J Neurol (2008) 255:17261730 DOI 10.

1007/s00415-008-0008-6

ORIGINAL COMMUNICATION

Martina Minnerop Martin Herbst Rolf Fimmers Bertfried Matz Thomas Klockgether Ullrich Wllner

Bells palsy
Combined treatment of famciclovir and prednisone is superior to prednisone alone

Received: 18 December 2007 Received in revised form: 29 March 2008 Accepted: 15 April 2008 Published online: 3 September 2008

R. Fimmers, PhD Institute of Medical Biometry, Informatics, and Epidemiology University of Bonn Sigmund-Freud-Str. 25 53105 Bonn, Germany B. Matz, MD Institute of Virology University of Bonn Sigmund-Freud-Str. 25 53105 Bonn, Germany

M. Minnerop, MD ( ) T. Klockgether, MD U. Wllner, MD Dept. of Neurology University Hospital of Bonn Sigmund-Freud-Str. 25 53105 Bonn, Germany Tel.: +49-228/287-16130 Fax.:+49-228/287-11511 E-Mail: m.minnerop@uni-bonn.de M. Minnerop, MD Brain Imaging Center West (BICW) Leo-Brandt-Str. 1 52425 Jlich, Germany M. Herbst, MD Max-Delbrck-Center for Molecular Medicine Robert-Rssle-Str. 10 13092 Berlin, Germany

Abstract There is insufficient evidence concerning the efficacy of antiviral treatment of Bells palsy (BP). We therefore compared the efficacy of prednisone and famciclovir to prednisone treatment alone in BP. A total of 167 consecutive patients with untreated acute BP were included. Severity of BP was evaluated using the HouseBrackmann scale (HBS) and virus antibody tests (herpes simplex virus, varicella zoster virus) were performed. Patients admitted on even dates were treated with prednisone (P group) and patients admitted on odd dates were treated

with prednisone and famciclovir (P+F group). 117 patients completed the follow-up after 3 months or later (67 P/51 P+F). While most patients showed at least partial recovery with both treatment types, improvement of at least 4 grades in the HBS was more common in the P+F group (29.4 % vs. 11.9 %), whereas smaller changes of less than 3 grades were more common in the P group (29.9 % vs. 17.6 %; Chi-square test, p = 0.02). Patients with complete BP (HBS grade of 5 or 6) had significantly better chances of reaching normal function if treated with famciclovir additionally instead with prednisone alone (73.7 % vs. 47.1 %; Cochran-Armitage trend test, p = 0.03). These results suggest that the combined treatment of famciclovir and prednisolone should be considered (at least) in patients with severe BP. Key words Bells palsy prednisone famciclovir antiviral therapy

Introduction
Bells palsy (BP) is the most common cranial nerve lesion, occurring with an annual incidence of 20:100 000 [4]. Although the majority of patients recover, up to 16 % of patients retain persistent sequelae [15]. The cause of

BP is presently unknown. Some studies point to herpes family viruses as causative agents: the HSV-1 genome was found in the geniculate ganglion post mortem in humans and in endoneural fluid from the facial nerve in patients with Bells palsy [14, 20]. These results support the earlier proposed hypothesis of an HSV-1 reactivation within the geniculate ganglion with subsequent in-

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flammation and entrapment of the nerve at the meatal foramen or in the labyrinthine segment as pathogenic mechanism of BP [13]. The antiviral drug aciclovir or its analogue, valaciclovir, has been applied in various trials with inconsistent results and a Cochrane review in 2004 concluded that treatment efficiency could not be assessed with the present data [2]. Interestingly, the same holds true for the use of steroids although most national and international guidelines recommend steroids for management of BP [9, 17]. Famciclovir, the most recent aciclovir analogue, offers important advantages in virostatic therapy with excellent oral bioavailability and longer intracellular half-life of its active metabolite than aciclovir in VZVinfected cells. [16, 18]. Therefore, we performed a controlled and prospective trial comparing the therapeutic effect of prednisone and famciclovir versus prednisone alone in BP. A placebo group was not included in our study as placebo treatment of BP would not comply with current guidelines. Clinical outcome and virus antibody titer were compared between both study arms.

