Evidence-based Guideline: Steroids

and antivirals for Bell palsy

Report of the Guideline Development
Subcommittee of the American Academy of
Neurology

2012 American Academy of Neurology

Authors
Gary Gronseth, MD, FAAN
Remia Paduga, MD

2012 American Academy of Neurology

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Presentation
Objectives

To present evidence published

since the 2001 American
Academy of Neurology (AAN)
practice parameter regarding the
effectiveness of steroids and
antiviral agents for Bell palsy.
To present evidence-based
recommendations

2012 American Academy of Neurology

Overview

Background
Gaps in care
AAN guideline process
Analysis of evidence, conclusions,
recommendations
Recommendations for future research

2012 American Academy of Neurology

Background
Bell palsy is an acute, peripheral facial
paresis of unknown cause.1 Usually
the diagnosis is established without
difficulty.2
Up to 30% of patients with Bell palsy
fail to recover facial function
completely.3 The disease is common,
with an annual incidence of 20 per
100,000.
Thousands of patients with Bell palsy
are left with permanent, potentially
disfiguring facial weakness each year.
2012 American Academy of Neurology

Background, cont.
In 2001 the Quality Standards

Subcommittee of the American

Academy of Neurology (AAN)
published an evidence-based practice
guideline for the treatment of Bell
palsy.4
The 2001 guideline concluded that
steroids were probably effective and
antivirals (acyclovir) possibly effective
in increasing the probability of
complete facial functional recovery in
patients with Bell palsy.

2012 American Academy of Neurology

Background, cont.
This update, developed by the AAN
Guideline Development Subcommittee
(see appendices e-1 and e-2 of the
published guideline), systematically
reviews studies published since June
2000 that are considered relevant to
this question: For patients with newonset Bell palsy, does treatment with
steroids or antiviral agents (acyclovir,
famciclovir, valacyclovir) improve
facial functional recovery?
2012 American Academy of Neurology

Gaps in Care
The 2001 guideline found moderate

evidence for steroid use and modest

evidence for antiviral use.
Since the 2001 guideline publication,
new, well-designed studies examining
steroid and antiviral treatment of Bell
palsy have been published.

2012 American Academy of Neurology

Gaps in Care, cont.

This new evidence led to modified
recommendations in the updated
guideline publication.
Stronger evidence supports steroid use.
Stronger evidence also indicates that
adding an antiviral to steroid treatment
does not improve outcome to a significant
extent.
However, a slight degree of improvement
from addition of antivirals cannot be
completely ruled out, especially in severe
cases of Bell palsy.
2012 American Academy of Neurology

AAN Guideline Process

Clinical Question

Evidence

Conclusions

Recommendations
2012 American Academy of Neurology

Clinical Questions
For patients with new-onset Bell palsy

does treatment with steroids improve

facial functional recovery?
For patients with new-onset Bell palsy
does treatment with antiviral agents
improve facial functional recovery?

2012 American Academy of Neurology

Literature
Search/Review

Rigorous, Comprehensive, Transparent

Search

Search
Review
abstracts
Review full
text

Relevant

2012 American Academy of Neurology

Select
articles

AAN Classification of
Evidence
All studies meeting

inclusion/exclusion criteria defined

a priori rated Class I, II, III, or IV
Five different classification
systems
Therapeutic
Randomization, control, blinding

Diagnostic
Comparison with gold standard

Prognostic
Screening
Causation
2012 American Academy of Neurology

AAN Level of
Recommendations
A = Established as effective, ineffective or
harmful (or established as useful/predictive or not
useful/predictive) for the given condition in the
specified population
B = Probably effective, ineffective or harmful (or
probably useful/predictive or not
useful/predictive) for the given condition in the
specified population
C = Possibly effective, ineffective or harmful (or
possibly useful/predictive or not useful/predictive)
for the given condition in the specified population
U = Data inadequate or conflicting; given current
knowledge, treatment (test, predictor) is
unproven
Note that recommendations can be positive or negative
2012 American Academy of Neurology

