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DOI 10.3233/RNN-150605
IOS Press
Abstract.
Background: A large number of patients with Bell’s palsy fail to recover facial function completely after steroid therapy.
Only a few small trials have been conducted to test whether outcomes can be improved by the addition of antiviral therapy.
Objective: To evaluate the efficacy of treatment with steroid alone versus steroid + antiviral in a group of patients with
moderately severe to severe acute Bell’s palsy.
Methods: Fifty eligible patients out of a total of 65 with acute onset Bell’s palsy were randomized to receive the two
treatments. Evaluation was performed before starting treatment, after 2 weeks of treatment and 3 months after onset, using
the House and Brackmann facial nerve grading system (HB) and the Sunnybrook grading system.
This study was registered with ClinicalTrials.gov, number NCT02328079.
Results: Both treatments had comparable demographics and clinical scores at baseline. There was greater improvement in
the mean HB and Sunnybrook scores of the steroid + antiviral group in comparison to steroid group at 3 months. At the end
of the 3rd month, 17 patients (68%) had good recovery and 8 patients (32%) had poor recovery in the steroid group compared
with 23 patients (92%) and 2 (8%) respectively in the steroid and antiviral group (p = 0.034).
Conclusion: The combination of steroid and antiviral treatment increases the possibility of recovery in moderately severe to
complete acute Bell’s palsy.
0922-6028/16/$35.00 © 2016 – IOS Press and the authors. All rights reserved
898 E.M. Khedr et al. / Steroid/Antiviral treatment for Bell’s palsy
palsy, but not in controls (Murakami et al., 1996). In In this study we address the question: is treat-
another study herpes simplex virus DNA was found in ment with steroids + antiviral drugs (acyclovir)
the endoneurial fluid of 11 of 14 patients with Bell’s superior to steroids alone for functional recovery of
palsy, but not in patients with Ramsay Hunt syndrome facial nerve in patients with severe new-onset Bell’s
or in controls with facial palsy due to fractures of the palsy? Recovery was quantified using the House &
temporal bone, bacterial infection, parotid tumours, Brackmann facial nerve grading system (HB) for pri-
or neuroma (Minnerop et al., 2008). These findings mary outcome and Sunnybrook grading system score
led to the idea that Bell’s palsy was due to reactiva- changes for secondary outcome.
tion of latent herpes viral infections in the geniculate
ganglia followed by spread to the facial nerve. In
the light of this finding, many physicians prescribed 2. Materials and methods
both antiviral drugs and steroids to treat Bell’s palsy,
despite the unclear added benefit of antiviral therapy. 2.1. This trial followed 2010 CONSORT
In 2001, the Quality Standards Subcommittee of guidelines
the American Academy of Neurology (AAN) pub-
lished an evidence-based practice guideline for the The study was conducted at the Neuropsychi-
treatment of Bell palsy (Grogan & Gronseth, 2001). atry department, Assiut University Hospital from
The 2001 guideline concluded that steroids were first of April 2014 to the end December 2014. All
probably effective and that antivirals (acyclovir) were patients aged between 20–60 years who were diag-
possibly effective in increasing the probability of nosed with acute onset facial palsy (unilateral) and
complete facial functional recovery in patients with within the first three days of onset were included.
Bell’s palsy. The status of antiviral therapy is still Diagnosis was based on impaired ipsilateral move-
unclear. Although some systematic reviews (Allen ment of the affected side of the face, drooping of
& Dunn, 2009; Quant et al., 2009; Turgeon et al., the eyebrow and corner of the mouth, loss of the
2015) found no clear evidence for the superiority of ipsilateral nasolabial fold as well as Bell’s phe-
combined steroids plus antiviral drugs compared to nomenon (upward movement of the eye on attempted
steroids alone, other research groups (Hato et al., closure of the lid due to weakness of the orbicu-
2007 & 2008; Minnerop et al., 2008; Shahidullah laris oculi). Computerized brain scan (CT brain) was
et al., 2011; Numthavaj et al., 2011; Lee et al., 2013) performed for each patient to exclude other causes
as well as Dong et al. (2015) in their systematic review of facial paralysis (brain infarction, hemorrhage,
found that combined use had a significantly better multiple sclerosis, tumor, and infection). Otologi-
outcome than steroids alone, especially in severely cal examination was performed to exclude cases
affected patients. The American Academy recom- with otitis media. Metabolic profiling was performed
mended in 2012 that large randomized trials should if needed, to exclude renal or liver impairment.
