CLINICAL RESEARCH STUDY

Steroid-antiviral Treatment Improves the Recovery Ratein Patients with Severe Bell’s PalsyHo 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.

E-mail address

0002-9343/$ -see fhttp://dx.doi.org/10

ABSTRACT

BACKGROUND: The extent of facial nerve damage is expected to be more severe in higher grades of facialpalsy, and the outcome after applying different treatment methods may reveal obvious differences betweensevere Bell’s palsy and mild to moderate palsy. This study aimed to systematically evaluate the effects ofdifferent treatment methods and related prognostic factors in severe to complete Bell’s palsy.METHODS: This randomized, prospective study was performed in patients with severe to complete Bell’spalsy. Patients were assigned randomly to treatment with a steroid or a combination of a steroid and anantiviral agent. We collected data about recovery and other prognostic factors.RESULTS: The steroid treatment group (S group) comprised 107 patients, and the combination treatmentgroup (S�A group) comprised 99 patients. There were no significant intergroup differences in age, sex,accompanying disease, period from onset to treatment, or results of an electrophysiology test (P �.05).There was a significant difference in complete recovery between the 2 groups. The recovery (grades I andII) of the S group was 66.4% and that of the S�A group was 82.8% (P � .010). The S�A group showeda 2.6-times higher possibility of complete recovery than the S group, and patients with favorableelectromyography showed a 2.2-times higher possibility of complete recovery.CONCLUSIONS: Combined treatment with a steroid and an antiviral agent is more effective in treatingsevere to complete Bell’s palsy than steroid treatment alone.© 2013 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2013) 126, 336-341

KEYWORDS: Bell’s Palsy; Electromyography; Electroneurography; Prognosis

mt

Bell’s palsy is a common disease that occurs in 20-30people of every 100,000 and is the most common cranialneuropathy.1,2 The reactivation of herpes simplex virus isknown to be one of the causes of Bell’s palsy.3 For treat-ment of Bell’s palsy, the use of prednisolone is known toresult in high recovery rates and less synkinesis, and there isno doubt that steroid treatment may prevent further nervedamage and is beneficial in most cases.4

Although there is consensus that early use of pred-nisolone is an effective treatment, the use of antiviral agentshas led to some controversy. Researchers who are against

Funding: This research was supported by the Kyung Hee UniversityResearch Fund in 2011(KHU-2011-1098).

Conflict 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 HeeUniversity, #1 Hoegi-dong, Dongdaemun-gu, Seoul 130-702, Korea.

: yeo2park@gmail.com

ront matter © 2013 Elsevier Inc. All rights reserved..1016/j.amjmed.2012.08.020

the use of antiviral agents argue that there is no proof ofadditional benefit.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 Bell’s palsy show a

ore favorable result with steroid-famciclovir combinationherapy.8 These findings 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, andthat patients with paresis have an excellent prognosis, irre-spective of treatment methods.4

Following a literature review, we hypothesized that theadditional effect of antiviral agents would be different ac-cording to the severity of the palsy and that, in cases ofsevere to complete palsy, there would be a difference inrecovery according to treatment methods. Increasing age;onset of treatment; and results of electrophysiologic tests,such as electromyography (EMG) and electroneurography

(ENoG), also may influence the prognosis. Therefore, we

gosa

puat(tplw

so

337Lee et al Steroid-Antiviral Treatment in Severe Bell’s Palsy

conducted a prospective study to evaluate systematically theeffects of different treatment methods and related prognos-tic factors in severe Bell’s palsy.

METHODSBetween September 2008 and Au-gust 2011, we conducted a pro-spective, randomized study of pa-tients who visited our tertiarymedical center due to acute uni-lateral peripheral facial paralysiswithout skin lesions or intraorallesions occurring within 7 days ofpresentation. The House-Brack-mann grading system was usedto evaluate the severity of facialpalsy, and only patients with se-vere to complete Bell’s palsy(House-Brackmann grade �5)were enrolled.9

All patients were hospitalizedfor 1 week. Age, sex, durationfrom onset to treatment, previoushistory of facial palsy, and associ-ated symptoms (such as painaround the ear, taste disturbance,and hyperacusis) were documented.

