LMN Facial Palsy, Corticosteroids, Acyclovir

1. Bell’s Palsy:
To Treat or Not to Treat

2. Road Map for the Session
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Historical Perspective and Introduction
Risk Factors
Study Proper
Strengths and Limitations
Review of evidence

3. Road Map for the Session
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•
Historical Perspective and Introduction
Risk Factors
Study Proper
Strengths and Limitations
Review of evidence

4. Early Treatment with
Prednisolone or Acyclovir
in Bell’s Palsy
NEJM 2008;357;1598-607

5. Historical Perspectives
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Sir Charles Bell (1774-1842)
– Studied facial anatomy
extensively during Battle of
Waterloo
– Concluded that facial nerve
controlled facial expression
– “Respiratory nerve of the Face”

6. Anatomy of Facial Canal
Tympanic
1.53 mm
Mastoid
1.48 mm
Labyrinthine
1.02 mm
0.68 mm
Coker NJ. Atlas of Otologic Surgery p.339

7. Bell’s Palsy
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Idiopathic facial paralysis
Diagnosis of Exclusion
Most common diagnosis
(> 60%) for acute facial palsy
30 per 100,000
Generally unilateral
Rapid onset < 48 hours

8. Complete Recovery
71
6
Peitersen E. Acta Otolaryngol 2002;549:4–30.

9. Favorable prognosis for
full recovery
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Incomplete palsy
Early recovery
Young patients
Normal taste, stapedial reflex, lacrimation
Lack of post-auricular pain
Peitersen E. Acta Otolaryngol 2002;549:4–30.

10. Road Map for the Session
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Historical Perspective and Introduction
Risk Factors
Study Proper
Strengths and Limitations
Review of evidence

11. Postulated mechanism of
Bell’s Palsy
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Viral inflammatory/ immune
mechanism
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HSV (based on serological evidence)
HZV
Other: CMV, EBV, adenovirus, rubella virus,
mumps, influenza B, and coxsackievirus
Alternate postulated mechanisms
– Ischemia of the facial nerve
– Hereditary predisposition

12. Diabetes Mellitus
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Bell’s patients with DM
– 14 % (Korczyn AD ’71)
– 21 % (Alford BR ’71)
– 38 % (Yasuda K ’75)
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66% demonstrate glucose intolerance
Functional recovery poorer in diabetics

13. Pregnancy
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Incidence of Bell’s palsy 3-4 x higher
(Hilsinger, Cohen et al.)
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Third trimester with highest risk
Higher risk of complete palsy
Lower chance of complete recovery
(Gillman et al.)
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Preeclampsia 6 x prevalence in pregnant
women with facial palsy

14. Role of HSV-1
Murakami: Ann Intern Med, Volume 124(1).January 1, 1996.27-30

15. Management of Bell’s Palsy
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Observation
Medical Treatment
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Surgery
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Steroid
Anti-viral agents
Decompression
Dynamic vs. static reanimation
Facial Rehabilitation

16. Road Map for the Session
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Historical Perspective and Introduction
Risk Factors
Study Proper
Strengths and Limitations
Review of evidence

17. Hypothesis
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To determine whether Prednisolone or
Acyclovir used early in the course of
Bell’s Palsy improves the chances of
recovery

18. Selection of Subjects
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> 16 YO age
Males and Females
Presenting with unilateral facial nerve
weakness of no identifiable cause who
could be referred to collaborating ENT
within 72 hours from the onset of
symptoms
17 hospitals throughout Scotland serving
88% of total population

19. Exclusion Criteria
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Pregnancy
Breast-feeding
Uncontrolled diabetes (Hgb A1C > 8%)
Peptic Ulcer Disease
Suppurative otitis media
Herpes zoster
Multiple Sclerosis
Systemic infection
Sarcoidosis and other rare conditions
Inability to provide informed consent

