUSSION.................................................................................................................................................................................................. 18
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 19
ACKNOWLEDGEMENTS................................................................................................................................................................................ 20
REFERENCES................................................................................................................................................................................................ 21
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 24
DATA AND ANALYSES.................................................................................................................................................................................... 35
Analysis 1.1. Comparison 1 Antivirals plus corticosteroids versus corticosteroids plus placebo or no treatment, Outcome 1 35
Incomplete recovery at end of study...................................................................................................................................................
Analysis 1.2. Comparison 1 Antivirals plus corticosteroids versus corticosteroids plus placebo or no treatment, Outcome 2 Motor 36
synkinesis or crocodile tears................................................................................................................................................................
Analysis 1.3. Comparison 1 Antivirals plus corticosteroids versus corticosteroids plus placebo or no treatment, Outcome 3 36
Adverse events......................................................................................................................................................................................
Analysis 2.1. Comparison 2 Antivirals versus corticosteroids, Outcome 1 Incomplete recovery at end of study............................. 37
Analysis 2.2. Comparison 2 Antivirals versus corticosteroids, Outcome 2 Motor synkinesis and crocodile tears............................ 37
Analysis 2.3. Comparison 2 Antivirals versus corticosteroids, Outcome 3 Adverse events............................................................... 37
Analysis 3.1. Comparison 3 Antivirals plus corticosteroids versus placebo, Outcome 1 Incomplete recovery at end of study........ 38
Analysis 3.2. Comparison 3 Antivirals plus corticosteroids versus placebo, Outcome 2 Adverse events......................................... 38
Analysis 4.1. Comparison 4 Antivirals versus placebo, Outcome 1 Incomplete recovery at end of study........................................ 39
Analysis 4.2. Comparison 4 Antivirals versus placebo, Outcome 2 Adverse events.......................................................................... 39
Analysis 5.1. Comparison 5 Antivirals plus corticosteroids versus corticosteroids plus placebo or no treatment in severe cases, 39
Outcome 1 Incomplete recovery at end of study...............................................................................................................................
ADDITIONAL TABLES.................................................................................................................................................................................... 40
APPENDICES................................................................................................................................................................................................. 42
WHAT'S NEW................................................................................................................................................................................................. 43
HISTORY........................................................................................................................................................................................................ 44
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 45
DECLARATIONS OF INTEREST..................................................................................................................................................................... 45
SOURCES OF SUPPORT............................................................................................................................................................................... 45
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 45
INDEX TERMS............................................................................................................................................................................................... 46
Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) i

Informed decisions.

[Intervention Review]
Antiviral treatment for Bell's palsy (idiopathic facial paralysis)
Ildiko Gagyor1, Vishnu B Madhok2, Fergus Daly3, Dhruvashree Somasundara2, Michael Sullivan4, Fiona Gammie2, Frank Sullivan5
1Department of General Practice/Family Medicine, University of Göttingen, Göttingen, Germany. 2Centre for Primary Care and Population
Research, Division of Clinical and Population Sciences and Education, University of Dundee, Dundee, UK. 3Frontier Science (Scotland) Ltd,
Kingussie, UK. 4School of Clinical Sciences, University of Edinburgh, Edinburgh, UK. 5Department of Family and Community Medicine,
North York General Hospital, University of Toronto, Toronto, Canada
Contact address: Ildiko Gagyor, Department of General Practice/Family Medicine, University of Göttingen, Humboldtalle 38, Göttingen,
Lower Saxony, 37073, Germany. Ildiko.Gagyor@medizin.uni-goettingen.de.
Editorial group: Cochrane Neuromuscular Group

Publication status and date: Edited (conclusions changed), published in Issue 11, 2015.
Citation: Gagyor I, Madhok VB, Daly F, Somasundara D, Sullivan M, Gammie F, Sullivan F. Antiviral treatment for Bell's palsy (idiopathic
facial paralysis). Cochrane Database of Systematic Reviews 2015, Issue 11. Art. No.: CD001869. DOI: 10.1002/14651858.CD001869.pub8.
ABSTRACT
Background
Corticosteroids are widely used in the treatment of idiopathic facial paralysis (Bell’s palsy), but the effectiveness of additional treatment
with an antiviral agent is uncertain. Significant morbidity can be associated with severe cases of Bell's palsy. This review was first published
in 2001 and revised several times, most recently in 2009. This version replaces an update of the review in Issue 7 of the Cochrane Library
subsequently withdrawn because of an ongoing investigation into the reliability of data from an included study.
Objectives
To assess the effects of antiviral treatments alone or in combination with any other therapy for Bell’s palsy.
Search methods
On 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS,
DARE, NHS EED, and HTA. We also reviewed the bibliographies of the identified trials and contacted trial authors and known experts in the
field and relevant drug companies to identify additional published or unpublished data. We searched clinical trials registries for ongoing
studies.
Selection criteria
We considered randomised controlled trials or quasi-randomised controlled trials of antivirals with and without corticosteroids versus
control therapies for the treatment of Bell's palsy. We excluded trials that had a high risk of bias in several domains.
Data collection and analysis

Pairs of authors independently assessed trials for relevance, eligibility, and risk of bias, using standard Cochrane procedures.
Main results
Ten trials, including 2280 participants, met the inclusion criteria and are included in the final analysis. Some of the trials were small, and
a number were at high or unclear risk of bias. Other trials did not meet current best standards in allocation concealment and blinding.
Incomplete recovery
We found a significant benefit from adding antivirals to corticosteroids in comparison with corticosteroids alone for people with Bell’s
palsy (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.39 to 0.97, n = 1315). For people with severe Bell’s palsy (House-Brackmann scores
Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 1

Informed decisions.

of 5 and 6 or the equivalent in other scales), we found a reduction in the rate of incomplete recovery at month six when antivirals plus
corticosteroids were used, compared to corticosteroids alone (RR 0.64, 95% CI 0.41 to 0.99, n = 478). The outcome for the participants
receiving corticosteroids alone was significantly better than for those receiving antivirals alone (RR 2.82, 95% CI 1.09 to 7.32, n = 768).
The treatment effect of placebo was significantly lower than that of antivirals plus corticosteroids (RR 0.56, 95% CI 0.41 to 0.76, n = 658).
Antivirals alone produced no benefit compared with placebo (RR 1.10, 95% CI 0.87 to 1.40, n = 658).
Motor synkinesis or crocodile tears
In two trials comparing antivirals and corticosteroids with corticosteroids and placebo that assessed this outcome, we found a significant
difference in long-term sequelae in favour of antivirals plus corticosteroids (RR 0.56, 95% CI 0.36 to 0.87, n = 469). Two trials comparing
antivirals alone with corticosteroids alone investigating this outcome showed fewer sequelae with corticosteroids (RR 1.52, 95% CI 1.08
to 2.12, n = 472). We found no data on long-term sequelae for other comparisons.
Adverse events
Adverse event data were available in three studies giving comparison data on 1528 participants. None of the four comparisons (antivirals
plus corticosteroids versus corticosteroids plus placebo or no treatment; antivirals versus corticosteroids; antivirals plus corticosteroids
versus placebo; antivirals versus placebo) showed significant differences in adverse events between treatment and control arms. We could
find no correlation with specific treatment within these results.
Authors' conclusions
Low-quality evidence from randomised controlled trials showed a benefit from the combination of antivirals with corticosteroids com-
pared to corticosteroids alone for the treatment of Bell's palsy of various degrees of severity. Low-quality evidence showed a benefit of
combination therapy compared with corticosteroids alone in severe Bell’s palsy. Corticosteroids alone were more effective than antivirals
alone and antivirals plus corticosteroids were more effective than placebo or no treatment. There was no benefit from antivirals alone
over placebo.
Moderate-quality evidence indicated that the combination of antivirals and corticosteroids reduced sequelae of Bell's palsy compared
with corticosteroids alone.
We found no significant increase in adverse events from the use of antivirals compared with either placebo or corticosteroids, based on
low-quality evidence.
PLAIN LANGUAGE SUMMARY
Antiviral treatment for Bell's palsy
Review question
We reviewed the evidence about the effect of antiviral therapy alone or in combination with any other therapy, on Bell's palsy.
Background
Bell's palsy is a disease of the facial nerve that causes one side of the face to be paralysed. Some studies have suggested that it is caused
by the same viral infections that cause cold sores (herpes simplex) or shingles (varicella zoster). If this is correct, antiviral drugs would be
likely to help recovery. The paralysis is usually temporary even when left untreated, although without treatment about one person in five
is left with permanent facial disfigurement or pain. A Cochrane review has already confirmed the effectiveness of corticosteroids in Bell’s
palsy. This review was first published in 2001 and has been revised several times, most recently in 2009. This version replaces an update
in Issue 7 of the Cochrane Library withdrawn because of an ongoing investigation into the reliability of data in one of the included studies.
Study characteristics
We identified 10 trials, which included 2280 participants with mild, moderate, or severe one-sided Bell’s palsy of unknown cause. Partici-
pants were aged from 14 to 84 years. The trials compared antivirals in combination with corticosteroids to corticosteroids; antivirals alone
to placebo or no treatment; antivirals alone to corticosteroid treatment alone; and antiviral treatment in combination with corticosteroids
to placebo or no treatment. The duration of the included studies ranged from three months to 12 months.
Key results and quality of the evidence
Incomplete recovery
According to low-quality evidence, combining antivirals with corticosteroids improved rates of incomplete recovery from Bell's palsy com-
pared to corticosteroids alone. This finding was based on data from eight trials involving 1315 people with Bell's palsy of various degrees
of severity.

Informed decisions.

We were able to use data from four of the studies (478 participants) to examine treatment effects in severe Bell's palsy (that is people
who have complete or almost-complete facial paralysis). The results showed that in this group, the addition of antiviral treatment to
corticosteroids probably improved rates of incomplete recovery over corticosteroid treatment alone, although we assessed this evidence
as low quality.
In other analyses, we found the following:
• corticosteroids alone were more effective than antivirals alone in terms of incomplete recovery (768 participants);
• antivirals plus corticosteroids were more effective than placebo or no treatment (658 participants); and
• antivirals alone were less effective than placebo (although this difference was not significant) (658 participants).
Long-term after-effects of Bell's palsy
Three trials (941 participants) assessed the long-term after-effects of Bell's palsy, such as excessive tear production and synkinesis (invol-
untary movement of muscles occurring at the same time as deliberate movement). The combination of antivirals and corticosteroids re-
duced long-term after-effects of Bell's palsy compared with corticosteroids alone. The evidence was of moderate quality.
There were fewer long-term after-effects of Bell's palsy after treatment with corticosteroids alone than with antivirals alone (two trials,
472 participants).
Adverse events
Based on the evidence from three trials (1528 participants), none of the treatments showed significant differences in adverse events, taking
into account that the evidence for this outcome was low quality.
The evidence in this review is current to October 2014.

SUMMARY OF FINDINGS

Summary of findings for the main comparison. Antivirals plus corticosteroids compared to corticosteroids plus placebo or no treatment for Bell's
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palsy (idiopathic facial paralysis)
Antivirals plus corticosteroids compared to corticosteroids plus placebo or no treatment for Bell's palsy (idiopathic facial paralysis)
Patient or population: People with one-sided mild, moderate, or severe Bell’s palsy of unknown cause
Settings: Primary and secondary care
Better health.
Informed decisions.
Trusted evidence.
Intervention: Antivirals plus corticosteroids
Comparison: Corticosteroids plus placebo or no treatment
Outcomes Illustrative comparative Relative effect No of partici- Quality of the Comments

risks* (95% CI) (95% CI) pants evidence
(studies) (GRADE)
Assumed risk Correspond-
ing risk
Corticos- Antivirals
teroids plus plus corticos-
placebo or no teroids
treatment
Incomplete recovery at end of study Study population RR 0.61 1315 ⊕⊕⊝⊝

House-Brackmann scale, Sunnybrook score, (0.39 to 0.97) (8 studies) low1
Yanagihara score 168 per 1000 102 per 1000
Follow-up: 3 to 12 months (66 to 163)
Moderate
149 per 1000 91 per 1000

(58 to 145)

Motor synkinesis or crocodile tears Study population RR 0.56 469 ⊕⊕⊕⊝
Clinical assessment (0.36 to 0.87) (3 studies) moderate2
Follow-up: 4 to 9 months 194 per 1000 109 per 1000
(70 to 169)
Moderate
228 per 1000 128 per 1000

(82 to 198)
Adverse events 108 per 1000 127 per 1000 RR 1.18 877 ⊕⊕⊝⊝
4

Follow-up: 6 to 12 months (89 to 182) (0.83 to 1.69) (3 studies) low3,4
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is
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based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Better health.
Informed decisions.
Trusted evidence.
Very low quality: We are very uncertain about the estimate.
1 The benefit to people with Bell's palsy was greater from the combination of antivirals with corticosteroids than with corticosteroids alone or with placebo. We downgraded
the quality of evidence for the outcome twice because the heterogeneity of the trials was high (inconsistency), the RR had wide CIs that included the possibility of very little
effect (imprecision), and for risk of bias in the included studies. Heterogeneity may be due to clinical variation of participant characteristics, disease severity at baseline, delay
in receiving treatment, different type of antiviral agent used, the choice of outcome assessment measures and recovery cut-off points, or the trial duration.
2 We assessed the quality of evidence for motor synkinesis or crocodile tears as moderate because only four of 10 trials provided data (selective reporting).
3 One of the trials did not report how adverse events were documented (Hato 2007). In this trial the numbers are very small.
4 We downgraded the quality of evidence for adverse events to low. We downgraded once for publication bias, as only three of the eight studies in this comparison reported
adverse events, and a second time for imprecision as the CIs were wide and encompassed the possibility of an effect in either direction.