Patients were randomized using simple randomizationcodes generated by Microsoft Excel 2007 (Microsoft Cor-poration, Redmond, Wash) to treatment with a steroid (Sgroup) or a steroid-antiviral combination (S�A group). Thedrug therapy protocol consisted of patients assigned tothe same group being treated on the same schedule. Both theresearchers and the enrolled patients were blinded to treat-ment assignment. Steroid treatment consisted of methyl-prednisolone for 10 days, 64 mg/d for the first 4 days,followed by tapering to 48 mg/d for 2 days, 32 mg/d for 2days, and 16 mg/d for 2 days. Antiviral therapy consisted oforal famciclovir (750 mg/d) for 7 days. Patients in the S�Aroup were administered steroid and famciclovir simultane-usly. An otolaryngologist who did not participate in thistudy was responsible for patient care during hospitalizationnd assessed outcomes after 6 months.

Bipolar needle EMG and ENoG were performed in allatients. ENoG was conducted during the hospitalizationsing bipolar cutaneous electrodes. A ground electrode wasttached to the arm and a recording electrode was placed inhe nasolabial fold. The compound muscle action potentialCMAP) was obtained from the nasalis muscle measured athe suprathreshold stimulation, and measurements were re-orted as the percent maximal amplitude on the side of theesion/maximal amplitude on the healthy side. Poor ENoGas defined 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-

CLINICAL SIGNIF

● Although thereuse of prednisoscription of ancontroversial.

● A combinationment was morealone in patienpalsy.

● Clinicians shoucombination theroid and an antiweek of the onspalsy.

pression were examined separately: the frontalis, orbicularis

oculi, major zygomatic, orbicularis oris, levator labii supe-rior, and depressor anguli oris. The presence or absence ofthe blink reflex was analyzed simultaneously and classifiedas favorable or unfavorable by the physical medicine andrehabilitation physician.

For follow-up, all patients wereinstructed to visit the hospital 6months after hospital discharge.Grades I and II at 6 months frompalsy onset were defined as com-plete recovery, and grade III orhigher was defined as incompleterecovery.

The criteria for exclusion were:

● Bell’s palsy that occurred morethan 7 days before presentation;

● Suspected Ramsay-Hunt syn-drome, meningitis, myelitis, orvasculopathy;

● 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-ity Hospital approved this study, and informed consent wasbtained from all patients.

RESULTSA total of 269 patients were enrolled in this study. Afterexcluding 32 patients who did not match the inclusioncriteria and 31 patients who did not complete this study dueto adverse effects of treatment and did not present forfollow-up, 206 patients completed the study (Figure 1).

The steroid treatment group (S group) comprised 107patients, and the combination treatment group (S�A group)comprised 99 patients. There was no significant differencein the distribution of facial grades between the 2 groups(P � .498).

There were no significant intergroup differences in age,sex, accompanying disease, period between onset and treat-ment, or results of electrophysiology tests (P �.05). Therewas no significant difference between the treatment meth-ods with regard to the final grade and its trend. However,there was a significant difference in complete recovery

CE

sensus that earlyis effective, pre-l agents remains

d/antiviral treat-tive than steroidith severe Bell’s

nsider initiatingwith an inert ste-f choice within 1high-grade Bell’s

ICAN

is conlonetivira

steroieffects w

ld corapyviral oet of

between the 2 groups. The recovery (grades I and II) of the

korsa

prSw

eac

ri

cbp

ew of

338 The American Journal of Medicine, Vol 126, No 4, April 2013

S�A group was 82.8% and that of the S group was 66.4%(P � .010) (Table 1).

Univariate analysis was performed using previouslynown prognostic factors in addition to the treatment meth-ds (Table 2). The prognostic factors predicting incompleteecovery were steroid treatment and unfavorable EMG re-ults, and the odds ratios for incomplete recovery were 2.0nd 1.6, respectively.

Multivariate analysis was performed on the identifiedrognostic factors (Table 3). The probability of completeecovery was 2.6 times higher in the S�A group than in thegroup, and the odds ratio for complete recovery in patientsith favorable EMG results was 2.2.

