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Corticosteroids vs Corticosteroids Plus • Abstract


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Antiviral Agents in the Treatment of Bell Palsy • Reply to article
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A Systematic Review and Meta-analysis
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John K. Goudakos, MD, MSc; Konstantinos D. Markou, MD, PhD

Arch Otolaryngol Head Neck Surg. 2009;135(6):558-564. Citing Articles


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Objective To review systematically and meta-analyze the results of all randomized


controlled trials (RCTs) for the treatment of patients with Bell palsy with corticosteroids vs
corticosteroids plus antiviral agents.

Data Sources A MEDLINE, EMBASE, Cochrane Library, and CENTRAL database search,
followed by extensive hand-searching for the identification of relevant studies. No time and
language limitations were applied.

Study Selection Prospective RCTs on the treatment of patients with Bell palsy.

Data Extraction Odds ratios (ORs), 95% confidence intervals (CIs), and tests for
heterogeneity were reported.

Data Synthesis Five studies were eventually identified and systematically reviewed. Meta-
analysis was performed for 4 studies. Regarding the complete recovery rate of facial nerve
paralysis 3 months after initiation of therapy, the current systematic review and meta-
analysis suggests that the addition of an antiviral agent does not provide any benefit (OR,
1.03 [95% CI, 0.74-1.42]; P = .88). The same conclusion emerged at posterior (fourth,
sixth, and ninth) months of assessment. Subgroup analysis, conducted on the basis of time
point of therapy initiation, type of antiviral agent, and blindness of assessments did not
change the results obtained. The occurrence rate of adverse effects attributable to therapy
choice was not significantly different between patients receiving corticosteroids and those
following combined treatment.

Conclusion The present systematic review and meta-analysis, based on the currently
available evidence, suggests that the addition of an antiviral agent to corticosteroids for the
treatment of Bell palsy is not associated with an increase in the complete recovery rate of
the facial motor function.

INTRODUCTION

Jump to Section
Bell palsy, or idiopathic facial paralysis, is the most common cause • Top
of acute facial paralysis, with an annual incidence reported to range • Introduction
from 20 to 45 cases per 100 000 persons.1-2 The main clinical • Methods
symptom of Bell palsy is facial motor dysfunction, the degree of • Results
which varies from minor weakness to complete paralysis depending • Comment
• Conclusions
on the amount of neural injury. • Author information
• References
Genetic factors, vascular ischemia, and inflammation owing to viral
infection or autoimmune disorders have been proposed as the possible underlying cause,
but the etiology remains unknown.3-5 The theory of viral etiology was first proposed by
McCormick,6 who suggested the acute inflammatory neuropathy of the seventh cranial
nerve, owing to the presence of herpes simplex virus (HSV) in the geniculate ganglion.7 In
1996, Murakami et al8 isolated the HSV genome from the facial nerve endoneurial fluid of
patients with Bell palsy, additionally supporting the viral etiology of the disease.

Considering the natural history of the disease, Peitersen,2 in a retrospective study of 2500
cases of Bell palsy, reported that 70% of the patients presented with complete paralysis of
the facial nerve at initial examination, with only 61% of them achieving ultimate recovery.
The same study2 also reported that partial regain of facial tone or movement was
established in 85% of all patients within 3 weeks, and full recovery was typically achieved
within 2 months.

Nowadays, the treatment of choice for Bell palsy has not yet been established. The
therapeutic drug choices for the treatment of the idiopathic facial paralysis are (1)
corticosteroids, (2) antiviral therapy (acyclovir sodium or valacyclovir hydrochloride), and
(3) a combination of corticosteroids with an antiviral agent (combined therapy).

Corticosteroids are considered to be the most widely accepted treatment for Bell palsy. The
rationale for early treatment with the use of corticosteroids for patients with Bell palsy is
based on the reports of facial nerve swelling during decompression operations.9-10 Several
nonrandomized controlled trials (non-RCTs) have advocated the use of corticosteroids in
facial palsy as the treatment of choice. In 2000, a meta-analysis by Ramsey et al11
suggested the significant improvement in recovery from facial paralysis in patients with Bell
palsy who received corticosteroids. However, a recently published systematic review and
meta-analysis12 indicated that, at present, the beneficial role of corticosteroids in Bell palsy
treatment remains in doubt.