be conducted comparing outcomes in patients with Exclusion criteria were: patients with brittle diabetes
Bell’s palsy receiving steroids with or without antivi- mellitus, morbid obesity, renal or liver impairment,
rals to determine whether the addition of antivirals to osteopenia, pregnancy or breast-feeding; uncon-
steroid treatment results in a modest benefit (Gron- trolled hypertension and a prior history of steroid
seth & Paduga, 2012). intolerance. A participants’ flow diagram is shown in
Previous electrophysiological investigations point Fig. 1.
to a special prognostic value of the amplitude of Sixty five patients with acute facial palsy were
muscle evoked potential (MEP) in Bell’s palsy. The recruited; 15 cases were excluded (8 had only mild
MEP amplitude depends on the number of respond- to moderate facial paralysis, three had severe uncon-
ing peripheral motor axons and it will be reduced trolled diabetes mellitus, another two were pregnant
following degeneration of nerve fibers (May et al., and last two cases had morbid obesity). The remain-
1983, Fish, 1997, Danielides et al., 1994). Fish (1997) ing 50 cases were eligible for the study. The mean
suggested that a decrease in MEP amplitude of more age of the patients was 27.2 ± 4.5 years ranging from
than 90%, compared to the healthy side, is a bad prog- 20–36 years (35 males and 15 females). They had
nostic sign. In contrast to the MEP amplitude, MEP moderately severe (grade IV) to complete Bell’s palsy
latency reflects in the function of the fastest axons, (grade VI) according to the criteria of the House &
so it can remain within a normal range for a long Brackmann facial nerve grading system (HB) (House
time. & Brackmann, 1985). All participants gave informed
E.M. Khedr et al. / Steroid/Antiviral treatment for Bell’s palsy 899
3.2. Randomization
3.3. Treatment
Table 1
Clinical and demographic data of studied groups
Steroid medication group N = 25 Steroid and Antiviral group N = 25
Age (years) 37.4 ± 13.4 36.2 ± 14
Onset of treatment (days) 1.84 ± 0.7 1.76 ± 0.9
House & Brackmann facial nerve grading system 4.8 ± 0.6 5 ± 0.8
Sunnybrook Facial Grading System
Resting Symmetry 17.6 ± 2.6 18.4 ± 2.4
Symmetry of Voluntary Movement 40.5 ± 5.3 39.5 ± 3.9
Synkinesis score 5.6 ± 3.9 4.3 ± 3.7
Composite score 17.2 ± 4.4 17.1 ± 5.1
Neurophysiological findings
Amplitude of CMAP of Facial nerve (mV)
Affected frontalis/Non affected frontalis (ratio %) 1.5 ± 0.9/2.2 ± 1.1* (61) 1.2 ± 1.1/2.6 ± 1.7* (47)
Amplitude of CMAP of Facial nerve (mV)
Affected orbicularis oris/Non affected orbicularis oris (ratio%) 3.1 ± 1.6/3.6 + 2.3* (54) 2.9 ± 3.4/3.6 + 2.3* (53)
P < 0.05 comparison between affected and unaffected side in each group separately.
