CLINICAL RESEARCH STUDY

Steroid-antiviral Treatment Improves the Recovery Rate

in Patients with Severe Bells Palsy
Ho Yun Lee, MD, Jae Yong Byun, MD, Moon Suh Park, MD, Seung Geun Yeo, MD, PhD
Department of Otorhinolaryngology, School of Medicine, Kyung Hee University, Seoul, Korea.
ABSTRACT
BACKGROUND: The extent of facial nerve damage is expected to be more severe in higher grades of facial
palsy, and the outcome after applying different treatment methods may reveal obvious differences between
severe Bells palsy and mild to moderate palsy. This study aimed to systematically evaluate the effects of
different treatment methods and related prognostic factors in severe to complete Bells palsy.
METHODS: This randomized, prospective study was performed in patients with severe to complete Bells
palsy. Patients were assigned randomly to treatment with a steroid or a combination of a steroid and an
antiviral agent. We collected data about recovery and other prognostic factors.
RESULTS: The steroid treatment group (S group) comprised 107 patients, and the combination treatment
group (SA group) comprised 99 patients. There were no signicant intergroup differences in age, sex,
accompanying disease, period from onset to treatment, or results of an electrophysiology test (P .05).
There was a signicant difference in complete recovery between the 2 groups. The recovery (grades I and
II) of the S group was 66.4% and that of the SA group was 82.8% (P.010). The SA group showed
a 2.6-times higher possibility of complete recovery than the S group, and patients with favorable
electromyography showed a 2.2-times higher possibility of complete recovery.
CONCLUSIONS: Combined treatment with a steroid and an antiviral agent is more effective in treating
severe to complete Bells palsy than steroid treatment alone.
2013 Elsevier Inc. All rights reserved. The American Journal of Medicine (2013) 126, 336-341
KEYWORDS: Bells Palsy; Electromyography; Electroneurography; Prognosis
Bells palsy is a common disease that occurs in 20-30
people of every 100,000 and is the most common cranial
neuropathy.
1,2
The reactivation of herpes simplex virus is
known to be one of the causes of Bells palsy.
3
For treat-
ment of Bells palsy, the use of prednisolone is known to
result in high recovery rates and less synkinesis, and there is
no doubt that steroid treatment may prevent further nerve
damage and is benecial in most cases.
4
Although there is consensus that early use of pred-
nisolone is an effective treatment, the use of antiviral agents
has led to some controversy. Researchers who are against
the use of antiviral agents argue that there is no proof of
additional benet.
5,6
However, additional use of valacyclo-
vir has been shown to be more effective than steroid treat-
ment alone,
7
and patients with severe Bells palsy show a
more favorable result with steroid-famciclovir combination
therapy.
8
These ndings have led some to advocate for the
use of antiviral agents.
Other researchers speculate that mixing patients with
different severities of palsy leads to inconsistent results, and
that patients with paresis have an excellent prognosis, irre-
spective of treatment methods.
4
Following a literature review, we hypothesized that the
additional effect of antiviral agents would be different ac-
cording to the severity of the palsy and that, in cases of
severe to complete palsy, there would be a difference in
recovery according to treatment methods. Increasing age;
onset of treatment; and results of electrophysiologic tests,
such as electromyography (EMG) and electroneurography
(ENoG), also may inuence the prognosis. Therefore, we
Funding: This research was supported by the Kyung Hee University
Research Fund in 2011(KHU-2011-1098).
Conict of Interest: None.
Authorship: All authors had full access to the data and played a role
in writing this manuscript.
Requests for reprints should be addressed to Seung Geun Yeo, MD,
PhD, Department of Otorhinolaryngology, School of Medicine, Kyung Hee
University, #1 Hoegi-dong, Dongdaemun-gu, Seoul 130-702, Korea.
E-mail address: yeo2park@gmail.com
0002-9343/$ -see front matter 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.amjmed.2012.08.020
conducted a prospective study to evaluate systematically the
effects of different treatment methods and related prognos-
tic factors in severe Bells palsy.
METHODS
Between September 2008 and Au-
gust 2011, we conducted a pro-
spective, randomized study of pa-
tients who visited our tertiary
medical center due to acute uni-
lateral peripheral facial paralysis
without skin lesions or intraoral
lesions occurring within 7 days of
presentation. The House-Brack-
mann grading system was used
to evaluate the severity of facial
palsy, and only patients with se-
vere to complete Bells palsy
(House-Brackmann grade 5)
were enrolled.