The possible association between Bell palsy and viral infection led to the use of an antiviral
agent in the therapeutic plan of the disease, either as monotherapy or in combination with
corticosteroids. Based on the results of a current systematic review and meta-analysis,
insufficient evidence exists to make definitive recommendations regarding the effect of
antiviral agents on Bell palsy.13 Recent multicenter controlled trials14-15 have evaluated the
combined treatment strategy (corticosteroids plus antiviral agents) vs corticosteroids alone
in the therapy of Bell palsy. Conflicting results about the benefit of adding antiviral agents
for the recovery of facial nerve paralysis have been presented.

The purpose of the present systematic review and meta-analysis is to address the following
question: Among patients with Bell palsy, is the full recovery of facial paralysis significantly
different between patients who receive corticosteroids and those who receive combined
treatment with corticosteroids and an antiviral agent?

METHODS

Jump to Section
SEARCH STRATEGY • Top
• Introduction
We performed a computer literature search in MEDLINE, EMBASE, • Methods
• Results
the Cochrane Library,16 and CENTRAL electronic databases from
• Comment
January 10 to February 10, 2008, to identify studies that answered • Conclusions
the question of interest. For this purpose, we used the following • Author information
free-text terms: "Bell palsy" or "idiopathic facial nerve paralysis" or • References
"facial palsy" combined with "drug therapy" or
"steroids/corticosteroids/cortisone/prednisolone/presolone/methylprednisolone/dexamethas
one/glucorticoids" or "antiviral/acyclovir/valacyclovir" or "treatment" or "therapy" and
limited to "human." In addition, extensive hand-searching of the references of all relevant
studies was also performed. No time and language limitations were applied.

SELECTION OF STUDIES

All criteria for inclusion or exclusion of studies in the present systematic review were
specified prior to the literature search. For a study to be eligible, the following criteria had
to be met: (1) the study had to be an RCT, comparing any type of corticosteroid therapy
with combined treatment of corticosteroids with any type of antiviral agent, regardless of
the route (oral or parenteral), the dose, and the duration of administration of the therapies;
(2) the study had to include patients with unilateral facial nerve weakness of no identifiable
cause seen within 7 days of the onset of weakness; (3) the follow-up protocol had to
include assessments of patients' clinical status at least 3 months after the initial onset of
the disease and start of therapy; and (4) the study had to include patients who started
therapy within 7 days from the onset of the disease.

The following exclusion criteria were established: (1) any studies that included patients with
uncontrolled diabetes mellitus, peptic ulcer disease, suppurative otitis media, herpes zoster,
multiple sclerosis, or systematic infection and (2) any study that included pregnant or
breastfeeding women were excluded.
In case the studies did not offer all the necessary information for the assessment of
potential eligibility, the authors of those studies were contacted and asked to provide the
missing data.

STUDIES IDENTIFIED

The electronic search resulted in the identification of 262 publications. Of these, 39 were
found to be potentially eligible publications. The abstracts of these studies were examined,
and 12 articles that could provide data to answer the research question of interest were
identified (Figure 1). The full text of these studies was examined thoroughly, resulting in
the exclusion of 7 publications. Specifically, these studies were excluded because (1) they
did not match with the research question of interest (n = 4), (2) the follow-up was less
than 3 months (n = 2), or (3) their data overlapped those of other publications (n = 1); the
study with the more extensive sample size was considered eligible in the present systematic
review. As a consequence, 5 studies14-15,17-19 comparing corticosteroids with the combined
therapy of corticosteroids plus antiviral agents in patients with Bell palsy were finally
identified (Table 1).

Figure 1. Flow diagram for study selection.