DISCUSSIONAdditional antiviral treatment in Bell’s palsy is based on thehypothesis that herpes simplex virus infection may causeinflammation 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-ver, antiviral agents cannot actually destroy virus that haslready replicated, because these drugs prevent viral repli-

Figure 1 Overvi

ation by interfering with viral DNA polymerase. In this

espect, Hato et al reported the importance of early admin-stration of the valacyclovir and prednisolone.7,10

The 3 commonly used antivirals are acyclovir, famciclo-vir, and valacyclovir. Although acyclovir is one of the mostcommonly used antiviral agents, it has some limitations.Patients must take acyclovir 5 times daily because it has avery low oral bioavailability (10%-20%), and correct ad-ministration is difficult to monitor because the drug is easilycompromised if taken with food.11,12 Famciclovir, a prodrugof 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-yclovir, a prodrug of acyclovir, is known to have greaterioavailability compared with acyclovir and yields similarlasma concentrations with only twice-daily dosing.13,14

In this study, we demonstrated that in severe to completepalsy, that is equal to or higher than grade 5, famciclovirtreatment plus steroid treatment significantly increased thechance of recovery. However, one important limitation ofthis study was the potential risk of imbalance by simplerandomization, the fact that no significant differences wereshown in age, sex, and other influencing factors between 2groups may imply that potential risks of bias were mini-

patient enrollment.

mally increased by using simple randomization.

or

wedpco

wBapc

339Lee et al Steroid-Antiviral Treatment in Severe Bell’s Palsy

Different researchers have reported different conclusionsabout whether combination treatment is effective in Bell’spalsy, and it is often difficult to come to a firm conclusion(Table 4, Figure 2).

One recent study reported that physicians discussed themerits, 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 keptwell hydrated. Side effects of antiviral agents occur in 10%to 20% of all cases, and the most common symptoms arenausea, vomiting, and headache. The combination therapy

Table 1 Patient Characteristics

Variable Steroid OnlyCombinationTherapy P Value

Total n (%) 107 (51.9) 99 (48.1)Age

Mean � SD 48.6 � 15.1 46.7 � 16.2 .381Range 16-77 16-76

Sex, n (%)Male 51 (47.7) 50 (50.5) .780Female 56 (52.3) 49 (49.5)

EMG, n (%)Favorable 85 (79.4) 75 (75.8) .616Unfavorable 22 (20.6) 24 (24.2)

ENoG, n (%)Poor 5 (4.7) 9 (9.1) .271Good 102 (95.3) 90 (90.9)

Onset of treatment, n (%)Within 3 days 84 (79.2) 67 (67.7) .0813-7 days 22 (20.8) 32 (32.3)

Final facial grade, n (%)Mean � SD 2.1 � 1.1 1.9 � 0.8 .216I 42 (39.3) 31 (31.3) .221II 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

ConditionOdds Ratios (95%Confidence Interval) P Value

Steroid only treatment 2.0 (1.2-3.3) .010Unfavorable EMG 1.6 (1.0-2.6) .048Poor ENoG 0.9 (0.4-2.1) .801Onset of treatment within3 days

0.9 (0.5-1.6) .728

Age �60 years 1.4 (0.8-2.4) .262

eEMG � electromyography; ENoG � electroneurography.

for Ramsay-Hunt syndrome is justified and essential giventhe possibility of a lifelong paralysis.19,20

This applies equally to Bell’s palsy as one of the otheracute peripheral facial palsies. The relatively low chance oflife-threatening major side effects makes combination treat-ment appropriate for severe Bell’s palsy, in which nervedamage is expected to be severe.

However, we do not endorse indiscriminate use of anti-viral agents. One previous study speculated that the initialgrade is not a significant predictor of prognosis,21 whereasthers reported that a higher initial House-Brackmann gradeeduces the probability of satisfactory recovery.22 Our find-

ings were consistent with those previously reported, andindicated that combination therapy was effective in patientswith severe to complete facial palsy. Further validation,however, is required in patients with mild to moderateBell’s palsy. Larger prospective clinical trials are requiredto validate our results, because it may have a ripple effect inclinical practice.

The detection of spontaneous fibrillation on needle EMGis known as a sign predicting unfavorable outcome.23,24 Anunfavorable EMG result was reported as one of the poorprognostic factors in recurrent facial palsy.25 Taken to-gether, EMG is a reliable diagnostic tool that physicians canuse to predict prognosis.

In addition, we found that age and onset of treatment didnot significantly influence recovery. There is controversyabout the effect of age on prognosis. Previously, age wasreported as a parameter that significantly influenced the finalrecovery.1 Others have assumed that increasing age reducesthe 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 significantly influ-ence the long-term prognosis of Bell’s palsy.22 Consistent

ith that study, a trend test showed no significant differ-nces between age and recovery.27 We assumed that theseifferent studies had different results because gerontologicalroblems might act as a confounding factor, and sophisti-ated history-taking and statistical analysis is required inrder to compensate.

