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List of Papers

This thesis is based on the following papers, which are referred to in the text by their Roman numerals.

I Berg T, Jonsson L, Engström M. Agreement between the Sun-

nybrook, House-Brackmann, and Yanagihara facial nerve grad-ing systems in Bell's palsy. Otol Neurotol 2004;25(6):1020-6.

II Engström M, Berg T, Stjernquist-Desatnik A, Axelsson S, Pit-käranta A, Hultcrantz M, Kanerva M, Hanner P, Jonsson L. Prednisolone and valaciclovir in Bell's palsy: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet Neu-rol 2008;7(11):993-1000.

III Berg T, Axelsson S, Engström M, Stjernquist-Desatnik A, Pit-käranta A, Kanerva M, Jonsson L. The course of pain in Bell’s palsy: treatment with prednisolone and valacyclovir. Accepted for publication 2009 in Otol Neurotol.

IV Berg T, Marsk E, Engström M, Hultcrantz M, Hadziosmanovic N, Jonsson L. The effect of study design and analysis methods on recovery rates in Bell’s palsy. Submitted for publication.

Reprints were made with permission from the respective publishers.

Contents

Introduction.....................................................................................................7 Anatomy of the facial nerve .......................................................................7 Acute peripheral facial palsy......................................................................8

History ...................................................................................................8 Etiological factors..................................................................................8 Grading facial function ........................................................................10

Bell’s palsy...............................................................................................13 Etiology ...............................................................................................13 Treatment.............................................................................................15 Pain in Bell’s palsy ..............................................................................18 Recovery rates in Bell’s palsy .............................................................18

Aims of the study ..........................................................................................19

Material and Methods ...................................................................................20 Patients .....................................................................................................20 Methods....................................................................................................21 Statistical analysis ....................................................................................22

Results...........................................................................................................24 Paper I ......................................................................................................24 Paper II .....................................................................................................25 Paper III....................................................................................................29 Paper IV ...................................................................................................32

Discussion .....................................................................................................35

Conclusions...................................................................................................39

Acknowledgements.......................................................................................40

References.....................................................................................................43

Abbreviations

CI Confidence interval DNA Deoxyribonucleic acid HR Hazard ratio IQR Interquartile range ITT Intention to treat MRI Magnetic resonance imaging HSV Herpes simplex virus PCR Polymerase chain reaction VAS Visual analogue scale VZV Varicella zoster virus

7

Introduction

Anatomy of the facial nerve A general knowledge of the anatomy of the seventh cranial nerve is essential for diagnosis and treatment of facial nerve disorders (May and Schaitkin 2000).

The greater part of the facial nerve is composed of motor fibres to the fa-cial muscles. In addition, the nerve carries secretomotor fibres for the sub-mandibular, sublingual, and lacrimal glands. The facial nerve also has two sensory, or afferent, components. One carries taste sensation from the ante-rior two thirds of the tongue and the palate, while the other transmits ordi-nary sensation from the skin in the region of the external ear (Diamond and Frew 1979, May and Schaitkin 2000).

The motor face area of the cerebral cortex is situated on the pre- and post-central gyri. Discharges from this area are carried through fascicles of the cor-ticobulbar tract to the lower brainstem where they synapse in the facial nerve nucleus located in the pons. The corticobulbar tracts arising from the upper face area cross and recross in reaching the facial motor nucleus, while the tracts to the lower face only cross. This anatomical arrangement allows the clinical distinction between a central and peripheral nerve dysfunction (Crosby and Dejonge 1963, Malone and Maisel 1988, May and Schaitkin 2000).

The facial nerve emerges from the brainstem at the pontomedullary junc-tion and enters the internal auditory meatus. It travels further into the bony fallopian canal, which is subdivided into three segments based upon changes of direction: the labyrinthine, tympanic, and mastoid segments. The labyrin-thine segment lies between the vestibule and cochlea and contains the geni-culate ganglion. At the geniculate ganglion, the greater and lesser petrosal nerves arise. The remaining fibres continue to the tympanic and mastoid segments before the nerve descends to the stylomastoid foramen. In the mas-toid segment, the facial nerve has three branches: the nerve to the stapedius muscle, the chorda tympani nerve, and the auricular branch of the vagus nerve (Malone and Maisel 1988, May and Schaitkin 2000).

As the nerve exits the stylomastoid foramen, the posterior auricular nerve forms the first branch. The facial nerve then passes forward to the parotid gland where it bifurcates into an upper and lower division. Within the pa-rotid gland, the facial nerve subdivides into the five terminal branches inner-vating the facial muscles: the temporal, zygomatic, buccal, marginal man-dibular and cervical branches (Malone and Maisel 1988).

8

Acute peripheral facial palsy History The first medical publications on facial nerve paralysis appeared in the 18th century. In 1798, Friedrich published his observations on three patients with facial nerve paralysis (Bird 1979). Charles Bell presented his discovery of the seventh cranial nerve and its role in innervation of the facial muscles in 1821 (Bell 1821). To support his thesis, Bell presented a series of cases of facial paralysis that resulted from direct trauma or infection (Bell 1829). His name was subsequently applied to the acute idiopathic peripheral facial palsy, so-called Bell’s palsy. In 1870, Tryde published the first report on facial palsy in association with herpes zoster (Tryde 1870). Later, J. Ramsay Hunt suggested that herpes zoster oticus is a result from a geniculate gangli-onitis (Hunt 1907). This syndrome, which now carries his name, is charac-terized by facial paralysis, severe pain, and ipsilateral vesicles (May and Schaitkin 2000).

Etiological factors Acute peripheral facial palsy is a diagnostic challenge, and often one cannot determine the etiology merely from its onset. The differential diagnostic possibilities are numerous and the most common causes are listed in Table 1. Peitersen studied 2,570 cases with peripheral facial nerve palsy during a period of 25 years. In his material, 349 of the patients (14%) were aged less than 15 years. Peitersen classified 1,701 patients as Bell’s palsy (66%) and 869 patients as non-Bells palsy (34%). Of the 869 non-Bell’s palsy patients, palsies in neonatal age (19%), herpes zoster (13%), trauma (11%), diabetes mellitus (9%), pregnancy (5%), polyneuritis including Borrelia (5%), and parotid tumors (5%) were the most common etiological and/or concomitant factors in the disease (Peitersen 2002). In endemic areas, Borrelia burgdor-feri has been reported to be the cause of palsy in 10% of adults (Ljøstad et al. 2005). Furthermore, Tveitnes and co-workers examined 115 children with acute peripheral facial palsy over a 9 year period in another endemic area of Norway, and 75 (65%) of these were diagnosed as Lyme borreliosis based on lumbal puncture (Tveitnes et al. 2007).

9

Table 1. Causes of Facial Paralysis (modified from May and Schaitkin 2000)

Birth Congenital Acquired

Trauma Basal skull fracture Facial injuries

Neurologic Multiple sclerosis Guillan-Barré syndrome

Infection External otitis Otitis media Mastoiditis Herpes zoster cephalicus Encephalitis Poliomyelitis Mumps Mononucleosis Tuberculosis Lyme disease Parotitis

Metabolic Diabetes mellitus Hyper- and hypothyreosis Pregnancy

Neoplastic Cholesteatoma Seventh nerve tumour Glomus jugulare tumour Meningioma Benign and malignant parotid lesions

Toxic Iatrogenic

Surgery Embolisation

Idiopathic Bell’s palsy Melkersson-Rosenthal syndrome Amyloidosis Sarcoidosis

10

Grading facial function Grading facial function is necessary for evaluating and communicating the spontaneous course of and the results of medical and surgical treatment of facial palsy (House 1983, House and Brackmann 1985, Croxson et al. 1990). There are two main types of facial grading systems; gross and regional sys-tems. Gross clinical 5-6-point scales with an overall assessment of facial motor function have been proposed (Botman and Jongkees 1955, Peitersen 1977, May et al. 1981, House and Brackmann 1985). Regional unweighted and weighted systems, evaluating different areas of facial function, have been devised by other authors (Janssen 1963, Yanagihara 1977, Smith et al. 1992, Lewis and Adour 1995, Ross et al. 1996). In addition to these main systems, specific and/or objective scales also exist (Stennert et al. 1977, Burres and Fisch 1986, Murty et al. 1994, Kang et al. 2002).

The House facial nerve grading system was proposed by House in 1983 (House 1983). After minor modifications, the system was presented by House & Brackmann in 1985 (House and Brackmann 1985). The House-Brackmann system was adopted as a standard of grading facial function by the Facial Nerve Disorders Committee of the American Academy of Otolar-yngology-Head and Neck Surgery. This system is based on a 6-grade score, (I to VI) that offers a gross evaluation of facial motor function and also in-cludes evaluation of sequelae (Table 2). It has become the most universally adopted scaling system for facial nerve disorders in the USA and Europe.

Table 2. House-Brackmann facial nerve grading system I to VI (summarised).

I Normal II Mild dysfunction; slight weakness noticeable only on close in-

spection III Moderate dysfunction; obvious, but not disfiguring, difference

between the two sides IV Moderately severe dysfunction; obvious weakness and/or disfig-

uring asymmetry V Only barely perceptive motion VI Loss of tone

The regional Yanagihara grading system, presented by Yanagihara in 1976 (Yanagihara 1977), assesses 10 separate aspects of function in the different facial muscles (Table 3). Each function is scored from 0 to 4, giving a maximum score of 40. This grading scale does not include any secondary effects. Yanagihara is the most widely used system in Japanese studies for evaluating facial nerve function in Bell’s palsy, herpes zoster oticus and following acoustic neuroma surgery (Satoh et al. 2000).

11

Table 3. Yanagihara 5-point facial nerve grading system 0 to 40. The scale consists of normal function, slight paralysis, moderate paralysis, severe paralysis, and total paralysis for which points 4, 3, 2, 1 and 0, respectively, are awarded.

