1. © 2011 AMERICAN ACADEMY OF NEUROLOGY Update: Plasmapheresis in Neurologic Disorders Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology Irene Cortese, MD; Vinay Chaudhry, MD, FAAN; Yuen T. So, MD, PhD; Fredric Cantor, MD, FAAN; David R. Cornblath, MD, FAAN; Alexander Rae-Grant, MD

2. © 2011 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. © 2011 AMERICAN ACADEMY OF NEUROLOGY Endorsed by the American Association of Neuromuscular and Electrodiagnostic Medicine. The section that relates directly to the use of plasmapheresis in multiple sclerosis has been endorsed by the National Multiple Sclerosis Society.

4. © 2011 AMERICAN ACADEMY OF NEUROLOGY The views expressed here are those of the authors and do not represent those of the National Institutes of Health or any other part of the US Government. No official support or endorsement by the National Institutes of Health is intended or should be inferred.

5. © 2011 AMERICAN ACADEMY OF NEUROLOGY Presentation Objectives To present a reassessment of the role of plasmapheresis in the treatment of neurologic disorders Acute inflammatory demyelinating polyneuropathy (AIDP)/Guillain-Barré syndrome (GBS) Chronic inflammatory demyelinating neuropathy (CIDP) Dysimmune neuropathies Myasthenia gravis (MG) CNS demyelinating disease Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) Sydenham chorea To present evidence-based recommendations

6. © 2011 AMERICAN ACADEMY OF NEUROLOGY Overview Background Gaps in care American Academy of Neurology (AAN) guideline process Analysis of evidence, conclusions, recommendations Recommendations for future research

7. © 2011 AMERICAN ACADEMY OF NEUROLOGY Background Plasmapheresis, also known as therapeutic plasma exchange, is a procedure that involves separating the blood, exchanging the plasma (typically with donor plasma or albumin solution), and returning the other components, primarily red blood cells, to the patient. The mechanics of plasmapheresis have not changed since the introduction of continuous flow machines.

8. © 2011 AMERICAN ACADEMY OF NEUROLOGY Background, cont. This guideline summarizes evidence for the usefulness of plasmapheresis in the treatment of neurologic disorders and updates the previous AAN assessment published in 1996. 1 This update employs revised methodology for the development of evidence-based guidelines.

9. © 2011 AMERICAN ACADEMY OF NEUROLOGY Gaps in Care There are surprising deficiencies in the evidence supporting plasmapheresis in a few indications, most notably, MG. The criteria for classifying evidence in AAN guidelines has grown more stringent since the original guideline publication, thus lowering the evidence for MG from Level C to Level U. There is growing evidence for plasmapheresis in demyelinating diseases; plasmapheresis is currently underutilized in such illnesses. Neurologists need to learn next which disease types respond best to plasmapheresis and at what point in care plasmapheresis is most beneficial.

10. © 2011 AMERICAN ACADEMY OF NEUROLOGY AAN Guideline Process Clinical Question Evidence Conclusions Recommendations

11. © 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Questions The first step in 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.

12. © 2011 AMERICAN ACADEMY OF NEUROLOGY Literature Search/Review Relevant Complete Search Review abstracts Review full text Select articles Rigorous, Comprehensive, Transparent

13. © 2011 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

14. © 2011 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.

15. © 2011 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 = Studies not meeting criteria for Class I through Class III.

16. © 2011 AMERICAN ACADEMY OF NEUROLOGY Translating Class to Recommendations, cont. *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. © 2011 AMERICAN ACADEMY OF NEUROLOGY Applying This Process to the Issue We will now turn our attention to the guidelines.

18. © 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Questions 1. What is the efficacy of plasmapheresis in the treatment of AIDP, also known as GBS? 2.What is the efficacy of plasmapheresis in the treatment of CIDP? 3.What is the efficacy of plasmapheresis in the treatment of dysimmune neuropathies? 4.What is the efficacy of plasmapheresis in the treatment of MG?