In this study, we found that the onset of treatment alsoas a nonsignificant factor in the prognosis of Bell’s palsy.ased on treatment within 3 days, early treatment did notffect recovery significantly (Table 2). Although Hato et alrovided the theoretical background for the use of earlyombination treatment, they did not clearly show a differ-

Table 3 Results of Multiple Logistic Regression Analysis forComplete Recovery

VariableOdds Ratios (95%Confidence Interval) P Value

Favorable EMG 2.2 (1.1-4.5) .034Steroid-antiviral treatment 2.6 (1.3-5.1) .006

EMG � electromyography.

nce in effect according to the onset of treatment and

t of d

M

E

Y

H

340 The American Journal of Medicine, Vol 126, No 4, April 2013

only highlighted the merits of combination treatment.7 Infact, in their earlier study, they reported that all patientswho were treated with acyclovir and prednisolone within3 days of onset recovered completely; however, thatstudy had limited significance because it was a retrospec-tive study.28 Consistent with our study, others have as-sumed that the onset of treatment is not a significantprognostic factor.18

With 7 days classified as a delayed start of treatment,another report demonstrated that there was no statisticallysignificant difference in recovery.22 Therefore, physiciansshould take into consideration that delayed treatment doesnot always lead to poor recovery, and combination treat-ment increases the possibility of recovery in severe to com-plete Bell’s palsy irrespective of onset, at least within 7days.

Clinicians should consider combination therapy withinert steroid and antiviral of choice in individuals with

Figure 2 A Forest plo

Table 4 Summary of the Findings of Recent Studies in Which

AuthorsSteroid(Initial Dose)

Antiviral(Initial D

Axelsson et al, 201215 Prednisolone (60 mg/d) Valacyclo

innerop et al, 20088 Prednisolone (1 mg/kg/d) Famciclo

ngström et al, 200817 Prednisolone (60 mg/d) Valacyclo

eo et al, 200816 Prednisolone (1 mg/kg perday, maximally 80 mg/d)

Acyclovir

ato et al, 20077 Prednisolone (60 mg/d) Valacyclo

high-grade Bell’s palsy within 1 week of onset. In con-

clusion, steroid plus antiviral treatment is more effectivein treating severe to complete Bell’s palsy than steroidtreatment alone.

References1. Peitersen E. Bell’s palsy: the spontaneous course of 2,500 peripheral

facial nerve palsies of different etiologies. Acta Otolaryngol Suppl.2002:549:4-30.

2. Yanagihara N. Incidence of Bell’s palsy. Ann Otol Rhinol LaryngolSuppl. 1988;137:3-4.

3. Murakami S, Mizobuchi M, Nakashiro Y, et al. Bell palsy and herpessimplex virus: identification of viral DNA in endoneural fluid andmuscle. Ann Intern Med. 1996;124:27-30.

4. Linder TE, Abdelkafy W, Cavero-Vanek S. The management ofperipheral facial nerve palsy: “paresis” versus “paralysis” andsources of ambiguity in study designs. Otol Neurotol. 2010;31:319-327.

5. Sullivan FM, Swan IR, Donnan PT, et al. Early treatment with pred-nisolone or acyclovir in Bell’s palsy. N Engl J Med. 2007;357:1598-

ata from recent studies.

al Agents Were Used to Treat Bell’s Palsy

Summary of ResultsFollow-upPeriod

00 mg/d) Prednisolone enhanced the completerecovery rate. Valacyclovir had noadditional significant effect.

12 months

0 mg/d) Combination treatment should beconsidered for patients withsevere Bell’s palsy.

3 months

00 mg/d) Prednisolone hastened completerecovery. Valacyclovir wasineffective, and combined steroid/antiviral therapy was no betterthan the steroid alone.

12 months

mg/d) No benefit of acyclovir wasdefinitely established.

6 months

00 mg/d) Early combined use of valacyclovirand prednisone was effective,especially in those with severe tocomplete palsy.

6 months

Antivir

ose)

vir (10

vir (75

vir (10

(2400

vir (10

1607.

1

341Lee et al Steroid-Antiviral Treatment in Severe Bell’s Palsy

6. Lockhart P, Daly F, Pitkethly M, et al. Antiviral treatment for Bell’spalsy (idiopathic facial paralysis). Cochrane Database Syst Rev. 2009;7:CD001869.

7. Hato N, Yamada H, Kohno H, et al. Valacyclovir and prednisolonetreatment for Bell’s palsy: a multicenter, randomized, placebo-con-trolled study. Otol Neurotol. 2007;28:408-413.