Translating Class to
Recommendations

A = Requires at least two consistent Class

I studies*
B = Requires at least one Class I study or
two consistent Class II studies
C = Requires at least one Class II study or
two consistent Class III studies
U = Assigned in cases of only one Class III
study, only Class IV studies, or evidence
that is conflicting and cannot be reconciled
* In exceptional cases, one convincing Class I study may suffice for an A
recommendation if 1) all criteria are met, 2) the magnitude of effect is
large (relative rate improved outcome >5 and the lower limit of the
confidence interval is >2).
2012 American Academy of Neurology

Applying the Process

to the Issue

We will now turn our attention to

the guideline.

2012 American Academy of Neurology

Methods
MEDLINE and Cochrane Database of
Systematic Reviews and Controlled
Clinical trials were searched.

June 2000 through January 2012

Used the term Bells Palsy and the sensitive,
therapeutic clinical filer

Both authors reviewed each article for

inclusion.
Risk of bias was determined using the
classification of evidence scheme for
therapeutic articles.
Strength of recommendations was
linked directly to evidence levels.
Conflicts of interest were disclosed.
2012 American Academy of Neurology

Literature
Search/Review

Rigorous, Comprehensive, Transparent

340
abstracts

9
articles
2012 American Academy of Neurology

Inclusion criteria:

-Controlled trials with

prospective data
collection comparing
outcomes in patients
treated with steroids or
antiviral agents with
patients not treated with
these medications
-Facial functional
recovery defined as
good or complete
using the same criteria
from the 2001 practice
guideline

Exclusion
criteria:

-Case reports, review

articles

AAN Classification of
Evidence
Class I: A randomized, controlled clinical trial
for
Therapeutic
of the intervention of interest with masked or
objective outcome assessment, in a
Intervention
representative population. Relevant baseline
characteristics are presented and
substantially equivalent among treatment
groups or there is appropriate statistical
adjustment for differences. The following are
also required:

Concealed allocation
Primary outcome(s) clearly defined
Exclusion/inclusion criteria clearly defined
Adequate accounting for dropouts (with at least 80%
of enrolled subjects completing the study) and
crossovers with numbers sufficiently low to have
minimal potential for bias.

2012 American Academy of Neurology

AAN Classification of
Evidence
For noninferiority or equivalence trials claiming
for
Therapeutic
to prove
efficacy for one or both drugs, the
following are also required*:
Intervention
The authors explicitly state the clinically meaningful

difference to be excluded by defining the threshold for

equivalence or noninferiority.
The standard treatment used in the study is
substantially similar to that used in previous studies
establishing efficacy of the standard treatment (e.g.,
for a drug, the mode of administration, dose and
dosage adjustments are similar to those previously
shown to be effective).
The inclusion and exclusion criteria for patient
selection and the outcomes of patients on the standard
treatment are comparable to those of previous studies
establishing efficacy of the standard treatment.
The interpretation of the results of the study is based
upon a per protocol analysis that takes into account
dropouts or crossovers.

2012 American Academy of Neurology

AAN Classification of
Evidence
Class II: A randomized controlled clinical trial of the
for
Diagnostic
Accuracy,
intervention
of interest in a representative
population with masked or objective outcome
cont.
assessment that lacks one criteria ae above or a
prospective matched cohort study with masked or
objective outcome assessment in a representative
population that meets be above. Relevant baseline
characteristics are presented and substantially
equivalent among treatment groups or there is
appropriate statistical adjustment for differences.
Class III: All other controlled trials (including welldefined natural history controls or patients serving
as own controls) in a representative population,
where outcome is independently assessed, or
independently derived by objective outcome
measurement.**
2012 American Academy of Neurology

AAN Classification of
Evidence
Class IV: Studies not meeting Class I, II or III
for
Diagnostic
Accuracy,
criteria including consensus or expert
cont.
opinion.
*Note that numbers 13 in Class I, item 5 are required for
Class II in equivalence trials. If any one of the three is
missing, the class is automatically downgraded to Class III.
**Objective outcome measurement: an outcome measure that
is unlikely to be affected by an observers (patient, treating
physician, investigator) expectation or bias (e.g., blood
tests, administrative outcome data).