5

Informed decisions.

BACKGROUND study of viral replication in participants with Bell’s palsy suggests

that the window might be extended (Abiko 2002).
Description of the condition
Why it is important to do this review
Bell's palsy is an acute, generally unilateral paralysis or weakness of
facial musculature consistent with peripheral facial nerve dysfunc- The 2009 update of this Cochrane review included large-scale ran-
tion, of no detectable cause (Niparko 1993). Additional symptoms domised controlled trials (RCTs) of antivirals (A) and corticosteroids
frequently include pain around or behind the ear on the affected (S) that had been published in the years before the review. The au-
side, sometimes extending into the occipital or cervical regions. Im- thors stated that, compared to placebo, A did not contribute to a
paired tolerance to ordinary levels of noise and disturbed sense of significant improvement in the rate or extent of recovery of trial
taste on the affected side may also be present (Burgess 1984). participants (Lockhart 2009), but that when added to S, the rate of
recovery was slightly better than S alone. The current review up-
Epidemiological studies have reported an annual incidence of 23 dates these findings based on three additional studies. An update
to 25 per 100,000 per year, but a recent study using a general-prac- of the review published earlier this year (most recently as Gagyor
tice database suggests it may be even higher, at 37 per 100,000 per 2015b) also included Abdelghany 2013, a trial currently undergoing
year (Victor 1994; Martyn 1997; Morales 2013). The condition affects investigation for potential data unreliability. We requested with-
men and women more or less equally, and was once thought to drawal of that version of the review and here republish our analy-
be most common in the 30- to 45-year age group (Peitersen 1982; ses having removed the data from that trial pending the outcome
Katusic 1986; Yanagihara 1988; Bateman 1992; Brandenberg 1993; of the investigation.
Peitersen 2002). However, a recent primary-care database study
suggests a second peak in the over-70s (Morales 2013). Bell's palsy OBJECTIVES
presents disproportionately amongst pregnant women and people
who have diabetes, influenza, a cold, or some other upper respira- To assess the effects of antiviral treatments alone or in combination
tory ailment. On average, a British general practitioner will see one with any other therapy for Bell’s palsy.
person who has developed the condition every 12 to 18 months.
Both sides of the face are affected equally often (Prescott 1988). METHODS
The aetiology of Bell's palsy is still debated. A viral infection, vas- Criteria for considering studies for this review
cular ischaemia, autoimmune inflammatory disorders, and hered- Types of studies
ity have been proposed as underlying causes (Adour 1982; Burgess
1984; Lorber 1996; Lackner 2010). A viral aetiology has gained pop- We searched for all randomised controlled trials (RCTs) or qua-
ularity since the isolation of herpes simplex virus type 1 genome si-RCTs (which are trials that employ alternate or other systemat-
from the saliva and facial nerve endoneurial fluid of people with ic allocation) involving aciclovir, valaciclovir, or famciclovir alone
this condition (Murakami 1996; Lackner 2010). On the whole, the or in combination with any other therapy in the treatment of Bell's
prognosis is favourable, though a significant proportion of people palsy, published in any language. The duration of studies included
who are left untreated have residual symptoms. One of the largest in this review ranges from 3 to 12 months; the minimum study du-
series of people with Bell's palsy, which included people receiving ration was 3 months. As in previous versions of the review, we used
no treatment, showed that 85% of people began to recover with- study quality as an exclusion criterion, excluding trials with a high
in three weeks after onset (Peitersen 1982). Partial recovery usual- risk of bias in several domains.
ly occurred within three to six months for the remaining 15%. The
same series showed that normal facial expression reappeared in Types of participants
71% of cases, 13% had insignificant sequelae (long-term after-ef- We considered all trials where participants had a diagnosis of uni-
fects), and the final 16% had permanently diminished function with lateral facial paralysis of unknown cause and satisfied the trial au-
aberrant innervation (expressed as motor synkinesis or autonomic thors’ requirements for eligibility and inclusion.
dysfunction), and postparalytic spasms.
Types of interventions
Description of the intervention
We considered all trials of treatment with any oral antiviral licensed
The treatment of Bell's palsy was highly controversial until 2008, for the treatment of herpes simplex infections in immunocompe-
at which time corticosteroids alone were shown to be effective in tent participants. The list comprised aciclovir; valaciclovir, which is
treating the condition (Salinas 2010). Previous Cochrane reviews a prodrug of aciclovir; and famciclovir, which is a prodrug of pen-
on the treatment of Bell’s palsy examined the effectiveness of ciclovir. We considered trials where participants received antiviral
oral prednisolone and aciclovir or valaciclovir (Allen 2004; Lock- therapy versus placebo or any other treatment.
hart 2009). Several studies excluded from the analysis in these re-
views either failed to randomise participants or, when correctly ran- Types of outcome measures
domised, results were erroneously interpreted in a favourable light We have described changes to outcome measures in this and pre-
(May 1976; Wolf 1978). High-dose corticosteroid therapy has sev- vious versions of the review in Differences between protocol and
eral potential side effects, including peptic ulceration, hyperten- review.
sion, and confusional states. Antiviral therapy was considered ex-
pensive, and treatment was reserved for circumstances in which a Primary outcomes
clear benefit appeared likely.Previous recommendations suggest-
ed that antivirals needed to be started within 48 hours, although a Incomplete recovery of facial function at the end of study measured
using a validated rating scale.

Informed decisions.

Secondary outcomes • not-A: treatment not including antiviral treatment (i.e. OS or

OO).
1. Motor synkinesis or crocodile tears at the end of the study.
2. Adverse events. Selection of studies
3. Incomplete recovery at month six in severe cases.
Six review authors working in pairs (FG and VM, DS and MS, IG and
Some trials have reported other symptoms (pain, discomfort, and FS) scrutinised titles and abstracts to determine eligibility for re-
embarrassment) as outcomes, but we did not consider them in this view of the full-text article. At least two review authors indepen-
review. dently assessed each full-text paper for relevance, eligibility, and
quality. We had no disagreements about inclusion. Two review au-
Search methods for identification of studies thors independently analysed each full-text report and selected
studies for inclusion.
Electronic searches
Data extraction and management
On 7 October 2014, we searched the Cochrane Neuromuscular Dis-
ease Group Specialized Register, the Cochrane Central Register of Two review authors extracted data onto a data extraction form and
Controlled Trials (CENTRAL; 2014, Issue 9), MEDLINE (January 1966 double-checked data extraction in pairs. Two review authors (IG
to September 2014), EMBASE (January 1980 to September 2014), and VM) agreed data input into the Cochrane authoring and statisti-
and LILACS (January 1982 to September 2014). On the same date cal software, Review Manager 5 (RevMan 2014). Any disagreements
we also searched the National Institute for Health Research Data- were discussed with FD to reach a resolution. We arranged transla-
base of Abstracts and Reviews of Effects (DARE), Health Technology tion of any papers where necessary.
Assessment (HTA) database, and the National Health Service Eco-
nomic Evaluation Database (NHS EED). We searched for registered Assessment of risk of bias in included studies
trials in ClinicalTrials.gov (www.clinicaltrials.gov) and in the World Two review authors (IG and VM) independently assessed the risk of
Health Organization International Clinical Trials Registry Platform bias in included studies using the 'Risk of bias' methodology de-
(www.who.int/ictrp/en/). scribed in the Cochrane Handbook for Systematic Reviews of Inter-
ventions (Higgins 2011). FD reviewed the 'Risk of bias' assessments.
We have provided detailed search strategies in the appendices:
The review authors considered methods of randomisation and al-
Cochrane Neuromuscular Disease Group Specialized Register (Ap-
location concealment, blinding (of treatment administrator, partic-
pendix 1), CENTRAL (Appendix 2), MEDLINE (Appendix 3), EMBASE
ipants, and outcome assessors), selective outcome reporting (for
(Appendix 4), and LILACS (Appendix 5).
example failure to report adverse events), and incomplete outcome
Searching other resources data (that is dropouts). We assessed each trial as at high, low, or
unclear risk of bias for each of these criteria.
We also reviewed the bibliographies of the identified trials and con-
tacted trial authors and known experts in the field and relevant Measures of treatment effect
drug companies to identify additional published or unpublished
All our outcomes were dichotomous. We analysed the data as risk
data.
ratios (RRs) with corresponding 95% confidence interval (CI).
Data collection and analysis When comparing studies that used differing symptom scores to as-
Since a significant benefit of S for the early management of Bell’s sess outcome, we used the House-Brackmann scale when avail-
palsy has been previously demonstrated (Lockhart 2009; Salinas able, as this was used most widely and could be compared with oth-
2010), the main focus of this review was to determine the effect of er scales.
A in combination with S.
When assessing adverse events, we used the number of partici-
Throughout we utilised the following notation: pants affected as opposed to the number of events, to facilitate da-
ta comparison.
• AO: antiviral treatment alone or in combination with placebo
• AS: antiviral treatment in combination with corticosteroids 'Summary of findings' table
• OO: placebo or no treatment only We created a 'Summary of findings' table for the comparison 'An-
• OS: corticosteroid treatment alone or in combination with tivirals plus corticosteroids versus corticosteroids plus placebo or
placebo no treatment' using the following outcomes.
Using these notations we conducted four comparisons altogether: 1. Incomplete recovery at the end of the study (House-Brackmann
scale)
• AS versus OS 2. Motor synkinesis or crocodile tears at the end of the study
• AO versus OO (House-Brackmann scale)
• AO versus OS 3. Adverse events
• AS versus OO
We used the five GRADE considerations (risk of bias, inconsisten-
For an overall comparison of treatment with and without A we used cy of effect, imprecision, indirectness, and publication bias) to as-
the following notations: sess the quality of a body of evidence (studies that contribute
data for the prespecified outcomes). We employed methods and
• A: antiviral treatment in any combination (i.e. AO or AS); recommendations described in Section 8.5 and Chapter 12 of the
Informed decisions.

Cochrane Handbook for Systematic Reviews of Interventions (Hig- Subgroup analysis and investigation of heterogeneity
gins 2011) using GRADEpro software (GRADEpro 2008). We justified
We calculated a subgroup analysis for incomplete recovery of peo-
all decisions to down- or upgrade the quality of studies using foot-
ple with severe Bell’s palsy at baseline using data from four trials
notes.
(Hato 2007; Sullivan 2007; Engström 2008; Lee 2013). Severe Bell’s
Unit of analysis issues palsy was defined as severe to complete facial paralysis, graded as
equal to or greater than V in the House-Brackmann grading system
Each of the included studies carried out randomisation at the (Table 1), equal to or less than 20 in the Sunnybrook score (Table
participant level. Nine trials used a simple parallel-group design 2), and equal to or less than 20 in the Yanagihara score (Table 3).
(Adour 1996; Li 1997; De Diego 1998; Hato 2007; Kawaguchi 2007;
Vázquez 2008; Yeo 2008; Lee 2013) and two trials used a factorial Sensitivity analysis
design (Sullivan 2007; Engström 2008).
We used sensitivity analyses to assess the effects of combining tri-
For studies with a factorial design, we aggregated groups accord- als with and without additional treatments in an analysis of A ver-
ing to whether or not antivirals were administered. We described sus S and to assess the impact of length of follow-up on the results
details in the Results. of the meta-analysis. We performed sensitivity analyses to assess
the potential difference in participant response to aciclovir versus
Dealing with missing data valaciclovir and further sensitivity analyses to investigate whether
the exclusion of trials not meeting current best standards (that is
We contacted authors of two studies (Kawaguchi and Engström)
those that had a high or unclear risk of bias in more than five cate-
for additional data that were required for analysis but which were
gories or trials with less than 200 participants) would influence the
not provided in their papers, and one (Engström) responded with
results. An analysis investigated whether our conclusions were al-
data. We contacted a previous review author (Lockhart) for infor-
tered when we excluded the study with a follow-up of less than six
mation on other studies and we received a response. We used the
months (Adour 1996). Furthermore, in the analysis of AS versus OS
Kawaguchi 2007 data provided in previous versions of this review.
in severe cases, we performed a sensitivity analysis to assess differ-
Assessment of heterogeneity ences between trials in which only a subgroup of participants had
severe Bell’s palsy versus the trials where almost all participants
We used the I2 statistic to assess heterogeneity among the included had severe Bell’s palsy.
studies in each analysis. If we found substantial unexplained het-
erogeneity, we reported it and explored possible causes. RESULTS
Assessment of reporting biases Description of studies

As a result of the small number of included trials, we were not able Results of the search
to produce meaningful funnel plots to assess the likelihood of pub-
For this review, we found 375 references in MEDLINE, 102 in EM-
lication bias (Egger 1997).
BASE, 4 in LILACS, 28 in the Cochrane Neuromuscular Disease
Data synthesis Group Specialized Register, and 39 in CENTRAL. We also found 12
additional trials in the Database of Abstracts of Reviews of Effects
We calculated a treatment effect using the Mantel-Haenszel (DARE), one in the Health Technology Assessments (HTA), one in the
method (Egger 2007). We used the random-effects model where we Economic Evaluation Database (EED) and two by hand searching.
found marked heterogeneity (I2 greater than 40%) between stud- We found two ongoing studies in the World Health Organization In-
ies. If we had found little or no heterogeneity, we would have used ternational Clinical Trials Registry Platform (IRCT201109187575N1;
a fixed-effect analysis. The main outcome in all trials was complete IRCT2012062210087N1). See Figure 1 for a flow chart of the study
recovery. For this review, the review authors calculated the number selection process.
of participants with incomplete recovery by subtracting the num-
ber of participants with complete recovery from the number of par-
ticipants in the reference group.


