Practice Parameter: The diagnostic evaluation and treatment of trigeminal neuralgia(an evidence-based review)

1. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies G. Gronseth, MD, FAAN; G. Cruccu, MD; J. Alksne, MD; C. Argoff, MD; M. Brainin, MD, FESO; K. Burchiel, MD; T. Nurmikko, MD, PhD; J. M. Zakrzewska, MD, FDSRCS, FFDRCSI Practice Parameter: The diagnostic evaluation and treatment of trigeminal neuralgia(an evidence-based review)

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3. Presentation Objectives • To perform an evidence-based review of the diagnosis and treatment of trigeminal neuralgia • To make evidence-based recommendations

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

5. Background • Trigeminal neuralgia (TN) is sudden, usually unilateral, severe, brief, stabbing, recurrent episodes of pain in the distribution of one or more branches of the trigeminal nerve.1 • The annual incidence of TN is 4 to 5 in 100,000.2 • Classic TN (CTN) includes cases without an established etiology, and symptomatic TN (STN) is diagnosed when investigations identify a structural abnormality (e.g., MS plaques, tumors, etc.).

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

7. Clinical Questions • The first step of developing guidelines is to clearly formulate questions to be answered. • Questions address areas of controversy, confusion, or variation in practice. • Questions must be answerable with data from the literature. • Answering the question must have the potential to improve care/patient outcomes.

8. Literature Search/Review Complete Search Review abstracts Review full text Select articles Relevant Rigorous, Comprehensive, Transparent

9. AAN Classification of Evidence • All studies rated Class I, II, III, or IV • Five different classification systems: • Therapeutic • Randomization, control, blinding • Diagnostic • Comparison to gold standard • Prognostic • Screening • Causation

10. AAN Level of Recommendations • A = Established as effective, ineffective, or harmful for the given condition in the specified population. • B = Probably effective, ineffective, or harmful for the given condition in the specified population. • C = Possibly effective, ineffective, or harmful for the given condition in the specified population. • U = Data is inadequate or conflicting; given current knowledge, treatment is unproven. • Note that recommendations can be positive or negative.

11. Translating Class to Recommendations • A = Requires two consistent Class I studies. • B = Requires one Class I study or two consistent Class II studies. • C = Requires one Class II study or two consistent Class III studies. • U = Studies not meeting criteria for Class I through Class III.

12. Applying This Processto the Issue We will now turn our attention to the guidelines.

13. Clinical Questions Diagnostic questions • How often does routine neuroimaging (CT, MRI) identify a structural cause of TN (excluding vascular contact with compression of the fifth cranial nerve? • Which clinical or laboratory features accurately identify patients with STN? • For patients with CTN, does high-resolution MRI accurately identify patients with neurovascular compression?

14. Clinical Questions Pharmacologic questions Which drugs effectively treat CTN? Which drugs effectively treat STN? 3. Is there evidence of efficacy of intravenous drugs in acute exacerbations of TN?

15. Clinical Questions Surgical questions When should surgery be offered? Which surgical technique gives the longest pain-free period with the fewest complications and good quality of life? Which surgical techniques should be used in patients with MS?

16. Methods • Medline, EMBASE and Cochrane Library: • Database creation to December 2007 • Relevant, fully published, peer-reviewed articles • Supplemented through manual searches by panel members • Search terms: • Trigeminal neuralgia, tic douloureux, facial pain, or trigeminal neuropathy

17. Methods • At least two panelists reviewed each article for inclusion. A third panelist was added for arbitrating disagreements • Risk of bias determined using the classification of evidence for each study (Class I–IV). • Strength of practice recommendations linked directly to level of evidence (Level A–U). • Conflicts of interest disclosed.

18. > 500 abstracts 47 articles Literature Review • Inclusion criteria: • - Relevant to the clinical questions • - Limited to human subjects • RCT, case control, cohort studies, case series > 6, meta-analysis • Exclusion criteria: • -Abstracts, reviews, and undocumented or unstated mention of improvement

19. AAN Classification of Evidencefor Therapeutic Intervention • Class I: Randomized, controlled clinical trial 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 required: a) concealed allocation b) primary outcome(s) clearly defined c) exclusion/inclusion criteria clearly defined, and d) adequate accounting for drop-outs (with at least 80% of enrolled subjects completing the study) and cross-overs with numbers sufficiently low to have minimal potential for bias.

