Steroid-antiviral Treatment Improves the Recovery Rate in Patients with Severe Bell s Palsy

CLINICAL RESEARCH STUDY Steroid-antiviral Treatment Improves the Recovery Rate in Patients with Severe Bell s 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 Bell s 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 Bell s palsy. METHODS: This randomized, prospective study was performed in patients with severe to complete Bell s 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 (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 and II) of the S group was 66.4% and that of the S A group was 82.8% (P.010). The S A 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 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 Bell s 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 Bell s palsy. 3 For treatment of Bell s 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 beneficial in most cases. 4 Although there is consensus that early use of prednisolone is an effective treatment, the use of antiviral agents has led to some controversy. Researchers who are against Funding: This research was supported by the Kyung Hee University Research 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 Hee University, #1 Hoegi-dong, Dongdaemun-gu, Seoul 130-702, Korea. E-mail address: yeo2park@gmail.com the use of antiviral agents argue that there is no proof of additional benefit. 5,6 However, additional use of valacyclovir has been shown to be more effective than steroid treatment alone, 7 and patients with severe Bell s palsy show a more favorable result with steroid-famciclovir combination therapy. 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, and that patients with paresis have an excellent prognosis, irrespective of treatment methods. 4 Following a literature review, we hypothesized that the additional effect of antiviral agents would be different according 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 influence the prognosis. Therefore, we 0002-9343/$ -see front matter 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2012.08.020

Lee et al Steroid-Antiviral Treatment in Severe Bell s Palsy 337 conducted a prospective study to evaluate systematically the effects of different treatment methods and related prognostic factors in severe Bell s palsy. METHODS Between September 2008 and August 2011, we conducted a prospective, randomized study of patients who visited our tertiary medical center due to acute unilateral peripheral facial paralysis without skin lesions or intraoral lesions occurring within 7 days of presentation. The House-Brackmann grading system was used to evaluate the severity of facial palsy, and only patients with severe to complete Bell s 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 associated symptoms (such as pain around the ear, taste disturbance, and hyperacusis) were documented. CLINICAL SIGNIFICANCE Patients were randomized using simple randomization codes generated by Microsoft Excel 2007 (Microsoft Corporation, Redmond, Wash) to treatment with a steroid (S group) or a steroid-antiviral combination (S A 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 treatment assignment. Steroid treatment consisted of methylprednisolone 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 2 days, and 16 mg/d for 2 days. Antiviral therapy consisted of oral famciclovir (750 mg/d) for 7 days. Patients in the S A group were administered steroid and famciclovir simultaneously. 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 reported as the percent maximal amplitude on the side of the lesion/maximal amplitude on the healthy side. Poor ENoG was 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 expression were examined separately: the frontalis, orbicularis Although there is consensus that early use of prednisolone is effective, prescription of antiviral agents remains controversial. A combination steroid/antiviral treatment was more effective than steroid alone in patients with severe Bell s palsy. Clinicians should consider initiating combination therapy with an inert steroid and an antiviral of choice within 1 week of the onset of high-grade Bell s palsy. oculi, major zygomatic, orbicularis oris, levator labii superior, and depressor anguli oris. The presence or absence of the blink reflex was analyzed simultaneously and classified 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 defined as complete recovery, and grade III or higher was defined as incomplete recovery. The criteria for exclusion were: Bell s palsy that occurred more than 7 days before presentation; Suspected Ramsay-Hunt syndrome, meningitis, myelitis, or vasculopathy; Patients who could not be observed for at least 6 months; The initial use of several different types of treatments; Age 16 years; Pregnancy or breast-feeding; Uncontrolled diabetes or hypertension; Poor general medical conditions in which steroid or antiviral 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 University 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 (S A group) comprised 99 patients. There was no significant difference in 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 treatment, or results of electrophysiology tests (P.05). There was no significant difference between the treatment methods with regard to the final grade and its trend. However, there was a significant difference in complete recovery between the 2 groups. The recovery (grades I and II) of the

338 The American Journal of Medicine, Vol 126, No 4, April 2013 Figure 1 Overview of patient enrollment. S A 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 methods (Table 2). The prognostic factors predicting incomplete recovery were steroid treatment and unfavorable EMG results, and the odds ratios for incomplete recovery were 2.0 and 1.6, respectively. Multivariate analysis was performed on the identified prognostic factors (Table 3). The probability of complete recovery was 2.6 times higher in the S A 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 Bell s palsy is based on the hypothesis that herpes simplex virus infection may cause inflammation of the facial nerve. Theoretically, the infectious agents are eradicated by antiviral treatment, and swelling of the facial nerve is reduced by corticosteroids. 6 However, antiviral agents cannot actually destroy virus that has already replicated, because these drugs prevent viral replication by interfering with viral DNA polymerase. In this respect, Hato et al reported the importance of early administration of the valacyclovir and prednisolone. 7,10 The 3 commonly used antivirals are acyclovir, famciclovir, 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 administration is difficult 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 bioavailability (60%-75%) and longer intracellular half-life than acyclovir and is not affected by concurrent food intake. 8 Valacyclovir, 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 significantly 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 significant differences were shown in age, sex, and other influencing factors between 2 groups may imply that potential risks of bias were minimally increased by using simple randomization.