Informed decisions.

Figure 1. Study selection flow diagram.


Informed decisions.

Figure 1. (Continued)


Informed decisions.

Figure 1. (Continued)

Informed decisions.

Included studies Yeo 2008 recruited 91 participants who were randomised to receive
either aciclovir and prednisolone or prednisolone alone, to pro-
We added three RCTs with 293 participants in total to the previous
vide a comparison AS versus OS. Participants also received phys-
version of this review, which had seven trials and 1987 participants.
ical therapy and plasma volume expanders as adjuncts. The trial
The newly added trials were Lee 2013, Li 1997, and Vázquez 2008.
was double blind and investigators followed up participants for six
Two of these were published after the search in the 2009 review (Lee
months or until complete recovery. Recovery was assessed using
2013; Vázquez 2008), and we identified Li 1997 via a Google search
the House-Brackmann scale and defined as a House-Brackmann
that was additional to our prespecified searches.
score of II or less.
The 10 studies in the current review included 2280 participants (see
Li 1997 recruited 51 participants within four days of onset of Bell's
Characteristics of included studies).
palsy. Participants were randomly assigned into two groups, re-
Engström 2008 recruited 829 participants who were treated within ceiving either aciclovir plus prednisolone or prednisolone. Good re-
72 hours of onset and randomised by a computerised mechanism covery was defined as a House-Brackmann score of II or I at month
in a two-stage process into four treatment groups: valaciclovir with six. Li 1997 reported outcomes for 46 participants; five were lost to
prednisolone or valaciclovir with placebo or placebo with pred- follow-up.
nisolone or double placebo in a factorial design. The trial was dou-
Lee 2013 was a RCT in participants with severe to complete Bell’s
ble blind (administrator and participant) for assessment of recov-
palsy that used the House-Brackmann score for assessment. The
ery status until the end of follow-up. Participants were assessed
trial included 201 participants with a score of V or more. After ran-
at onset, after 2 weeks (11 to 17 days), and after 1, 2, 3, 6, and 12
domisation into two groups, participants received either famci-
months. Disease status was measured using the House-Brackmann
clovir plus prednisolone simultaneously or prednisolone alone. Re-
grading system and the Sunnybrook scale. Complete recovery sta-
covery rate was designated as scores of I or II on the House-Brack-
tus was defined by a Sunnybrook score of 100 and a House-Brack-
mann scale at month six.
mann grade of 1. Time to recovery was estimated. Data analysis in-
cluded an assessment of treatment interaction. Vázquez 2008 included 42 participants and reported outcomes at
6 and 12 months using the Sunnybrook Facial Grading System.
For this review, we aggregated groups and analysed AS plus AO
Scores of greater than 90 were defined as a satisfactory recov-
versus OS plus OO as A versus not-A in order to achieve the most
ery. Participants in the intervention group were treated with pred-
powerful comparison for the effect of treatment with valaciclovir
nisone and valaciclovir and in the control group with prednisone
on recovery rates at 12 months. We analysed the recovery rates 12
and placebo. The main study outcome was rate of participants with
months after the onset of facial palsy using the Sunnybrook defin-
total recovery at six months’ follow-up in each group and average
ition and defined complete recovery as a House-Brackmann grade
time to recovery in each group.
of I.
Adour 1996 recruited 119 participants, of whom 99 were included
Hato 2007 randomised 296 participants within seven days of onset
in the published analysis. The study was double blind and placebo
using sealed envelopes into two treatment groups: valaciclovir with
controlled. Participants were recruited within three or days or less
prednisolone or placebo with prednisolone, to provide a compari-
of onset of paralysis and received either aciclovir and prednisolone
son AS versus OS. The final analysis included 221 participants. Ad-
or placebo and prednisolone. The study duration was four months;
ministrators were not blinded to the treatment allocation, but par-
participants were reviewed at two weeks, two months, and four
ticipants were blinded to treatment received. Those assessing re-
months. This was a single-centre study. The Facial Paralysis Recov-
covery status were not blinded to treatment. Participants’ disease
ery Index (FPRI) was used to measure facial function; the primary
severity was assessed using the Yanagihara 40-point scoring sys-
trial outcome was incomplete recovery defined by a FPRI of 7 or
tem; participants were considered completely recovered if attain-
less.
ing a score greater than 36. Participants were assessed at onset and
monthly thereafter for six months or until completely recovered if De Diego 1998 recruited 113 participants, including 101 in the final
recovery occurred before six months. analysis. Participants were randomly assigned to treatment. Base-
line assessment was carried out within 48 hours of onset of symp-
Sullivan 2007 recruited 551 participants who were treated with-
toms. Participants received either aciclovir for 10 days or pred-
in 72 hours of onset and randomised by a dedicated remote tele-
nisolone for 16 days (reducing dose). Reviews were scheduled for 1,
phone-computerised mechanism in a two-stage process into four
3, 6, and 12 weeks after initial contact, with further contact if per-
treatment groups: aciclovir with prednisolone or aciclovir with
sistent incomplete recovery was noted. The primary study outcome
placebo or placebo with prednisolone or double placebo in a fac-
was recovery as defined by a House-Brackmann score of II or less or
torial design. The trial was blinded for administrator, participant,
a Facial Paralysis Recovery Profile of 8 or more. The report did not
and assessment of recovery status until the end of follow-up. Par-
give the final length of follow-up but stated that it continued "until
ticipants were assessed at onset, after three months, and if still un-
complete recovery or stabilization of the paralysis".
well at three months, after nine months. Recovery status was mea-
sured using the House-Brackmann scale, with complete recovery Kawaguchi 2007 recruited 150 participants who were treated with-
defined by House-Brackmann grade I. Data analysis included an in seven days of onset and randomised using sealed envelopes in-
assessment of treatment interaction. Sullivan 2007 reported final to two treatment groups: valaciclovir plus prednisolone or pred-
outcomes on 496 completed participants at three months and nine nisolone alone. There was inadequate blinding of the clinician.
months in treatment groups that were aggregated as for Engstrom. Kawaguchi et al. provided unpublished data on incomplete recov-
ery for the previous update. Participants were assessed at 1, 2, 3,
4, 5, and 6 months after inclusion using the Yanagihara scale. We

Informed decisions.

could not contact the authors to obtain data for this review, but we Overall, we excluded five studies for not being RCTs (Ibarrondo
have included the data previously published in this review. 1999; Axelsson 2003; Hato 2003; Hultcrantz 2005; Ahangar 2006);
two for having a very short follow-up (Zhou 1999; Chen 2005); three
Excluded studies because reports provided insufficient information to assess meth-
Authors of the previous version of this review excluded Antunes ods or outcomes (Antunes 2000; de Aquino 2001; Roy 2005); four be-
2000 because of incomplete data in 44 participants. Despite our at- cause of high risk of bias in several domains: Minnerop 2008 (inad-
tempts to contact the authors, there was still insufficient informa- equate randomisation, unblinded, 50 of 167 participants lost to fol-
tion for the data to be usefully included in the analyses. low-up), Ramos Macias 1992 (only abstract available, 15 of 45 par-
ticipants had Ramsay Hunt syndrome and were given intravenous
The authors of a previous version of this review reassessed the therapy), Roy 2005 (lack of outcome data, as described above),
inclusion of the two studies that were awaiting assessment (de Shahidullah 2011 (inadequate randomisation, unblinded, 39 of 107
Aquino 2001; Roy 2005). Dr. D. Allen, the author of a previous ver- participants lost to follow-up); and one paper was not available
sion of this review, attempted to contact the lead author of the for- (Inanli 2001).
mer paper for clarification of the data, but this was not forthcom-
ing and so we have excluded this trial because of a lack of adequate Ongoing studies
information. The latter study recruited 82 participants, of whom 18 We identified two trial reports in a search of ClinicalTrials.gov just
dropped out, and compared aciclovir plus methylprednisolone to prior to completion of the review. The current status of these trials
methylprednisolone alone, reporting no benefit from the addition is unknown; we will assess them fully in a future update of the re-
of aciclovir. The authors did not provide outcome data in the ab- view. See Ongoing studies.
stract, which appeared in a journal supplement, and according to
the search strategies employed, the trial has not been published as Studies awaiting classification
a full paper to date. We excluded this trial due to a lack of adequate
Abdelghany 2013 is awaiting classification pending the results of an
information.
investigation into the reliability of the trial data.
A further study was classified as awaiting assessment in the previ-
ous version of this review (Inanli 2001). This paper was included in a Risk of bias in included studies
systematic review and a meta-analysis (de Almeida 2009; Goudakos We have summarised our 'Risk of bias' assessments in Figure 2.
2009). We excluded the paper from the current review because we
could not find it in print or electronic form. See Characteristics of
excluded studies.


Informed decisions.

Figure 2. A summary of review authors' 'Risk of bias' assessments for included studies. Red = high risk of bias;
yellow = unclear risk of bias; green = low risk of bias.

Allocation 2007; Engström 2008). Two other studies were at low risk of bias
from randomisation but at high risk of bias from inadequate allo-
Three studies were at low risk of selection bias, being adequate-
cation concealment (Kawaguchi 2007; Lee 2013). In the remaining
ly randomised with allocation concealment (Adour 1996; Sullivan
studies, the risk of bias from the method of randomisation was un-
Informed decisions.

clear, and the risk of bias for allocation concealment was either un- and Lee 2013 presented results using the House-Brackmann scale
clear, in Li 1997, Hato 2007, Vázquez 2008, and Yeo 2008, or high, in (House 1985). Engström 2008 supplemented this with use of the
De Diego 1998. Sunnybrook scale to minimise the effects of interrater variability
(Ross 1996). Vázquez 2008 used a facial grading scale related to
Blinding Sunnybrook (Ross 1996).
Adour 1996, Li 1997, Sullivan 2007, Engström 2008, and Vázquez
Statistical analysis
2008 were described as double blind and placebo controlled. Lee
2013 did not use a placebo to ensure blinding. De Diego 1998, Ha- Nine of the 10 studies analysed gave adequate detail; they clearly
to 2007, and Kawaguchi 2007 did not describe blinding or placebo stated and then used appropriate statistical tests. Only Hato 2007
use. The Yeo 2008 report stated that the study was double blind, scored 'unclear' in this category, as it did not state the tests used.
however, the text does not describe this, so we assessed the risk of
bias for blinding as unclear. Baseline differences between groups
Eight of the 10 trials were adequate in this category. De Diego 1998
Incomplete outcome data
found a significant difference in rates of hypertension between the
All studies except Yeo 2008 reported frequencies, and often rea- two groups, but further analysis revealed that there was no signif-
sons, for failure to complete follow-up. icant difference in trial outcomes as a result. Kawaguchi 2007 re-
ported a significant difference between mean ages of the treatment
Most trials reported a dropout rate of 10% or less (Li 1997; De Diego groups, but further analysis of the age distribution using Chi2 test
1998; Kawaguchi 2007; Sullivan 2007; Engström 2008; Vázquez revealed no significant difference. Lee 2013 reported a later on-
2008; Yeo 2008). Exceptions were Lee 2013 with a dropout rate of set of the treatment in the combination treatment without signifi-
13.1%, Adour 1996 with a dropout rate of 17%, and Hato 2007 with cance.
a dropout rate of 25%.
Effects of interventions
Selective reporting
See: Summary of findings for the main comparison Antivirals
All studies except Adour 1996 and Kawaguchi 2007 reported all plus corticosteroids compared to corticosteroids plus placebo or
their intended primary outcomes. Adour 1996 failed to report on no treatment for Bell's palsy (idiopathic facial paralysis)
audiometry and stapedial reflex testing. Engström 2008 reported
all primary outcomes; secondary outcomes were reported in later As the included trials reported different intervals and lengths of
published papers (Axelsson 2012; Berg 2012). follow-up, we performed the analyses on data reported at three
months (De Diego 1998), six months (Li 1997; Hato 2007; Kawaguchi
Five studies did not report adverse events (Li 1997; De Diego 1998; 2007; Vázquez 2008; Yeo 2008; Lee 2013), nine months (Sullivan
Kawaguchi 2007; Yeo 2008; Lee 2013). 2007), or 12 months (Engström 2008) after the start of treatment.
Other potential sources of bias For the subgroup analysis of incomplete recovery in participants
Diagnostic criteria with severe Bell’s palsy at onset, we either extracted data at month
six, in Hato 2007 and Lee 2013, or imputed data to month six, in
Nine studies gave adequate information (Li 1997; De Diego 1998; Sullivan 2007 and Engström 2008.
Hato 2007; Kawaguchi 2007; Sullivan 2007; Engström 2008; Vázquez
2008; Yeo 2008; Lee 2013). All studies explicitly mentioned a diagno- Antivirals plus corticosteroids versus corticosteroids plus
sis of Bell's palsy and stated that they had considered and excluded placebo or no treatment (AS versus OS)
other causes of facial palsy. Two trials, Hato 2007 and Kawaguchi
2007, retrospectively excluded participants on the basis of posi- Incomplete recovery
tive serology for herpes simplex or varicella zoster viruses. Lee 2013 This comparison contained eight studies with 1315 participants in
excluded participants who did not fulfil inclusion criteria, without total (Adour 1996; Li 1997; Hato 2007; Kawaguchi 2007; Sullivan
specifying the reasons. Two studies mentioned referral to special- 2007; Engström 2008; Vázquez 2008; Yeo 2008). We excluded Lee
ists for diagnostic confirmation (Sullivan 2007; Engström 2008). The 2013 from this analysis due to its selected participants (severe cas-
remaining study, Adour 1996, stated participants were diagnosed es only).
with Bell's palsy but did not give any further information.
The risk ratio (RR) of incomplete recovery at the end of the study
Outcome criteria showed a statistically significant difference between AS and OS
All studies used referenced facial function scoring systems to grade treatments, favouring AS over OS. The RR of incomplete recovery
recovery from facial paralysis. Adour 1996 and De Diego 1998 used was 0.68 (95% confidence interval (CI) 0.52 to 0.89). Heterogeneity
the Facial Paralysis Recovery Profile and Adour 1996 also used the was substantial when we used the fixed-effect model (Chi2 = 13.19,
Facial Paralysis Recovery Index. Hato 2007 and Kawaguchi 2007 df = 7 (P value = 0.007), I2 = 47%); we used the random-effects mod-
used the Yanagihara scoring system (Yanagihara 2003), which has el to partially correct for this (RR 0.61, 95% CI 0.39 to 0.97) (Analysis
a validated system for conversion to the House-Brackmann scale 1.1, Figure 3).
(House 1985). Li 1997, Sullivan 2007, Engström 2008, Yeo 2008,


Informed decisions.