Scale of five rating At rest 0 1 2 3 4 Wrinkle forehead 0 1 2 3 4 Blink 0 1 2 3 4 Slight closure of eye 0 1 2 3 4 Tight closure of eye 0 1 2 3 4 Closure of eye on involved side only 0 1 2 3 4 Wrinkle nose 0 1 2 3 4 Whistle 0 1 2 3 4 Grin 0 1 2 3 4 Depress lower lip 0 1 2 3 4

In 1996, Ross et al. (Ross et al. 1996) proposed a grading system designated the Sunnybrook facial grading system. This is a regional weighted system based on evaluation of resting symmetry, degree of voluntary excursion and incorporation of secondary defects (synkinesis) to form a maximum compos-ite score of 100 (Table 4). Its purpose was to develop a clear, well-defined system that provides an accurate description of facial motor function and that is responsive to clinically important changes (Ross et al. 1996). The Sunny-brook system reports facial function in a more continuous manner and has a wider response range than House-Brackmann (Ross et al. 1996). The intra-rater and inter-rater reliability of the Sunnybrook system is high, both when applied by novice and expert users (Hu et al. 2001), and is more reliable than House-Brackmann (Kanerva et al. 2006).

Tabl

e 4.

The

Sun

nybr

ook

faci

al n

erve

gra

ding

sys

tem

. Thi

s re

gion

al w

eigh

ted

syst

em is

bas

ed o

n ev

alua

tion

of d

iffer

ent f

acia

l reg

ions

incl

udin

g re

stin

g sy

m-

met

ry, s

ymm

etry

of v

olun

tary

mov

emen

t and

synk

ines

is to

form

a c

ompo

site

scor

e fr

om 0

to 1

00. S

umm

ariz

ed fr

om R

oss e

t al.

(199

6).

Eye

no

rmal

0

nar

row

1

w

ide

1

e

yelid

surg

ery

1

Che

ek (n

aso-

labi

al fo

ld)

n

orm

al

0

a

bsen

t

2

le

ss p

rono

unce

d

1

mor

e pr

onou

nced

1

Mou

th

nor

mal

0

c

orne

r dro

oped

1

c

orne

r pul

led

1

up/

out

Res

ting

sym

met

ry sc

ore:

Vol

unta

ry m

ovem

ent s

core

x 4

– R

estin

g sy

mm

etry

scor

e x

5 –

Synk

ines

is sc

ore

x 1

= C

ompo

site

scor

e

Synk

ines

is

Sym

met

ry o

f Vol

unta

ry M

ove-

men

t

No movement Slight movement Mild excursion Movement almost complete Movement complete

None Mild Moderate Severe

Fore

head

w

rinkl

e 1

2

3

4

5

Gen

tle e

ye

clos

ure

1

2

3

4

5

O

pen

mou

th

smile

1

2

3

4

5

Snar

l

1

2

3

4

5

Li

p pa

cker

1

2

3

4

5

Vol

unta

ry m

ovem

ent s

core

:

0

1

2

3

0

1

2

3

0

1

2

3

0

1

2

3

0

1

2

3

Syn

kine

sis s

core

:

Res

ting

Sym

met

ry

13

Bell’s palsy Bell’s palsy is unilateral weakness or paralysis of the face due to acute pe-ripheral facial nerve dysfunction, with no readily identifiable cause, and with some recovery of function within six months (May and Hughes 1987). It is a diagnosis of exclusion and trauma, otitis media, borreliosis, herpes zoster infection and neoplastic lesions of the temporal bone or parotid gland have therefore to be ruled out. Bell’s palsy represents 70% of the cases with acute peripheral facial palsy and the incidence is about 30 per 100,000 inhabitants (Katusic et al. 1986, Yanagihara 1988, Peitersen 2002). Approximately 70% of the patients with Bell’s palsy recover completely within six months with-out treatment. The remaining 30% suffer sequelae, including residual pare-sis, contracture, and synkinesis (Peitersen 2002).

Etiology Many theories have been proposed to explain the origin of Bell’s palsy. Ischemia, immunological reactions, and viral infections have all been sug-gested to be a part of the etiology, for example.

Some authors have suggested that ischemia (due to disturbed circulation in the vasa nervorum) leads to the nerve injury in Bell’s palsy. Vascular spasm causes a swelling of the nerve in the Fallopian canal, and secondary compressive edema ensues (Miehlke et al. 1981). This theory is the back-ground for the surgical decompression in the treatment of the disease.

An immunological hypothesis was introduced by McGovern and co-workers based on their experimental work on animals (McGovern et al. 1972, McGovern et al. 1977). Later, Hughes et al. demonstrated abnormal lymphocyte transformation in patients with Bell’s palsy and suggested that some instances of Bell's palsy result from cell-mediated immunity against peripheral nerve antigens (Hughes et al. 1986). Their results encouraged further research into steroid and other immunotherapies.

During recent decades, the viral theory has gained the most interest, and especially the neurotropic herpes viruses, which are known to become latent after primary infection, are considered important candidates in disease de-velopment. In 1972 McCormick (McCormick 1972) suggested herpes sim-plex virus (HSV) as a cause of Bell’s palsy. His theory was supported by the results in the serological study of HSV antibodies by Adour and co-workers in 1975 (Adour et al. 1975). Even more compelling data linking HSV to Bell’s palsy were presented by Murakami et al. in 1996 (Murakami et al. 1996). Endoneurial fluid from the facial nerve and biopsies from the poste-rior auricular muscle were tested for HSV-1 DNA and varicella zoster virus (VZV) DNA using polymerase chain reaction (PCR) in 14 Bell’s palsy pa-tients undergoing decompression surgery. HSV-1 genomes were detected in 11 of 14 patients and VZV in none. They concluded that HSV-1 is the major

14

etiologic agent in Bell’s palsy (Murakami et al. 1996). This finding was fur-ther supported by Furuta et al. who found significantly increased levels of HSV DNA in the saliva from 47 patients with Bell’s palsy (Furuta et al. 1998). However, more recent studies have failed to support this theory and the role of HSV in the disease is still unclear (Linder et al. 2005, Stjernquist-Desatnik et al. 2006). In the study by Stjernquist-Desatnik et al., biopsies were taken from the posterior auricular muscle within 72 hours after the onset of palsy and cerebrospinal fluid was analyzed by nested PCR for HSV-1 and VZV DNA in 20 patients. They detected HSV-1 DNA in only one of the muscle biopsies and none of the cerebrospinal fluid samples. Linder et al. (Linder et al. 2005) performed PCR specific for DNA of HSV-1, HSV-2, and VZV in facial muscle biopsies from patients with Bell's palsy. As con-trol specimens, the Scarpa’s ganglion of patients with Meniere's disease and the geniculate ganglion harvested at autopsy from patients without history of facial palsy were used. The investigators were not able to detect HSV or VZV genomic DNA in ganglion scarpae or muscle biopsies in Bell’s palsy patients or controls. HSV-1 DNA was detected in 86% and VZV DNA in 43% of the geniculate ganglions from patients without history of facial palsy. Their findings thus contradict the results of Murakami and co-workers (Murakami et al. 1996). Linder et al. concluded that the sole presence of HSV genomic DNA within the geniculate ganglion does not explain a direct association with Bell’s palsy (Linder et al. 2005).

Other studies suggest that VZV plays an important etiological role in Bell’s palsy, causing acute peripheral facial palsy without vesicles, so-called zoster sine herpete. Furuta et al. (Furuta et al. 2000), using the combination of serological assays and PCR, found VZV reactivation in 35 of 121 patients (29%) clinically diagnosed with Bell’s palsy. Based on their studies, they consider VZV to be one of the major etiological agents in Bell’s palsy, both in adults and in children (Furuta et al. 2000, Furuta et al. 2005). On the other hand, after studying the saliva of healthy individuals without facial palsy, Mehta et al. (Mehta et al. 2004) found that VZV can reactivate subclinically in healthy individuals after non-surgical stress. These findings might indicate that the VZV reactivation seen in other studies is a result of the psychologi-cal stress caused by Bells’ palsy, and not the cause of the disease.

Whatever the cause of the initial damage of the facial nerve in Bell’s palsy, substantial data indicate that the injury causes edema with mechanical compression of the facial nerve within the Fallopian canal. Entrapment of the swollen facial nerve in the narrow meatal segment and in the labyrinthine portion is suggested to be a critical component in the pathogenesis of Bell’s palsy (Fisch and Esslen 1972, Saito 2000, Linder et al. 2005). Based on the MRI findings with gadolinium enhancement of the facial nerve in the meatal and labyrinthine portion, this edema has been suggested to be due to an in-flammatory reaction (Schwaber et al. 1990, Tien et al. 1990, Engström et al. 1993, Song et al. 2008).

15

Treatment Treatment of Bell’s palsy has been a matter of debate for decades and no international consensus has yet been reached. Many different treatment methods have been suggested, but decompression surgery, corticosteroids, and antiviral treatments dominate the literature. However, the high sponta-neous recovery rates in Bell’s palsy make evaluation of treatment effect dif-ficult and require a large number of patients to be studied (Grogan and Gronseth 2001, Allen and Dunn 2004, Salinas et al. 2004).

Surgical treatment: In 1932, Balance and Duel (Balance and Duel 1932) advocated decompression surgery for Bell’s palsy. Indication for surgery was based on the theory of swelling and entrapment of the facial nerve in the bony Fallopian canal. The number of operations increased dramatically, and several surgical approaches were reported (May 1979, Yanagihara et al. 1979, Fisch 1981). Because of the lack of conclusive trials and complica-tions reported, surgical procedures have declined and decompression surgery is no longer recommended in Bell’s palsy (May and Schaitkin 2000, Grogan and Gronseth 2001, Adour 2002, Peitersen 2002).