3rd month using HB facial function scoring system + antiviral) and “time” (before, following 2 weeks
and Sunnybrook grading system. Primary outcome: treatment, and at 2 and 3 months after onset) as
change in HB assessment score 3 months after palsy the main factors was used to compare the differen-
onset. Grades I and II of HB were defined as com- tial effects of the treatments on changes in rating
plete or good recovery, and grade III or higher were scores. When necessary, a Greenhouse–Geisser cor-
defined as poor or incomplete recovery. Secondary rection was applied to correct for non-sphericity.
outcome was measured using changes in scores of T-tests were carried out for comparisons at each time
the Sunnybrook grading system. In the protocol we point of assessment, and P-values in the text are
had intended to use electrophysiology measures as Bonferroni-corrected for the number of comparisons.
another secondary outcome. However, since most of Non parametric Spearman correlation was performed
the patients found this too painful to be performed between Score Sunnybrook score or grading of HB
at the follow up, it was performed at baseline only and the CMAP amplitude ratio (affected /Unaffected
and we tested whether it was a possible predictor of side) of frontalis and orbicularis oris.
recovery.
Table 2
Changes in Sunnybrook Facial Grading System among studied groups along the course of illness
Groups Baseline 2weeks 2 months 3 months One way ANOVA Two way ANOVA
Mean ± SD Mean ± SD Mean ± SD Mean ± SD Repeated Repeated
measure analysis measure analysis
(effect of time) Time × group
Changes of Resting Symmetry(Sunnybrook Facial Grading System)
Steroid group 17.6 ± 2.6 15.8 ± 1.9 14.8 ± 1.0 13.2 ± 2.5 Df = 2.7, f = 26.9, P = 0.0001 F = 16.6, Df = 2.5,
Steroid + Antiviral group 18.4 ± 2.4 15 ± 0.02 14 ± 2.0 8.6 ± 0.4.2∗∗ Df = 1.9, f = 79.3, P = 0.001 P = 0.001
Changes of Symmetry of Voluntary Movement(Sunnybrook Facial Grading System)
Steroid group 40.5 ± 5.5 44.8 ± 5.5 53.9 ± 7 62.2 ± 7.1 Df = 2.3, f = 92.5, P = 0.0001 F = 15.2, Df = 2.4,
Steroid + Antiviral group 39.5 ± 3.9 48.0.±6.0 60.9 ± 7.4∗∗ 75.7 ± 11.1∗∗∗ Df = 1.8, f = 172, P = 0.001 P = 0.001
Changes of Synkinesis score (Sunnybrook Facial Grading System)
Steroid group 2.4 ± 1.9 5.2 ± 1.8 3.4 ± 1.2 2.6 ± 2.3 Df = 2.2, f = 14.6, P = 0.0001 F = 0.560, Df = 2.6
Steroid + Antiviral group 1.8 ± 1.7 5.1 ± 2.0 2.9 ± 1.6 1.7 ± 2 Df = 2.8, f = 23.6, P = 0.001 P = 0.619
Changes of Composite score(Sunnybrook Facial Grading System)
Steroid group 17.6 ± 4.9 20.85 ± 5.0 32.3 ± 8.1 45.8 ± 7.7 Df = 1.9, f = 175.2, P = 0.0001 F = 20.5 df = 2.207
Steroid + Antiviral group 17.9 ± 4.8 24.8 ± 7.1∗ 41.8 ± 9.8∗∗ 65.2 ± 15.5∗∗ Df = 1.9, f = 173, P = 0.001 P = 0.001
NB: The difference between groups at each time of assessment ∗ p<0.01, ∗∗ p<0.001.
Fig. 3. A, B, C, and D: Shows changes in the mean score of each item of Sunnybrook scale; (A): resting symmetry, (B): symmetry of
voluntary movement score, (C): Changes of synkinesis score, (D): Composite score in patients with Bell’s palsy in the studied groups at
different points of assessment ((before treatment, 2 weeks after treatment, and then at the end of 2nd and 3rd month of onset). There was
significant effect of time for each group separately for each item of scale along the course of follow up (P = 0.0001 for each), however to
way ANOVA (time × groups interaction) show that the improvement are significantly higher in steroid + antiviral group than steroid group
in resting symmetry, symmetry of voluntary movement, and composite scores (P = 0.0001 for each). The significant between groups at each
time of assessment are demonstrated in the figure with * for p < 0.05; ** for p < 0.01 and *** for p < 0.001.