19. © 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Questions, cont. 5.What is the efficacy of plasmapheresis in the treatment of CNS demyelinating disease? 6.What is the efficacy of plasmapheresis in the treatment of PANDAS? 7.What is the efficacy of plasmapheresis in the treatment of Sydenham chorea?

20. © 2011 AMERICAN ACADEMY OF NEUROLOGY Methods MEDLINE, Cochrane Library, Web of Science, and EMBASE  1995 to September 2009  A secondary bibliography search of all full-text articles  Relevant, fully published, peer-reviewed articles  Search terms –“plasmapheresis” –“neurologic disease (exploded)” –key text words and index words for plasmapheresis, plasma exchange, immunoadsorption, and double filtration plasmapheresis

21. © 2011 AMERICAN ACADEMY OF NEUROLOGY Methods, cont. At least two authors reviewed each article for inclusion. Risk of bias was determined using the classification of evidence for each study (Classes I–IV). Strength of practice recommendations were linked directly to levels of evidence (Levels A, B, C, and U). Conflicts of interest were disclosed.

22. © 2011 AMERICAN ACADEMY OF NEUROLOGY Literature Review 59 articles 2263 abstracts Inclusion criteria: - Articles reporting results from controlled clinical trials in humans - Abstracts available in English Exclusion criteria: - Articles that were not controlled clinical trials - Abstracts in languages other than English

23. © 2011 AMERICAN ACADEMY OF NEUROLOGY 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

24. © 2011 AMERICAN ACADEMY OF NEUROLOGY AAN Classification of Evidence for Diagnostic Accuracy, cont.  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.  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.

25. © 2011 AMERICAN ACADEMY OF NEUROLOGY AAN Classification of Evidence for Therapeutic Intervention 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.

26. © 2011 AMERICAN ACADEMY OF NEUROLOGY AAN Classification of Evidence for 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 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 are missing, the class is automatically downgraded to Class III.

27. © 2011 AMERICAN ACADEMY OF NEUROLOGY Analysis of Evidence Question 1: What is the efficacy of plasmapheresis in the treatment of AIDP, also known as GBS?

28. © 2011 AMERICAN ACADEMY OF NEUROLOGY Conclusion/Recommendation Conclusion:  On the basis of consistent findings from Class I studies, plasmapheresis is established as effective for the treatment of AIDP/GBS severe enough to impair the ability to walk independently or severe enough to require mechanical ventilation. Recommendation :  Plasmapheresis should be offered in the treatment of AIDP/GBS severe enough to impair independent walking or to require mechanical ventilation (Level A).

29. © 2011 AMERICAN ACADEMY OF NEUROLOGY Conclusion/Recommendation Conclusion:  For milder AIDP/GBS, in which ambulation is preserved, plasmapheresis is probably effective, based on a single Class I study. Recommendation:  Plasmapheresis should be considered in the treatment of milder clinical presentations of AIDP/GBS (Level B).

30. © 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Context  IV immunoglobulin (IVIg) is an alternative treatment used in patients with AIDP/GBS. There is insufficient evidence to demonstrate the superiority of one treatment over the other. 2–5

31. © 2011 AMERICAN ACADEMY OF NEUROLOGY Analysis of Evidence Question 2: What is the efficacy of plasmapheresis in the treatment of CIDP?

32. © 2011 AMERICAN ACADEMY OF NEUROLOGY Conclusion/Recommendation Conclusion:  Based on two Class I studies, plasmapheresis is established as effective in the short-term treatment of CIDP; both studies showed the beneficial effect is not sustained, with worsening beginning 1 to 5 weeks after last plasmapheresis treatment. Recommendation :  Plasmapheresis should be offered as a short-term treatment for patients with CIDP (Level A).

33. © 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Context  Steroids, IVIg, and immunosuppressants have also been used in the treatment of CIDP. 6,7

34. © 2011 AMERICAN ACADEMY OF NEUROLOGY Analysis of Evidence Question 3: What is the efficacy of plasmapheresis in the treatment of dysimmune neuropathies?