Lee et al Steroid-Antiviral Treatment in Severe Bell s Palsy 339 Table 1 Variable Patient Characteristics 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. Different researchers have reported different conclusions about whether combination treatment is effective in Bell s palsy, and it is often difficult to come to a firm conclusion (Table 4, Figure 2). One recent study reported that physicians discussed the merits, drawbacks, and the cost of additional antiviral treatment with patients, and after this information was provided, patients chose the combination therapy. 18 Oral antivirals are known to be well tolerated if administered 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 Table 2 Condition Univariate Analysis for Incomplete Recovery Odds Ratios (95% Confidence 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 0.9 (0.5-1.6).728 3 days 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% Confidence Interval) P Value Favorable EMG 2.2 (1.1-4.5).034 Steroid-antiviral treatment 2.6 (1.3-5.1).006 EMG electromyography. for Ramsay-Hunt syndrome is justified and essential given the possibility of a lifelong paralysis. 19,20 This applies equally to Bell s palsy as one of the other acute peripheral facial palsies. The relatively low chance of life-threatening major side effects makes combination treatment appropriate for severe Bell s palsy, in which nerve damage is expected to be severe. However, we do not endorse indiscriminate use of antiviral agents. One previous study speculated that the initial grade is not a significant predictor of prognosis, 21 whereas others reported that a higher initial House-Brackmann grade reduces the probability of satisfactory recovery. 22 Our findings 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 Bell s 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 fibrillation 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 together, 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 significantly influence recovery. There is controversy about the effect of age on prognosis. Previously, age was reported as a parameter that significantly influenced the final recovery. 1 Others have assumed that increasing age reduces the probability of a satisfactory recovery because of peripheral vascular degeneration. 26 In contrast, another study reported that age above 50 years did not significantly influence the long-term prognosis of Bell s palsy. 22 Consistent with that study, a trend test showed no significant differences between age and recovery. 27 We assumed that these different studies had different results because gerontological problems might act as a confounding factor, and sophisticated history-taking and statistical analysis is required in order to compensate. In this study, we found that the onset of treatment also was a nonsignificant factor in the prognosis of Bell s palsy. Based on treatment within 3 days, early treatment did not affect recovery significantly (Table 2). Although Hato et al provided the theoretical background for the use of early combination treatment, they did not clearly show a difference in effect according to the onset of treatment and

340 The American Journal of Medicine, Vol 126, No 4, April 2013 Table 4 Summary of the Findings of Recent Studies in Which Antiviral Agents Were Used to Treat Bell s Palsy Authors Steroid (Initial Dose) Antiviral (Initial Dose) Summary of Results Axelsson et al, 2012 15 Prednisolone (60 mg/d) Valacyclovir (1000 mg/d) Prednisolone enhanced the complete recovery rate. Valacyclovir had no additional significant effect. Minnerop et al, 2008 8 Prednisolone (1 mg/kg/d) Famciclovir (750 mg/d) Combination treatment should be considered for patients with severe Bell s palsy. Engström et al, 2008 17 Prednisolone (60 mg/d) Valacyclovir (1000 mg/d) Prednisolone hastened complete recovery. Valacyclovir was ineffective, and combined steroid/ antiviral therapy was no better than the steroid alone. Yeo et al, 2008 16 Prednisolone (1 mg/kg per Acyclovir (2400 mg/d) No benefit of acyclovir was day, maximally 80 mg/d) definitely established. Hato et al, 2007 7 Prednisolone (60 mg/d) Valacyclovir (1000 mg/d) Early combined use of valacyclovir and prednisone was effective, especially in those with severe to complete palsy. Follow-up Period 12 months 3 months 12 months 6 months 6 months Figure 2 A Forest plot of data from recent studies. 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 significance because it was a retrospective study. 28 Consistent with our study, others have assumed that the onset of treatment is not a significant prognostic factor. 18 With 7 days classified as a delayed start of treatment, another report demonstrated that there was no statistically significant difference in recovery. 22 Therefore, physicians should take into consideration that delayed treatment does not always lead to poor recovery, and combination treatment increases the possibility of recovery in severe to complete Bell s 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 Bell s palsy within 1 week of onset. In conclusion, steroid plus antiviral treatment is more effective in treating severe to complete Bell s palsy than steroid treatment alone. References 1. 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 Laryngol Suppl. 1988;137:3-4. 3. Murakami S, Mizobuchi M, Nakashiro Y, et al. Bell palsy and herpes simplex virus: identification of viral DNA in endoneural fluid and muscle. Ann Intern Med. 1996;124:27-30. 4. Linder TE, Abdelkafy W, Cavero-Vanek S. The management of peripheral facial nerve palsy: paresis versus paralysis and sources of ambiguity in study designs. Otol Neurotol. 2010;31:319-327. 5. Sullivan FM, Swan IR, Donnan PT, et al. Early treatment with prednisolone or acyclovir in Bell s palsy. N Engl J Med. 2007;357:1598-1607.

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