Corticosteroid treatment: The most commonly prescribed medication for Bell’s palsy has been oral corticosteroids. However, treatment with corticos-teroids is controversial and has been a matter of debate for several decades. In a 1954 controlled trial, Taverner (Taverner 1954) treated 14 patients within 10 days after onset of palsy with oral cortisone acetate (200 mg daily for 3 days, 100 mg for 3 days and 50 mg for 2 days) and did not find a sig-nificant reduction in the incidence of denervation compared with 12 un-treated patients. In a study published in 1972, Adour and co-workers (Adour et al. 1972) compared 194 Bell’s palsy patients treated with prednisone (40 mg daily for 4 days and tapering to 8 mg daily for 8 days) with 110 patients who received no treatment. In patients with a clinically complete paralysis, none in the treated group showed complete denervation (measured by nerve excitability test) compared to 24 percent in the untreated group (p<0.001). In the prospective, controlled, double-blind study conducted between 1972 and 1974 by May et al. (May et al. 1976), 26 patients were treated with predni-sone (total of 410 mg over 10 days in descending doses) plus vitamins com-pared with 25 patients treated with vitamins only. No statistically significant beneficial effect of steroid therapy upon recovery from Bell’s palsy was demonstrated. In the prospective, randomised, controlled study published in 1999 by Ünüvar and colleagues (Ünüvar et al. 1999), 21 children with Bell’s palsy were treated with oral methylprednisolone (1 mg/kg daily for 10 days then gradually withdrawn over 3-5 days) and compared with 21 children in whom no treatment was given. The improvement rates between the treated and untreated children did not differ significantly. In the double-blind, ran-domised, placebo-controlled study by Lagalla and co-workers in 2002 (Lagalla et al. 2002), 62 consecutive patients were enrolled within 72 hours

16

of palsy onset and assigned to high-dose intravenous prednisone (1,000 mg daily for three days and then 500 mg daily for three days) in combination with intramuscular polyvitaminic therapy, or polyvitaminic therapy alone. The time needed to recover facial function to House-Brackmann grade III or better was significantly shorter in the 32 treated patients compared with the 30 controls (p=0.005), but this result was not confirmed in the long-term after 6-12 months of follow-up.

Reviews of the literature have been made to determine the effectiveness of corticosteroids in Bell’s palsy. The report of the Quality Standards Sub-committee of the American Academy of Neurology (Grogan and Gronseth 2001) noted that the pooled results of the four trials meeting their inclusion criteria (Taverner 1954, May et al. 1976, Brown 1982, Austin et al. 1993) showed significantly better facial outcomes in steroid-treated patients com-pared with non-steroid-treated patients (relative rate good outcome 1.16, 95%, CI 1.05 to 1.29). It was, however, concluded that a benefit from ster-oids has not been definitively established, even though the available evi-dence suggests that they probably are effective (Grogan and Gronseth 2001). In the Cochrane review by Salinas et al. (Salinas et al. 2004), two of studies in the report of Grogan (Grogan and Gronseth 2001) were excluded due to the use of alternation in “matched patients” as the method of randomisation, so-called quasi-randomisation (Brown 1982), and to the exclusion of a large number of patients after randomisation (Austin et al. 1993). It was stated that the four individual trials (Taverner 1954, May et al. 1976, Ünüvar et al. 1999, Lagalla et al. 2002) which met the inclusion criteria in the Cochrane review were too small (in all only including 179 patients) to detect moderate but important benefits with the use of corticosteroid therapy for Bell’s palsy (Salinas et al. 2004). None of the trials commented on side effects of the medical therapy. It was further concluded that there is a need for a random-ised controlled trial with a large number of patients to determine reliably whether the use of corticosteroid therapy in patients with Bell’s palsy offers a real benefit (Salinas et al. 2004).

Antiviral treatment: There is increasing evidence that the nerve injury in Bell’s palsy is caused by reactivation of viruses of the herpes group (McCormick 1972, Adour et al. 1975, Murakami et al. 1996, Furuta et al. 2000). The proposed link between Bell’s palsy and herpes viruses has led to the use of an antiviral agent (aciclovir or valaciclovir) in the treatment of the disease. Valaciclovir is a prodrug that is rapidly and nearly completely con-verted to aciclovir, and its bioavailability is three-fold to five-fold that of aciclovir (Beutner 1995). In 1996, Adour et al. (Adour et al. 1996) compared the outcome of 99 Bell’s palsy patients treated with aciclovir (400 mg 5 times daily for 10 days) in combination with prednisone (30 mg twice daily for five days gradually reduced to 5 mg twice daily during the next 5 days) versus placebo plus prednisone with a 4-month follow-up. Treatment with aciclovir plus prednisone was statistically more effective in returning volitional muscle

17

motion (recovery profile of 10; p=0.02) and in preventing nerve degeneration (p=0.05) than in patients treated with placebo plus prednisone (Adour et al. 1996). The prospective, controlled, randomised study of 101 patients by De Diego and co-workers (De Diego et al. 1998), reported that 47 patients treated with prednisone (1 mg/kg body weight for 10 days, then tapering over the next 6 days) had a better clinical recovery at 3 months than 54 patients treated with aciclovir (2,400 mg in three daily doses for 10 days). In 2000, Antunes et al. (Antunes et al. 2000) published a double-blind, randomised, placebo-controlled trial that included 46 patients receiving placebo or deflazocort (60 mg daily for 2 days, then tapering over the next 5 days) or deflazocort plus valaciclovir (1,500 mg daily for one week). No statistical difference in time to recovery of facial function among the three groups was found. In 2007, Hato et al. (Hato et al. 2007) presented a prospective, randomised, placebo-controlled study that compared a combination of valaciclovir (1,000 mg daily for 5 days) plus prednisolone (60 mg daily for 5 days, then tapering for a total treatment of 10 days) with placebo plus prednisolone. They reported a sig-nificantly higher recovery rate in the valaciclovir plus prednisolone group compared with placebo plus prednisolone. However, criticism has been voiced regarding this trial because it was not double-blinded and only 75% of the patients enrolled were analysed (Gilden and Tyler 2007). The review of Grogan et al. (Grogan and Gronseth 2001) included three studies using aci-clovir to treat of Bell’s palsy (Ramos et al. 1992, Adour et al. 1996, De Diego et al. 1998). They concluded that aciclovir (combined with prednisone) is possibly effective in improving facial function in Bell’s palsy, but that further well-designed studies are needed (Grogan and Gronseth 2001). The Cochrane review by Allen and co-workers (Allen and Dunn 2004) included three con-trolled trials (Adour et al. 1996, De Diego et al. 1998, Antunes et al. 2000) involving aciclovir or valaciclovir in the treatment of Bell’s palsy. The au-thors concluded that more data are needed from a large multicentre, random-ised, controlled, and blinded study with at least 12 months follow-up before a definitive recommendation can be made regarding the effect of aciclovir or valaciclovir (Allen and Dunn 2004).

To clarify the effect of corticosteroids and anti-viral treatment in Bell’s palsy, two large randomised, double-blind, placebo-controlled trials were performed in Europe in the 2000’s; the Scandinavian Bell’s palsy trial test-ing prednisolone and valaciclovir (Engström et al. 2008) and a Scottish trial testing prednisolone and aciclovir (Sullivan et al. 2007). The recently pub-lished Scottish trial included 551 patients recruited within 72 hours of onset of palsy and randomly assigned to 10 days of treatment with prednisolone (25 mg twice daily), aciclovir (400 mg five times daily), both agents, or pla-cebo. It was concluded that early treatment with prednisolone significantly improves the chances of complete recovery (House-Brackmann grade I) at 3 and 9 months, and that there was no benefit of aciclovir, neither as mono-therapy nor in combination with prednisolone (Sullivan et al. 2007).

18

Pain in Bell’s palsy Ipsilateral pain around the ear, in the face and/or neck occurs in 33 to 70% of patients in the early stage of Bell’s palsy (Adour et al. 1972, May et al. 1976, Adour et al. 1978, Hydén et al. 1982, Katusic et al. 1986, Gavilan et al. 1988, Peitersen 2002). The aetiopathological background for this pain is unclear. It has, however, been reported that the presence of pain indicates a worse prognosis for facial recovery (Hydén et al. 1982, Katusic et al. 1986, Gavilan et al. 1988, Peitersen 2002). In contrast, other workers claim that pain has no prognostic value in the disease (May et al. 1976, Adour et al. 1978, Chida et al. 2002). The effect of prednisolone and/or valaciclovir on ipsilateral pain is controversial and needs further evaluation. Adour et al. stated that prednisone relieves pain in Bell’s palsy and that 15% of patients experience return of postauricular pain when prednisone is tapered (Adour et al. 1972). These results were not confirmed by Austin and co-workers who found no significant difference in pain between patients treated with predni-sone or placebo (Austin et al. 1993).

Recovery rates in Bell’s palsy Earlier Bell’s palsy trials have reported diverging rates of facial recovery, both in treated and untreated patients. In the large non-controlled study on the spon-taneous course of Bell’s palsy, including 1,701 cases studied over a period of 25 years, Peitersen reported that about 70% of the patients recovered without medical treatment within six months (Peitersen 2002). He concluded that no kind of treatment, including prednisone, was able to improve prognosis and stated that the time had now come to stop the use (or misuse) of prednisone (Peitersen 2002). In contrast, the world’s two largest (and recently published) randomised controlled Bell’s palsy trials both concluded that prednisolone does improve restitution of facial function, whereas antiviral treatment had no proven effect (Sullivan et al. 2007, Engström et al. 2008). Sullivan and co-workers reported complete recovery of facial function, defined as House-Brackmann Grade I, in 90% of patients treated with prednisolone and in 75% in patients not receiving prednisolone (Sullivan et al. 2007). In the study of Eng-ström et al., the corresponding proportions of patients with complete recovery, defined as Sunnybrook scale score of 100, were 72% and 57% (Engström et al. 2008). In two recent Japanese trials, in which the Yanagihara grading system was used to evaluate facial function, treatment with prednisolone resulted in recovery rates of 80% (Kawaguchi et al. 2007) and 90% (Hato et al. 2007). The studies mentioned above have important methodological differences that may affect the recovery rates, i.e. inclusion/exclusion criteria, facial grading sys-tems, follow-up time, statistical methods and definitions of facial recovery. This impact of study design on recovery rates has recently been to the subject of discussion since studies of similar treatments report varying rates of recovery (Gilden and Tyler 2007, Davenport et al. 2008, Hato et al. 2008).