2012 American Academy of Neurology

Clinical Question 1
For patients with new-onset Bell palsy
does treatment with steroids improve
facial functional recovery?

2012 American Academy of Neurology

Steroids: Conclusion
For patients with new-onset Bell
palsy, it is highly likely that steroids
are effective in increasing the
probability of complete facial
functional recovery (number needed
to treat 6 to 8, two Class I studies).
.

2012 American Academy of Neurology

Steroids:
Recommendation
For patients with new-onset Bell palsy,
oral steroids should be offered to
increase the probability of recovery of
facial nerve function (Level A).

2012 American Academy of Neurology

Clinical Question 2
For patients with new-onset Bell palsy
does treatment with antiviral agents
improve facial functional recovery?

2012 American Academy of Neurology

Antivirals: Conclusions
For patients with acute-onset Bell palsy,
it is highly likely that antivirals do not
moderately (risk difference [RD] > 7%)
increase the likelihood of improved
facial functional recovery (two Class I
studies).
The pooled results of studies with a low
risk of bias lack the statistical precision
to exclude a modest benefit (RD
favoring antivirals < 7%) or modest
harm (RD favoring steroids alone < 8%).
.
2012 American Academy of Neurology

Antivirals:
Recommendations
For patients with new-onset Bell palsy,

antivirals (in addition to steroids)

might be offered to increase the
probability of recovery of facial
function (Level C).
Patients offered antivirals should be
counseled that a benefit from
antivirals has not been established,
and, if there is a benefit, it is likely
that it is modest at best (RD < 7%).

2012 American Academy of Neurology

Clinical Context
Although there is strong evidence that
steroid use increases the probability of
good facial functional recovery in patients
with Bell palsy, it does not necessarily
follow that all patients with Bell palsy
need to take steroids.
For example, it would be reasonable for a
clinician to opt not to use steroids in a
patient with brittle diabetes mellitus.
Other comorbidities potentially requiring
further consideration include morbid
obesity, osteopenia, and a prior history of
steroid intolerance.
2012 American Academy of Neurology

Clinical Context, cont.

We found limited evidence of the efficacy
of steroids and antivirals in important Bell
palsy subgroups, including those with a
lower probability of recovery because of
severe palsy at presentation and those
with possible zoster sine herpete.
Such studies are particularly important
relative to the efficacy of the addition of
antivirals to steroids given the lack of
evidence for moderate efficacy in the
typical patient with Bell palsy.

2012 American Academy of Neurology

Clinical Context, cont.

Authors of one Class I study5 performed
a preplanned subgroup analysis on
patients with severe palsy at
presentation6 defined by a Sunnybrook
scale score of 0 to 25.
This analysis showed no significant difference
in 12-month recovery rates between patients
treated with prednisolone alone as compared
with patients treated with prednisolone plus
valacyclovir (RD 0.2% favoring valacyclovir
95% CI, -18% to 17.6%).
The analysis lacked the statistical precision to
exclude an important beneficial effect (or
harm) from the addition of valacyclovir.
2012 American Academy of Neurology

Clinical Context, cont.

A Class IV study7 observed a
significant improvement in recovery
(RD 26.6%) between patients with
severe Bell palsy treated with
prednisone alone and patients with
severe Bell palsy treated with
prednisone plus famciclovir (HouseBrackmann Scale score of 5 or 6).
This study had a high risk of bias because
of pseudo-randomized treatment allocation
and unmasked outcome assessment.
2012 American Academy of Neurology

Clinical Context, cont.