Figure 3. Forest plot of comparison: 1 Antivirals plus corticosteroids versus corticosteroids plus placebo or no
treatment, outcome: 1.1 Incomplete recovery at end of study.

Motor synkinesis or crocodile tears Antivirals versus corticosteroids (A versus S)
Adour 1996 and Engström 2008 provided data for the outcome mo- Incomplete recovery
tor synkinesis or crocodile tears at the end of the study (Analysis
This comparison contained three studies (De Diego 1998; Sullivan
1.2). The analysis included 469 participants and showed a signifi-
2007; Engström 2008).
cant difference between AS and OS (RR 0.56, 95% CI 0.36 to 0.87).
All studies (768 participants) provided data for our primary out-
Adverse events
come of incomplete recovery at the end of the study. Incomplete
Adverse events were not significantly less likely in AS versus OS (RR recovery was significantly less common in the participants treat-
1.18, 95% CI 0.83 to 1.69). This analysis included data from 877 pared with A versus those treated with S. Initial calculations using the
ticipants in three studies (Hato 2007; Sullivan 2007; Engström 2008) fixed-effect model showed a RR of 1.96 (95% CI 1.48 to 2.59), but
(Analysis 1.3). with a high degree of heterogeneity (Chi2 = 8.78, df = 2, P value =
0.01, I2 = 77%). We repeated the analysis using the random-effects
model to partially correct for this, and the RR was 2.82 (95% CI 1.09
to 7.32) (Analysis 2.1, Figure 4).

Figure 4. Forest plot of comparison: 2 Antivirals versus corticosteroids, outcome: 2.1 Incomplete recovery at end of
study.

Motor synkinesis or crocodile tears Analysis 2.3), but the CIs included the possibility of the opposite ef-
fect.
De Diego 1998 and Engström 2008 provided data for the outcome
motor synkinesis or crocodile tears at the end of the study (Analy- Antivirals plus corticosteroids versus placebo (AS versus OO)
sis 2.2). The analysis included 472 participants and showed signifi-
cantly fewer sequelae in S than in A (RR 1.52, 95% CI 1.08 to 2.12). Incomplete recovery
This comparison contained two studies and outcome data on 658
Adverse events
participants (Sullivan 2007; Engström 2008).
Fewer participants experienced adverse events in the antiviral
group than the corticosteroids group (RR 0.85, 95% CI 0.57 to 1.28,

Informed decisions.

Incomplete recovery at the end of the study was significantly much

less common with AS versus OO (RR 0.56, 95% CI 0.41 to 0.76)
(Analysis 3.1, Figure 5).

Figure 5. Forest plot of comparison: 3 Antivirals plus corticosteroids versus placebo, outcome: 3.1 Incomplete
recovery at end of study.

Motor synkinesis or crocodile tears Motor synkinesis or crocodile tears
Not reported Not reported
Adverse events Adverse events

Adverse events (among 649 participants) were slightly but not sig- Adverse events (among 651 participants) were not significantly
nificantly more common with AS than with OO (RR 1.14, 95% CI 0.79 more common in OO (RR 0.83, 95% CI 0.56 to 1.24) (Analysis 4.2).
to 1.65) (Analysis 3.2).
Antivirals plus corticosteroids versus corticosteroids plus
Antivirals versus placebo (AO versus OO) placebo or no treatment (AS versus OS) in severe cases
Incomplete recovery Incomplete recovery
For two trials (658 participants) that compared antivirals versus For this comparison, we extracted data from four studies with 478
placebo without any complicating additional treatment, the RR of participants (Hato 2007; Sullivan 2007; Engström 2008; Lee 2013).
incomplete recovery was non-significant (RR 1.10, 95% CI 0.87 to The RR of incomplete recovery in this subgroup was just significant-
1.40) (Sullivan 2007; Engström 2008). The heterogeneity was mod- ly less in AS versus OS (RR 0.64, 95% CI 0.41 to 0.99, random-effects
erate (Chi2 = 0.63, P value = 0.20, I2 = 39%) (Analysis 4.1). model). The heterogeneity was moderate (Chi2 = 5.2, P value = 0.16,
I2 = 42%) (see Analysis 5.1, Figure 6).

Figure 6. Forest plot of comparison: 5 Antivirals plus corticosteroids versus corticosteroids plus placebo or no
treatment in severe cases, outcome: 5.1 Incomplete recovery at the end of the study.

Sensitivity analyses We performed sensitivity analyses to investigate whether the exclu-
sion of trials not meeting current best standards (that is a high or
We investigated the effect of using the comparison AS versus OS
unclear risk of bias in more than five categories or trials with less
by performing further analysis to investigate whether excluding the
than 200 participants) would influence the results.
study with a follow-up of less than six months altered our conclu-
sions (Adour 1996). We performed further sensitivity analyses to as-
sess the potential difference in participant response to aciclovir,
in Adour 1996, Li 1997, Sullivan 2007, and Yeo 2008, versus valaci-
clovir, in Hato 2007, Engström 2008, and Vázquez 2008.

Informed decisions.

Antivirals plus corticosteroids versus corticosteroids plus Heterogeneity may be due to clinical variation, for example in study
placebo or no treatment (AS versus OS) participant characteristics, disease severity at baseline, and delay
in receiving treatment or different type of antiviral agent used and
When we excluded Adour 1996, the RR of incomplete recovery was
the small numbers in the subgroups. Equally, variation may be due
0.67 (95% CI 0.41 to 1.07, n = 1216). This represents a small but sta-
to methodological considerations such as method of randomisa-
tistically significant change compared with the main analysis (RR
tion, the use of blinding, the choice of outcome assessment mea-
0.61, 95% CI 0.39 to 0.97, n = 1315, Analysis 1.1) with the removal of
sures and recovery cut-off points or the trial duration. In partic-
outcomes that reported follow-up at six months or less.
ular, Li 1997, Hato 2007, and Kawaguchi 2007 had methodologi-
When we performed sensitivity analyses to assess the potential dif- cal weaknesses in baseline group assessment, completeness of fol-
ference in participant response to aciclovir versus valaciclovir, we low-up, and adequacy of blinding. Any of these factors could re-
found no significant difference from the results of the main analysis sult in bias and introduce inaccuracy. The heterogeneity was ex-
(Analysis 1.1). When we excluded Adour 1996, Li 1997, Kawaguchi acerbated in many studies by keeping the inclusion criteria fairly
2007, Sullivan 2007, and Yeo 2008, the RR of incomplete recovery broad; this maximises data inclusion and therefore power, but re-
was 0.74 (95% CI 0.42 to 1.31, n = 678). When we excluded trials us- sults must be interpreted with this in mind. The sensitivity analysis
ing aciclovir, the RR was 0.65 (95% CI 0.36 to 1.16, n = 678). of participants with severe Bell’s palsy showed a remarkable differ-
ence between the studies with data from subgroups and trials with
Exclusion of trials with fewer than 200 participants (Adour 1996; a complete dataset. The different definitions of severe Bell’s palsy
Li 1997; Vázquez 2008; Yeo 2008; Kawaguchi 2007), and trials not depending on the symptom scores used in the trial should also be
meeting current best standards (Li 1997; Hato 2007; Kawaguchi considered a potential source of heterogeneity.
2007; Vázquez 2008; Yeo 2008), did not significantly change the re-
sults of Analysis 1.1 (RR 0.83, 95% CI 0.41 to 1.71, n = 888 and RR Sensitivity analysis of trials with a six-month endpoint or longer
0.81, 95% CI 0.38 to 1.74, n = 766, respectively). showed a change of results from significant into non-significant
compared to the whole-group analysis. This change was probably
Antivirals plus corticosteroids versus corticosteroids plus caused by the heterogeneity of the studies.
placebo or no treatment (AS versus OS) in severe cases
Subgroup analysis of the relative treatment difference with differ-
We performed a sensitivity analysis to assess differences between ent antivirals showed no significant changes in the outcomes for
Sullivan 2007 and Engström 2008, where only a subgroup of partici- combined treatment versus treatment with steroids alone. Given
pants had severe Bell’s palsy, versus Hato 2007 and Lee 2013, where this finding, it is unlikely that different antiviral compounds will
almost all participants had severe Bell’s palsy. The results showed have a significant effect on the outcome 'Incomplete recovery at
a remarkable difference between the analyses: RR 0.47 (95% CI 0.30 the end of the study', despite the difference in bio-availability (Sul-
to 0.75) versus RR 0.82 (95% CI 0.57 to 1.17). livan 2007).
DISCUSSION We found insufficient data to examine any of the other variables

reported in the studies, such as pain, quality of life, and variation
Summary of main results in response due to time to treatment and severity at onset. These
The results of this updated review show a benefit from combining variables may be useful for hypothesis generation for future work
antivirals with steroids in comparison with steroids alone for peo- in this area.
ple with Bell’s palsy of various degrees of severity at commence- From the data available for comparison of motor synkinesis or
ment of treatment. This is based on a reduction of incomplete re- crocodile tears at the end of the study, the results of three stud-
covery (RR 0.61, 95% CI 0.39 to 0.97, n = 1315). Comparing the da- ies with a total of 941 participants were significant in two compar-
ta of participants with severe Bell’s palsy, we also demonstrated a isons (Adour 1996; De Diego 1998; Engström 2008). De Diego 1998
reduction in the rate of incomplete recovery for the combination and Engström 2008 compared antivirals with corticosteroids and
treatment at month six. found fewer episodes of these long-term sequelae in the corticos-
Remarkably, the data of Sullivan 2007 and Vázquez 2008 showed teroid-treated participants, while Adour 1996 and Engström 2008
a non-significant detrimental effect of antivirals on recovery com- compared antivirals plus corticosteroids with corticosteroids alone
pared with Hato 2007, Engström 2008, and Lee 2013 (Analysis 1.1). and found fewer episodes of these sequelae in the antiviral treat-
Possible reasons for this are that the trials were heterogeneous in ment group. A degree of clinical heterogeneity (different clinical as-
ways that we discuss below. sessment scales used) and methodological heterogeneity (differ-
ent treatment regimens and follow-up plans) limit the interpreta-
The reduction in incomplete recovery was significantly better in tion of these data.
participants receiving corticosteroids compared with antivirals.
The treatment effect of antivirals plus corticosteroids was signifi- Adverse event data were available in three studies giving compari-
cantly better than placebo. son data for 1528 participants (Hato 2007; Sullivan 2007; Engström
2008). None of the comparisons showed significant differences in
Overall completeness and applicability of evidence adverse events between arms. We could find no correlation with
specific treatment within these results.
When antivirals were compared to placebo, antivirals produced no
benefit. This result was influenced by the Sullivan 2007 trial, which We found variation in the clinical endpoints chosen as defining re-
suggested that antiviral treatment had a non-significant detrimen- covery: Sullivan 2007 and Engström 2008 used House-Brackmann
tal effect on recovery. Grade 1, while Yeo 2008 used House-Brackmann Grade 2. The oth-
er studies used a variety of different scales that show more or less

Informed decisions.