19

Aims of the study

• To assess the agreement between the Sunnybrook facial nerve grading system and the House-Brackmann and Yanagihara systems

• To study the short and long-term treatment effect of prednisolone and valaciclovir on facial nerve recovery in a large number of patients with Bell’s palsy

• To study the effect of prednisolone and valaciclovir on synkinesis, as well as side effects of the study drugs

• To evaluate the effect of prednisolone and valaciclovir on ipsilateral pain around the ear and in the face or neck in Bell’s palsy

• To study the incidence and intensity of pain during the first two months of palsy and to assess its prognostic value

• To evaluate the influence of different analysis methods and definition of facial recovery on recovery rates in Bell’s palsy

20

Material and Methods

Patients Paper I From March 2001 to May 2003, 100 examinations were performed on 62 patients (30 women, 32 men) with varying degrees of peripheral facial palsy. The palsy was left/right-sided in equal numbers of the 62 patients. Their median age was 48 years (range 15–87) and median time between onset of palsy (day 1) and assessment was 50 days (average 129 days, range 1–4,000 days). Sixty patients were diagnosed as having Bell’s palsy (94 evaluations) and 2 herpes zoster oticus (six evaluations).

Papers II–IV From May 2001 to September 2007, a prospective, randomised, double-blind, placebo-controlled, multicentre trial with a 12-month follow-up was performed in patients with Bell’s palsy. Patients aged 18 to 75 years with onset of palsy within 72 hours were recruited in 16 public otorhinolaryn-gological centres in Sweden and one in Finland. Altogether, 1,953 patients (910 women, 1,043 men) with acute peripheral facial palsy were screened. At the initial examination, 1,114 of the 1,953 patients did not meet the inclu-sion criteria and were registered in separate forms.

Accordingly, 839 of the 1,953 patients met the inclusion criteria and were randomised into four treatment arms. Ten randomised patients did not take any study drug and were excluded. Consequently, 829 patients (341 women, 488 men) were included in the modified intention-to-treat (ITT) analysis. Of these, 206 received placebo, 210 prednisolone, 207 valaciclovir, and 206 prednisolone plus valaciclovir. Thus, 416 of the patients received predniso-lone and 413 did not. Similarly, 413 received valaciclovir while 416 were not treated with valaciclovir. Baseline characteristics of the four treatment groups were similar with regard to median age, gender, side of palsy, time from onset of palsy to treatment start, and the median Sunnybrook and House-Brackmann scores.

During follow-up, the investigating physicians diagnosed diseases that may have been the cause of palsy; 67 borreliosis, 5 herpes zoster oticus, and 18 pa-tients with other diseases (e.g. sarcoidosis, multiple sclerosis, cerebrovascular disease, and parotid tumour). These 90 patients were included in the ITT analy-sis. The 12-month follow-up visit was made by 743 of the 829 patients (90%).

21

Methods Paper I Case histories were obtained and the patients were examined by an otolaryn-gologist. They were asked to perform the facial movements at least three times and clinical grading was carried out according to the Sunnybrook (Ross et al. 1996), House-Brackmann (House and Brackmann 1985) and Yanagihara facial nerve grading systems (Yanagihara 1977). Thirty-six pa-tients were examined once during the course of palsy, 19 patients twice, 3 three times, 3 four times and one patient five times. Hence, the total number of evaluations was 100. Three clinicians with special interest in facial nerve disorders conducted the study; two were consultants and one was a registrar.

Papers II–IV Patients were assigned to one of four equally large treatment groups in a factorial fashion: placebo plus placebo; prednisolone 60 mg daily for five days, then tapering by 10 mg per day for the next five days plus placebo; valaciclovir 1,000 mg three times daily for seven days plus placebo; or pred-nisolone plus valaciclovir. Treatment started within 72 hours of onset of palsy. Facial function was assessed by Sunnybrook and House-Brackmann grading systems. Baseline assessment before treatment start included otorhi-nolaryngological examination, grading of facial function, measurement of ipsilateral pain, registration of concurrent medication, and serum analysis for Borrelia burgdorferi antibodies. Follow-up visits were scheduled for day 11 to 17, 1 month, 2 months, 3 months, 6 months, and 12 months after inclu-sion. If recovery was complete (Sunnybrook=100) at 2 or 3 months, the next follow-up was at 12 months. Otorhinolaryngological examination and regis-tration of ipsilateral pain was performed at each visit during the first 2 months. The incidence and intensity of ipsilateral pain around the ear and in the face or neck was registered at baseline, day 11 to 17, 1 month, and 2 months. Patients graded the intensity of pain by marking a cross on a visual analogue scale (VAS) and they were not allowed to see their previous grad-ings. The VAS grading ranges from 0 to 10, where 0 represents no pain and 10 very severe pain.

Convalescent serum for Borrelia burgdorferi antibodies was taken at 2 months.

22

Statistical analysis Paper I To assess the agreement between the grading systems, we used weighted Kappa values (with 95% confidence intervals) of quintiles of the original scales. The interpretations of the numerical values of Kappa coefficients by Landis & Koch have become standard (Landis and Koch 1977). A Kappa value in the interval 0.00–0.20 means slight agreement, 0.21–0.40 fair, 0.41–0.60 moderate, 0.61–0.80 substantial and 0.81–1.00 almost perfect agree-ment. The assessments were stratified into the time periods 1–14 days, 15–60 days, 61–180 days and >180 days. For each period/stratum, Kappa values were calculated (95% confidence intervals) and the null hypothesis of equal Kappa values between strata was tested.

Papers II and III The ITT principle was used for the analyses. All randomised patients receiv-ing at least one dose of study medication were included in the analysis, but subjects who did not initiate therapy were excluded. Therefore, our ITT an-alysis should be considered a modified ITT analysis. Last-observation-carried-forward method was applied; missing data points were imputed in the post-baseline follow-up visits from the last observation available for each patient. An interaction test was performed on the primary endpoint to reveal any synergistic effect of the combination of prednisolone and valaciclovir. Results are given with continuous variables as median values with interquar-tile range (IQR; 25th to 75th percentiles) and dichotomous data as propor-tions with 95% confidence interval (CI), using the normal approximation approach. Kaplan-Meier methods were used to generate the survival curves. Categorical variables were compared by Fisher’s exact test. Continuous variable comparisons were performed using Kruskal-Wallis test. Cox pro-portional hazards models were used to estimate the hazard ratio (HR) of recovery, including 95% CI. The assumption for proportional hazards was tested using Schoenfeld residuals (p=0.73) (paper II).

Paper IV Recovery rates of facial function were assessed with four different analysis methods: a) Recovery defined as Sunnybrook scale score of 100 at 12 months based

on the intention-to-treat principle and last-observation-carried-forward method (n=829). This analysis is referred to as “last observation carried forward, Sunnybrook=100”.

b) Recovery defined as House-Brackmann Grade I at 12 months based on the intention-to-treat principle and last-observation-carried-forward method (n=829). This analysis is referred to as “last observation carried forward, House-Brackmann=I”.

23

c) Recovery defined as House-Brackmann Grade I in patients followed until recovery plus those remaining at the 12-month follow-up (n=782) (47 pa-tients were lost to follow-up before recovery and were excluded). This analysis is referred to as “complete-case analysis, House-Brackmann=I”.

d) Recovery defined as House-Brackmann Grade II in patients followed until recovery plus those remaining at the 12-month follow-up (n=797) (32 patients were lost to follow-up before recovery and were excluded in this analysis). This analysis is referred to as “complete-case analysis, House-BrackmannII”.

24

Results

Paper I Agreement between the Sunnybrook, House-Brackmann and Yanagihara facial nerve grading systems in Bell’s palsy Overall agreement between the Sunnybrook, House-Brackmann and Yanagihara facial grading systems When comparing the overall agreement between the Sunnybrook and the House-Brackmann facial grading system in 100 evaluations, the weighted Kappa value was 0.59 (Spearman correlation coefficient=0.76) (Table 5). Patients graded as House-Brackmann II had Sunnybrook composite scores ranging from 53 to 87 (scoring interval=35), House-Brackmann III was Sun-nybrook gradings 25 to 64 (scoring interval=40), House-Brackmann IV cor-responded to Sunnybrook gradings 9 to 55 (grading interval=47), House-Brackmann V was Sunnybrook gradings 4 to 42 (interval=39), and patients with House-Brackmann VI were graded 8 to 17 (interval=10) in the Sunny-brook system.

The best overall agreement was demonstrated between the Sunnybrook and Yanagihara grading systems with a weighted Kappa value of 0.72 (Spearman correlation coefficient=0.84) (Table 5). If a direct conversion (Sunnybrook=Yanagihara x 2.5) was made, these results would indicate that Sunnybrook gradings generally score lower than the corresponding values in the Yanagihara system, both in the interval with low scoring values (severe palsy) and the interval with high values (mild palsy).

Weighted Kappa was 0.64 (Spearman correlation coefficient=0.75) when comparing the overall agreement between House-Brackmann and Yanagi-hara scores (Table 5). If the conversion table suggested by Satoh et al. (Satoh et al. 2000) is used, the number of individual Yanagihara gradings within the converted House-Brackmann percentage intervals will be 41 (41%).

