Plasma pharesis in neurological disorders

Plasma pharesis in neurological disorders

1. PLASMA PHARESIS IN NEUROLOGICAL DISORDERS Dr. Sunil Kumar Sharma Senior Resident Moderator Dr. Vijay Sardana Sr. Professor And HOD Dept. Of Neurology GMC Kota

2. Outline Introduction Principles and Procedure Complications Indications Contraindications Guidelines and recommendations Conclusion

3. Terminology Apheresis (Greek aphairesis –withdrawal)- An umbrella term for "taking away" a blood component. Plasmapheresis : Automated, selective removal of plasma by centrifugation. Plasma exchange [TPE]- Removal of patient plasma and replacement with another fluid ( eg , donor plasma, colloid, crystalloid).

4. Terminology… Hemapheresis (also called cytapheresis ) – Selective removal of abnormal blood cells or excessive numbers of cells. Dialysis – A diffusion-based treatment best suited for the removal of fluid or small molecules ( eg , uremic toxins, some drugs) from the blood using a filter. Plasma filtration – A technique that separates plasma from cellular components with a highly permeable filter (plasma filter) using a dialysis or hemofiltration machine.

5. Principles and Procedure The aim of plasma exchange is to significantly reduce circulating pathologic substances ( antibodies) from the plasma . Substance to be removed must have a sufficiently long half life. Substance to be removed must acutly toxic and resistent to conventional therapy.

6. TECHNIQUES Centrifugal cell separators Membrane plasma filtration

7. Centrifugal devices There is no upper limit to the molecular weight of proteins removed by this method. Circuits are single use and disposable. Platelet can decrease by as much as 50%. Membrane plasma filtration All immunoglobulins will cross the membrane however, some large immune complexes and cryoglobulins may not be adequately cleared. Reuse of plasma ilters is not advised, but performance data do not indicate a major loss of function during routine plasma exchange. There is no loss of platelets

8. Estimate plasma volume (in liters) = 0.07 x weight (kg) x (1 - hematocrit ) . Usually 1-1.5 TPV or 30-40 ml/Kg of plasma is removed/ cycle and replacement with plasma expanders like albumin or FFP. 3-5 alt. day cycle.

9. Choice of Replacement solution-Albumin Advantage: No risk of hepatitis/HIV Stored at room temperature Allergic reaction are rare No concern about ABO blood group Depletes inflammation mediators Disadvantage: Expensive No coagulation factors No immunoglobulin's

10. Choice of Replacement solution-FFP Advantage: Coagulation factors Immunoglobulin‘s Disadvantage: Risk of hepatitis, HIV transmission Allergic reaction Hemolytic reaction ABO incompatibility Citrate load

11. There is no consensus on the ideal replacement solution during PE. The use of albumin and cross matching plasma have been recommended*. Colloid replacement can be achieved with the use of fresh-frozen plasma, albumin, albumin and saline, or albumin and plasma expander solutions.* Korach JM, Berger P, Giraud C, Le Perff -Desman C, Chillet P. Role of replacement fluids in the immediate complications of plasma exchange. French Registry Cooperative Group. Intensive Care Med 1998;24:452-8. Clark WF, Rock GA, Buskard N, Shumak KH, LeBlond P, Anderson D, et al. Therapeutic plasma exchange: An update from the Canadian Apheresis Group. Ann Intern Med 1999;131:453-62 .

12. Immunoadsorption technique In addition to PE, the immunoadsorption technique represents a newer approach that allows a more selective removal of circulating antibodies. By binding to a ligand , removal of immunoglobulin fractions can be achieved. After adsorption, the cellular blood components and plasma are combined and reinfused . Weinstein R. Therapeutic apheresis in neurological disorders. J Clin Apher 2000;15:74-128.

13. Complications Kaplan AA. American Journal of Kidney Diseases, 2008.

14. Indications AIDP/GBS CIDP MG Polyneuropathy associated with paraproteinemia . PANDAS LEMS MS NMOSD SREAT NMDA R Autoimmune encephalopathy

15. Contraindications Active infection Hemodynamic unstability Allergy to fresh frozen plasma or albumin . Allergic to Heparin Hypocalcemia Plasmapheresis; Updated : Aug 29, 2016 Author: Elliot Stieglitz, MD; Chief Editor: Emmanuel C Besa , MD

16. Update: Plasmapheresis in Neurologic Disorders AAN-2011

17. AAN Level of Recommendations A = Established as effective, ineffective or harmful. B = Probably effective, ineffective or harmful. C = Possibly effective, ineffective or harmful. U = Data inadequate or conflicting ; given current knowledge, treatment (test, predictor) is unproven. Note that recommendations can be positive or negative.