Relative to zoster sine herpete, a Class IV

study8 observed no significant difference in

recovery after treatment with prednisolone
alone as compared with treatment with
prednisolone plus valacyclovir in a
subgroup of 28 patients with evidence of
zoster reactivation (hazard ratio for
recovery 1.6 favoring prednisolone plus
valacyclovir, 95% CI 0.4 to 6.1).

The small sample size and high risk of bias make

this observation inconclusive.
These studies in aggregate do not provide
strong evidence to identify subgroups of patients
that might benefit more or less from treatment.
2012 American Academy of Neurology

Clinical Context, cont.

Because the studies included only
patients presenting early after palsy
onset, it is difficult to determine the effect
of steroid or antiviral treatment in
patients presenting later in the course of
their illness (e.g., one week after the
onset of facial weakness).
Likewise, although it seems reasonable to
assume that an equivalent dose of
alternative steroids would also be
effective, decisions regarding alternative
steroid dosing regimens necessarily
require clinician judgment.
2012 American Academy of Neurology

Future Research
Recommendations
It is unlikely that additional research

regarding the efficacy of steroids will

change the current estimate of its effect.
Large randomized trials comparing
outcomes in patients with Bell palsy
receiving steroids with or without
antivirals would help in determining
whether the addition of antivirals to
steroid treatment results in a modest
benefit.
Such trials should be powered to allow
prespecified subgroup analyses of
patients with a poorer prognosis and of
patients with possible zoster sine herpete.
2012 American Academy of Neurology

Future Research
Recommendations,
Further future research efforts should be
cont.
directed toward finding the optimal dose
and timing of steroids, the effect of other
therapeutic modalities, and the
identification of the effect of steroids in
specific populations, such as in children.

2012 American Academy of Neurology

References
1.
2.
3.
4.

5.
6.
7.
8.

Hauser WA, Karnes WE, Annis J, Kurland LT. Incidence and prognosis of
Bells palsy in the population of Rochester, Minnesota. Mayo Clin Proc
1971;46:258264.
Katusic SK, Beard CM, Wiederholt WC, et al. Incidence, clinical features,
and prognosis in Bell's palsy. Ann Neurol 1986;20:622627.
Peitersen E. The natural history of Bells palsy. Am J Otology 1982;4:107
111.
Grogan PM, Gronseth GS. Practice parameter: Steroids, acyclovir, and
surgery for Bells palsy (an evidence-based review): report of the Quality
Standards Subcommittee of the American Academy of Neurology.
Neurology 2001;56:830836.
Engstrm M, Berg T, Stjemquist-Desatnik A, et al. Prednisolone and
valaciclovir in Bells palsy: a randomised double-blind, placebo controlled,
multicentre trial. Lancet Neurology 2008;7:9931000.
de Ru JA, van Benthem PPG, Janssen LM. Is antiviral medication for severe
Bells palsy still useful? Lancet Neurol 2009;8:509; author reply 509510.
Minnerop M, Herbst M, Fimmers R, Matz B, Klockgether T, Wullner U. Bells
palsy: Combined treatment of famciclovir and prednisone is superior to
prednisone alone. J Neurol 2008;255:17261730.
Kawaguchi K, Inamura H, Abe Y, et al. Reactivation of herpes simplex virus
type 1 and varicella-zoster virus and therapeutic effects of combination
therapy with prednisolone and valacyclovir in patients with Bells Palsy.
The Laryngoscope 2007;117:147156.

2012 American Academy of Neurology

References, cont.
For a complete list of
references, please access the
full guideline at
www.aan.com/guidelines.

2012 American Academy of Neurology

Question-and-Answer
Period
Questions/comments?

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Closing
To access the complete guideline
and related guideline summary
tools, visit
www.aan.com/guidelines.
Thank you for your participation!

2012 American Academy of Neurology