Agreement between the Sunnybrook, House-Brackmann and Yanagihara facial grading systems during the course of palsy days 1–14, 15–60, 61–180 and after day 180 The agreement between the four grading systems was analysed for the inter-vals: days 1–14 (38 evaluations), days 15–60 (28 evaluations), days 61–180 (20 evaluations) and after day 180 (14 evaluations) (Table 5). The congru-ence values of Sunnybrook vs. House-Brackmann scores, measured by

25

weighted Kappa for the four time intervals, were: 0.56, days 1–14; 0.53, days 15–60; 0.71, days 61–180; and 0.55, after day 180. The corresponding Kappa values for Sunnybrook vs. Yanagihara scores, were 0.76, 0.74, 0.71 and 0.38, respectively. The weighted Kappa scores for House-Brackmann vs. Yanagihara grades were: 0.64, days 1–14; 0.66, days 15–60; 0.74 days 61–180; and 0.37 after day 180.

Table 5. Overall agreement in 100 evaluations and agreement over time between the Sunnybrook, House-Brackmann and Yanagihara facial grading systems in Bell’s palsy (n = 94) and herpes zoster oticus (n = 6). Weighted

Kappa values n = 100

Spearman correlation coefficient n = 100

Days 1-14 Weighted

Kappa n = 38

Days 15-60 Weighted

Kappa n = 28

Days 61-180Weighted

Kappa n = 20

Days181- Weighted

Kappa n = 14

Sunnybrook vs. House–Brackmann

0.59 0.76 0.56 0.53 0.71 0.55

Sunnybrook vs. Yanagihara

0.72 0.84 0.76 0.74 0.71 0.38

House-Brackmann vs. Yanagihara

0.64 0.75 0.64 0.66 0.74 0.37

Total between all grading systems

0.65 0.78 0.65 0.64 0.72 0.43

Paper II Prednisolone and valaciclovir in Bell's palsy: a randomised, double-blind, placebo-controlled, multicentre trial A multivariate Cox analysis showed that time to complete recovery (Sunny-brook=100) was significantly shorter in the 416 patients receiving predniso-lone compared with the 413 not treated with prednisolone (HR 1.40; 95% CI 1.18 to 1.64; p<0.0001). Time to recovery did not differ between the 413 patients who received valaciclovir and the 416 who did not receive valaci-clovir (HR 1.01; 95% CI 0.85 to 1.19; p=0.90). Interaction between the ef-fects of prednisolone and valaciclovir was not found (p=0.59).

The median time to complete recovery was 75 days in the prednisolone plus placebo arm, which was less than the 104 days in placebo plus placebo (p=0.04) and 135 days in valaciclovir plus placebo (p=0.03) (Figure 1).

Patients receiving prednisolone had significantly higher recovery rates at 3, 6, and 12 months than no-prednisolone patients (Table 6 and 7). At 12 months, 300 (72%) of patients in the prednisolone group (n=416) had recov-ered compared with 237 (57 %) in no-prednisolone (n=413) (p<0.0001). The outcome for the 413 patients treated with valaciclovir did not differ from the 416 in the no-valaciclovir group (p=0.66) (Table 7).

Of the 743 patients with a 12-month follow-up, synkinesis was present in 51 of 370 (13.8%) patients treated with prednisolone compared with 107 of

26

373 (28.7%) in those who did not receive prednisolone (difference -14.9%, 95% CI -20.7 to -9.1; p<0.0001). In the 369 patients receiving valaciclovir, 73 (19.8%) had synkinesis compared with 85 of 374 (22.7%) in the no-valaciclovir group (difference -2.9%, 95% CI -8.8 to 2.9; p=0.37).

Non-serious adverse events were reported by 92 patients; 25 in the pla-cebo plus placebo arm, 21 in prednisolone plus placebo, 19 in valaciclovir plus placebo, and 27 in patients who received prednisolone plus valaciclovir. There was no difference in the number of patients with adverse events (Fisher’s exact test) between prednisolone plus placebo and placebo plus placebo (difference -2.1%, 95% CI -8.3 to 4.1; p=0.53), valaciclovir plus placebo and placebo plus placebo (difference -3.2%, 95% CI -9.2 to 2.9; p=0.34), or prednisolone plus valaciclovir and placebo plus placebo (differ-ence 0.9%, 95% CI -5.7 to 7.5; p=0.88).

0 100 200 300 400

0

20

40

60

80

100

Days

Com

plet

e R

ecov

ery

(%)

Placebo (PL)Prednisolone (P)Valacyclovir (V)Prednisolone plus valacyclovir (PV)

50

Md PV

Md P

Md PL

Md V

194 180 143 113 98 77 (PL)200 184 130 99 73 57 (P)202 181 138 115 102 84 (V)200 174 123 94 77 54 (PV)

Numbers at risk (time points)t1 t2 t3 t4 t5 t6

Figure 1. Kaplan-Meier estimates of patients with complete recovery (Sunny-brook=100) in the four treatment groups (n=829). The median time (Md) to com-plete recovery for each treatment group is also illustrated. Numbers at risk; t1=day 11-17, t2=1 month, t3=2 months, t4=3 months, t5=6 months, and t6=12 months.

Tabl

e 6.

The

pro

porti

on o

f pa

tient

s in

the

int

entio

n-to

-trea

t an

alys

is w

ith c

ompl

ete

reco

very

def

ined

as

Sunn

ybro

ok=1

00 o

r H

ouse

-B

rack

man

n=I a

t day

s 11

-17,

1 m

onth

, and

2, 3

, 6, a

nd 1

2 m

onth

s. La

st-o

bser

vatio

n-ca

rrie

d-fo

rwar

d w

as a

pplie

d fo

r mis

sing

dat

a po

ints

. Dat

a ar

e nu

mbe

r of p

atie

nts (

n), %

in e

ach

treat

men

t gro

up w

ith c

ompl

ete

reco

very

(95%

CI)

.

At 1

1-17

day

s A

t 1 m

onth

A

t 2 m

onth

s A

t 3 m

onth

s A

t 6 m

onth

s A

t 12

mon

ths

n,

% (9

5% C

I)

n, %

(95%

CI)

n,

% (9

5% C

I)

n, %

(95%

CI)

n,

% (9

5% C

I)

n, %

(95%

CI)

Pl

aceb

o pl

us p

lace

bo (n

=206

)

Sunn

ybro

ok=1

00

16, 7

.8 (4

.1–1

1.4)

56

, 27.

2 (2

1.1–

33.3

) 88

, 42.

7 (3

5.9–

49.5

) 10

5, 5

1.0

(44.

1–57

.9)

117,

56.

8 (5

0.0–

63.6

) 11

8, 5

7.3

(50.

5–64

.1)

Hou

se-B

rack

man

n=I

16, 7

.8 (4

.1–1

1.4)

63

, 30.

6 (2

4.2–

36.9

) 94

, 45.

6 (3

8.8–

52.5

) 11

1, 5

3.9

(47.

0–60

.8)

127,

61.

7 (5

4.9–

68.4

) 13

3, 6

4.6

(58.

0–71

.1)

Pred

niso

lone

plu

s pla

cebo

(n=2

10)

Su

nnyb

rook

=100

14

, 6.7

(3.3

–10.

1)

65, 3

1.0

(24.

7–37

.3)

107,

51.

0 (4

4.1–

57.8

) 13

5, 6

4.3

(57.

8–70

.8)

143,

68.

1 (6

1.7–

74.5

) 14

8, 7

0.5

(64.

3–76

.7)

Hou

se-B

rack

man

n=I

18, 8

.6 (4

.8–1

2.4)

71

, 33.

8 (2

7.4–

40.3

) 11

1, 5

2.9

(46.

1–59

.7)

137,

65.

2 (5

8.7–

71.7

) 15

0, 7

1.4

(65.

3–77

.6)

160,

76.

2 (7

0.4–

82.0

) V

alac

iclo

vir

plus

pla

cebo

(n=2

07)

Su

nnyb

rook

=100

12

, 5.8

(2.6

–9.0

) 60

, 29.

0 (2

2.8–

35.2

) 89

, 43.

0 (3

6.1–

49.8

) 10

4, 5

0.2

(43.

4–57

.1)

111,

53.

6 (4

6.8–

60.5

) 11

9, 5

7.5

(50.

7–64

.3)

Hou

se-B

rack

man

n=I

13, 6

.3 (3

.0–9

.6)

65, 3

1.4

(25.

0–37

.8)

94, 4

5.4

(38.

6–52

.2)

113,

54.

6 (4

7.8–

61.4

) 12

0, 5

8.0

(51.

2–64

.8)

133,

64.

3 (5

7.7–

70.8

) Pr

edni

solo

ne p

lus v

alac

iclo

vir

(n=2

06)

Su

nnyb

rook

=100

12

, 5.8

(2.6

–9.0

) 71

, 34.

5 (2

7.9–

41.0

) 10

9, 5

2.9

(46.

0–59

.8)

124,

60.

2 (5

3.4–

66.9

) 14

1, 6

8.5

(62.

1–74

.9)

152,

73.

8 (6

7.7–

79.8

) H

ouse

-Bra

ckm

ann=

I 15

, 7.3

(3.7

–10.

9)

78, 3

7.9

(31.

2–44

.5)

116,

56.

3 (4

9.5–

63.1

) 13

4, 6

5.0

(58.

5–71

.6)

149,

72.

3 (6

6.2–

78.5

) 16

4, 7

9.6

(74.

1–85

.2)

Tabl

e 7.

Rat

es o

f com

plet

e re

cove

ry (S

unny

broo

k=10

0). D

ata

are

num

ber (

n) o

f pat

ient

s, %

for e

ach

treat

men

t mod

ality

with

com

plet

e re

cov-

ery

(95%

CI)

and

diff

eren

ces i

n %

(95%

CI)

.

At 3

mon

ths

At 6

mon

ths

At 1

2 m

onth

s

n D

iff

P n

Diff

P

n D

iff

P Pr

edni

solo

ne (n

=416

) vs

259,

62%

(58–

67)

12%

0.