View larger version (33K):


[in this window]
[in a new window]
[as a PowerPoint slide]

View this table: Table 1. Demographic Data of the 5 Studies Included in the
[in this window]
[in a new window] Systematic Review
[as a PowerPoint slide]

Each of us independently assessed eligibility of these studies for the present systematic
review. Any disagreement was resolved unanimously by discussion.
DATA EXTRACTION

Both of us performed data extraction, and the following data were recorded from each of
the eligible studies: general characteristics (type of study, citation data, number of patients
included, and their baseline characteristics), procedural data (type of randomization,
inclusion criteria, protocol of follow-up, protocol of corticosteroid therapy or combined
treatment and the number of patients who dropped out of the study), and outcome data
(facial nerve recovery based on specific grading scale, adverse effects of each therapy
strategy). To perform the intention-to-treat analysis, all patients who were initially
allocated to each treatment group were analyzed together, regardless of whether they
completed or received that treatment.

OUTCOME MEASURES

The main outcome measure chosen for the systematic review and meta-analysis was the
complete recovery of facial motor function 3 months after the initiation of therapy.
Assessments of facial motor function at posterior months (at 4, 6, and 9 months) after the
therapy started were also conducted. Many facial grading systems have been introduced for
the assessment of motor function of facial nerve. In the present systematic review, the
House and Brackmann20 facial nerve grading system, which has been adopted as a standard
by the Facial Nerve Disorders Committee of the American Academy of Otolaryngology–Head
and Neck Surgery, was chosen for the assessment of the primary outcome. Conversion of
scores of other grading systems to the scales of the House-Brackmann system was
performed, owing to its universal acceptance for calculation of dysfunction of facial nerve
disorders.

Secondary outcome measures included the occurrence rate of adverse effects in each study
group attributable to treatment strategies (corticosteroids and corticosteroids plus antiviral
drugs). These adverse effects included dizziness, dyspepsia, nausea, constipation, hunger,
vomiting, insomnia, night sweats, and other symptoms attributable to drug choice.

QUANTITATIVE DATA SYNTHESIS

The dichotomous data results for each of the eligible studies for meta-analysis were
expressed as an odds ratio (OR) with 95% confidence intervals (CIs). These results were
combined for meta-analysis by applying the Mantel-Haenszel model21 when using the fixed-
effects method, and the DerSimonian and Laird model22 when using the random-effects
method.

Revman software (version 4.2 for Windows; Nordic Cochran Centre, the Cochrane
Collaboration, Copenhagen, Denmark) was used to combine the results for meta-analysis.
Inconsistency of studies (study-to-study variation) was assessed by using the 2 statistic
(the hypothesis tested was that the studies were all drawn from the same population, ie,
from a population with the same effect size). A fixed-effects model was used in which no
heterogeneity was present. In the presence of significant heterogeneity (P <.05), a
random-effects model was applied.

Subgroup analyses were performed depending on (1) the duration between disease onset
and the start of therapy (early treatment was considered to be the therapy starting within 3
days of the disease onset), (2) the type and dosage of the corticosteroid and antiviral agent
used in each study group, and (3) studies in which physicians who performed assessments
of the outcomes were actually aware of allocated treatment.
Sensitivity analyses were performed to check the stability of the results obtained by
excluding (1) studies that did not report the procedure of randomization and patient
allocation clearly and (2) studies that did not provide detailed data regarding the diagnostic
criteria of Bell palsy.

RESULTS

Jump to Section
Five studies14-15,17-19 fulfilled the inclusion criteria. Characteristics of • Top
the eligible studies are listed in Table 1 and Table 2. • Introduction
• Methods
• Results
• Comment
• Conclusions
• Author information
• References

View this table: Table 2. Characteristics of the 5 Studies Included in the Systematic
[in this window]
[in a new window] Review
[as a PowerPoint slide]

SYSTEMATIC REVIEW

T he eligible studies14-15,17-19 were published from 1996 to 2007. All studies were RCTs in
design, and their sample sizes ranged from 29 to 272 patients. A total of 738 patients were
reviewed (corticosteroids group, n = 372; combined therapy group, n = 366) (Table 1).