equivalence to these. We have provided details of the symptoms Agreements and disagreements with other studies or
scales and comparison where available (Table 1, Table 2, Table 3). reviews
Neither Kawaguchi 2007 nor Yeo 2008 found a significant associa- We have included studies conducted in Asia, North and Middle
tion between time to treatment and final recovery status. America, and Europe. It is possible that genetic differences in drug
metabolism or response or even different aetiological processes
We found differences in severity at recruitment: Li 1997, Hato 2007, may account for some of the observed variation in response.
Vázquez 2008, Yeo 2008, and Lee 2013 included a more severe spec-
trum of palsy than Engström 2008. Hato 2007 and Engström 2008 We found two systematic reviews and two meta-analyses com-
stratified participants by severity-of-disease status at onset. Hato paring steroids and antivirals for the treatment of Bell’s palsy (de
2007 found that in cases of complete or severe palsy, the recovery Almeida 2009; Goudakos 2009; Quant 2009; Numthavaj 2011). De
rate for the combination treatment was significantly greater than Almeida et al. compared any corticosteroid treatment with antivi-
for participants treated with steroids only. Lee 2013 included on- rals and included 18 trials in the meta-analysis. Most of the trials did
ly severe cases and found a significantly higher rate of recovery in not meet the inclusion criteria for this review. De Almeida states a
the group receiving a combination treatment using famciclovir. In benefit of corticosteroids for people with Bell’s palsy and the prob-
contrast, Engström 2008 could not confirm these findings in treat- ability of an additional benefit when corticosteroids are combined
ment of participants with severe Bell's palsy, whereas Sullivan 2007 with antivirals. A systematic review and meta-analysis by Goudakos
showed a non-significant detrimental effect on complete recovery. et al. compared corticosteroids with corticosteroids plus antivirals
for the treatment of Bell’s palsy. This review included only four trials
The primary-outcome result raises another important considera- and omitted other important studies, for example Engström 2008,
tion, that is the health economic issues: a 10-day course of aciclovir which is the largest trial conducted on this topic. Goudakos did not
400 mg 5 times per day costs GBP 5.33 (USD 8.75, EUR 6.47); an find an additional benefit from combining corticosteroids with an-
equivalent course of valaciclovir costs GBP 8.50 (USD 13.96, EUR tivirals. The meta-analyses by Numthavaj and Quant each includ-
10.31). Famciclovir is significantly more expensive at GBP 138.79 ed six trials for analysis, with a great overlap. In both papers the
(USD 227.89, EUR 168.42). A 10-day course of prednisolone (two 25 authors reported higher rates of recovery when steroids were com-
mg tablets daily) costs about GBP 7.14 (USD 11.72, EUR 8.66) (BNF bined with antivirals compared to steroids alone, but the difference
2013). These cost data are specific to the UK market (2013); costs was non-significant.
vary significantly in other countries (Hernández 2008).
AUTHORS' CONCLUSIONS
Quality of the evidence
Implications for practice
We downgraded the evidence on incomplete recovery for the com-
parison antivirals plus corticosteroids versus corticosteroids alone Among participants with Bell's palsy of various degrees of sever-
to low due to heterogeneity, imprecision of the study results, and ity, low-quality evidence shows an additional benefit from com-
risk of bias. We further downgraded the evidence to low quality in bination therapy with antivirals and corticosteroids over corticos-
the group with severe Bell's palsy, as the effect in this group was teroids alone on incomplete recovery.
particularly sensitive to removal of studies at high risk of bias. We
found the quality of the evidence for other outcomes such as mo- Low-quality evidence from trials involving people with severe Bell's
tor synkinesis and crocodile tears, and adverse events to be low be- palsy indicates a benefit on rates of incomplete recovery from com-
cause of imprecision and publication bias—only three of the includ- bined corticosteroids and antivirals over corticosteroids alone.
ed trials reported these outcomes.
Corticosteroids alone were more effective than antivirals alone and
Potential biases in the review process antivirals plus corticosteroids were more effective than placebo or
no treatment.
To help ensure that decisions about which studies to include in this
review were reproducible, two review authors repeated the review There was no benefit from antivirals alone over placebo.
process (we divided the studies into three groups). We made no dis-
tinction on the experience and expertise of each review author in Moderate-quality evidence indicated that the combination of an-
the reviewing pairs. Regarding applying the eligibility criteria and tivirals and corticosteroids reduced sequelae of Bell's palsy com-
assessing the relevance of studies, review authors were aware of pared with corticosteroids alone.
the names of the study authors, institutions, journal of publica-
tion, and results. FS and FD were excluded from the assessment of We found no significant increase in adverse events from the use of
their own trial (Sullivan 2007). We had no final disagreements about antivirals compared with either placebo or corticosteroids, based
which studies should be included. on low-quality evidence.
According to previous practice in this review, we excluded sever- Implications for research
al studies and a published abstract that provided insufficient infor- The novel finding in this analysis of a benefit in terms of incom-
mation. As a result there could be some risk of publication and se- plete recovery of Bell's palsy through the combination of antivirals
lective reporting bias due to data from some studies being unavail- with corticosteroids may merit further investigation. We also found
able. a benefit in people with severe Bell's palsy. Additional work in this
area could address the question of the best treatment for mild-to-
moderate and severe Bell’s palsy raised by the possible causes of
heterogeneity in some of the comparisons in this review. This may

Informed decisions.

be achieved through a meta-analysis of individual participant da- ACKNOWLEDGEMENTS

ta of both participants with severe and participants with mild-to-
moderate Bell's palsy separately. Depending upon the results of Dr J Sipe, Mrs L Dunn, Dr D Allen, Dr P Lockhart, Ms N Comerford,
this analysis, an adequately powered randomised controlled trial and Ms M Pitkethly authored the previous editions of this review;
in people with Bell’s palsy comparing different potential treatment we are very grateful for their hard work and enthusiasm. We also
options such as additional antiviral agents or immune modulators extend our thanks to Ruth Brassington for her valuable assistance
may be indicated. with the writing process; to Angela Gunn, who provided search re-
sults; and to Cochrane Neuromuscular for their extensive technical
More work is needed to assess the likelihood of long-term cosmetic assistance and support.
sequelae, which should be reported in each further trial. There is no
further need to conduct trials with a placebo group on this topic, This project was supported by the National Institute for Health Re-
as a clear benefit from steroid therapy is evident. Moreover, antivi- search via Cochrane Infrastructure funding to Cochrane Neuromus-
rals should be tested in combination with steroids and not alone in cular. The views and opinions expressed therein are those of the
future studies. Subgroup analysis of existing data and future stud- review authors and do not necessarily reflect those of the System-
ies should be done to assess the impact on the outcome of vari- atic Reviews Programme, NIHR, NHS, or the Department of Health.
ables such as time from diagnosis until treatment, severity of palsy Cochrane Neuromuscular is also supported by the MRC Centre for
at baseline, and age of participants at presentation. Work assess- Neuromuscular Diseases.
ing a wider range of endpoints, such as quality of life and perceived
disability, should be undertaken with the goal of developing a bet-
ter understanding of Bell's palsy for the affected person.

Informed decisions.

REFERENCES

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steroid alone in the treatment of Bell's palsy. American Journal
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2007;357(16):1598-607. [PUBMED: 17942873] recommendations. Lakartidningen 2005;102(10):744-75.
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Berg 2012
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acyclovir in relation to severity of Bell's palsy at presentation.
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IRCT2012062210087N1. Efficacy of corticosteroid and Health Care: Meta-Analysis in Context. 6th Edition. London: BMJ
acyclovir in Bell's palsy. http://www.irct.ir/searchresult.php? Books, 2007. [ISBN: 978-0-7279-1488-0]
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CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Adour 1996
Methods Double-blind, placebo-controlled
Participants 119 randomised, 99 included in published analysis. Initial diagnosis of idiopathic facial paralysis in pri-
mary care clinics or emergency departments confirmed in facial paralysis research clinic. Enrolment
criteria: paralysis commenced ≤ 3 days before treatment; all participants over 18 years of age; good
physical health determined by history and physical exam; no contraindication for steroid or aciclovir
treatment; all women of childbearing age had a negative pregnancy test result
lack of clear definition of diagnostic criteria (possibly affects generalisability/validity)
Exclusion criteria: any other medication for idiopathic facial paralysis; urea nitrogen or creatinine >
2x upper limit of normal; liver transaminase > 3x upper limit of normal; haemoglobin level < 100 g/L;
platelet count < 75,000/mm3; or neutrophil count < 1 x 10 to the 6/L
Interventions Aciclovir (2000 mg per day for 10 days) and prednisone (1 mg/kg for 5 days tapered to 10 mg/day for re-
maining 5 days) or placebo and prednisone (1 mg/kg for 5 days tapered to 10 mg/day for remaining 5
days)
Outcomes Primary outcome: recovery on facial paralysis recovery index where incomplete recovery is Facial
Paralysis Recovery Profile ≤ 7 at 4 months
Maximal stimulation test with or without electroneurography at follow-up at 2 weeks, 2, 3, and 4

months (if incomplete recovery) after paralysis onset
Final outcomes reported at 3 months or when recovered or palsy stabilised (not more clearly defined)
Notes Single centre

Informed decisions.

Adour 1996 (Continued)
The authors stated a dropout rate of 16.8%. The reason for dropout was documented for each partici-
pant, such as inability to keep appointments, low adherence to the treatment regimen, adverse events,
and moving from the area.
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence genera- Low risk Quote "the bottles [of aciclovir and placebo], provided by Burroughs Well-
tion (selection bias) come, were randomised in groups of 10"
Allocation concealment Low risk Quote "Each bottle...had a sealed identification label which was removed in-
(selection bias) tact and kept with the patient's record"
Blinding of participants? Low risk Quote "eligible patients were given identical, unlabeled bottles of 100 cap-
sules that contained either placebo or aciclovir (Zovirax), 200 mg"
Participants in each group received identical follow-up
Blinding of assessors? Low risk The study was reported as double blind; the method reported was consistent
with being able to achieve this
Incomplete outcome da- High risk The numbers of participants unable to complete the study was given. High
ta? dropout rate reported: 16.8%
Selective outcome report- High risk Primary outcomes of facial paralysis recovery profile and bilateral facial nerve
ing? electrical testing reported, but no data given on audiometry with stapedial re-
flex testing, adverse events were not specified
Other sources of bias? Low risk No other risks of bias reported

De Diego 1998
Methods Randomised controlled trial with 2 parallel groups
Participants 113 participants with Bell's palsy were randomised, 101 were included in published analysis: 54 in the
aciclovir group, 47 in the prednisone group; baseline assessment was carried out within 96 hours
Interventions Aciclovir (2400 mg/day for 10 days) or prednisone (1 mg/kg for 10 days then tapered to zero over the
next 6 days)
Outcomes Primary outcome: complete recovery using the House-Brackmann scale (≤ II) and the Facial Paralysis
Recovery Profile (≥ 8)
Secondary outcomes: sequelae and synkinesis reported separately
Final outcomes reported at 4 months
Follow-up at 1, 3, 6, 12 weeks after first visit. Participants with incomplete recovery at 12 weeks were
followed up until recovery or stabilisation of paralysis
Notes Single centre
Risk of bias

Informed decisions.

De Diego 1998 (Continued)
Random sequence genera- Unclear risk Quote "patients were randomly assigned". Randomisation method not de-
tion (selection bias) scribed
Allocation concealment High risk No clear information on concealment

(selection bias)
Blinding of participants? High risk Presence of blinding not clearly described, although groups received different
treatment regimens
No placebo
Blinding of assessors? High risk Not done
Incomplete outcome da- Low risk Number of dropouts was reported: 10% were lost to follow-up
ta?
Selective outcome report- Unclear risk Adverse events were not reported
ing?
Other sources of bias? Low risk No other potential risk of bias

Engström 2008
Methods Randomised, placebo-controlled trial with 4 treatment groups
Participants 829 participants randomised within 72 hours of facial palsy onset. No contraindications to corticos-
teroid or antiviral use
Interventions Participants allocated into 1 of 4 treatment groups: valaciclovir with prednisolone, valaciclovir with
placebo, placebo with prednisolone, or double placebo
Dosages: valaciclovir 1000 mg 3 times daily for 7 days; prednisolone 60 mg daily for 5 days
Outcomes Primary outcome: recovery of facial function, as assessed at all visits with the Sunnybrook scale and
the House-Brackmann scale. Complete recovery was taken as Sunnybrook scale 100 and House-Brack-
mann scale grade I
Other outcomes:
Degree of pain, as recorded during the first 2 months; adverse events recorded for the first month
Frequency of severe pain, synkinesis, facial spasm, and residual facial symptoms at 12 months
Follow-up at 2 weeks, 1, 2, 3, 6, and 12 months after randomisation, according to recovery
Notes Multicentre
Some secondary outcomes were reported in papers published separately (Axelsson 2012; Berg 2012)
Risk of bias
Random sequence genera- Low risk Quote "...randomization code was developed by Glaxo Wellcome GmBH, with a
tion (selection bias) computer number generator to select random permuted blocks of eight"

Informed decisions.

Engström 2008 (Continued)
Allocation concealment Low risk Randomisation code double blind and held by a third party. Medication dis-
(selection bias) pensed in identical containers to conceal allocation
Blinding of participants? Low risk Study drugs issued in identical containers. All participants blinded to treat-
ment group until study completion
Blinding of assessors? Low risk All study personnel and data analysts blinded to treatment group until study
completion
Incomplete outcome da- Low risk Numbers lost to follow-up and reasons given
ta?
Selective outcome report- Low risk All primary outcomes reported. Other outcomes were reported in another pa-
ing? per due to space constrictions
Other sources of bias? Low risk No other potential sources of bias identified

Hato 2007
Methods Randomised, parallel-group, placebo-controlled
Participants 296 participants recruited, 221 randomised: 114 to valaciclovir and prednisolone, 107 to prednisolone
and placebo. All participants commenced treatment within 7 days of onset of palsy. All participants
were over 15 years of age and had no contraindications to antivirals or corticosteroids. The final analy-
sis included 221 participants
Interventions Randomised to receive prednisolone 60 mg for 5 days, 30 mg for 3 days, and 10 mg for 2 days ± valaci-
clovir 1000 mg/day for 5 days. Following corticosteroids, all participants received methylcobalamin
1500 µg per day for 6 months or until complete recovery
Outcomes Primary outcome: full recovery based on a score of ≥ 36 on the Yanagihara scale (conversion scale to
House-Brackmann scale included in paper)
Follow-up at 1, 3, and 6 months after commencing treatment
Notes Multicentre: 6 academic tertiary referral centres. 23 participants were excluded after randomisation be-
cause of herpes zoster; 52 were lost to follow-up (25.3%). Frequency and reasons for drop out of partici-
pants who did not complete the study were documented.
Risk of bias
Random sequence genera- Unclear risk Quote "the patients were randomly divided into two groups using the enve-
tion (selection bias) lope method". Randomisation was carried out without stratification. No cen-
tral randomisation
Allocation concealment Unclear risk Participants were assigned to one of the groups by moderators, but the alloca-
(selection bias) tion concealment was not clearly described
Blinding of participants? High risk Inadequate. Participants blinded to treatment, but different treatments with
different frequencies meant that true blinding was not achieved
Blinding of assessors? High risk Not done. Assessors were not blinded to treatment

Informed decisions.