9
All patients were hospitalized
for 1 week. Age, sex, duration
from onset to treatment, previous
history of facial palsy, and associ-
ated symptoms (such as pain
around the ear, taste disturbance,
and hyperacusis) were documented.
Patients were randomized using simple randomization
codes generated by Microsoft Excel 2007 (Microsoft Cor-
poration, Redmond, Wash) to treatment with a steroid (S
group) or a steroid-antiviral combination (SA group). The
drug therapy protocol consisted of patients assigned to
the same group being treated on the same schedule. Both the
researchers and the enrolled patients were blinded to treat-
ment assignment. Steroid treatment consisted of methyl-
prednisolone for 10 days, 64 mg/d for the rst 4 days,
followed by tapering to 48 mg/d for 2 days, 32 mg/d for 2
days, and 16 mg/d for 2 days. Antiviral therapy consisted of
oral famciclovir (750 mg/d) for 7 days. Patients in the SA
group were administered steroid and famciclovir simultane-
ously. An otolaryngologist who did not participate in this
study was responsible for patient care during hospitalization
and assessed outcomes after 6 months.
Bipolar needle EMG and ENoG were performed in all
patients. ENoG was conducted during the hospitalization
using bipolar cutaneous electrodes. A ground electrode was
attached to the arm and a recording electrode was placed in
the nasolabial fold. The compound muscle action potential
(CMAP) was obtained from the nasalis muscle measured at
the suprathreshold stimulation, and measurements were re-
ported as the percent maximal amplitude on the side of the
lesion/maximal amplitude on the healthy side. Poor ENoG
was dened as a loss of amplitude 90%.
The EMG was conducted after about 2 weeks from the
onset of the facial palsy. The following 6 muscles of ex-
pression were examined separately: the frontalis, orbicularis
oculi, major zygomatic, orbicularis oris, levator labii supe-
rior, and depressor anguli oris. The presence or absence of
the blink reex was analyzed simultaneously and classied
as favorable or unfavorable by the physical medicine and
rehabilitation physician.
For follow-up, all patients were
instructed to visit the hospital 6
months after hospital discharge.
Grades I and II at 6 months from
palsy onset were dened as com-
plete recovery, and grade III or
higher was dened as incomplete
recovery.
The criteria for exclusion were:
Bells palsy that occurred more
than 7 days before presentation;
Suspected Ramsay-Hunt syn-
drome, meningitis, myelitis, or
vasculopathy;
Patients who could not be ob-
served for at least 6 months;
The initial use of several differ-
ent types of treatments;
Age 16 years;
Pregnancy or breast-feeding;
Uncontrolled diabetes or hyper-
tension;
Poor general medical conditions in which steroid or an-
tiviral therapy cannot be used;
Suspicion of Borrelia infection;
A tendency for neuropsychiatric disease; and
Refusal to participate in the study.
The Institutional Review Board of Kyung Hee Univer-
sity Hospital approved this study, and informed consent was
obtained from all patients.
RESULTS
A total of 269 patients were enrolled in this study. After
excluding 32 patients who did not match the inclusion
criteria and 31 patients who did not complete this study due
to adverse effects of treatment and did not present for
follow-up, 206 patients completed the study (Figure 1).
The steroid treatment group (S group) comprised 107
patients, and the combination treatment group (SA group)
comprised 99 patients. There was no signicant difference
in the distribution of facial grades between the 2 groups
(P.498).
There were no signicant intergroup differences in age,
sex, accompanying disease, period between onset and treat-
ment, or results of electrophysiology tests (P .05). There
was no signicant difference between the treatment meth-
ods with regard to the nal grade and its trend. However,
there was a signicant difference in complete recovery
between the 2 groups. The recovery (grades I and II) of the
CLINICAL SIGNIFICANCE
Although there is consensus that early
use of prednisolone is effective, pre-
scription of antiviral agents remains
controversial.
A combination steroid/antiviral treat-
ment was more effective than steroid
alone in patients with severe Bells
palsy.
Clinicians should consider initiating
combination therapy with an inert ste-
roid and an antiviral of choice within 1
week of the onset of high-grade Bells
palsy.