20. AAN Classification of Evidencefor Therapeutic Intervention • Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets b-d above OR a randomized controlled trial in a representative population that lacks one criteria a-d.

21. AAN Classification of Evidencefor Therapeutic Intervention • 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.* • Class IV: Studies not meeting Class I, II, or III criteria including consensus, expert opinion, or a case report. *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).

22. Class I: A statistical, population-based sample of patients studied at a uniform point in time (usually early) during the course of the condition. All patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients’ clinical presentations. AAN Classification of Evidencefor Screening

23. AAN Classification of Evidencefor Screening • Class II: A statistical, non-referral-clinic-based sample of patients studied at a uniform point in time (usually early) during the course of the condition. Most patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients’ clinical presentations.

24. AAN Classification of Evidencefor Screening • Class III: A sample of patients studied during the course of the condition. Some patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation by someone other than the treating physician. • Class IV: Studies not meeting Class I, II, or III criteria including consensus, expert opinion, or a case report.

25. Class I:A cohort study with prospective data collection of a broad spectrum of persons with the suspected condition, using an acceptable reference standard for case definition. The diagnostic test is objective or performed and interpreted without knowledge of the patient’s clinical status. Study results allow calculation of measures of diagnostic accuracy. AAN Classification of Evidencefor Diagnosis

26. AAN Classification of Evidencefor Diagnosis • Class II:A case control study of a broad spectrum of persons with the condition established by an acceptable reference standard compared to a broad spectrum of controls or a cohort study where a broad spectrum of persons with the suspected condition where the data was collected retrospectively. The diagnostic test is objective or performed and interpreted without knowledge of disease status. Study results allow calculation of measures of diagnostic accuracy.

27. AAN Classification of Evidencefor Diagnosis • Class III:A case control study or cohort study where either persons with the condition or controls are of a narrow spectrum. The condition is established by an acceptable reference standard. The reference standard and diagnostic test are objective or performed and interpreted by different observers. Study results allow calculation of measures of diagnostic accuracy. • Class IV:Studies not meeting Class I, II, or III criteria including consensus, expert opinion, or a case report.

28. Analysis of Evidence Question 1: How often does routine neuroimaging (CT, MRI) identify a structural cause (excluding vascular contact with compression of the fifth cranial nerve)?

29. Conclusion/Recommendation Conclusion: For patients with TN, routine neuroimaging may identify a cause in up to 15% of patients (four Class III studies). These reported yields are most representative of those expected from referral centers. Recommendation: Weak evidence indicates that for patients with TN, routine imaging may be considered to identify a cause in up to 15 percent of patients with STN (Level C).

30. Clinical Context • The initial diagnostic evaluation of a patient with TN naturally focuses on those clinical characteristics known to identify patients with symptomatic trigeminal neuralgia (STN). Those characteristics include the presence of trigeminal sensory deficits and bilateral involvement.

31. Analysis of Evidence Question 2: Which clinical or laboratory features accurately identify patients with STN?

32. Conclusion/Recommendation Conclusion: For patients with TN, younger age (one Class I and three Class II studies) and abnormal trigeminal nerve evoked potentials (two Class II and two Class III studies) are probably associated with an increased risk of STN. However, there is too much overlap in patients with CTN and STN for these predictors to be considered clinically useful. Recommendation: Good evidence indicates that measuring trigeminal reflexes in a qualified electrophysiogical laboratory should be considered useful for distinguishing STN from classic trigeminal neuralgia (CTN) (Level B).

33. Clinical Context • If after the initial evaluation the clinician remains suspicious of STN, further testing is desirable. Based upon cost, local expertise and availability, and patient preferences, obtaining trigeminal reflex testing or head imaging are both reasonable next steps.

34. Analysis of Evidence Question 3: Does high-resolution MRI accurately identify patients with neurovascular compression?