20. Study Design
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Double-blind, placebo-controlled, randomized, 2 x 2
factorial trial
Conducted from 6/2004 ~ 6/2006, f/u till 3/2007 for 9
month assessments
Patients were recruited through their family doctors,
emergency departments, the national 24-hour
medical telephone consultancy service, and dentists’
office
Referrals mainly from primary care to 17 hospitals
serving 88% of total population in mainland Scotland
Collaborating senior ENT confirmed eligibility

21. Study Design
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Patient was randomly assigned to a study group by an
independent, secure, automated telephone-randomization
service
Patients underwent randomization twice which resulted in 4
study groups
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Prednisolone + Placebo
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Acyclovir + Placebo
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Prednisolone + Acyclovir
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Placebo + Placebo
*Prednisolone (25mg PO BID)
*Acyclovir (400mg PO 5X/Day)
*Placebo (Lactose pill)
Each patient received 2 bottles of odorless capsules with an
identical appearance prepared by Tayside pharmaceuticals

22. Enrollment & Outcomes
551 randomized
Acyclovir
(N=272)
Placebo
(N=279)
Prednisolone
(N=134)
Placebo
(N=138)
Prednisolone
(N=138)
Placebo
(N=141)
Acyclovir + Prednisolone
124 completed Tx
Acyclovir + Placebo
123 completed Tx
Placebo + Prednisolone
127 completed Tx
Placebo + Placebo
122 completed Tx

23. Study Design
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Patients were instructed to take the first dose of the study drug
before leaving the hospital and the remaining doses at home
during the next 10 days
Within 3 to 5 days after randomization, a researcher visited
patients to complete a baseline assessment
Repeat visits to assess recovery occurred at 3 months
If recovery was incomplete (> grade 2 on House-Brackmann
scale), the visit was repeated at 9 months
Compliance with the drug regimen was reviewed at the first visit
and via telephone calls on day 7 after randomization and within
a week after the last scheduled dose (day 10)

24. Outcome Measurements
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Primary outcome measure
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House-Brackmann grading system for facial nerve function
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Assigns to one of six categories with grade 1 indicating normal
function
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Assessed by documenting the facial appearance of patients in
digital photographic images in four facial expressions:
• At rest
• Raised eyebrows
• Eyes tightly closed
• Forced smile
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Graded by panel of 3 experts (ENT, Neurologist, Plastic
surgeon), discrepancies were reassessed

25. House-Brackmann Grading
System
Grade
Gross characteristics
Motion characteristics
I. Normal
Normal in all areas
Normal in all areas
II. Mild dysfunction
Slight weakness noticeable on close
Forehead: moderate to good
III. Moderate dysfunction
Obvious but not disfiguring difference
Forehead: slight to moderate
IV. Mod severe dysfunction
Obvious weakness and/or disfiguring
Forehead: none
Eye: incomplete closure
Mouth: asymmetry at rest
V. Severe dysfunction
Only barely perceptible motion
Asymmetry at rest
Forehead: none
Eye: incomplete closure
Mouth: slight movement
VI. Total paralysis
No movement
No movement
inspection
May have slight synkinesis
Normal symmetry and tone at rest
between the two sides
Noticeable but not severe synkinesis,
contracture, or hemifacial spasm
Normal symmetry and tone at rest
asymmetry
Normal symmetry and tone at rest
function
Eye: complete closure with
minimal effort
Mouth: slight asymmetry
movement
Eye: complete closure with effort
Mouth: slight weak with maximum
effort

26. Outcome Measurements
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Secondary outcomes
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Health Utilities Index Mark 3
• System for classifying health-related quality of life status
in 8 dimensions: vision, hearing, speech, ambulation,
dexterity, emotion, cognition, and pain
• Responses converted into single score ranging from
-0.36 to 1.00 with 1 indicating full health
Derriford Appearance Scale 59
• 59 questions covering aspects of self-consciousness
and confidence
• Scores range from 8 to 262 with higher scores indicating
a greater severity of distress/ dysfunction
Brief Pain Inventory
• Measures both the severity of pain and the extent to
which pain interferes with normal activities
• Scores range from 0 to 110 with higher scores indicating
greater severity