337 Lee et al Steroid-Antiviral Treatment in Severe Bells Palsy
SA group was 82.8% and that of the S group was 66.4%
(P.010) (Table 1).
Univariate analysis was performed using previously
known prognostic factors in addition to the treatment meth-
ods (Table 2). The prognostic factors predicting incomplete
recovery were steroid treatment and unfavorable EMG re-
sults, and the odds ratios for incomplete recovery were 2.0
and 1.6, respectively.
Multivariate analysis was performed on the identied
prognostic factors (Table 3). The probability of complete
recovery was 2.6 times higher in the SA group than in the
S group, and the odds ratio for complete recovery in patients
with favorable EMG results was 2.2.
DISCUSSION
Additional antiviral treatment in Bells palsy is based on the
hypothesis that herpes simplex virus infection may cause
inammation of the facial nerve. Theoretically, the infec-
tious agents are eradicated by antiviral treatment, and swell-
ing of the facial nerve is reduced by corticosteroids.
6
How-
ever, antiviral agents cannot actually destroy virus that has
already replicated, because these drugs prevent viral repli-
cation by interfering with viral DNA polymerase. In this
respect, Hato et al reported the importance of early admin-
istration of the valacyclovir and prednisolone.
7,10
The 3 commonly used antivirals are acyclovir, famciclo-
vir, and valacyclovir. Although acyclovir is one of the most
commonly used antiviral agents, it has some limitations.
Patients must take acyclovir 5 times daily because it has a
very low oral bioavailability (10%-20%), and correct ad-
ministration is difcult to monitor because the drug is easily
compromised if taken with food.
11,12
Famciclovir, a prodrug
of penciclovir, is known to have excellent oral bioavailabil-
ity (60%-75%) and longer intracellular half-life than acy-
clovir and is not affected by concurrent food intake.
8
Vala-
cyclovir, a prodrug of acyclovir, is known to have greater
bioavailability compared with acyclovir and yields similar
plasma concentrations with only twice-daily dosing.
13,14
In this study, we demonstrated that in severe to complete
palsy, that is equal to or higher than grade 5, famciclovir
treatment plus steroid treatment signicantly increased the
chance of recovery. However, one important limitation of
this study was the potential risk of imbalance by simple
randomization, the fact that no signicant differences were
shown in age, sex, and other inuencing factors between 2
groups may imply that potential risks of bias were mini-
mally increased by using simple randomization.
Figure 1 Overview of patient enrollment.
338 The American Journal of Medicine, Vol 126, No 4, April 2013
Different researchers have reported different conclusions
about whether combination treatment is effective in Bells
palsy, and it is often difcult to come to a rm conclusion
(Table 4, Figure 2).
One recent study reported that physicians discussed the
merits, drawbacks, and the cost of additional antiviral treat-
ment with patients, and after this information was provided,
patients chose the combination therapy.
18
Oral antivirals are known to be well tolerated if admin-
istered at standard doses, providing that patients are kept
well hydrated. Side effects of antiviral agents occur in 10%
to 20% of all cases, and the most common symptoms are
nausea, vomiting, and headache. The combination therapy
for Ramsay-Hunt syndrome is justied and essential given
the possibility of a lifelong paralysis.
19,20
This applies equally to Bells palsy as one of the other
acute peripheral facial palsies. The relatively low chance of
life-threatening major side effects makes combination treat-
ment appropriate for severe Bells palsy, in which nerve
damage is expected to be severe.
However, we do not endorse indiscriminate use of anti-
viral agents. One previous study speculated that the initial
grade is not a signicant predictor of prognosis,
21
whereas
others reported that a higher initial House-Brackmann grade
reduces the probability of satisfactory recovery.
22
Our nd-
ings were consistent with those previously reported, and
indicated that combination therapy was effective in patients
with severe to complete facial palsy. Further validation,
however, is required in patients with mild to moderate
Bells palsy. Larger prospective clinical trials are required
to validate our results, because it may have a ripple effect in
clinical practice.
The detection of spontaneous brillation on needle EMG
is known as a sign predicting unfavorable outcome.
23,24
An
unfavorable EMG result was reported as one of the poor
prognostic factors in recurrent facial palsy.