Hato 2007 (Continued)
Incomplete outcome da- High risk Frequency and reasons for dropouts documented. High dropout rate reported;
ta? 25.3%
Selective outcome report- Low risk Main outcome measures, adverse events all reported
ing?
Other sources of bias? High risk Statistical tests employed not clearly stated

Kawaguchi 2007
Methods Randomised, controlled, parallel-group design
Participants 150 participants randomly assigned to prednisolone group (66) or prednisolone and aciclovir group
(84). All participants received treatment within 7 days of onset of Bell's palsy
Interventions Participants received either 20 mg prednisolone 3 times daily for 5 days, then 10 mg 3 times daily for
2 days, then 10 mg daily for 2 days plus valaciclovir 500 mg twice daily for 5 days or prednisolone (the
same regimen) alone
Outcomes Virological examination for anti-herpes simplex virus and anti-varicella zoster virus antibodies; detec-
tion of herpes simplex virus and herpes zoster virus reactivation
Facial movement and recovery measured using the Yanagihara rating scale, defined as a score of ≥ 36
Follow-up for 6 months at 1 and 2 weeks after treatment and then at 1, 2, 3, 4, 5, and 6 months after
treatment
Frequency of incomplete recovery at end of the study and adverse events
Notes Multicentre: 12 university hospitals
Risk of bias
Random sequence genera- Low risk Sequence generation using envelope method
tion (selection bias)
Allocation concealment High risk Not used; when participants were entered into the trial, the allocation enve-
(selection bias) lope contained the name of the treatment group
Blinding of participants? High risk Not done
Blinding of assessors? High risk Not done
Incomplete outcome da- Low risk Numbers of participants who did not complete clearly documented: 10% were
ta? lost to follow-up
Selective outcome report- High risk Frequency of incomplete recovery at end of the study and adverse events not
ing? reported in the paper

Informed decisions.


Lee 2013
Methods Randomised, controlled, parallel-group
Participants 269 participants with severe Bell's palsy were recruited; 206 were included in the final analysis. 99
participants were assigned to the famciclovir and prednisolone group, 107 participants to the pred-
nisolone group. All participants received treatment within 7 days of onset of palsy
Interventions Randomised to receive prednisolone 64 mg for 4 days, 48 mg for 2 days, 32 mg for 2 days, and 16 mg for
2 days ± famciclovir 750 mg/day for 7 days intravenously. In the famciclovir and prednisolone group,
both drugs were given simultaneously
Outcomes Primary outcome: full recovery based on the House-Brackmann scale (grades I and II) at 6 months
Follow-up at 2 weeks and 6 months after commencing treatment
Apart from 2 excluded participants with adverse events, no further information reported
Notes Single centre
Risk of bias
Random sequence genera- Low risk Random sequence generation using computer codes
Allocation concealment High risk No information on concealment. No placebo

(selection bias)
Blinding of participants? High risk No placebo. No information on concealment
Blinding of assessors? High risk Different treatment regimens in both groups. No information on concealment
Incomplete outcome da- High risk Per protocol analysis only. High dropout rate reported: 13.1%
ta?
Selective outcome report- Unclear risk Adverse events were not reported
ing?
Other sources of bias? Unclear risk Two participants with adverse events in the steroid group (not clearly speci-
fied) were excluded from the analysis
Diagnostic criteria not clearly defined in paper

Li 1997
Methods Randomised, placebo-controlled, double-blind trial
Participants Included 51 participants, 5 of whom were lost to follow-up. Participants with other causes of facial pal-
sy were excluded. The age range was 15 to 73 years
Interventions Randomised to receive either aciclovir and prednisone or placebo and prednisone. Prednisone was ad-
ministered to both groups in a dose of 60 mg for 5 days then tapered in steps of 10 mg for a further 5
days. In the intervention group 800 mg aciclovir was given 5 times daily for 7 days. All participants re-
ceived artificial tears and ophthalmic ointments

Informed decisions.

Li 1997 (Continued)
Outcomes Primary outcome: recovery of facial motor function up to 6 months
House-Brackmann scale was used for assessment; recovery was taken as grade I to II
Follow-up weekly for the first month, then monthly until recovery
Final outcomes reported at 6 months, adverse events were not reported
Notes Single centre
Risk of bias
Random sequence genera- Unclear risk Simple randomisation by coding of treatment drugs.
Little information provided
Allocation concealment Unclear risk Allocation concealment not clearly described

(selection bias)
Blinding of participants? High risk Blinding procedure not clearly described
Blinding of assessors? Unclear risk Blinding procedure not clearly described
Incomplete outcome da- Low risk Per protocol analysis, 5 participants were lost to follow-up
ta?
Selective outcome report- Unclear risk Primary outcomes were reported, adverse events were not reported
ing?
Other sources of bias? Low risk Not given

Sullivan 2007
Methods Double-blind, placebo-controlled, randomised, factorial trial
Participants 551 participants randomised; 496 included in final outcome assessment. Referred for assessment and
treatment within 72 hours of paralysis onset. All participants aged 16 or older and no contraindications
to corticosteroids or antivirals
Interventions Participants allocated to 1 of 4 treatment groups: either aciclovir, prednisolone, both agents, or place-
bo. Participants received prednisolone 25 mg twice daily for 10 days or aciclovir 400 mg 5 times daily
for 10 days, both treatments, or neither treatment, depending upon allocation
Outcomes Primary outcome measure: recovery rated on House-Brackmann scale, where recovery was grade I
Secondary outcomes included health-related quality of life, Health Utilities Index Mark 3, facial appear-
ance (Derriford Appearance Scale), pain, and adverse outcomes. Frequency of incomplete recovery at
end of study was recorded
Follow-up at 3 and 9 months
Notes Multicentre: 17 hospitals

Informed decisions.

Sullivan 2007 (Continued)
Risk of bias
Random sequence genera- Low risk Quote "...patient was randomly assigned to a study group by an independent,
tion (selection bias) secure, automated telephone randomisation service."
Allocation concealment Low risk All parties blinded to allocation

(selection bias)
Blinding of participants? Low risk Participants not receiving active drug received placebo. All administered med-
ication identical and in identical containers
Blinding of assessors? Low risk Assessors blinded to treatment group
Incomplete outcome da- Low risk All participants who were unable to complete were documented -- both fre-
ta? quency and reason
Selective outcome report- Low risk All planned outcome measures reported
ing?

Vázquez 2008
Methods Double-blind, randomised trial. Simple randomisation
Participants Included 42 participants assigned to 2 treatment groups. Participants with other causes of facial palsy
were excluded
Interventions Randomised to receive either valaciclovir plus prednisone or prednisone plus placebo. Both groups re-
ceived 1 mg/kg weight prednisone for 7 days, then reduced doses for 14 days
Participants in the treatment group received 2 g valaciclovir for 7 days
All participants undertook eye protection and received rehabilitation
Outcomes Primary outcome: recovery on facial grading system (Sunnybrook scale), where recovery was taken as
> 90
Follow-up at 1, 2, 4, 8, and 12 months
Adverse events were not reported
Notes Single centre
Risk of bias
Random sequence genera- Unclear risk Simple randomisation, not specified


Informed decisions.

Vázquez 2008 (Continued)
Allocation concealment Unclear risk Not reported
(selection bias)
Blinding of participants? Unclear risk Different treatment regimens in both groups, blinding and usage of placebo
not described
Blinding of assessors? Unclear risk Blinding not clearly described
Incomplete outcome da- Low risk All outcome data were reported
ta?
Selective outcome report- Unclear risk All planned outcome measures reported; authors reported synkinesis and ad-
ing? verse effects, but without assigning the cases to the groups

Yeo 2008
Methods Randomised, double-blind, 2-arm design
Participants 91 participants; other causes of facial palsy were excluded. No maximum period after onset stated, but
actual time to treatment recorded. All participants were admitted to hospital and received physical
therapy and plasma volume expanders as adjuncts
Interventions Randomised to receive either aciclovir and prednisolone or prednisolone alone. Aciclovir given at a
dose of 2400 mg/day for 5 days. Prednisolone given as 1 mg/kg/day for 5 days, then tapered on days
6 to 10. All participants admitted to hospital and received physical therapy and plasma volume ex-
panders as adjuncts
Outcomes Primary outcome: recovery on House-Brackmann scale, where recovery was grade ≤ II
Subgroup analysis of early versus delayed treatment
Follow-up at 2 and 6 months
Notes Single centre. All participants admitted
Risk of bias
Random sequence genera- Unclear risk States 'randomised' in study title, but no description of this in the article
Allocation concealment Unclear risk No clear statement of this in the study

(selection bias)
Blinding of participants? Unclear risk States 'double-blind' in study title, but no description of methods employed
for this in text
Blinding of assessors? Unclear risk States 'double-blind' in study title, but no description of methods employed
for this in text

Informed decisions.

Yeo 2008 (Continued)
Incomplete outcome da- Unclear risk Incomplete follow-up data not mentioned in the study
ta?
Selective outcome report- Unclear risk Stated primary outcome measure reported, no adverse events reported
ing?
Other sources of bias? Low risk No further potential risks

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion
Ahangar 2006 Allocation was not randomised
Antunes 2000 Small study numbers and insufficient information in original paper to assign a participant with in-
complete recovery to the correct control group. Author contacted by Dr D Allen, but no response
received
Axelsson 2003 Use of a historical control group
Chen 2005 Follow-up data for only 4 weeks from palsy onset
de Aquino 2001 Methodology not clear from original paper. An author of a previous version of this review (D Allen)
attempted to obtain further information but obtained no response
Hato 2003 Retrospective analysis of treatment
Hultcrantz 2005 Allocation was not randomised
Ibarrondo 1999 Retrospective study. 100 participants collected between 1983 and 1989 received corticotherapy.
100 participants treated after 1989 received aciclovir
Inanli 2001 The paper was not available
Minnerop 2008 Inadequate random allocation to treatment group, no blinding, 30% lost to follow-up, intervention
group and control group of unequal size
Ramos Macias 1992 Inadequate allocation concealment. No information reported about methods of randomisation, di-
agnostic criteria used, length of follow-up, or number of participants lost to follow-up. Thirty-three
percent had Ramsay Hunt syndrome, abstract only available
Roy 2005 Inadequate information on outcome data, 22% lost to follow-up, abstract only published in journal
supplement and not traced as a full publication
Shahidullah 2011 Inadequate random allocation to treatment group, no blinding, 36% lost to follow-up
Zhou 1999 Prospective study. 69 participants with Bell's palsy followed up for only 2 weeks. Not double blind,
and allocation concealment not described. Used own scale for palsy grading, outcome measures
not met. Did report adverse events. Four participants receiving aciclovir treatment had gastric
malaise

Informed decisions.

Characteristics of studies awaiting assessment [ordered by study ID]

Abdelghany 2013
Methods
Participants
Interventions
Outcomes
Notes To be assessed following completion of an investigation into the reliability of the trial da-
ta

Characteristics of ongoing studies [ordered by study ID]

IRCT201109187575N1
Trial name or title Comparison of therapeutic effects of prednisolone, aciclovir, and combination of these drugs in
Bell's palsy
Methods Randomised, parallel assignment
Participants People with Bell's palsy over 10 years of age, less than 7 days from the onset of paralysis
Interventions Group 1: prednisone 1 mg/kg body weight daily for 3 days. The treatment was tapered over the
next 12 days
Group 2: aciclovir, 400 mg every 5 hours per day for 10 days
Group 3: combination of aciclovir and prednisone
Outcomes Primary: House-Brackmann score every 15 days
Treatment failure (no reduction of House-Brackmann score) at the end of month 3
Starting date 22 May 2010
Contact information Dr Alireza Rezaei Ashtiani
Department of Internal Medicine,Valie-Asr Hospital, Arak
Islamic Republic of Iran
dr.ashtiani@arakmu.ac.ir
Notes

IRCT2012062210087N1
Trial name or title Efficacy of corticosteroid and aciclovir in Bell's palsy
Methods Randomised, parallel group
Participants Children 2 to 18 years old with Bell's palsy less than 3 days after the start of symptoms

Informed decisions.