18. 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

19. Methods... At least two authors reviewed each article for inclusion. Strength of practice recommendations were linked directly to levels of evidence (Levels A, B, C, and U). Conflicts of interest were disclosed.

20. Literature Review 2263 abstracts and 59 articles Inclusion criteria : A rticles 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

21. Clinical Questions What is the efficacy of plasmapheresis in the treatment of AIDP, also known as GBS? What is the efficacy of plasmapheresis in the treatment of CIDP? What is the efficacy of plasmapheresis in the treatment of dysimmune neuropathies? What is the efficacy of plasmapheresis in the treatment of MG?

22. Clinical Questions… What is the efficacy of plasmapheresis in the treatment of CNS demyelinating disease? What is the efficacy of plasmapheresis in the treatment of PANDAS? What is the efficacy of plasmapheresis in the treatment of Sydenham chorea?

23. Update: Plasmapheresis in Neurologic Disorders-AAN 2011

24. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach American Society for Apheresis June 2016

25. ASFA Categories

26. ASFA Category I indications for therapeutic plasma exchange AIDP/ Guillain–Barré syndrome Chronic inflammatory demyelinating polyneuropathy Myasthenia gravis Polyneuropathy associated with paraproteinaemias N-methyl D- aspartate receptor antibody encephalitis(2016)

27. ASFA Category II indications for therapeutic plasma exchange ADEM Lambert–Eaton myasthenic syndrome Multiple sclerosis (Acute exacerbation) Neuromyelitis optica (acute) PANDAS Hashimoto’s encephalopathy: SREAT(2016)

28. ASFA Category III indications for therapeutic plasma exchange Paraneoplastic neurological syndromes Chronic progressive Multiple sclerosis NMOSD- maintainance

29. ASFA Category IV indications for therapeutic plasma exchange Amyotrophic lateral sclerosis Inclusion body myositis POEMS syndrome

30. Some common neurological diseases and ASFA guideline for TPE

31. AIDP/GBS Primary treatment TPE- Category I TPE After IVIG –category III In GBS – There are autoantibodies against various gangliosides including GM1, GD1a, GalNAc-GD1a, GD1b, GQ1b, GD3, and GT1a, particularly in AMAN and Miller Fisher syndrome subtypes.

32. AIDP/GBS… The Cochrane Neuromuscular Disease Group review of TPE in AIDP (2012)- found that TPE is most effective when initiated within 7 days of disease onset. Evidence-based guidelines of the AAN –TPE=IVIG in the treatment of GBS (Winters, 2011). Volume treated: 1–1.5 TPV, Frequency: Every other day, Replacement fluid: Albumin Exchange 200–250 mL of plasma /kg body weight over 10–14 days.

33. CIDP Recommendation Category-I Volume treated: 1–1.5 TPV Frequency: 2–3/week until improvement, then taper as tolerated Replacement fluid: Albumin TPE provides short-term benefit but rapid deterioration may occur afterwards The frequency of maintenance TPE may range from weekly to monthly .

34. HASHIMOTO’S ENCEPHALOPATHY; SREAT High dose steroid is first line Rx. Recommendation Category-II Volume treated: 1–1.5 TPV Frequency: Daily to every other day Replacement fluid: Albumin 3–9 procedures, mostly commonly 5.

35. MULTIPLE SCLEROSIS Acute CNS inflammatory demyelinating –Cat. II Chronic progressive MS , TPE – Cat. III Standard treatment for MS exacerbation – High dose IV MPS. If unresponsive, a second steroid pulse is given after an interval of 10–14 days.

36. MULTIPLE SCLEROSIS… In acute, severe attacks of MS in patients who fail initial treatment with high-dose steroids, TPE may be beneficial (Gwathmey,2014). TPE has also been used for drug removal in MS patients treated with Natalizumab who developed PML.

37. MS… Volume treated: 1–1.5 TPV Frequency: Acute: 5–7 over 14 days Chronic progressive: weekly Replacement fluid: Albumin In acute MS relapse unresponsive to steroids, 5–7 TPE procedures have a response rate of 50%.