25
Taken to-
gether, EMG is a reliable diagnostic tool that physicians can
use to predict prognosis.
In addition, we found that age and onset of treatment did
not signicantly inuence recovery. There is controversy
about the effect of age on prognosis. Previously, age was
reported as a parameter that signicantly inuenced the nal
recovery.
1
Others have assumed that increasing age reduces
the probability of a satisfactory recovery because of periph-
eral vascular degeneration.
26
In contrast, another study re-
ported that age above 50 years did not signicantly inu-
ence the long-term prognosis of Bells palsy.
22
Consistent
with that study, a trend test showed no signicant differ-
ences between age and recovery.
27
We assumed that these
different studies had different results because gerontological
problems might act as a confounding factor, and sophisti-
cated history-taking and statistical analysis is required in
order to compensate.
In this study, we found that the onset of treatment also
was a nonsignicant factor in the prognosis of Bells palsy.
Based on treatment within 3 days, early treatment did not
affect recovery signicantly (Table 2). Although Hato et al
provided the theoretical background for the use of early
combination treatment, they did not clearly show a differ-
ence in effect according to the onset of treatment and
Table 1 Patient Characteristics
Variable Steroid Only
Combination
Therapy P Value
Total n (%) 107 (51.9) 99 (48.1)
Age
Mean SD 48.6 15.1 46.7 16.2 .381
Range 16-77 16-76
Sex, n (%)
Male 51 (47.7) 50 (50.5) .780
Female 56 (52.3) 49 (49.5)
EMG, n (%)
Favorable 85 (79.4) 75 (75.8) .616
Unfavorable 22 (20.6) 24 (24.2)
ENoG, n (%)
Poor 5 (4.7) 9 (9.1) .271
Good 102 (95.3) 90 (90.9)
Onset of treatment, n (%)
Within 3 days 84 (79.2) 67 (67.7) .081
3-7 days 22 (20.8) 32 (32.3)
Final facial grade, n (%)
Mean SD 2.1 1.1 1.9 0.8 .216
I 42 (39.3) 31 (31.3) .221
II 29 (27.1) 51 (51.5)
III 26 (24.3) 12 (12.1)
IV 7 (6.5) 5 (5.1)
V 2 (1.9) 0 (0.0)
VI 1 (0.9) 0 (0.0)
Recovery rate (%) 66.4 82.8 .010
EMG electromyography; ENoG electroneurography.
Table 2 Univariate Analysis for Incomplete Recovery
Condition
Odds Ratios (95%
Condence Interval) P Value
Steroid only treatment 2.0 (1.2-3.3) .010
Unfavorable EMG 1.6 (1.0-2.6) .048
Poor ENoG 0.9 (0.4-2.1) .801
Onset of treatment within
3 days
0.9 (0.5-1.6) .728
Age 60 years 1.4 (0.8-2.4) .262
EMG electromyography; ENoG electroneurography.
Table 3 Results of Multiple Logistic Regression Analysis for
Complete Recovery
Variable
Odds Ratios (95%
Condence Interval) P Value
Favorable EMG 2.2 (1.1-4.5) .034
Steroid-antiviral treatment 2.6 (1.3-5.1) .006
EMG electromyography.
339 Lee et al Steroid-Antiviral Treatment in Severe Bells Palsy
only highlighted the merits of combination treatment.
7
In
fact, in their earlier study, they reported that all patients
who were treated with acyclovir and prednisolone within
3 days of onset recovered completely; however, that
study had limited signicance because it was a retrospec-
tive study.
28
Consistent with our study, others have as-
sumed that the onset of treatment is not a signicant
prognostic factor.
18
With 7 days classied as a delayed start of treatment,
another report demonstrated that there was no statistically
signicant difference in recovery.
22
Therefore, physicians
should take into consideration that delayed treatment does
not always lead to poor recovery, and combination treat-
ment increases the possibility of recovery in severe to com-
plete Bells palsy irrespective of onset, at least within 7
days.
Clinicians should consider combination therapy with
inert steroid and antiviral of choice in individuals with
high-grade Bells palsy within 1 week of onset. In con-
clusion, steroid plus antiviral treatment is more effective
in treating severe to complete Bells palsy than steroid
treatment alone.
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341 Lee et al Steroid-Antiviral Treatment in Severe Bells Palsy