Evidence-based Guideline: Steroids and antivirals for Bell palsy

1. Evidence-based Guideline: Steroids and antivirals for Bell palsy Report of the Guideline Development Subcommittee of the American Academy of Neurology

2. Authors • Gary Gronseth, MD, FAAN • RemiaPaduga, MD

3. Questions or Feedback • If you have questions or feedback regarding this slide presentation, or would like to modify the contents for presentation in a lecture, please contact guidelines@aan.com

4. 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

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

6. 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.

7. 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.

8. 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?

9. 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.

10. 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.

11. AAN Guideline Process • Clinical Question • Evidence • Conclusions • Recommendations

12. 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?

13. Literature Search/Review • Rigorous, Comprehensive, Transparent Search Search Review abstracts Review full text Relevant Select articles

14. 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

15. 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

16. 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).

17. Applying the Process to the Issue • We will now turn our attention to the guideline.

18. 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 classification of evidence scheme for therapeutic articles. • Strength of recommendations was linked directly to evidence levels. • Conflicts of interest were disclosed.

19. Literature Search/Review • Rigorous, Comprehensive, Transparent 340 abstracts • 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 9 articles

20. AAN Classification of Evidencefor 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.

21. AAN Classification of Evidencefor 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.

22. AAN Classification of Evidencefor 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.**

23. AAN Classification of Evidencefor 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).

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

25. 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). .

26. 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).

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

28. 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%). .

29. 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%).

30. 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.

31. 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.

32. Clinical Context, cont. • Authors of one Class I study5performed a preplanned subgroup analysis on patients with severe palsy at presentation6defined 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.

33. Clinical Context, cont. • A Class IV study7observed 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 pseudo-randomized treatment allocation and unmasked outcome assessment.

34. Clinical Context, cont. • Relative to zoster sine herpete, a Class IV study8observed 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.

35. 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.

36. 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.

37. 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.

38. References • Hauser WA, Karnes WE, Annis J, Kurland LT. Incidence and prognosis of Bell’s palsy in the population of Rochester, Minnesota. Mayo ClinProc 1971;46:258–264. • Katusic SK, Beard CM, Wiederholt WC, et al. Incidence, clinical features, and prognosis in Bell's palsy. Ann Neurol1986;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 Neurology2008;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 Laryngoscope2007;117:147–156.

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

40. Question-and-Answer Period • Questions/comments?

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