35. © 2011 AMERICAN ACADEMY OF NEUROLOGY Conclusion/Recommendation Conclusion:  Plasmapheresis is probably effective in IgA- and IgG- monoclonal gammopathy of undetermined significance (MGUS)-associated polyneuropathy, based on one Class I study. Recommendation :  Plasmapheresis should be considered in polyneuropathy associated with IgA and IgG MGUS (Level B).

36. © 2011 AMERICAN ACADEMY OF NEUROLOGY Conclusion/Recommendation Conclusion:  On the basis of 1 Class I and 1 Class III study, plasmapheresis is probably not effective in polyneuropathy associated with IgM MGUS. Recommendation :  Plasmapheresis should not be considered in the treatment of polyneuropathy associated with IgM MGUS (Level B).

37. © 2011 AMERICAN ACADEMY OF NEUROLOGY Analysis of Evidence Question 4: What is the efficacy of plasmapheresis in the treatment of MG ?

38. © 2011 AMERICAN ACADEMY OF NEUROLOGY Conclusion/Recommendation Conclusion:  There are inadequate data to evaluate the use of plasmapheresis in the treatment of myasthenic crisis or in the treatment of MG prethymectomy. Recommendation:  Because of the lack of randomized controlled studies with masked outcomes, there is insufficient evidence to support or refute the efficacy of plasmapheresis in the treatment of myasthenic crisis (Level U) or MG prethymectomy (Level U).

39. © 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Context  Despite the fact that the use of plasmapheresis in myasthenic crisis and MG prethymectomy receives a Level U recommendation, plasmapheresis is used at many medical centers for these indications.

40. © 2011 AMERICAN ACADEMY OF NEUROLOGY Analysis of Evidence Question 5: What is the efficacy of plasmapheresis in the treatment of CNS demyelinating disease ?

41. © 2011 AMERICAN ACADEMY OF NEUROLOGY Conclusion/Recommendation Conclusion:  Plasmapheresis as adjunctive therapy is probably effective for management of exacerbations in relapsing forms of MS, based on a single Class I study. Recommendation:  Plasmapheresis should be considered for the adjunctive treatment of exacerbations in relapsing forms of MS (Level B).

42. © 2011 AMERICAN ACADEMY OF NEUROLOGY Conclusion Conclusion:  Based on a single Class II study, plasmapheresis is possibly effective for acute fulminant CNS demyelinating diseases (including MS, acute disseminated encephalomyelitis [ADEM], neuromyelitis optica [NMO], and transverse myelitis [TM]) that fail to respond to high- dose corticosteroid treatment. Because the study included subgroups of patients with demyelinating diseases, it is not possible to determine if plasmapheresis is more or less effective in patients with different demyelinating diseases.

43. © 2011 AMERICAN ACADEMY OF NEUROLOGY Recommendation Recommendation:  Plasmapheresis may be considered in the treatment of fulminant CNS demyelinating diseases that fail to respond to high-dose corticosteroid treatment (Level C).

44. © 2011 AMERICAN ACADEMY OF NEUROLOGY Conclusion/Recommendation Conclusion:  For chronic progressive or secondary progressive MS, plasmapheresis is established as ineffective based on consistent Class I evidence. (Note: the term chronic progressive MS is no longer used, but previously included patients are now described as having either primary progressive MS or secondary progressive MS.) Recommendation:  Plasmapheresis should not be offered for chronic progressive or secondary progressive MS (Level A).

45. © 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Context  No studies on the efficacy of plasmapheresis compared to other treatment options in MS are available.

46. © 2011 AMERICAN ACADEMY OF NEUROLOGY Analysis of Evidence Question 6: What is the efficacy of plasmapheresis in the treatment of PANDAS ?