0007

28

4, 6

8% (6

4–73

) 13

%

0.00

01

300,

72%

(68–

76)

15%

<0

.000

1 no

Pre

dnis

olon

e (n

=413

) vs

209

, 51%

(46–

55)

(5–1

8)

vs

228

, 55%

(50–

60)

(7–2

0)

vs

237

, 57%

(53–

62)

(8–2

1)

V

alac

iclo

vir (

n=41

3) v

s 22

8, 5

5% (5

0–60

) -3

%

0.48

25

2, 6

1% (5

6–66

) -2

%

0.06

8 27

1, 6

6% (6

1–70

) 2%

0.

66

no V

alac

iclo

vir (

n=41

6)

vs 2

40, 5

8% (5

3–63

) (-

9–4)

vs 2

60, 6

3% (5

8–67

)(-

8–5)

vs 2

66, 6

4% (5

9–69

)(-

5–8)

Pred

niso

lone

plu

s Pla

cebo

(n

=210

) vs

135,

64%

(58–

71)

14%

0.

004

143,

68%

(62–

75)

15%

0.

003

148,

71%

(64–

77)

13%

0.

006

Val

acic

lovi

r plu

s Pla

cebo

(n

=207

) vs

104

, 50%

(43–

57)

(5–2

4)

vs

111

, 54%

(47–

61)

(5–2

4)

vs

119

, 58%

(51–

64)

(4–2

2)

29

Paper III The course of pain in Bell’s palsy: treatment with prednisolone and valaciclovir At baseline (within 72 hours of onset of palsy), 412 of 826 patients (50%) in the ITT-analysis reported ipsilateral pain around the ear, in the face or in the neck. The incidence of pain in this acute stage was similar in all four treat-ment arms (Table 8). The median intensity of pain measured with VAS in the treatment arms is also shown in Table 8.

At the first follow-up (day 11 to 17), 369 of 807 patients (46%) experi-enced pain (Table 8). Of these 369 patients, 118 (32%) reported pain for the first time, i.e. they had not experienced pain at baseline. Intensity of pain was similar between the arms (Table 8). Factorial analysis showed no sig-nificant difference in incidence or intensity of pain between the 403 patients treated with prednisolone compared with the 404 patients not treated with prednisolone (p=0.57, p=0.58 respectively), or between the 407 patients receiving valaciclovir compared with the 400 patients not receiving this medication (p=0.72, p=0.08 respectively).

At 1 month, 128 of 717 patients (18%) exhibited ipsilateral pain around the ear, in the face or the neck (Table 8). Six of these 128 (5%) reported pain for the first time. The intensity of pain was similar between the four arms at 1 month (Table 8). Treatment with prednisolone or valaciclovir did not af-fect the incidence (p=0.92, p=0.38 respectively) or intensity of pain (p=0.37, p=0.37 respectively) at 1 month (factorial analysis).

Two months after palsy onset, 53 of 637 patients (8%) reported pain (Ta-ble 8). Of these 53 patients, six (11%) experienced pain for the first time. As in the earlier follow-ups, the incidence and intensity of pain was similar among the four treatment arms (Table 8). Furthermore, treatment with pred-nisolone or valaciclovir did not influence incidence (p=0.89, p=0.77 respec-tively) or intensity of pain (p=0.85, p=0.69 respectively).

During the first 2 months of palsy, 542 of 829 patients (65%) reported pain at some point; 133 of 206 (65%) receiving placebo plus placebo, 140 of 210 (67%) receiving prednisolone plus placebo, 145 of 207 (70%) receiving valaciclovir plus placebo, and 124 of 206 (60%) receiving prednisolone plus valaciclovir.

Table 9 presents recovery rates for facial motor function at 12 months in relation to pain in the first two weeks of palsy as determined by factorial analysis. There was no significant difference in recovery rates at 12 months within any of the treatment groups in relation to pain within 72 hours (Table 9). In patients reporting pain at day 11 to 17, 204 of 369 (55%) had complete recovery at 12 months in comparison with 323 of 438 (74%) without pain at this follow-up (p<0.0001) (Table 9). Significant differences in recovery rates

Tabl

e 8.

Cha

ract

eris

tics o

f the

pat

ient

s in

the

four

trea

tmen

t arm

s

Plac

ebo

plus

Pr

edni

solo

ne p

lus

Val

acic

lovi

r plu

s Pr

edni

solo

ne p

lus

p To

tal

Pl

aceb

o Pl

aceb

o Pl

aceb

o V

alac

iclo

vir

n=

206

n=21

0 n=

207

n=20

6

n=82

9 Se

x

Fe

mal

e, n

(%)

93 (4

5%)

82 (3

9%)

86 (4

2%)

80 (3

9%)

—34

1 (4

1%)

M

ale,

n (%

) 11

3 (5

5%)

128

(61%

) 12

1 (5

8%)

126

(61%

) —

488

(59%

) A

ge, m

edia

n (I

QR

) 39

(30–

53)

40 (3

0–52

) 40

(32–

54)

42 (3

1–56

) —

40 (3

1–54

)

With

in 7

2 ho

urs

Faci

al n

erve

gra

ding

scor

e

Su

nnyb

rook

, med

ian

(IQ

R)

38 (2

3–51

) 38

(25–

56)

41 (2

1–54

) 38

(23–

54)

—39

(23–

54)

H

ouse

-Bra

ckm

ann,

med

ian

(IQ

R)

4 (3

–5)

4 (3

–5)

4 (3

–5)

4 (3

–5)

—4

(3–5

) Ip

sila

tera

l pai

n, n

(%)a

93/2

04 (4

6%)

107/

210

(51%

) 11

1/20

6 (5

4%)

101/

206

(49%

) —

412/

826

(50%

)

VA

S, m

edia

n (I

QR

) 2

(1–5

) 3

(2–5

) 3

(1–5

) 2

(1–5

) —

2 (1

–5)

11–1

7 da

ys

Ipsi

late

ral p

ain,

n (%

)b 84

/199

(42%

) 96

/201

(48%

) 10

5/20

5 (5

1%)

84/2

02 (4

2%)

0.16

369/

807

(46%

)

VA

S, m

edia

n (I

QR

) 3

(1–5

) 3

(2–5

) 3

(2–5

) 3

(2–5

) 0.

363

(2–5

) 1

Mon

th

Ipsi

late

ral p

ain,

n (%

)c 29

/179

(16%

) 39

/174

(22%

) 37

/186

(20%

) 23

/178

(13%

) 0.

1012

8/71

7 (1

8%)

V

AS,

med

ian

(IQ

R)

2 (1

–3)

2 (1

–4)

1 (1

–3)

2 (1

–3)

0.70

2 (1

–3)

2 M

onth

s

Ip

sila

tera

l pai

n, n

(%)d

15/1

62 (9

%)

13/1

59 (8

%)

13/1

65 (8

%)

12/1

51 (8

%)

0.98

53/6

37 (8

%)

V

AS,

med

ian

(IQ

R)

1 (1

–2)

2 (1

–3)

1 (1

–3)

1 (0

–2)

0.85

1 (1

–3)

— In

dica

tes d

ata

not p

rese

nted

; IQ

R, i

nter

quar

tile

rang

e; V

AS,

vis

ual a

nalo

gue

scal

e.

a D

ata

mis

sing

for t

hree

pat

ient

s,b D

ata

mis

sing

for 2

2 pa

tient

s,c Dat

a m

issi

ng fo

r 122

pat

ient

s,d D

ata

mis

sing

for 1

92 p

atie

nts

Tabl

e 9.

Com

plet

e re

cove

ry ra

tes (

Sunn

ybro

ok=1

00) a

t 12

mon

ths i

n re

latio

n to

inci

denc

e of

pai

n w

ithin

72

hour

s and

at d

ay 1

1 to

17

C

ompl

ete

reco

very

at 1

2 m

onth

sa

(n, %

[95%

CI]

) C

ompl

ete

reco

very

at 1

2 m

onth

sb

(n, %

[95%

CI]

)

Pa

in w

ithin

72

hour

s (n

=412

) N

o pa

in w

ithin

72

hour

s (n

=414

) p

Pain

at d

ay 1

1 to

17

(n=3

69)

No

pain

at d

ay 1

1 to

17

(n=4

38)

p

A

ll pa

tient

s (n=

829)

26

0/41

2, 6

3.1%

(58.

4–67

.8)

276/

414,

66.

7% (6

2.1–

71.2

) 0.

31

204/

369,

55.

3% (5

0.2–

60.4

) 32

3/43

8, 7

3.7%

(69.

6–77

.9)

<0.0

001

Pr

edni

solo

ne (n

=416

) 14

9/20

8, 7

1.6%

(65.

5–77

.8)

151/

208,

72.

6% (6

6.5–

78.7

) 0.

91

117/

180,

65.

0% (5

8.0–

72.0

) 17

7/22

3, 7

9.4%

(74.

0–84

.7)

0.00

15

No

Pred

niso

lone

(n=4

13)

111/

204,

54.

4% (4

7.5–

61.3

) 12

5/20

6, 6

0.7%

(54.

0–67

.4)

0.23

87

/189

, 46.

0% (3

8.9–

53.2

) 14

6/21

5, 6

7.9

% (6

1.6–

74.2

) <0

.000

1

Val

acic

lovi

r (n=

413)

14

1/21

2, 6

6.5%

(60.

1–72

.9)

130/

200,

65.

0% (5

8.3–

71.7

) 0.

76

103/

189,

54.

5% (4

7.3–

61.7

) 16

7/21

8, 7

6.6%

(70.

9–82

.3)

<0.0

001

No

Val

acic

lovi

r (n=

416)

11

9/20

0, 5

9.5%

(52.

6–66

.4)

146/

214,

68.

2% (6

1.9–

74.5

) 0.

07

101/

180,

56.

1% (4

8.8–

63.4

) 15

6/22

0, 7

0.9%

(64.