27. Statistical Analysis
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Compared primary outcome measure of complete
recovery (grade 1 on House-Brackmann scale) at 3
months and 9 months using a two-sided Fisher’s exact
test for:
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Prednisolone vs. no prednisolone
Acyclovir vs. no acyclovir
Prednisolone vs. Placebo
Acyclovir vs. Placebo
Prednisolone + Acyclovir vs. Placebo
Prespecified secondary analyses compared scores
with the use of t-tests (or Mann-Whitney tests in cases
in which the data was not normally distributed)

28. Study Population
Baseline Characteristics of the
Patients
Characteristic
Prednisolone
(N=251)
No
Prednisolone
(N=245)
Acyclovir
(N=247)
No
Acyclovir
(N=249)
Total
(N=496)
Sex – no. (%)
 Male
 Female
135 (53.8)
116 (46.2)
118 (48.2)
127 (51.8)
119
(48.2)
128
(51.8)
134
(53.8)
115
(46.2)
253
(51.0)
243
(49.0)
Age - year
43.2±16.2
44.9±16.6
45.0±16.6
43.0±16.1
44.0±16.4
House-Brackmann Scale
3.5±1.2
3.8±1.3
3.6±1.3
3.7±1.2
3.6±1.3
Health Utilities Index Mark 3
Derriford Appearance Scale
0.80±0.22
71±37
10±18
0.78±0.21
75±41
16±21
0.79±0.21
72±39
12±18
0.78±0.22
74±38
14±21
0.79±0.22
73±39
13±20
120 (47.8)
95 (37.8)
147 (60.0)
64 (26.1)
137
(55.5)
130
(52.2)
267
(53.8)
59
Brief Pain Inventory
Time between onset of Sx and
Tx – no. (%)
 Within 24 hours
 >24 to ≤48 hours

29. Adjusted Outcome Data
Primary and Secondary Outcomes at 3
Months and 9 Months
Variable
Primary Outcome Measure1
Grade 1 on House-Brackmann
Scale
 At 3 Months
 At 9 Months
Seconday outcome Measures2
Prednisolone
(N=251)
No./Total No.
205/247 (83.0)
237/251 (94.4)
Unadjusted
No
Prednisolone
(N=245)
Adjusted Odds
Ratio (95% CI)
P Value
(%)
Acyclovir
(N=247)
No./Total No.
152/239 (63.6)
200/245 (81.6)
2.44 (1.55–3.84)
3.32 (1.72–6.44)
Mean
<0.001
<0.001
Adjusted Beta
173/243 (71.2)
211/247 (85.4)
Unadjusted
No Acyclovir
(N=249)
Adjusted Odds
Ratio (95% CI)
P Value
184/243 (75.7)
226/249 (90.8)
0.86 (0.55–1.34)
0.61 (0.33–1.11)
0.50
0.10
Mean
Adjusted Beta
(%)
Health Utilities Index Mark 3
 At 3 Months
 At 9 Months
0.91±0.17
0.84±0.26
0.91±0.13
0.88±0.16
−0.01±0.01
−0.06±0.03
0.40
0.04
0.90±0.16
0.86±0.21
0.92±0.14
0.88±0.19
−0.01±0.01
−0.02±0.03
0.32
0.38
Derriford Appearance Scale 59
 At 3 Months
 At 9 Months
42.4±32.3
40.0±36.1
43.2±33.4
49.9±35.5
1.72±2.88
−2.40±5.71
0.55
0.67
44.2±35.0
49.4±35.2
41.4±30.4
43.2±36.6
3.08±2.85
8.53±5.36
0.28
0.11
Brief Pain Inventory
 At 3 Months
 At 9 Months
1.51±6.41
1.36±5.29
2.04±8.14
1.83±6.37
−0.12±0.67
−0.08±1.02
0.85
0.94
1.83±7.00
1.61±5.87
1.72±7.62
1.72±6.19
0.13±0.66
0.05±0.96
0.84
0.96
For the primary outcome measure, odds ratios and P values have been adjusted for age, sex, the baseline score on the House-Brackmann scale, the receipt or
nonreceipt of acyclovir and prenisolone, and the interval between the onset of symptoms and the initiation of a study drug
2.
For the secondary outcome measures, odds ratios and P values have been adjusted for baseline measurement of age, sex, score on the House-Brackmann scale, the
receipt or nonreceipt of acyclovir and prenisolone, and the time from the onset of symptoms to the initiation of treatment.
**Beta regression coefficients were calculated by adjusted multiple regression analysis.
1.