47. © 2011 AMERICAN ACADEMY OF NEUROLOGY Conclusion/Recommendation Conclusion:  There are inadequate data to determine the efficacy of plasmapheresis in the treatment of acute obsessive– compulsive disorder (OCD) and tic symptoms in the setting of PANDAS (one Class III study). Recommendation:  There is insufficient evidence to support or refute the use of plasmapheresis in the treatment of acute OCD and tic symptoms in the setting of PANDAS (Level U).

48. © 2011 AMERICAN ACADEMY OF NEUROLOGY Analysis of Evidence Question 7: What is the efficacy of plasmapheresis in the treatment of Sydenham chorea ?

49. © 2011 AMERICAN ACADEMY OF NEUROLOGY Conclusion/Recommendation Conclusion:  There are inadequate data to determine the efficacy of plasmapheresis in Sydenham chorea (one Class III study). Recommendation:  There is insufficient evidence to support or refute the use of plasmapheresis in the treatment of Sydenham chorea (Level U).

50. © 2011 AMERICAN ACADEMY OF NEUROLOGY Future Research For all indications, the optimal plasma exchange protocol (number of exchanges and volumes exchanged) remains to be established through future research. The role of plasmapheresis in mild AIDP/GBS, in which ambulation is preserved, and the role of plasmapheresis in patients with AIDP/GBS who fail to respond or who relapse after an initial response remains to be defined. The role of plasmapheresis in the long-term management of CIDP remains to be clarified.

51. © 2011 AMERICAN ACADEMY OF NEUROLOGY Future Research, cont. Adequately powered studies that address the duration of benefit are needed to confirm the role of plasmapheresis in the treatment of neuropathies associated with IgA or IgG gammopathy, and to clarify its role in neuropathies associated with IgM gammopathy. Furthermore, differentiation between demyelinating and axonal neuropathies as well as between IgM neuropathies with and without anti-myelin associated glycoprotein (anti- MAG) will be needed in future studies. The use of plasmapheresis in myasthenic crisis and MG prethymectomy requires further research.

52. © 2011 AMERICAN ACADEMY OF NEUROLOGY Future Research, cont. The role of plasmapheresis in fulminant demyelinating CNS disease that has not responded to first-line treatment with corticosteroids will need to be confirmed. Individual demyelinating diseases (e.g., NMO, MS, TM) should be addressed separately in future studies to clarify the role of plasmapheresis in each. Initial data suggest a role of plasmapheresis in accelerating the clearance of natalizumab and restoring leukocyte function. 8 Whether this translates into a clinical benefit in the setting of infectious complications of treatment with natalizumab remains to be determined.

53. © 2011 AMERICAN ACADEMY OF NEUROLOGY References 1.Assessment of plasmapheresis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1996;47:840–843. 2.van der Meché FGA, Schmitz PIM, and Dutch Guillain-Barré Study Group. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome. NEJM 1992;326(17):1123–1129. 3.Bril V, Ilse WK, Pearce R, Dhanani A, Sutton D, Kong K. Pilot trial of immunoglobulin versus plasma exchange in patients with Guillain-Barré syndrome. Neurology 1996;46(1):100-–03. 4.Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Lancet 1997;349(9047):225–230. 5.Nomura T, Hamaguchi K, Hosakawa T, et al. A randomized controlled trial comparing intravenous immunoglobulin and plasmapheresis in Guillain-Barré syndrome. Neurological Therapeutics 2001;18(1):69–81.

54. © 2011 AMERICAN ACADEMY OF NEUROLOGY References, cont. 6. Dyck PJ, Litchy WJ, Kratz KM, et al. A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy. Annals of Neurology 1994;36:838–845. 7. Hughes R, Bensa S, Willison HJ, et al. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Annals of Neurology 2001;50:195–201. 8. Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 2009;72:402- 409. For a complete list of references, please access the full guideline at www.aan.com/guidelineswww.aan.com/guidelines

55. © 2011 AMERICAN ACADEMY OF NEUROLOGY Questions/Comments

56. © 2011 AMERICAN ACADEMY OF NEUROLOGY Thank you for your participation!