8. Minnerop M, Herbst M, Fimmers R, et al. Bell’s palsy: combinedtreatment of famciclovir and prednisone is superior to prednisonealone. J Neurol. 2008;255:1726-1730.

9. House JW, Brackmann DE. Facial nerve grading system. OtolarynogolHead Neck Surg. 1985;93:146-147.

10. Wagstaff AJ, Faulds D, Goa KL. Aciclovir. A reappraisal of itsantiviral activity, pharmacokinetic properties and therapeutic efficacy.Drugs. 1994;47:153-205.

11. De Diego JI, Prim MP, De Sarriá MJ, et al. Idiopathic facial paralysis:a randomized, prospective, and controlled study using single-doseprednisone versus acyclovir three times daily. Laryngoscope. 1998;108:573-575.

12. De Miranda P, Blum MR. Pharmacokinetics of acyclovir after intra-venous and oral administration. J Antimicrob Chemother. 1983;12:29-37.

13. Kawaguchi K, Inamura H, Abe Y, et al. Reactivation of herpes simplexvirus type 1 and varicella-zoster virus and therapeutic effects of com-bination therapy with prednisolone and valacyclovir in patients withBell’s palsy. Laryngoscope. 2007;117:147-156.

14. Axelsson S, Lindberg S, Stjernquist-Desatnik A. Outcome of treatmentwith valacyclovir and prednisone in patients with Bell’s palsy. AnnOtol Rhinol Laryngol. 2003;112:197-201.

15. Axelsson S, Berg T, Jonsson L, Engström M, Kanerva M, Stjernquist-Desatnik A. Bell’s palsy—the effect of prednisolone and/or valaciclo-vir versus placebo in relation to baseline severity in a randomisedcontrolled trial. Clin Otolaryngol. 2012;37(4):283-290.

6. Yeo SG, Lee YC, Park DC, et al. Acyclovir plus steroid vs steroidalone in the treatment of Bell’s palsy. Am J Otolaryngol. 2008;29:163-

166.

17. Engström M, Berg T, Stjernquist-Desatnik A, et al. Prednisolone andvalaciclovir in Bell’s palsy: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet Neurol. 2008;7:993-1000.

18. Van der Veen EL, Rovers MM, de Ru JA, et al. A small effect ofadding antiviral agents in treating patients with severe Bell palsy.Otolaryngol Head Neck Surg. 2012;146:353-357.

19. Uscategui T, Dorée C, Chamberlain IJ, et al. Antiviral therapy forRamsay Hunt syndrome (herpes zoster oticus with facial palsy) inadults. Cochrane Database Syst Rev. 2008;8(4):CD006851.

20. de Ru JA, van Benthem PP. Combination therapy is preferable forpatients with Ramsay Hunt syndrome. Otol Neurotol. 2011;32:852-855.

21. Takemoto N, Horii A, Sakata Y, et al. Prognostic factors of peripheralfacial palsy: multivariate analysis followed by receiver operating char-acteristic and Kaplan-Meier analyses. Otol Neurotol. 2011;32:1031-1036.

22. Mantsopoulos K, Psillas G, Psychogios G, et al. Predicting the long-term outcome after idiopathic facial nerve paralysis. Otol Neurotol.2011;32:848-851.

23. Sittel C, Stennert E. Prognostic value of electromyography in acuteperipheral facial nerve palsy. Otol Neurotol. 2001;22:100-104.

24. Grosheva M, Wittekindt C, Guntinas-Lichius O. Prognostic value ofelectroneurography and electromyography in facial palsy. Laryngo-scope. 2008;118:394-397.

25. Chung DH, Park DC, Byun JY, et al. Prognosis of patients withrecurrent facial palsy. Eur Arch Otorhinolaryngol. 2012;269:61-66.

26. Danielidis V, Skevas A, Van Cauwenberge P, et al. A comparativestudy of age and degree of facial nerve recovery in patients with Bell’spalsy. Eur Arch Otorhinolaryngol. 1999;256:520-522.

27. Yeo SW, Lee DH, Jun BC, et al. Analysis of prognostic factors inBell’s palsy and Ramsay Hunt syndrome. Auris Nasus Larynx. 2007;34:159-164.

28. Hato N, Matsumoto S, Kisaki H, et al. Efficacy of early treatment ofBell’s palsy with oral acyclovir and prednisolone. Otol Neurotol.

2003;24:948-951.