9–77

.0)

0.00

24

a D

ata

mis

sing

for t

hree

pat

ient

s,b Dat

a m

issi

ng fo

r 22

patie

nts

32

at 12 months in relation to pain vs. no pain at day 11 to 17 were found in the prednisolone (65% vs. 79%, p=0.0015), no-prednisolone (46% vs. 68%, p=<0.0001), valaciclovir (55% vs. 77%, p=<0.0001), and no-valaciclovir groups (56% vs. 71%, p=0.0024) (Table 9). Time to facial recovery was shorter in patients with no pain compared with pain at day 11 to 17 (p<0.0001).

During the first month, painkillers were taken by 36 of 206 patients (17%) in the placebo plus placebo arm, 28 of 210 (13%) in prednisolone plus pla-cebo, 41 of 207 (20%) in valaciclovir plus placebo, and 32 of 206 (16%) in prednisolone plus valaciclovir (p=0.33). The most common painkillers were non-steroidal anti-inflammatory drugs followed by paracetamol.

Paper IV The effect of study design and analysis methods on recovery rates in Bell’s palsy a) Recovery rates for last observation carried forward, Sunnybrook=100 (n=829) With recovery defined as Sunnybrook scale score of 100, analysis of the 829 patients based on the intention-to-treat principle and last-observation-carried-forward method showed that 300 of the 416 patients (72%) in the prednisolone group had recovered at 12 months compared with 237 of 413 patients (57%) who did not receive prednisolone (Table 10 and Figure 2). For valaciclovir, the corresponding values at 12 months were 271 of 413 (66%) for the valaciclovir group and 266 of 416 (64%) in the no-valaciclovir group (Table 10).

b) Recovery rates for last observation carried forward, House-Brackmann=I (n=829) When House-Brackmann Grade I was defined as recovery, the recovery rates at 12 months in the 829 intention-to-treat patients were 324 of 416 (78%) for those receiving prednisolone and 266 of 413 (64%) for patients not receiving prednisolone (Table 10 and Figure 2). In the valaciclovir group, 297 of 413 (72%) had recovered, while in patients not treated with valaciclovir this fig-ure was 293 of 416 (70%) (Table 10).

c) Recovery rates in complete-case analysis, House-Brackmann=I (n=782) With recovery defined as House-Brackmann Grade I in patients followed until recovery (39 patients had House-Brackmann Grade I before 12-months) plus the remaining patients with a 12-month follow-up (n=782), 335 of 389 patients (86%) in the prednisolone group had recovered compared with 277 of 393 (70%) in the no-prednisolone group (Table 10 and Figure 2). The corresponding rates for valaciclovir/no-valaciclovir groups were 307 of 386 (80%) and 305 of 396 (77%) respectively (Table 10).

33

d) Recovery rates in complete-case analysis, House-Brackmann�II (n=797) When definition of recovery was House-Brackmann Grade II in patients followed until recovery plus the remaining patients with a 12-month follow-up (n=797), recovery rates were 380 of 396 (96%) in prednisolone-treated pa-tients and 353 of 401 (88%) in those not treated with prednisolone (Table 10 and Figure 2). The corresponding recovery in the valaciclovir group was 363 of 393 (92%) and in the no-valaciclovir group, 370 of 404 (92%) (Table 10).

Figure 2. Recovery rates in Bell’s palsy patients receiving prednisolone (n=416) and not receiving prednisolone (n=413). Last-observation-carried-forward method with recovery defined as Sunnybrook scale score of 100 and House-Brackmann Grade I, and complete-case analysis method with recovery defined as House-Brackmann Grade I and Grade II respectively.

Tabl

e 10

. Rec

over

y ra

tes i

n th

e tre

atm

ent g

roup

s acc

ordi

ng to

the

diff

eren

t met

hods

of a

naly

sis a

nd d

efin

ition

s of r

ecov

ery.

Pr

edni

solo

ne

n, %

(95%

CI)

N

o pr

edni

solo

ne

n, %

(95%

CI)

p

valu

e V

alac

iclo

vir

n, %

(95%

CI)

N

o va

laci

clov

ir n,

% (9

5% C

I)

p va

lue

a) L

ast o

bser

vatio

n ca

rrie

d fo

rwar

d,

Sunn

ybro

ok=1

00, n

=829

30

0/41

6, 7

2% (6

8–76

)23

7/41

3, 5

7% (5

3–62

) <0

.000

127

1/41

3, 6

6% (6

1–70

)26

6/41

6, 6

4% (5

9–69

)0.

66

b) L

ast o

bser

vatio

n ca

rried

forw

ard,

H

ouse

-Bra

ckm

ann=

I, n=

829

324/

416,

78%

(74–

82)

266/

413,

64%

(60–

69)

<0.0

001

297/

413,

72%

(68–

76)

293/

416,

70%

(66–

75)

0.65

c) C

ompl

ete-

case

ana

lysi

s, H

ouse

-Bra

ckm

ann=

I, n=

782

33

5/38

9, 8

6% (8

3–90

)27

7/39

3, 7

0% (6

6–75

) <0

.000

130

7/38

6, 8

0% (7

5–84

)30

5/39

6, 7

7% (7

3–81

)0.

44

d) C

ompl

ete-

case

ana

lysi

s, H

ouse

-Bra

ckm

ann≤

II, n

=797

38

0/39

6, 9

6% (9

4–98

)35

3/40

1, 8

8% (8

5–91

) <0

.000

136

3/39

3, 9

2% (9

0–95

)37

0/40

4, 9

2% (8

9–94

)0.

70

35

Discussion

In the large Scandinavian Bell’s palsy trial including 829 patients (Paper II), we found that patients who received prednisolone had a shorter time to com-plete recovery of facial function and a more favourable outcome at 12 months than patients who did not receive prednisolone. Furthermore, synki-nesis was less common in patients treated with prednisolone. Valaciclovir was not proven effective and not found to add effect to prednisolone.

Similar results of corticosteroid and antiviral treatment were reported in a recent Scottish trial including 551 patients randomly assigned to 10 days of prednisolone 25 mg twice daily, aciclovir 400 mg five times daily, both agents, or placebo (Sullivan et al. 2007). The investigators of that trial concluded that early treatment with prednisolone significantly improved the chances of com-plete recovery at 3 and 9 months, while there was no benefit of aciclovir.

The effect of prednisolone indicates that inflammation and edema of the facial nerve is part of the pathogenesis in Bell’s palsy. This agrees with pre-vious findings in per-operative (Fisch and Esslen 1972) and MRI studies (Schwaber et al. 1990, Engström et al. 1993). The anti-inflammatory effect of prednisolone may reduce neural and perineural edema, which in turn af-fects motor function.

Our study is the first large, placebo-controlled Bell’s palsy study testing valaciclovir alone against placebo. The bioavailability of valaciclovir is three-fold to five-fold that of aciclovir, implying a much higher anti-viral activity against herpes viruses (Lycke et al. 2003). We gave valaciclovir orally, 1,000 mg three times daily for seven days, providing a concentration well above the inhibitory level for herpes simplex virus but maybe only par-tially inhibitory for varicella zoster virus (Lycke et al. 2003). The ineffec-tiveness of valaciclovir may also be due to virus replication having declined before treatment start (Stjernquist-Desatnik et al. 2006), or that herpes vi-ruses are not the main cause of Bell’s palsy.

Prednisolone plus valaciclovir was not more effective on facial motor re-covery than prednisolone alone (Figure 1). This is in accordance with previ-ous findings using valaciclovir (Kawaguchi et al. 2007) or aciclovir (De Diego et al. 1998, Sullivan et al. 2007) plus corticosteroids. Nevertheless, an additional effect of aciclovir (Adour et al. 1996) or valaciclovir (Hato et al. 2007) on corticosteroids has been reported. However, the Adour trial (Adour et al. 1996) only followed patients for four months and the Hato study (Hato

36

et al. 2007) was not double-blinded; the results of both trials should therefore be interpreted with caution.

Although we found that prednisolone was effective in facial motor recov-ery, there was no significant treatment effect of prednisolone or valaciclovir on the incidence or intensity of pain around the ear, in the face or in the neck in Bell’s palsy (Paper III). This finding is in agreement with the study of Austin et al., which included 35 patients receiving prednisone and 41 receiv-ing placebo (Austin et al. 1993). They found no difference between the groups in the amount of pain after one week of treatment or at the time of facial recovery. On the contrary, Adour and co-workers reported that 15% of patients experienced a return of postauricular pain as prednisone was ta-pered, indicating that prednisone alleviated pain (Adour et al. 1972). How-ever, the Adour study was not blinded or randomised.

In total, 65% of patients experienced pain during the first 2 months. The incidence of ipsilateral pain was similar in all treatment groups during the first two weeks and then decreased. Surprisingly, 8% of patients still re-ported pain at 2 months. We also noted that many patients without pain at baseline experienced pain during follow-up; 118 of 369 patients (32%) re-ported pain for the first time at day 11 to 17.

There was no correlation between pain at baseline and recovery rates at 12 months. On the other hand, patients with pain at day 11 to 17 had signifi-cantly lower recovery rates at 12 months, which indicates that pain at 2 weeks is a negative prognostic factor for facial recovery. Pain as a risk factor for incomplete recovery has previously been reported (Hydén et al. 1982, Katusic et al. 1986, Gavilan et al. 1988, Peitersen 2002) while other workers found pain of no prognostic value (May et al. 1976, Adour et al. 1978, Chida et al. 2002). These conflicting results may be explained by a difference in time from onset of palsy to registration of pain, discrepancy in follow-up time, or definition of complete recovery.