Regarding the type of corticosteroid, patients in 4 studies received prednisolone, whereas in


1 study deflazacort was used. In the combined therapy group, the regimen included the
corticosteroid plus an antiviral agent, acyclovir or valacyclovir. In all studies the drugs were
administered orally. Details about the daily dose and the length of regimen of each study
group are presented in Table 2.

In all studies, the procedure of follow-up included assessments of the patients for at least 3
months. The number of patients who were lost during the follow-up period (dropouts) in
each study group was reported in 4 of 5 eligible studies.14-15,17-18 All trials used the full
recovery of facial nerve motor function as the main outcome measure. Patients in 4 trials14-
15,17, 19
commenced therapy within 3 days of onset of the disease. The initial severity of the
facial nerve dysfunction was reported in 3 studies14-15,17 (Table 2).

The House-Brackmann grading system was used in 3 studies15, 18-19 for scoring the facial
nerve paralysis and its recovery. The Yanagihara grading system and Facial Paralysis
Recovery Profile (FPRP) were used in the remaining 2 studies,14, 17 and in these 2 studies,
the authors reported the conversion of the used grading system (Yanagihara or FPRP) to
the scores of House-Brackmann system. In 2 studies,15, 17 clinicians assessing the recovery
profile of the patients were blinded to allocated treatment.

Three studies15, 18-19 reported that there is no evidence that antiviral agents provide
additional recovery benefit for patients with Bell palsy. In contrast, the 2 remaining
studies14, 17 reported that therapy with corticosteroids plus antiviral agents is superior to
corticosteroids alone, regarding the complete recovery of facial motor function of patients
with idiopathic acute facial paralysis. Three studies14-15,17 provided data about the adverse
effects that occurred in each study group, which could be attributed to treatment
strategies.

META-ANALYSIS

Four14-15,17, 19 of 5 eligible studies provided relevant data for quantitative synthesis. The
complete recovery rate of facial motor function at 3 months after the initiation of therapy
was not significantly different between the corticosteroids group and the combined therapy
group (OR, 1.03 [95% CI, 0.74-1.42]; P = .88; heterogeneity, P = .66; fixed-effects
model) (Figure 2).

Figure 2. Odds ratio (OR) of complete recovery


rate of facial motor function 3 months after the
initiation of therapy. CI indicates confidence
View larger version (18K): interval; M-H, Mantel-Haenszel.21 Combined
[in this window] therapy group indicates corticosteroids plus
[in a new window]
antiviral agents.
[as a PowerPoint slide]

Regarding assessment at 4, 6, and 9 months after initiation of therapy, meta-analysis was


not feasible because results from only 1 study were available at each time point. It should
be noted, though, that in the individual studies the observed recovery rate of facial motor
function was not considerably different between the corticosteroids group and combined
therapy group 4 (OR, 0.48 [95% CI, 0.17-1.38]; P = .17), 6 (OR, 0.76 [95% CI, 0.46-
1.25]; P = .29), and 9 months after the initiation of therapy (OR, 1.53 [95% CI, 0.74-
3.17]; P = .25).

Sensitivity analysis including only the studies that reported a detailed analysis of
randomization procedure and patient allocation suggested that the recovery rate of facial
motor function did not differ significantly between the corticosteroids group and combined
therapy group (OR, 1.02 [95% CI, 0.71-1.47]; P = .91; heterogeneity, P = .52; fixed-
effects model) (Figure 3). Finally, these results did not change substantially by excluding
the studies not clearly reporting the diagnostic criteria of Bell palsy (OR, 1.02 [95% CI,
0.71-1.47]; P = .91; heterogeneity, P = .52; fixed-effects model).
Figure 3. Odds ratio (OR) of complete recovery
rate of facial motor function at 3 months after the
initiation of therapy, excluding studies that did not
View larger version (15K): report detailed analysis of randomization
[in this window]
[in a new window]
procedure and patient allocation. CI indicates
[as a PowerPoint slide] confidence interval; M-H, Mantel-Haenszel.21
Combined therapy group indicates corticosteroids
plus antiviral agents.