IRCT2012062210087N1 (Continued)
Interventions Combination therapy with prednisolone 2 mg/kg of body weight for 7 days and aciclovir or pred-
nisolone alone 20 mg/kg of body weight for 7 days
Outcomes Severity of Bell's palsy at House-Brackmann score 1 and 2 months after treatment
Starting date Recruitment completed
Contact information Ali Khwaja
Imam Ali Hospital in Zahedan
Zahedan
Sistan and Baluchestan
drkhajehneuro@gmail
Notes

DATA AND ANALYSES

Comparison 1. Antivirals plus corticosteroids versus corticosteroids plus placebo or no treatment
Outcome or subgroup title No. of No. of Statistical method Effect size

studies partici-
pants
1 Incomplete recovery at end of 8 1315 Risk Ratio (M-H, Random, 95% CI) 0.61 [0.39, 0.97]
study
2 Motor synkinesis or crocodile 2 469 Risk Ratio (M-H, Fixed, 95% CI) 0.56 [0.36, 0.87]
tears
3 Adverse events 3 877 Risk Ratio (M-H, Fixed, 95% CI) 1.18 [0.83, 1.69]

Analysis 1.1. Comparison 1 Antivirals plus corticosteroids versus corticosteroids
plus placebo or no treatment, Outcome 1 Incomplete recovery at end of study.
Study or subgroup AS OS Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
Li 1997 4/25 13/21 12.89% 0.26[0.1,0.67]
Adour 1996 4/53 11/46 11.27% 0.32[0.11,0.92]
Hato 2007 4/114 11/107 10.77% 0.34[0.11,1.04]
Yeo 2008 3/44 7/47 8.86% 0.46[0.13,1.66]
Kawaguchi 2007 8/84 9/66 13.88% 0.7[0.29,1.71]
Engström 2008 42/206 50/210 25.01% 0.86[0.6,1.23]
Vázquez 2008 3/22 2/19 5.94% 1.3[0.24,6.96]
Sullivan 2007 9/124 5/127 11.39% 1.84[0.64,5.35]

Total (95% CI) 672 643 100% 0.61[0.39,0.97]
Favours AS 0.1 0.2 0.5 1 2 5 10 Favours OS

Informed decisions.


Total events: 77 (AS), 108 (OS)
Heterogeneity: Tau2=0.18; Chi2=13.19, df=7(P=0.07); I2=46.91%
Test for overall effect: Z=2.11(P=0.03)

Analysis 1.2. Comparison 1 Antivirals plus corticosteroids versus corticosteroids
plus placebo or no treatment, Outcome 2 Motor synkinesis or crocodile tears.
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Adour 1996 7/53 13/46 30.43% 0.47[0.2,1.07]
Engström 2008 19/184 32/186 69.57% 0.6[0.35,1.02]

Total (95% CI) 237 232 100% 0.56[0.36,0.87]
Total events: 26 ( AS), 45 (OS)
Heterogeneity: Tau2=0; Chi2=0.25, df=1(P=0.62); I2=0%
Favours AS 0.05 0.2 1 5 20 Favours OS

Analysis 1.3. Comparison 1 Antivirals plus corticosteroids versus
corticosteroids plus placebo or no treatment, Outcome 3 Adverse events.
Engström 2008 27/202 21/203 44.83% 1.29[0.76,2.21]
Hato 2007 3/114 2/107 4.42% 1.41[0.24,8.26]
Sullivan 2007 25/124 24/127 50.75% 1.07[0.65,1.76]

Total (95% CI) 440 437 100% 1.18[0.83,1.69]
Favours AS 0.05 0.2 1 5 20 Favours OS

Comparison 2. Antivirals versus corticosteroids

studies partici-
pants
1 Incomplete recovery at end of 3 768 Risk Ratio (M-H, Random, 95% CI) 2.82 [1.09, 7.32]
study
2 Motor synkinesis and crocodile 2 472 Risk Ratio (M-H, Fixed, 95% CI) 1.52 [1.08, 2.12]
tears

Informed decisions.


studies partici-
pants

Analysis 2.1. Comparison 2 Antivirals versus corticosteroids, Outcome 1 Incomplete recovery at end of study.
Study or subgroup A S Risk Ratio Weight Risk Ratio
De Diego 1998 12/54 3/47 26.03% 3.48[1.05,11.6]
Engström 2008 74/207 50/210 42.55% 1.5[1.11,2.03]
Sullivan 2007 27/123 5/127 31.42% 5.58[2.22,14.01]

Total (95% CI) 384 384 100% 2.82[1.09,7.32]
Total events: 113 (A), 58 (S)
Favours A 0.05 0.2 1 5 20 Favours S

Analysis 2.2. Comparison 2 Antivirals versus corticosteroids, Outcome 2 Motor synkinesis and crocodile tears.
De Diego 1998 13/54 11/47 26.93% 1.03[0.51,2.07]
Engström 2008 54/185 32/186 73.07% 1.7[1.15,2.5]

Total (95% CI) 239 233 100% 1.52[1.08,2.12]
Heterogeneity: Tau2=0; Chi2=1.5, df=1(P=0.22); I2=33.34%

Analysis 2.3. Comparison 2 Antivirals versus corticosteroids, Outcome 3 Adverse events.
Engström 2008 19/205 21/203 47.19% 0.9[0.5,1.62]
Sullivan 2007 19/123 24/127 52.81% 0.82[0.47,1.41]

Total (95% CI) 328 330 100% 0.85[0.57,1.28]

Informed decisions.


Comparison 3. Antivirals plus corticosteroids versus placebo

studies partici-
pants
1 Incomplete recovery at end of study 2 658 Risk Ratio (M-H, Fixed, 95% CI) 0.56 [0.41, 0.76]

Analysis 3.1. Comparison 3 Antivirals plus corticosteroids
versus placebo, Outcome 1 Incomplete recovery at end of study.
Study or subgroup AS OO Risk Ratio Weight Risk Ratio
Engström 2008 42/206 73/206 80.09% 0.58[0.41,0.8]
Sullivan 2007 9/124 18/122 19.91% 0.49[0.23,1.05]

Total (95% CI) 330 328 100% 0.56[0.41,0.76]
Total events: 51 (AS), 91 (OO)
Test for overall effect: Z=3.79(P=0)
Favours AS 0.2 0.5 1 2 5 Favours OO

Analysis 3.2. Comparison 3 Antivirals plus corticosteroids versus placebo, Outcome 2 Adverse events.
Study or subgroup AS OO Risk Ratio Weight Risk Ratio
Engström 2008 27/202 25/201 55.42% 1.07[0.65,1.79]
Sullivan 2007 25/124 20/122 44.58% 1.23[0.72,2.09]

Total (95% CI) 326 323 100% 1.14[0.79,1.65]
Total events: 52 (AS), 45 (OO)
Favours AS 0.2 0.5 1 2 5 Favours OO

Comparison 4. Antivirals versus placebo

studies partici-
pants
1 Incomplete recovery at end of study 2 658 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.87, 1.40]

Informed decisions.


Analysis 4.1. Comparison 4 Antivirals versus placebo, Outcome 1 Incomplete recovery at end of study.
Study or subgroup AO OO Risk Ratio Weight Risk Ratio
Engström 2008 74/207 73/206 80.19% 1.01[0.78,1.31]
Sullivan 2007 27/123 18/122 19.81% 1.49[0.87,2.56]

Total (95% CI) 330 328 100% 1.1[0.87,1.4]
Total events: 101 (AO), 91 (OO)
Heterogeneity: Tau2=0; Chi2=1.63, df=1(P=0.2); I2=38.67%
Favours AO 0.2 0.5 1 2 5 Favours OO

Analysis 4.2. Comparison 4 Antivirals versus placebo, Outcome 2 Adverse events.
Study or subgroup AO OO Risk Ratio Weight Risk Ratio
Engström 2008 19/205 25/201 55.7% 0.75[0.42,1.31]
Sullivan 2007 19/123 20/122 44.3% 0.94[0.53,1.68]

Total (95% CI) 328 323 100% 0.83[0.56,1.24]
Total events: 38 (AO), 45 (OO)
Favours AO 0.2 0.5 1 2 5 Favours OO

Comparison 5. Antivirals plus corticosteroids versus corticosteroids plus placebo or no treatment in severe cases
Outcome or subgroup title No. of No. of par- Statistical method Effect size
studies ticipants
1 Incomplete recovery at end of study 4 478 Risk Ratio (M-H, Random, 95% CI) 0.64 [0.41, 0.99]

Analysis 5.1. Comparison 5 Antivirals plus corticosteroids versus corticosteroids plus
placebo or no treatment in severe cases, Outcome 1 Incomplete recovery at end of study.
Engström 2008 16/26 18/23 43.15% 0.79[0.54,1.14]
Hato 2007 4/92 11/82 12.64% 0.32[0.11,0.98]
Lee 2013 17/99 36/107 34.08% 0.51[0.31,0.85]
Sullivan 2007 4/21 4/28 10.13% 1.33[0.38,4.72]

Total (95% CI) 238 240 100% 0.64[0.41,0.99]

Informed decisions.



ADDITIONAL TABLES

Table 1. House-Brackmann Scale
Grade Description
I Normal
II Mild dysfunction; slight weakness noticeable only on close inspection; may have slight synkinesis
III Moderate dysfunction; obvious but not disfiguring difference between the 2 sides; noticeable but
not severe synkinesis
IV Moderately severe dysfunction; obvious weakness or disfiguring asymmetry, or both
V Only barely perceptible motion
VI No movement
House JW. Facial nerve grading systems. Laryngoscope 1983; 93: 1056-69.
House JW, Brackmann DE. Facial nerve grading system. Otolaryngology, Head and Neck Surgery 1985; 93: 146-7.

Table 2. Sunnybrook Scale
Facial Grading System
Resting symmetry Symmetry of voluntary movement Synkinesis
Compared to normal side Degree of muscle EXCURSION compared to normal side Degree of INVOLUNTARY MUSCLE CON-
TRACTION associated with each expres-
sion
Eye STANDARD EXPRESSIONS STANDARD EXPRESSIONS
Normal = 0 Forehead wrinkle Forehead wrinkle
Gentle eye closure Gentle eye closure

Narrow = 1
Open mouth smile Open mouth smile
Wide =1
Snarl Snarl
Eyelid
Lip pucker Lip pucker
surgery = 1
Score each out of 5, where 5 is normal and 1 is gross Score each facial movement listed under
Cheek asymmetry/no movement standard expressions on a scale 0 to 3,
where 0 is no asymmetry and 3 is severe
Normal = 0 asymmetry

Informed decisions.

Table 2. Sunnybrook Scale (Continued)

Absent = 2
Less pro-
nounced = 1
More pro-
nounced =1
Mouth
Normal = 0
Corner
drooped =1
Corner
pulled up/
out = 1
TOTAL TOTAL TOTAL
Resting Voluntary movement score Synkinesis score

symmetry
score x 5 Total x 4
Voluntary Movement Score - Resting Symmetry Score - Synkinesis Score = Composite Score
Weighted regional evaluation using five separate expressions. Composite score from 0 (total paralysis) to 100 (normal function).
Ross BG, Fradet G, Nedzelski JM. Development of a sensitive clinical facial grading system. Otolaryngology, Head and Neck Surgery 1996;
114: 380-6.

Table 3. Yanagihara Scale
Mode Degree of paralysis
4 3 2 1 0
normal slight moderate severe total
At rest
Wrinkle forehead
Blink
Normal closure of eye
Forced closure of eye
Closure of eye on involved side
Wrinkle nose
Whistle
Grin

Informed decisions.

Table 3. Yanagihara Scale (Continued)

Depress lower lip/ blow out cheek
Ten separate categories of function, each scored 0 (total paralysis) to 4 (normal), then summed, giving a total score from 0 (total paralysis)
to 40 (normal function).
Yanighara N. Grading of facial palsy. Proceedings of the 3rd International Symposium on Facial Nerve Surgery, Zurich 1976. In Fish U ed.
Facial Nerve Surgery. Amstelveen, The Netherlands: Kugler Medical Publications 1977: 533-5.

APPENDICES
Appendix 1. Cochrane Neuromuscular Disease Group Specialized Register (CRS) search strategy
#1 MeSH DESCRIPTOR Facial Nerve Diseases [REFERENCE] [STANDARD]
#2 MeSH DESCRIPTOR Bell Palsy [REFERENCE] [STANDARD]
#3 MeSH DESCRIPTOR Facial Paralysis [REFERENCE] [STANDARD]
#4 MeSH DESCRIPTOR Hemifacial Spasm [REFERENCE] [STANDARD]
#5 (((bell* or facial* or hemifacial* or cranial*) NEAR3 (pals* or paralys* or paresi* or spasm*))) [REFERENCE] [STANDARD]
#6 #1 or #2 or #3 or #4 or #5 [REFERENCE] [STANDARD]
#7 MeSH DESCRIPTOR Acyclovir Explode 1 [REFERENCE] [STANDARD]
#8 MeSH DESCRIPTOR 2-Aminopurine [REFERENCE] [STANDARD]
#9 MeSH DESCRIPTOR Antiviral Agents Explode 1 [REFERENCE] [STANDARD]
#10 (aciclovir or valaciclovir or famciclovir or antiviral*) [REFERENCE] [STANDARD]
#11 (acyclovir or valacyclovir or famcyclovir) [REFERENCE] [STANDARD]
#12 #7 or #8 or #9 or #10 or #11 [REFERENCE] [STANDARD]
#13 #6 and #12 [REFERENCE] [STANDARD]
#14 (#13) AND (INREGISTER) [REFERENCE] [STANDARD]
Appendix 2. CENTRAL search strategy

#1 (Bell or "Bell's" or Bells or facial or hemifacial or cranial) NEAR (palsy or palsies or paralysis or paresis or spasm or spasms)
#2 aciclovir or acyclovir or valaciclovir or valacyclovir or famciclovir or famcyclovir or antiviral*
#3 (#1 AND #2)
Appendix 3. MEDLINE (OvidSP) search strategy

Database: Ovid MEDLINE(R) <1946 to September Week 4 2014>
Search Strategy:
--------------------------------------------------------------------------------
1 randomized controlled trial.pt. (389226)
2 controlled clinical trial.pt. (89867)
3 randomized.ab. (285185)
4 placebo.ab. (151031)
5 drug therapy.fs. (1748071)
6 randomly.ab. (201598)
7 trial.ab. (296312)
8 groups.ab. (1285103)
9 or/1-8 (3290339)
10 exp animals/ not humans.sh. (4016034)
11 9 not 10 (2802960)
12 exp Facial Nerve Diseases/ (6620)
13 bell palsy/ (743)
14 facial paralysis/ or hemifacial spasm/ (11010)
15 ((Bell$ or facial$ or hemifacial$ or cranial$) adj3 (pals$ or paralys$ or paresi$ or spasm$)).mp. (18408)
16 12 or 13 or 14 or 15 (22556)
17 Acyclovir/ (7824)
18 exp Acyclovir/ (12494)
19 2-Aminopurine/ (1203)
20 exp Antiviral Agents/ (293597)
21 (aciclovir or valaciclovir or famciclovir or antiviral$).tw. (54604)
22 (acyclovir or valacyclovir or famcyclovir).tw. (6662)

Informed decisions.