35. Conclusion/Recommendation Conclusion: Because of inconsistency of results, there is insufficient evidence to support or refute the usefulness of MRI to identify vascular contact in CTN or to indicate the most reliable MRI technique. Recommendation: There is insufficient evidence to support or refute the usefulness of MRI to identify vascular contact in CTN or to indicate the most reliable MRI technique (Level U).

36. Clinical Context • Because of a high diagnostic accuracy, MRI might reasonably be foregone in a patient with normal trigeminal reflexes.

37. Analysis of Evidence Question 4: Which drugs effectively treat CTN pain?

38. Conclusion/Recommendation Conclusion: Carbamazepine is established as effective for controlling pain in patients with CTN (multiple Class I and II studies). Oxcarbazepine is probably effective for treating pain in CTN (three Class II studies). Baclofen, lamotrigine, and pimozide are possibly effective for controlling pain in patients with CTN (single Class II study for each drug). Topical ophthalmic anesthesia is probably ineffective for controlling pain in patients with CTN (single Class I study). There is insufficient evidence to support or refute the efficacy of clonazepam, gabapentin, phenytoin, tizanidine, topical capsaicin, and valproate for controlling pain in patients with CTN. Recommendation: Strong evidence supports that carbamazepine should be offered to treat CTN pain (Level A). Good evidence supports that oxcarbazepine should be considered to treat CTN pain (Level B). Weak evidence supports that baclofen, lamotrigine, and pimozide may be considered to treat CTN pain (Level C). Good evidence supports that topical ophthalmic anesthesia should not be considered to treat CTN pain (Level B).

39. Clinical Context • The two drugs to consider as first-line therapy in TN are CBZ (200-1200 mg/day) and OXC (600-1800 mg/day). Although the evidence for CBZ is stronger than for OXC, the latter may pose fewer safety concerns. • There is little evidence to guide the clinician on the treatment of TN patients that who fail first-line therapy. Some evidence supports add-on therapy with lamotrigine or a switch to baclofen (pimozide being no longer in use).

40. Analysis of Evidence Question 5. Which drugs effectively treat STN pain?

41. Conclusion/Recommendation Conclusion: There is insufficient evidence to support or refute the effectiveness of any medication in treating pain in STN (Class IV studies). Recommendation: There is insufficient evidence to support or refute the effectiveness of any medication in treating pain in STN (Level U).

42. Clinical Context • The effect of other drugs commonly used in neuropathic pain is unknown. There are no published studies directly comparing polytherapy with monotherapy.

43. Analysis of Evidence Question 6: Is there evidence of efficacy of intravenous administration of drugs in acute exacerbations of TN?

44. Conclusion/Recommendation Conclusion: There is insufficient evidence to support or refute the efficacy of IV medications for the treatment of pain from TN (Class IV study). Recommendation: There is insufficient evidence to support or refute the efficacy of intravenous medications for the treatment of pain from TN (Level U).

45. Analysis of Evidence Question 7: When should surgery be considered?

46. Conclusion/Recommendation Conclusion: There is insufficient evidence to allow conclusions as to when surgery should be offered (two Class IV studies). Recommendation: There is insufficient evidence to allow conclusions as to when surgery should be offered (Level U).

47. Clinical Context • Referral for a surgical consultation seems reasonable in TN patients refractory to medical therapy. Some TN experts believe TN patients failing to respond to first-line therapy are unlikely to respond to alternative medications and suggest early surgical referral.

48. Analysis of Evidence Question 8: Which surgical technique gives the longest pain-free period with the fewest complications and good quality of life?

49. Conclusion/Recommendation Conclusion: Percutaneous procedures on the Gasserian ganglion, gamma knife, and microvascular decompression are possibly effective in the treatment of TN (multiple Class III studies). The evidence about peripheral techniques is either negative (two Class I studies about streptomycin/lidocaine) or insufficient (Class IV studies for all the other peripheral techniques). Recommendation: There is weak evidence to support that early surgical therapy may be considered for patients with TN refractory medical therapy (Level C). There is weak evidence to support percutaneous procedures on the Gasserian ganglion, gamma knife, and microvascular decompression may be considered (Level C).

50. Analysis of Evidence Question 9. Which surgical techniques should be used in patients with multiple sclerosis?