30. Summary of Table 2
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Statistically significant recovery rate between Prednisolone
comparison groups at 3 months
At 9 months, the rates of complete recovery were 94.4% for
patients who received Prednisolone and 81.6% for those who
did not, a difference of 12.8% points (95% CI, 7.2 to 18.4;
P<0.001)
No significant difference in complete recovery rates between the
Acyclovir comparison groups
For patients receiving double Placebo, 64.7% were fully
recovered after 3 months, and 85.2% after 9 months
Generally there were no significant differences among the
groups in secondary outcome measures, including patients who
received Prednisolone

31. Proportion of normal facial
function
Figure 2.
NEJM 2008;357;1605
at baseline, at 3 months, and at 9 months
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Full recovery was defined as grade 1 on the HouseBrackmann facial nerve grading scale, which
ranges from 1 to 6, with higher grades indicating
worse facial paralysis.

32. Adjusted Outcome Data
Table 3.
NEJM 2008;357;1604
Complete Recovery at 3 Months and 9
Months
Variable
(+) Prednisolone
(−) Prednisolone
Odds Ratio (95% CI)
P Value
Odds Ratio (95% CI)
P Value
At 3 Months
(+) Acyclovir
(−) Acyclovir
1.73 (0.96–3.12)
2.58 (1.37–4.88)
0.07
0.003
0.85 (0.49–1.47)
1.00
0.57
At 9 Months
(+) Acyclovir
(−) Acyclovir
1.76 (0.74–4.16)
3.23 (1.13–9.22)
0.20
0.03
0.58 (0.29–1.16)
1.00
0.12
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Significance testing for comparisons at 3 and 9 months had the following results:
combination therapy versus prednisolone only, P = 0.18 (3 months) and P = 0.28 (9
months)
combination therapy versus acyclovir only, P = 0.004 (3 months) and P = 0.001 (9 months)
acyclovir only versus double placebo, P = 0.79 (3 months) and P = 0.19 (9 months)
prednisolone only versus double placebo, P<0.001 (3 months) and P = 0.004 (9 months)
**
P values are for the comparison with double placebo
Conclusion: Prednisolone was highly effective, both separately and in
combination with Acyclovir. Acyclovir was ineffective, both separately and
as an addition to Prednisolone.

33. Discussion
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For patients receiving double Placebo, 64.7% of
patients fully recovered at 3 months and 85.2% at 9
months, which shows a generally favorable outcome
without treatment
Early treatment (within 72 hours from onset of
symptoms) with Prednisolone increased the rate of
complete recovery to 83.0% at 3 months and 94.4%
at 9 months
Acyclovir produced no benefit over Placebo and
there was no benefit in its addition to Prednisolone
No benefits observed with respect to secondary
outcome measures in any study group

34. Discussion
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A total of 426 patients (86%) returned pill
containers. Of these patients,
– 383 (90%) returned empty containers, indicating
complete compliance
– 32 (8%) returned doses for 5 days or less
– 11 (3%) patients returned doses for 6 days or
more
Dizziness was the most reported adverse reaction
in all four study groups

35. Road Map for the Session
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Historical Perspective and Introduction
Risk Factors
Study Proper
Strengths and Limitations
Review of evidence

36. Strengths
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Most patients recruited from primary care practices,
thus reducing selection bias in hospital-based studies
High rate of acceptance of randomization and low
dropout rate during the study
Since the study design was factorial, the power was
the same for each pairwise comparison of treatment
Drugs used in this study are relatively inexpensive and
readily available

