1. © 2006 American Academy of Neurology Practice Parameter: The diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review) 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

2. © 2006 American Academy of Neurology The AAN develops these presentation slides as educational tools for neurologists and other health care practitioners. You may download and retain a single copy for your personal use. Please contact guidelines@aan.com to learn about options for sharing this content beyond your personal use.guidelines@aan.com

3. © 2006 American Academy of Neurology Presentation Objectives To perform an evidence-based review of the diagnosis and treatment of trigeminal neuralgia To make evidence-based recommendations

4. © 2006 American Academy of Neurology Overview Background Gaps in care AAN guideline process Analysis of evidence, conclusions, recommendations Recommendations for future research

5. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology AAN Guideline Process Clinical Question Evidence Conclusions Recommendations

7. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology Literature Search/Review Relevant Complete Search Review abstracts Review full text Select articles Rigorous, Comprehensive, Transparent

9. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology Applying This Process to the Issue We will now turn our attention to the guidelines.

13. © 2006 American Academy of Neurology Clinical Questions Diagnostic questions 1.How often does routine neuroimaging (CT, MRI) identify a structural cause of TN (excluding vascular contact with compression of the fifth cranial nerve? 2.Which clinical or laboratory features accurately identify patients with STN? 3.For patients with CTN, does high-resolution MRI accurately identify patients with neurovascular compression?

14. © 2006 American Academy of Neurology Clinical Questions Pharmacologic questions 1.Which drugs effectively treat CTN? 2.Which drugs effectively treat STN? 3.Is there evidence of efficacy of intravenous drugs in acute exacerbations of TN?

15. © 2006 American Academy of Neurology Clinical Questions Surgical questions 1.When should surgery be offered? 2.Which surgical technique gives the longest pain-free period with the fewest complications and good quality of life? 3.Which surgical techniques should be used in patients with MS?

16. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology Literature Review 47 articles > 500 abstracts 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. © 2006 American Academy of Neurology AAN Classification of Evidence for 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. © 2006 American Academy of Neurology 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. AAN Classification of Evidence for Therapeutic Intervention

21. © 2006 American Academy of Neurology 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). AAN Classification of Evidence for Therapeutic Intervention

22. © 2006 American Academy of Neurology 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 Evidence for Screening

23. © 2006 American Academy of Neurology AAN Classification of Evidence for 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. © 2006 American Academy of Neurology AAN Classification of Evidence for 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. © 2006 American Academy of Neurology 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 Evidence for Diagnosis

26. © 2006 American Academy of Neurology AAN Classification of Evidence for 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. © 2006 American Academy of Neurology AAN Classification of Evidence for 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. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology Analysis of Evidence Question 2: Which clinical or laboratory features accurately identify patients with STN?

32. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology Analysis of Evidence Question 3: Does high-resolution MRI accurately identify patients with neurovascular compression?

35. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology Clinical Context Because of a high diagnostic accuracy, MRI might reasonably be foregone in a patient with normal trigeminal reflexes.

37. © 2006 American Academy of Neurology Analysis of Evidence Question 4: Which drugs effectively treat CTN pain?

38. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology Analysis of Evidence Question 5. Which drugs effectively treat STN pain?

41. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology Analysis of Evidence Question 6: Is there evidence of efficacy of intravenous administration of drugs in acute exacerbations of TN?

44. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology Analysis of Evidence Question 7 : When should surgery be considered?

46. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology Analysis of Evidence Question 8: Which surgical technique gives the longest pain-free period with the fewest complications and good quality of life?

49. © 2006 American Academy of Neurology 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. © 2006 American Academy of Neurology Analysis of Evidence Question 9. Which surgical techniques should be used in patients with multiple sclerosis?

51. © 2006 American Academy of Neurology Conclusion/Recommendation Conclusion: There is insufficient evidence to support or refute the effectiveness of the surgical management of TN in patients with MS. Recommendation: There is insufficient evidence to support or refute the effectiveness of the surgical management of TN in patients with MS (Level U).

52. © 2006 American Academy of Neurology Future Research To establish a better estimate of the yield of routine brain imaging in identifying patients with STN, we need a population-based study of consecutive, newly diagnosed patients with TN all undergoing head imaging. To improve our knowledge of the diagnostic accuracy of clinical characteristics and electrophysiologic studies to distinguish STN from CTN, we need prospective cohort surveys of large populations of patients with TN all undergoing standardized diagnostic assessments reported using STARD criteria. 3

53. © 2006 American Academy of Neurology Future research It would also be useful to determine if finding a neurovascular contact on high-resolution MRI accurately identifies patients who will respond to microvascular decompression. This question could be answered with a prospective study comparing longterm outcomes in patients with TN undergoing microvascular decompression with and without neurovascular contact identified on preoperative high-resolution MRI.

54. © 2006 American Academy of Neurology Future research The efficacy of new drugs and, in particular, surgical interventions, needs to be determined in well-designed RCTs. Although double-blinded studies are impractical for surgical trials, randomized treatment allocation and independent outcome assessment would go a long way to establish the efficacy of the surgical techniques. The optimal timing of surgical referral remains a crucial question. How many different drugs should be tried before referring a patient for surgery? What is the likelihood that a patient with TN failing OXC or CBZ will respond to alternative drugs? These are questions that could be answered by a large prospective cohort survey of patients with TN treated in a standardized, stepwise fashion.

55. © 2006 American Academy of Neurology References 1.Merskey H, Bogduk N. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. Seattle: IASP Press; 1994;59–71. 2.Katusic S, Williams DB, Beard CM, et al. Epidemiology and clinical features of idiopathic trigeminal neuralgia and glossopharyngeal neuralgia: similarities and differences, Rochester, Minnesota, 1945–1984. Neuroepidemiology 1991;10:276–281. 3.Bossuyt P, Reitsma J, Bruns D, et al. Towards complete assessment and accurate reporting studies of diagnostic accuracy: the STARD initiative. Clin Radiol 2003;58:575-580. For a complete list of references, please access the full guideline at www.aan.com/guidelineswww.aan.com/guidelines

56. © 2006 American Academy of Neurology Questions/Comments

57. © 2006 American Academy of Neurology Thank you for your participation!