23 or/17-22 (315614)
24 11 and 16 and 23 (375)
Appendix 4. EMBASE (OvidSP) search strategy

Database: Embase <1980 to 2014 Week 40>
Search Strategy:
--------------------------------------------------------------------------------
1 crossover-procedure.sh. (40306)
2 double-blind procedure.sh. (115609)
3 single-blind procedure.sh. (18869)
4 randomized controlled trial.sh. (350916)
5 (random$ or crossover$ or cross over$ or placebo$ or (doubl$ adj blind$) or allocat$).tw,ot. (1065137)
6 trial.ti. (163276)
7 or/1-6 (1198699)
8 (animal/ or nonhuman/ or animal experiment/) and human/ (1290984)
9 animal/ or nonanimal/ or animal experiment/ (3256545)
10 9 not 8 (2727334)
11 7 not 10 (1100982)
12 limit 11 to embase (913119)
13 bell palsy/ (2339)
14 facial nerve paralysis/ or hemifacial spasm/ (17444)
15 ((Bell$ or facial$ or hemifacial$ or cranial$) adj3 (pals$ or paralys$ or paresi$ or spasm$)).mp. (27210)
16 or/13-15 (27210)
17 exp antivirus agent/ (651212)
18 aciclovir/ (30615)
19 famciclovir/ (3428)
20 (aciclovir or valaciclovir or famciclovir or antiviral$).tw. (70997)
21 (acyclovir or valacyclovir or famcyclovir).tw. (9086)
22 or/17-21 (672393)
23 12 and 16 and 22 (103)
24 remove duplicates from 23 (102)
Appendix 5. LILACS (IAHx) search strategy

("Bell palsy" or "paralisis de Bell" or "paralisia de Bell" or "facial or paralysis" or "paralisis facial" or "paralisia facial" or "hemi-
facial spasm" or "espasmo hemifacial") and (MH:D03.438.759.758.399.454.250$ or acyclovir or 2-Aminopurine or 2-Aminopurina or
MH:D27.505.954.122.388$ or aciclovir or acyclovir or valaciclovir or valacyclovir or famciclovir or famcyclovir or antivira$) and ((PT:"Ran-
domized Controlled Trial" or "Randomized Controlled trial" or "Ensayo Clínico Controlado Aleatorio" or "Ensaio Clínico Controlado
Aleatório" or PT:"Controlled Clinical Trial" or "Ensayo Clínico Controlado" or "Ensaio Clínico Controlado" or "Random allocation" or "Dis-
tribución Aleatoria" or "Distribuição Aleatória" or randon$ or Randomized or randomly or "double blind" or "duplo-cego" or "duplo-cego"
or "single blind" or "simples-cego" or "simples cego" or placebo$ or trial or groups) AND NOT (B01.050$ AND NOT (humans or humanos
or humanos)))
WHAT'S NEW

Date Event Description
14 September 2015 Amended Authors have removed a previously included study (Abdelghany
2013) from the included studies owing to potential unreliabili-
ty of evidence. Future substantive updates of the review will in-
clude Abdelghany 2013 only if investigations conclude that the
trial data are reliable.
14 September 2015 New citation required and conclusions With the removal of Abdelghany 2013, this review concludes that
have changed there is a benefit from the combination of antivirals with corti-
costeroids compared to corticosteroids alone for the treatment
of Bell's palsy of various degrees of severity. The evidence con-
tinues to support a benefit of combination therapy compared
with corticosteroids alone in severe Bell’s palsy. The evidence on
which these findings are based is of low quality.

Informed decisions.


HISTORY
Protocol first published: Issue 3, 1999
Review first published: Issue 2, 2001

Date Event Description
22 May 2015 New citation required and conclusions The authors have reviewed and reworded the conclusions, which
have changed bear re-reading for clarification.
12 May 2015 Amended As an updated search was recently incorporated, there has been
no new search for this amended version.
28 February 2014 New citation required but conclusions Review updated with no change to conclusions. New authors:
have not changed Ildiko Gagyor, Vishnu B Madhok, Dhruvashree Somasundara,
Michael Sullivan, and Fiona Gammie. Previous authors Pauline
Lockhart, Marie Pitkethly, and Natalia Comerford withdrew.
22 January 2014 New search has been performed New trials added, text rewritten, new calculations, references up-
dated.
12 May 2010 Amended Correction to reference
10 November 2009 Amended Correction of minor error in Discussion.
25 February 2009 New citation required and conclusions This is a substantive update to the previous edition of the review
have changed with a new review team. Five new studies added to the analysis
with changes made to Results and Discussion sections as neces-
sary.
5 February 2009 New search has been performed Substantive update to previous edition of review.
Abstract and background information re-written. Modification

of outcomes: all data from trials, whatever the trial length as
opposed to 6 month outcomes. Five new studies added to the
analysis with necessary changes made to Results and Discussion
sections. One study removed from the previous review as no da-
ta contributed and none forthcoming to previous authors when
approached.
1 November 2007 Amended Two trials, one with 551 participants comparing prednisolone
with aciclovir with both and with neither, another with 221 par-
ticipants comparing prednisolone and valaciclovir with pred-
nisolone and placebo have just been published and will be in-
cluded in an update of this review.
1 March 2004 New citation required and conclusions Substantive amendment

have changed
1 January 2004 New search has been performed The review was updated in January 2004. Searches were up-
dated as follows: Neuromuscular Disease Group Trials Register
(searched April 2003), MEDLINE (searched January 1966 to April
2003), EMBASE (searched January 1980 to April 2003), and LILACS
(searched January 1982 to April 2003).

Informed decisions.

CONTRIBUTIONS OF AUTHORS
All review authors contributed to the review and data extraction process. Dr I Gagyor wrote the first draft of the report with additional
clinical input from Professor F Sullivan, Dr V Madhok, Dr F Daly, Dr D Somasundara, and Dr M Sullivan. Dr I Gagyor incorporated the work
into the existing review and was responsible for the 'Risk of bias' assessment, data analysis, and use of the RevMan 5 software.
DECLARATIONS OF INTEREST
Ildiko Gagyor: None known
Vishnu B Madhok: I have received payment for reviewing a review prepared by BMJ Evidence.
Fergus Daly: The fact that I am a named author on one of the included articles (Sullivan 2007) did not influence in any way my thinking,
presentation or contribution to this review.
Dhruvashree Somasundara: None known
Michael Sullivan: None known
Fiona Gammie: None known
Frank Sullivan: I am the author of one of the included studies (Sullivan 2007). I have no other known conflicts of interest.
SOURCES OF SUPPORT
Internal sources
• University of Dundee, UK.
External sources
• No sources of support supplied
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
There were several differences between the published review protocol and the 2009 update of the review (Lockhart 2009). These main-
ly reflected changes over time to treatment options and Cochrane methodology. As for the previous update, the search for studies now
includes treatment with valaciclovir and famciclovir, either alone or in combination with any other therapy, to reflect the treatment op-
tions now available for Bell's palsy. We undertook the methodological assessment according to Chapter 8 of the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011).
As implemented in previous versions of the review, we documented in this update the selection criteria relating to high risk of bias and
study duration. The minimum study duration was three months. As in previous updates, we used study quality as an exclusion criterion,
especially in trials with a high risk of bias in several domains.
For this update, seven review authors read a selection of papers, reviewed them for quality, and extracted data. The review authors dis-
tributed the work so that at least two review authors reviewed each paper. IG performed the final 'Risk of bias' assessment, which FS and
VM independently reviewed.
We focused this search on people who were immunocompetent, which we did not stipulate in the original protocol. We did this as treat-
ment protocols for immunocompromised individuals and treatment response may differ significantly from other individuals and could
not be fully explored in this analysis.
The authors of Lockhart 2009 widened the outcome criteria to include outcomes at the end of the study, as opposed to one year or six
months after treatment, in order to allow for the inclusion of a maximal number of published studies. This previous update included
studies with durations of three to 12 months, which allowed for maximum data inclusion. As it was understood that this method might
introduce significant heterogeneity to the results, the review authors included a sensitivity analysis looking at outcomes in participants in
studies reporting at 12 weeks or less and 6 months or less in order to assess the influence this had on the robustness of published results.
The authors of the current review accepted these changes. For the subgroup analysis of incomplete recovery, we extracted data on the
severity Bell’s palsy at month six or imputed using the last measure carried forward. As for the previous update, we omitted the outcome
'Complete facial paralysis at the end of the study'.
We have added in this update the outcome 'incomplete recovery in severe cases', measured at month six or imputed using the last measure
carried forward. We defined severe cases as a severe-to-complete facial paralysis, graded as equal to or greater than V in the House-
Brackmann grading system, equal to or less than 20 in the Sunnybrook score, and equal to or less than 20 in the Yanagihara score.

Informed decisions.

We modified the outcome measures since the previous review to take into account the heterogeneity of this group of studies.
We altered incomplete recovery to include the range of definitions used by the included studies in order to allow for maximum data capture:
As opposed to the previous definition of moderate dysfunction, the term now includes participants with a lack of full function. By this
definition, more participants will be classified as 'incomplete recovery'.
The Lockhart 2009 update replaced 'adverse events attributable to antiviral treatment' with 'adverse events'; in studies where both agents
are administered, it is difficult to assess which agent is causing the adverse event. Similarly, even when only an antiviral is being prescribed,
it is difficult to know whether a specific event should be attributed to the medication or to another intercurrent cause. The level of detailed
analysis of adverse events in studies did not permit such a judgement to be made. This review reported adverse events for each analysis
separately.
The review authors added a 'Summary of findings' table and additional sections to the methods to comply with current Cochrane stan-
dards.
We performed sensitivity analyses to investigate whether the exclusion of trials not meeting current best standards (that is a high or unclear
risk of bias in more than five categories or trials with less than 200 participants) would influence the results.
INDEX TERMS
Medical Subject Headings (MeSH)

Acyclovir [analogs & derivatives] [*therapeutic use]; Anti-Inflammatory Agents [therapeutic use]; Antiviral Agents [*therapeutic use]; Bell
Palsy [*drug therapy] [virology]; Drug Therapy, Combination [methods]; Herpes Simplex [complications] [*drug therapy]; Prednisolone
[therapeutic use]; Randomized Controlled Trials as Topic; Valacyclovir; Valine [analogs & derivatives] [therapeutic use]
MeSH check words

Humans


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Gagyor I, Madhok VB, Daly F, Somasundara D, Sullivan M, Gammie F, Sullivan F

Gagyor I, Madhok VB, Daly F, Somasundara D, Sullivan M, Gammie F, Sullivan F.

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) i

Antiviral treatment for Bell's palsy (idiopathic facial paralysis)

Editorial group: Cochrane Neuromuscular Group

Data collection and analysis

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 1

Motor synkinesis or crocodile tears

Antiviral treatment for Bell's palsy

Key results and quality of the evidence

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 2

In other analyses, we found the following:

Long-term after-effects of Bell's palsy

The evidence in this review is current to October 2014.

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 3

Outcomes Illustrative comparative Relative effect No of partici- Quality of the Comments

Incomplete recovery at end of study Study population RR 0.61 1315 ⊕⊕⊝⊝

149 per 1000 91 per 1000

Cochrane Database of Systematic Reviews

228 per 1000 128 per 1000

GRADE Working Group grades of evidence

Cochrane Database of Systematic Reviews

BACKGROUND study of viral replication in participants with Bell’s palsy suggests

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 6

Secondary outcomes • not-A: treatment not including antiviral treatment (i.e. OS or

Assessment of reporting biases Description of studies

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 8

Figure 1. Study selection flow diagram.

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 9

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 10

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 11

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 12

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 13

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 15

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 16

Incomplete recovery at the end of the study was significantly much

Adverse events Adverse events

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 17

DISCUSSION We found insufficient data to examine any of the other variables

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 18

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 19

be achieved through a meta-analysis of individual participant da- ACKNOWLEDGEMENTS

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 20

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 21

aciclovir versus empirico]. Acta Otorrinolaringologica Espanola

Minnerop 2008 {published data only} Adour 1982

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 22

Goudakos 2009 Murakami 1996

GRADEpro 2008 [Computer program] Niparko 1993

Katusic 1986 Prescott 1988

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 23

Wolf 1978 Gagyor 2015a

Characteristics of included studies [ordered by study ID]

lack of clear definition of diagnostic criteria (possibly affects generalisability/validity)

Maximal stimulation test with or without electroneurography at follow-up at 2 weeks, 2, 3, and 4

Notes Single centre

Antiviral treatment for Bell's palsy (idiopathic facial paralysis) (Review) 24

Bias Authors' judgement Support for judgement

Participants in each group received identical follow-up

Other sources of bias? Low risk No other risks of bias reported

Secondary outcomes: sequelae and synkinesis reported separately

Final outcomes reported at 4 months

Notes Single centre