Results
A total of 167 patients with BP were included and allocated to treatment according to the day of admission (95 P/72 P+F). Forty-eight patients (30 %), 28 of the P group (29.5 %, initial HBS 3.8 1.1) and 20 of the P+Fgroup (27.9 %, initial HBS 3.8 1.0), were lost to followup. Two of them (P+F) discontinued the study because of adverse effects. A final outcome was available in 117 patients, 67 belonging to P group and 50 to P+F group. There were no statistical differences between groups regarding age, sex or affected side (see Table 1 for patient characteristics). The initial severity of facial palsy (HBS grading) was moderate to severe and did not differ between groups. However, a tendency towards more severe involvement in the P+F group was detected (trend test, p = 0.12). Possible risk factors for an unfavorable outcome (diabetes mellitus, arterial hypertension, initial taste disturbance or post-auricular pain) did neither correlate with the initial HBS nor differed significantly between both groups. Initial HBS at first visit did not correlate with age (Spearman correlation, p = 1.00). Elderly patients (> 60 years) were equally distributed between both treatment groups and did not have more severe palsies than younger patients. No seasonal variation of BP during the year was observed. Half of the patients (53 %) attended the scheduled follow-up appointment; the remaining were seen within 12 months after onset of BP. The interval between follow-up visits did not differ between the two treatment groups (Table 2, chi-square test: p = 0.81). At follow-up, 91 % patients in the P group and 96 % in the P+F-group had at least some improvement of voluntary movement. An improvement of at least 4 grades at the HBS was more common in P+F group (28.0 %) than in P group (12 %), whereas no or only minor improvements in the HBS were more common in
Table 1 Baseline characteristics of patients P group N Age (years; mean SD) Older patients (> 60 years) Sex (m/f) Affected face side (right/left) Diabetes mellitus (non-insulin dependent) Arterial hypertension Taste disturbance Post-auricular pain Initial HBS (mean SD) Time between onset of symptoms and start of treatment (days; mean SD) 67 40.6 20.5 14 34/33 38/29 3 9 19 16 3.9 1.0 2.4 1.9 P + F group 50 42.6 30.9 13 26/24 25/25 1 9 19 11 4.1 1.0 2.6 1.9

Patients and methods

Consecutive adult patients (age > 18 years) with an untreated acute facial palsy (onset < 5 days), admitted to our hospital between January 2001 and June 2005, underwent complete neurological and otological examination. Laboratory testing including cerebrospinal fluid (CSF) and serum examination were performed. CSF and serum samples were analyzed for antibodies (abs) against Borrelia burgdorferi and various viruses, e.g., herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus, Epstein-Barr virus, tick-borne encephalitis, measles, mumps, rubella and enterovirus using standard complement fixation (CFA) and enzyme-linked immunosorbent assays. Patients with Lyme disease, zoster oticus, or other symptomatic causes were excluded. The severity of BP was evaluated using the House-Brackmann scale (HBS) [11]. Therapy was started within 5 days after first symptoms had been noticed. Contraindications to steroid or famciclovir therapy were peptic ulcer, insulin-dependent diabetes mellitus, renal or hepatic dysfunction, immune suppression, and pregnancy. Patients admitted on even dates were assigned to prednisone (P group), patients admitted on odd dates to prednisone and famciclovir (P+F group); treatment was initiated by the resident on call. Prednisone was administered orally once a day (1 mg/kg body weight) for 4 days and tapered subsequently over the following 8 days; famciclovir was administered orally three times a day (250 mg) for 7 days. All patients received H2-receptor blockers, artificial tears and ophthalmic ointment for eye care. A follow-up visit was scheduled 3 months after the onset of BP. All patients were clinically re-examined by a single investigator (MM, blind to the initial treatment) and serum samples were drawn for possible virus ab-titer changes. The study was approved by the ethics committee of the University Clinics Bonn, and informed consent was obtained from all patients. Differences in HBS between treatment groups were compared using the Cochran-Armitage trend test. The Mann-Whitney test or ttest was used to compare quantitative variables between the treatment groups. Spearmans correlation coefficient was used to analyze the correlation between quantitative variables.

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Table 2 Time between first visit and follow-up visit 3 months P Group P+F Group Total 36 26 62 6 months 16 14 30 712 months 9 8 17 > 12 months 6 2 8 Total 67 50 117

of 17 patients (P group); trend test, p = 0.04; Fig. 2). Older patients in the P+F group did not benefit more from additional famciclovir than younger patients (trend test, p = 0.37). The time between onset of symptoms and start of treatment did not differ between groups or correlate with clinical improvement at followup.

the P group (30 % compared to 18 % in P+F group (trend-test, p = 0.028; Fig. 1). Patients with severe BP (initial HBS grade of 5 or 6) had a better chance to achieve normal function if they additionally received famciclovir (72 % of 18 patients (P+F group) vs. 47 %
Fig. 1 Clinical improvement in both groups according to a reduction in HBS
30%

Serological findings
VZV-ab titer (CFA) at first visit were available in 40 patients allocated to the P group (60 %) and 35 patients

20%

10%

0% P group P+F group

0 9.0% 4.0%

1 20.9% 14.0%

2 26.9% 24.0%

3 31.3% 30.0%

4 10.4% 22.0%

5 1.5% 6.0%

Fig. 2 HBS grade at follow-up visit in both groups of patients with an initial HBS grade of 5 or 6

80%

60%

40%

20%

0% P group P+F group

1 47.1% 72.2%

2 17.7% 16.7%

3 17.7% 11.1%

4 5.9% 0.0%

5 11.8% 0.0%

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allocated to the P+F group (70 %). Ab-titer change of VZV and HSV between the first and second visits did not differ between groups, nor did they correlate with HBS improvement between visits (Spearman correlation, p = 0.38 (HSV), p = 0.63 (VZV)).