Subgroup analysis including only results of studies in which initiation of treatment was
performed within 3 days of disease onset did not lead to a significant difference of complete
recovery between the study groups (OR, 0.94 [95% CI, 0.63-1.4]; P = .77; heterogeneity,
P = .54; fixed-effects model) (Figure 4). In the study by Hato et al,14 treatment started
within 7 days of disease onset, and for this subgroup analysis the results of patients
recruited within 3 days were used. In a further subgroup analysis, in which studies
administering the same type of antiviral agent (acyclovir or valacyclovir) were analyzed, the
rate of patients with complete recovery of facial motor function did not differ significantly
(P < .05) between the 2 treatment groups (corticosteroids and corticosteroids plus antiviral
agent). Finally, subgroup analysis, based on the type of corticosteroid administrated, could
not be performed because all the studies that were included in meta-analysis used the
same type of steroid (prednisolone) in similar parenteral dosage.

Figure 4. Odds ratio (OR) of complete recovery


rate of facial motor function at 3 months after the
initiation of therapy, including studies in which
View larger version (18K): patients started treatment within 3 days of the
[in this window] onset of Bell palsy. CI indicates confidence
[in a new window]
interval; M-H, Mantel-Haenszel.21 Combined
[as a PowerPoint slide]
therapy group indicates corticosteroids plus
antiviral agents.

It should be noted that the recovery rate of facial motor function between the corticosteroid
group and combined therapy group was not considerably different, excluding studies in
which physicians performing the assessments of the outcome were aware of treatment
allocation (OR, 0.99 [95% CI, 0.63-1.57]; P = .97; heterogeneity, P = .28; fixed-effects
model).

The occurrence rate of adverse effects attributable to therapy choice did not differ
significantly between the study groups (OR, 0.89 [95% CI, 0.50-1.60]; P = .70;
heterogeneity, P = .78; fixed-effects model).
COMMENT

Jump to Section
Treatment decisions regarding patients with Bell palsy are doubtful • Top
and remain a common problem in medical practice. Corticosteroids • Introduction
have been established as the therapy of choice, despite the fact • Methods
that the available evidence from RCTs does not exhibit a clear • Results
benefit. However, the largest available RCT published recently • Comment
• Conclusions
suggested a benefit from the use of corticosteroids in patients with • Author information
idiopathic acute facial paralysis.15 The role of antiviral agents has • References
been revealed since the establishment of the virus involvement in
the etiology of Bell palsy.

The natural course of Bell palsy, based on analysis of history of numerous cases, indicates
that most patients recover within 3 months after the onset of the disease.2 Regarding the
complete recovery rate of the facial nerve paralysis 3 months after the disease occurrence,
the current systematic review and meta-analysis suggests that the addition of an antiviral
agent does not provide any benefit. This conclusion seems to be in agreement with the
results of a recent report23 dealing with the virologic background of Bell palsy, which
indicates that, at first examination, reactivation of the HSV was detected in only 8% of
patients. The lack of recovery advantage in patients receiving antiviral agents remained
invariable at the 4-, 6-, and 9-month assessments after the therapy initiation.

According to supporters of virus involvement in the etiopathogenesis of Bell palsy, except in


the case of HSV, the reactivation of varicella–zoster virus (VZV) is involved in the
pathophysiologic course of a considerable proportion of patients. Valacyclovir, a prodrug of
acyclovir, has been proposed as the antiviral agent that can improve the recovery rate of
facial paralysis owing to its high bioavailability, which implies a much higher antiviral
activity. However, in the present study, a subgroup analysis, based on the type of antiviral
agent (acyclovir or valacyclovir), did not detect a benefit in the recovery of facial paralysis
by adding either of the 2 agents.