In most Bell’s palsy trials (De Diego et al. 1998, Ünüvar et al. 1999, Lagalla et al. 2002, Sullivan et al. 2007), facial function is evaluated with the universally adopted House-Brackmann scale (House and Brackmann 1985). However, criticism has been raised to the House-Brackmann system. Crox-son and co-workers stated that House-Brackmann gives an overall impres-sion without measuring the strength of facial recovery. It is a discontinuous system as it places groups of patients into six categories (Croxson et al. 1990). Lewis & Adour concluded that House-Brackmann grading relies on the late, secondary defects of contracture and synkinesis and cannot be used to establish the extent of paralysis at onset or to evaluate rate of recovery (Lewis and Adour 1995). In contrast, the Sunnybrook system relies upon more precise measurements and the results are reported in a continuous manner by composite scores ranging from zero to 100 (Ross et al. 1996). The intra-rater and inter-rater reliability of the Sunnybrook system is high both when applied by novice and expert users (Hu et al. 2001), and is more

37

reliable than House-Brackmann (Kanerva et al. 2006). We found a moderate Kappa value (0.59) for the agreement between Sunnybrook and House-Brackmann systems (Paper I). Furthermore, the wide range of Sunnybrook gradings in House-Brackmann III to VI shows that there is an evaluative difference between these systems.

Most Japanese Bell’s palsy trials report facial function with the Yanagi-hara system (Yanagihara 1977, Hato et al. 2003, Hato et al. 2007, Kawaguchi et al. 2007). We found the overall highest agreement between the Sunnybrook and Yanagihara grading systems with a weighted Kappa value of 0.72 (Paper I). Both scales are regional, with evaluation of resting symme-try and assessment of function in different facial regions. In contrast to the Yanagihara scale, the Sunnybrook system also includes evaluation of secon-dary defects. Maximum deduction for secondary defects, using the Sunny-brook scale, is 15 points (severe sequelae) from a maximum score of 100 points.

The rates of complete facial recovery in Paper II were lower than those previously reported (De Diego et al. 1998, Peitersen 2002, Hato et al. 2007, Kawaguchi et al. 2007, Sullivan et al. 2007). We used Sunnybrook as our main grading system, but also included the widely used House-Brackmann system. Although the overall results were comparable between the two grad-ing systems, we found lower complete recovery rates when using Sunny-brook grading compared with House-Brackmann. This most probably re-flects the higher sensitivity for sequelae in the Sunnybrook system.

The analysis methods used in a Bell’s palsy trial also affect the results for complete recovery rates. The revised CONSORT statement for reporting randomised trials (Altman et al. 2001) advocates that all randomised patients are included in the ITT analysis. Consequently, the ITT population in Paper II was based on all 839 randomised patients, except for the 10 patients that did not take any study drug.

Paper IV highlights the impact of different analysis methods on recovery rates in Bell’s palsy. The choice of method substantially influenced the rate of recovery, which varied from 72% to 96% in the prednisolone group and from 66% to 92% in patients receiving valaciclovir. When we applied the complete-case analysis method with recovery defined as House-Brackmann=I (n=782), the recovery rate was 86% in the prednisolone group. By altering the definition of recovery from House-Brackmann Grade I to Grade ≤II, this rate increased from 86% to 96% in patients receiving predni-solone. In the trial of De Diego and co-workers (De Diego et al. 1998), the corresponding recovery rate in patients treated with prednisolone (followed until complete recovery or stabilization of the paralysis) was 94% (recovery defined as House-Brackmann score ≤II).

Several methods are available for dealing with missing data and dropouts in a clinical trial, but none is fully adequate (Streiner 2002, Lane 2008). In the Scandinavian Bell’s palsy trial, we applied the intention-to-treat principle

38

and used the last-observation-carried-forward method for missing data (Pa-per II). The rationale behind this approach is that it is conservative; it oper-ates against the hypothesis that people will improve over time, and thus un-derestimates rather than overestimates the degree of improvement (Streiner 2002, Lane 2008). Statisticians have, however, warned that imputing missing values with last observation carried forward can introduce bias (Lane 2008, Simpson et al. 2008).

In contrast to last observation carried forward, the complete-case analysis method excludes dropout patients and only includes patients with complete data. In Paper IV, the recovery rate (with recovery defined as House-Brackmann Grade I) in the prednisolone group was 86% with complete-case analysis and 78% with last-observation-carried-forward method. Thus, the complete-case analysis resulted in higher recovery rates than last observation carried forward. Criticism of the complete-case analysis method is that it reduces the sample size (and thus the power of the study) and that it may produce biased results unless data are missing completely at random (Fielding et al. 2008). Furthermore, this method does not analyse all random-ised patients according to the intention-to-treat principle, which is that rec-ommended in the CONSORT guidelines (Altman et al. 2001).

Inclusion and/or exclusion criteria in a study determine which patients may be evaluated, and thereby also influence the severity of palsy at base-line. This will affect the prognosis of the palsy (Gilden and Tyler 2007) and thereby also recovery rates. Another factor that impinges on recovery rates is the method used to assess facial function (Hato et al. 2008); grading facial function from photos (Sullivan et al. 2007, Hato et al. 2008) or videos has a lower sensitivity for minor sequelae and most probably results in higher recovery rates compared with live grading.

The impact of study design on recovery rates in Bell’s palsy has recently been aired (Gilden and Tyler 2007, Davenport et al. 2008, Hato et al. 2008). The results in Paper IV show that the comparison of recovery rates between different studies has to be carefully interpreted. If the study design is not taken into account, important methodological differences may be overlooked and comparisons between recovery rates in untreated patients (Peitersen 2002) and patients treated with prednisolone (Sullivan et al. 2007) may thereby result in erroneous conclusions (Romijn et al. 2008).

39

Conclusions

• Prednisolone shortened time to complete recovery of facial function in Bell’s palsy.

• Patients receiving prednisolone had higher recovery rates and lower rates of synkinesis at 12 months than those who did not receive predni-solone.

• Valaciclovir was not proven effective in Bell’s palsy and did not add any effect to prednisolone.

• Prednisolone and/or valaciclovir did not affect the incidence or intensity of ipsilateral pain in Bell’s palsy.

• In total, 65% of Bell’s palsy patients experienced ipsilateral pain at some time during the first two months of palsy and 8% still had pain after 2 months.

• Presence of pain at day 11 to 17 indicated a worse prognosis for facial recovery at 12 months.

• Recovery rates in a Bell’s palsy study are substantially affected by the choice of analysis method and definition of recovery.

• In terms of agreement, the Sunnybrook system scored at the same level as the predominating House-Brackmann and Yanagihara grading sys-tems. The highest agreement level was found between the Sunnybrook and Yanagihara grading scales.

• There is an evaluative difference between the Sunnybrook and House-Brackmann systems.

40

Acknowledgements

This investigation was carried out at the Departments of Otorhinolaryngol-ogy in the following hospitals in Sweden and Finland: Uppsala University Hospital, Uppsala; Helsinki University Central Hospital, Helsinki; Karolin-ska University Hospital, Stockholm; Lund University Hospital, Lund; Sahl-grenska University Hospital, Göteborg; Örebro University Hospital, Örebro; Hudiksvall County Hospital, Hudiksvall; Helsingborg County Hospital, Helsingborg; Malmö University Hospital, Malmö; Kristianstad County Hos-pital, Kristianstad; Karlstad County Hospital, Karlstad; Borås County Hospi-tal, Borås; Växjö Central Hospital, Växjö; Kalmar County Hospital, Kalmar; Sundsvall County Hospital, Sundsvall; Gävle County Hospital, Gävle. It was approved by Regional Ethics Review Boards and conducted in accor-dance with the Declaration of Helsinki and Good Clinical Practice guide-lines. Written informed consent was obtained from all patients. Firstly, I want to express my sincere gratitude to my supervisors: Lars Jonsson, for being my mentor and teaching me everything about Bell’s palsy and research – you are the ideal supervisor! I am very grateful for your expertise and enthusiasm plus all the time and energy you have put into my research over the years. Lasse, thank you for all the fun we’ve had together and for your close friendship! Mats Engström, for your supervision and enthusiasm. Thank you for all your hard work in making the Scandinavian Bell’s palsy study possible. Your enormous capacity and positive attitude makes everything possible. I even want to thank you for the “scientific” golf rounds in the mornings! Mats Holmström, for your supervision and enormous support. I am espe-cially grateful for your broad knowledge and experience within research and clinics that you so willingly share. You have always taken the time for dis-cussions and provided much valuable advice.

41

Furthermore I wish to thank:

Anne Pitkäranta, Mervi Kanerva, Anna Stjernquist-Desatnik, Sara Ax-elsson, Malou Hultcrantz, and Per Hanner, co-authors and members of the steering committee for the Scandinavian Bell’s palsy study, for most valuable collaboration over many years, fruitful discussions and helpful ad-vice with the manuscripts.

All particpating doctors, nurses and staff in the Scandinavian Bell’s palsy study for the tremendous work with the patients.

Morten Kildal, head of my department, for support and help in combining research and clinical work.

Nermin Hadziosmanovic, biostatistician and co-author, for valuable help with the statistics as well as interesting discussions.

Elin Marsk, co-author, for collaboration in one of the manuscripts.

Lars Berglund and Niclas Eriksson, biostatisticians, for help with the sta-tistics.

Pär Lundqvist, system developer, for developing the database.

Per Engervall, for help to initiate and implement the Scandinavian Bell’s palsy study.

Professor Adam Taube, for help with planning and final analysis of the study.

Professor Matti Anniko, for encouraging support.

Professor Bengt Gerdin, for valuable advice.

Michael Wainwright, for revision of the English.

Annette Johansson, for all the practical help with the Scandinavian Bell’s palsy study.

Colleagues and friends at the Departments of Plastic Surgery and Otorhi-nolaryngology for friendship, support and making my work a lot of fun.

My family; Mom and Dad for your endless support and always being there for me. You always respect and encourage my decisions. My brothers, Eirik and Elling, for being my best friends and always taking care of your little brother.

42

Financial support was received from Uppsala University, GlaxoSmithKline, Sweden, Pfizer AB, Sweden, Acta Otolaryngologica Foundation, Rosa and Emanuel Nachmansson’s Foundation, Stig and Ragna Gorthon Foundation, Torsten Birger Segerfalk Foundation, Margit Arstrup’s Foundation, County Council of Skåne, and Helsinki University Central Hospital Research Funds.

43

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