Transcript Evidence-based Guideline Update: NSAIDs, and other

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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©2012 American Academy of Neurology
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
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
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
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
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 new-onset 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, welldesigned 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
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

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 “Bell’s Palsy” and the sensitive, therapeutic
clinical filer
 Both authors reviewed each article for inclusion.
 Risk of bias was determined using the
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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
Inclusion criteria:
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-
9 articles
©2012 American Academy of Neurology
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
for Therapeutic Intervention
 Class I: A randomized, controlled clinical trial of the
intervention of interest with masked or objective outcome
assessment, in a 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 Therapeutic Intervention
• For noninferiority or equivalence trials claiming to prove
efficacy for one or both drugs, the following are also
required*:
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
for Diagnostic Accuracy, cont.
 Class II: A randomized controlled clinical trial of the
intervention of interest in a representative population with
masked or objective outcome assessment that lacks one
criteria ae above or a prospective matched cohort study
with masked or objective outcome assessment in a
representative population that meets be 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 well-defined
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
for Diagnostic Accuracy, cont.
 Class IV: Studies not meeting Class I, II or III criteria
including consensus or expert opinion.
*Note that numbers 13 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 observer’s (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
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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
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(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
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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 12month 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
(House-Brackmann Scale score of 5 or 6).
• This study had a high risk of bias because of pseudorandomized 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
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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, cont.
 Further future research efforts should be 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
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2.
3.
4.
5.
6.
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8.
Hauser WA, Karnes WE, Annis J, Kurland LT. Incidence and prognosis of Bell’s palsy in the
population of Rochester, Minnesota. Mayo Clin Proc 1971;46:258–264.
Katusic SK, Beard CM, Wiederholt WC, et al. Incidence, clinical features, and prognosis in
Bell's palsy. Ann Neurol 1986;20:622–627.
Peitersen E. The natural history of Bell’s palsy. Am J Otology 1982;4:107–111.
Grogan PM, Gronseth GS. Practice parameter: Steroids, acyclovir, and surgery for Bell’s
palsy (an evidence-based review): report of the Quality Standards Subcommittee of the
American Academy of Neurology. Neurology 2001;56:830–836.
Engström M, Berg T, Stjemquist-Desatnik A, et al. Prednisolone and valaciclovir in Bell’s
palsy: a randomised double-blind, placebo controlled, multicentre trial. Lancet
Neurology 2008;7:993–1000.
de Ru JA, van Benthem PPG, Janssen LM. Is antiviral medication for severe Bell’s palsy
still useful? Lancet Neurol 2009;8:509; author reply 509–510.
Minnerop M, Herbst M, Fimmers R, Matz B, Klockgether T, Wullner U. Bell’s palsy:
Combined treatment of famciclovir and prednisone is superior to prednisone alone. J
Neurol 2008;255:1726–1730.
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 Bell’s Palsy. The Laryngoscope 2007;117:147–156.
©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?
©2012 American Academy of Neurology
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