37. Limitations
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Application in some populations with prevalent genetic
polymorphisms?
Could other environmental factors such as diet alter the response?
House-Brackmann scale has been criticized for insufficient sensitivity
to change and difficulty in assigning grades in patients with contrasting
degrees of function in different parts of the face
Previous h/o Bell’s Palsy (recurrence)?
Drug compliance with Acyclovir?
Age of study population?
Outbreak of HSV or any signs of other viral infection prior to Bell’s
Palsy?
Any underlying diseases/ illnesses and possible drug interactions?

38. Road Map for the Session
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Historical Perspective and Introduction
Risk Factors
Study Proper
Strengths and Limitations
Review of evidence

39. Cochrane review on Efficacy of
steroids
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4 trials of 179 patients
Trial 1: Cortisone vs. placebo
Trial 2: Prednisone + vitamins vs. vitamins
Trial 3: High dose prednisone vs. saline
Trial 4: Methylprednisolone
Primary endpoint: VII recovery @ 6 mos
Conclusions: NO significant benefit for giving
steroids to Bell’s palsy patients
Drawbacks: Individual studies underpowered.
Steroid regimens differ.

40. Efficacy of Steroid treatment
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Prospective RCT
56 patients
Arm I: Steroids
Arm II: Placebo
Success = HB I or II
F/u @ 3 and 6 weeks
No significant difference in response in the
2 groups
Turk-Boru U et al. Kulak Burun Bogaz Ihtis Derg. 2005;14(3-4):62-6.

41. Steroids in Complete paralysis
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Meta-analysis of 3 prospective trials
– 230 patients with HB VI
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Treatment within 7 days of onset
Total prednisone dose > 400 mg
(405-425 mg)
Complete Recovery: HB VI  I
– Steroid group has 17% higher rate of CR
than control (placebo/ no treatment)
Ramsey MJ et al. Laryngoscope 2000; 110: 335-341

42. Steroid vs. Steroid + Acyclovir
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Double-blind RCT
99 Bell’s palsy patients
– 53 treated with acyclovir- prednisone
– 46 with placebo – prednisone
– Prednisone dose 400 mg five times daily x 10 days
Combined therapy is better in terms of:
– Return of muscle motion
– Prevention of partial nerve degeneration
Adour KK 1996 Ann Otol Rhinol Laryngol. 1996 May;105(5):371-8

43. Steroid vs. Steroid + Acyclovir
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Prednisolone
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Prednisolone +
Valacyclovir
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Prospective RCT of
150 patients
Prednisolone (20 tid x
5d, 10 tid x 3 d, 10 qD
x 2 d)
Predisolone +
Valacyclovir (500 bid x
5 d)
No significant
difference in recovery
Kawaguchi: Laryngoscope, Volume 117(1).January 2007.147-156

44. History of Surgical Decompression
Adour KK. 2002 Jan;259(1):40-7

45. Controversy over
Surgical Decompression
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In favor of:
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Gantz BJ ’99
Sillman JS ’92
Huges GB ’88
Goin DW ’82
Fisch U ’81
Brackmann DE ’80
Giancarlo HR ’70
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Against:
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Adour KK ’01
Aoyagi M ’88
May M ’84
Gacek RR ’81
McNeill R ’94
Adour KK ’91
Mechelse K ’98

46. Applications to Clinical
Practice
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No data are available regarding how best
to treat patients who present more than
72 hours from the onset of symptoms, so
all patients with suspected Bell’s Palsy
should be assessed as early as possible
Withholding treatment will remain an
appropriate strategy for some patients as
most patients recover fully without any
treatment

47. Future Studies
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Use of Valcyclovir 1g PO TID x 7 days
since higher absorption and serum
levels are possible than Acyclovir
Exclusion of recurrent Bell’s Palsy
Study in populations with prevalent
genetic polymorphisms

48. ANY QUESTIONS???