Adverse effects
Two patients developed a skin rash, most likely due to famciclovir and discontinued the medication. These patients were not included in our statistical analysis. One young male patient reported subacute onset of hairloss after completion of the medical treatment.

Discussion
We found a significantly better chance for BP patients to reach normal function if they were treated with prednisone and famciclovir combined instead with prednisone alone. In particular, patients with severe BP had a more favorable outcome with additional antiviral therapy. Some methodological issues however need to be considered: The use of pseudo-randomization may have led to bias in our study results. However, comparison of putative influencing factors detected no differences between the two groups. The drop-out rate was higher than in similar studies. This is in part due to the German health care system where patients find medical advice readily and may be more reluctant to return to the university clinic for follow-up visits. The good prognosis of BP in general may further reduce the motivation for a followup visit, but at least the initial HBS did not differ between patients with and without follow-up. Furthermore, drop-out rates did not differ between treatment groups. As we compared the therapeutic benefit between groups, the high drop-out rate should not have influenced our study results. The different time interval until follow-up, not differing between groups, may have led to reduced power but not to a bias preferring one therapeutic regime. With respect to antiviral therapy, available studies gave contradictory results: compared with prednisone alone, a combined therapy of aciclovir and prednisone showed favorable outcome in patients receiving both [1], whereas a study comparing single aciclovir with prednisone only therapy resulted in a better clinical outcome in the prednisone group [5]. A comparison of prednisone and valaciclovir with a placebo group found a better clinical outcome only in elderly patients [3], thought to have a poorer prognosis [15]. A recent large Japanese study described the combination of valaciclovir and prednisolone superior to prednisolone and placebo [10], whereas another study using valaciclovir did not find differences between the combined therapy and

prednisolone alone [12]. Most recently, a British study found a favorable outcome only in patients treated with prednisone alone, whereas additional or single antiviral therapy had no significant effect [19]. The different results in these studies can partly be attributed to different study designs, but even studies with a similar design come to different conclusions [10, 12]. The initial severity of BP may further influence study results [7]. Study patients of Hato et al. [10], showing a positive effect of a combined therapy of prednisolone and valaciclovir, appear to have had more severe BP than those in the study by Sullivan et al. [19], who could not find a benefit in patients treated with aciclovir alone or in combination with prednisolone. In our study, the severity of BP was similar to the study of Hato et al. and like them we found the benefit of the combined treatment to be dependent on the severity of facial palsy. The used antiviral substances, dosage, start and duration of therapy may cause further heterogeneity between the conducted studies. Aciclovir has a low oral bioavailability of 1020 % [6] and must be administered five times daily, which was not complied with in one study [5]. The systemic availability of aciclovir, already low in the fasted state, is further compromised if taken with food. Even if study patients are well instructed, the correct administration is difficult to monitor. Valaciclovir, used in both Japanese studies, is a prodrug of aciclovir and has a higher bioavailability (54 %) compared with orally administered aciclovir [8]. Famciclovir, the most recent aciclovir analogue, exhibits excellent oral bioavailability (6075 %), not affected by concurrent food intake. Its active metabolite penciclovir triphosphate has a much longer intracellular half-life in VZV-infected cells than aciclovir. Therefore, famciclovir offers important advantages in virostatic therapy [16, 18]. In our study, famciclovir was used for the first time in the treatment of BP. In fact, a considerable number of our patients benefited from additional antiviral therapy with famciclovir, yielding circumstantial evidence for a pathogenic relevance of herpesviruses in BP (HSV, VZV or others) at least in a subset of BP cases. Beside methodological problems to detect reactivation of a widespread virus, it is possible that another, yet unidentified (herpes) virus, might be the causative agent. In summary our data suggest that a combined treatment of famciclovir and prednisolone should be considered (at least) in patients with severe BP. Further larger double-blind multi-center studies will be essential to validate the therapeutic benefit of combined treatment with famciclovir and prednisolone and may help to elucidate a potentially pathogenic role of herpes virus in BP.
Conflict of interest The authors declare no conflict of interest.

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