Table 3
Correlation between amplitude ratio of affected/ non affected CMAP and rating scores (House & Brackmann and Sunnybrook score) at 4th
assessment point
Variable CMAP amplitude ratio of frontalis
Steroid group Antiviral group Total cases
HB of facial grading system R = –0.372 R = 0.092 R = –0.56
P = 0.067 P = 0.663 P = 0.697
Composite score of Sunnybrook score R = –0.126 R = –0.185 R = –0.149
P = 0.549 P = 0.376 P = 0.301
CMAP amplitude ratio of orbicularis oris
HB of facial grading system R = –0.132 r = 0.200 R = –0.013
P = 0.528 p = 0.338 P = 0.928
Composite score of Sunnybrook score R = 0.301 R = –0.063 R = 0.154
P = 0.057 P = 0.763 P = 0.285
HB; House & Brackmann.
ery. Many systematic reviews (Allen et al., 2009; participants did not know who was getting the antivi-
Quant et al., 2009; Turgeon et al., 2015) also found ral and who was not. In this selected group the data
no clear evidence for the superiority of combining suggests quite strongly that treatment with antiviral +
steroids with antiviral drugs compared to steroids steroid improves final outcome and shortens the time
alone. However many of these studies examined to achieve it. Two months after treatment, 17 (68%)
patients with paralysis ranging from mild to severe of 25 patients treated with steroid alone had good
so that any improvements in particular subsets of recovery and 8 patients (32%) had poor recovery.
patients might not have been apparent (Linder et al., In contrast, of the 25 patients treated with com-
2010). bined steroid + antiviral therapy, 23 patients (92%)
The present study was a randomized, double-blind, had good recovery whereas only 2 (8%) had poor
controlled trial in patients with moderate to severe recovery.
forms of acute Bell’s palsy. The results differ from
the studies above in that we found a positive addi-
tional effect of combined treatment. Our hypothesis 6. Conclusion
is that the difference is due to the higher initial levels
of severity in our group. In fact, our findings are Although treatment with prednisolone is likely to
consistent with those previously reported by Hato et be cost-effective, the combined treatment increases
al. (2007) who also found that patients with severe the possibility of recovery in moderately severe to
Bell’s palsy had a more favorable result with steroid- complete Bell’s palsy. Therefore, the use of antivirals
Valacyclovircombination therapy than steroid should be considered in this category of patients.
alone.
Data on the predictive value of electrophysiolog- 6.1. Limitation of the study
ical tests are conflicting, mainly due to selection
biases: etiology and degree of palsy; tests involved; The small sample size and short term follow up are
and initial timing for evaluation, prognostic follow- important limitations. Further validation is required
up time, and small sample size. In the present study in a large prospective clinical trial for patients with
there was no evidence that CMAP amplitude ratio of different degrees of Bell’s palsy in order to find the
affected /unaffected sides at base line predicted the optimal dose and timing of steroids and antiviral.
clinical rating score at the end of the study. How- More laboratory investigations to check for evidence
ever, this null conclusion may be related to the small of zoster reactivation are also needed. Other ther-
sample size and the early time point at which elec- apeutic options have still to be explored such as
trophysiology was assessed (within the first 3 days of enhancing motor cortical excitability of facial mus-
onset). cles through non-pharmacological means such as
It should be noted that although this was not repetitive transcranial magnetic stimulation of the
placebo-controlled trial, since it was an add-on design brain or peripheral magnetic stimulation of facial
to test the effect of administering an antiviral drug, nerves (Khedr et al., 2014; 2011; 2012).
904 E.M. Khedr et al. / Steroid/Antiviral treatment for Bell’s palsy
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