The rationale for early (within 3 days of onset of disease) treatment with corticosteroids in
patients with Bell palsy was based on its theoretical effect on early occurring cytotoxic
edema, being proposed as a prevention strategy to neural degeneration of facial nerves and
as a therapy method for complete recovery of facial paralysis.24-25 However, the results of
the present meta-analysis do not confirm this assumption because the subgroup analysis on
the basis of the timing of therapy initiation (within or not within 3 days of disease onset)
supports the conclusion that early treatment does not provide any recovery advantage in
patients with Bell palsy. The lack of benefit from the addition of antiviral agents to the
therapeutic plan of patients with Bell palsy was also confirmed in the sensitivity analysis by
excluding the studies that did not clearly report the diagnostic criteria of disease or the
procedure of randomization and patient allocation.

The accurate diagnosis of the acute idiopathic facial nerve paralysis depends on the
exclusion of other causes that have similar symptoms. Particularly, zoster sine herpete,
which can mimic the signs and symptoms of Bell palsy, which is caused by VZV, has an
incidence rate ranging from 29% to 34% among patients with Bell palsy.26-27 Consequently,
data are needed regarding the virologic backgrounds of all participating patients and
obtained by means of serologic and polymerase chain reaction examinations. In the present
systematic review, only 1 study14 excluded patients with VZV reactivation.
The results of the present systematic review are liable to certain limitations. In 2 studies,15,
17
the investigators who were administering the treatment and assessing the outcome were
not aware of study-group assignments. Moreover, because facial functional outcome
assessments are semisubjective, a level of bias in the final outcome assessment scores
should be considered in all trials. Revealing the statistical significance of treatment benefit
in studies of Bell palsy requires a large number of patients owing to the variable and
spontaneous recovery profile of patients.2

In the present systematic review, time-to-event analysis was not incorporated in any of the
eligible studies. Time-to-event analysis and estimation of the relative risk are considered to
be the most appropriate methods for comparison of the recovery of facial nerve motor
function between the 2 groups so that the time interval between the intervention and the
event (recovery of facial nerve) will not be disguised. None of the eligible studies in the
present systematic review reported their results on the basis of the intention-to-treat
analysis. The rationale of the specific analysis is to provide the pragmatic estimate of the
benefit of a change to treatment policy rather than an estimate of potential benefit to
patients receiving treatment exactly as planned.28-29 The results of the eligible studies in the
present review were included in the quantitative data synthesis after their calculation on
the basis of intention-to-treat analysis.

CONCLUSIONS

Jump to Section
The current systematic review and meta-analysis suggests that • Top
addition of an antiviral agent to corticosteroids for the treatment of • Introduction
patients with Bell palsy is not associated with an increase in the • Methods
complete recovery rate of facial motor function. Additional well- • Results
designed RCTs are needed to assess the potential value of antiviral • Comment
• Conclusions
addition to the recovery of facial palsy with more confidence. • Author information
However, based on the currently available evidence, the addition of • References
an antiviral agent to corticosteroids for the treatment of patients
with Bell palsy is not justified.

AUTHOR INFORMATION

Jump to Section
Correspondence: John K. Goudakos, MD, MSc, First Department of • Top
Otolaryngology–Head and Neck Surgery, AHEPA Hospital, Aristotle • Introduction
University of Thessaloniki, 54636 Thessaloniki, Greece • Methods
(jgoudakos@gmail.com ). • Results
• Comment
• Conclusions
Submitted for Publication: June 4, 2008; final revision received • Author information
November 3, 2008; accepted November 16, 2008. • References

Author Contributions: Both authors had full access to all the data in the study and take
responsibility for the integrity of the data and the accuracy of the data analysis. Study
concept and design: Goudakos. Acquisition of data: Goudakos. Analysis and interpretation
of data: Goudakos and Markou. Drafting of the manuscript: Goudakos. Critical revision of
the manuscript for important intellectual content: Goudakos and Markou. Statistical
analysis: Goudakos. Obtained funding: Goudakos. Administrative, technical, and material
support: Goudakos and Markou. Study supervision: Goudakos and Markou.

Financial Disclosure: None reported.

Additional Contributions: K. K. Adour, M. L. Antunes, N. Hato, S. Inanli, and F. M.


Sullivan contributed to this study.

Author Affiliations: First Department of Otorhinolaryngology–Head and Neck Surgery,


AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

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