38. ADEM Recommendation Category-II Indication-Steroid refractory ADEM High-dose IV steroids ;IV MPS 20–30 mg/kg/day (maximum 1 g/day) for 3–5 days first-line therapy. It may be followed by a prolonged oral prednisolone taper over 3–6 weeks.

39. ADEM… In one study ( Llufriu , 2009) early initiation of TPE (within 15 days of disease onset) in acute attacks of CNS demyelination (including seven cases of ADEM) was identified as a predictor of clinical improvement at 6 months. Volume treated: 1–1.5 TPV Frequency Every other day Replacement fluid: Albumin Llufriu S, Castillo J, Blanco Y, Ramio-Torrenta L, Rıo J, Valle`s M, Lozano M, Castella MD, Calabia J, Horga A, Graus F, Montalban X, Saiz A. Plasma exchange for acute attacks of CNS demyelination : predictors of improvement at 6 months. Neurology 2009;73:949–953.

40. ADEM… No clear recommendations for optimal regimen . In one of the largest ADEM case series (Keegan, 2002), TPE achieved moderate and marked sustained improvement in 50% of the patients. In the majority of studies, clinical response was noticeable within days, usually after 2–3 exchanges. In published studies, TPE therapy often consisted of 3–6 treatments. Keegan M, Pineda AA, McClelland RL, Darby CH, Rodrigues M, Weinshenker BG. Plasma exchange for severe attacks of CNS demyelination : predictors of response. Neurology 2002;58:143–146.

41. NEUROMYELITIS OPTICA SPECTRUM DISORDERS Recommendation Category- Acute -II Maintenance TPE –III Acute attacks are managed by high-dose intravenous steroids (usually intravenous pulse steroids ( methylprednisone 1 g daily 3- 5 days followed by oral steroid taper) and, if symptoms fail to resolve, TPE is added.

42. NMOSD … Volume treated: 1–1.5 TPV Frequency: Acute: Daily or every other day; Maintenance: Variable Replacement fluid: Albumin

43. NMOSD… The majority of studies performed five procedures on average for acute exacerbation. In one case series, 5 out 7 patients who were on maintenance TPE therapy (3 per week for 2 weeks, 2 per week for 2 weeks, then weekly for 3–5 weeks) showed varying degrees of improvement and reduction in the number of NMOSD exacerbation

44. MYASTHENIA GRAVIS Recommendation Category Moderate–severe TPE –Cat. I Pre- thymectomy TPE –Cat. I Myasthenic crisis is characterized by acute respiratory failure requiring intubation, prolonged intubation following thymectomy , or bulbar weakness causing dysphasia and high risk of aspiration.

45. MG… Four major treatment approaches- Cholinesterase inhibitors Thymectomy Immunosuppression , TPE or IVIG.

46. MG… TPE is used to remove circulating autoantibodies , particularly in- Myasthenic crisis Perioperatively for thymectomy , As an adjunct to other therapies to maintain optimal clinical status

47. MG… IVIG and TPE appear equivalent in the literature Typical induction regimen consists of processing 225 mL /kg of plasma over a period of up to two weeks but smaller volumes process can also be beneficial. Number and frequency of procedures depends upon clinical scenario. Some patients may require long-term maintenance TPE.

48. LEMS Recommendation category-II Autoimmune disorder of presynaptic neuromuscular transmission- anti VGCC antibody. Its classical clinical triad include: Muscle weakness (most prominent in proximal muscles of the lower extremities) Hyporeflexia Autonomic dysfunction ( e.G. , Dry mouth, constipation, and male impotence).

49. LEMS In contrast to myasthenia gravis (MG), brain stem symptoms such as diplopia and dysarthria are uncommon. Associated with SCLC Other CA –lymphoma and malignant thymoma No controlled trials exist on the use of TPE in the LEMS.

50. LEMS… In one series, 8 out 9 patients (Newsom-Davis, 1984) had increase in electromyographic muscle action potential (P<0.01) while receiving TPE and immunosuppression . 5 to 15 daily TPE over 5–19 days to 8–10 TPE carried out at 5–7 day intervals. Improvement may not be seen for 2 weeks or more after initiation of TPE.

51. LEMS… Treatment should continue until a clear clinical and EMG response is obtained or at least until a 2–3 week course of TPE has been completed. Repeated courses -in case of neurological relapse, Effect may last only upto 6 weeks in the absence of immunosuppressive therapy.

52. NMDA RECEPTOR ANTIBODY ENCEPHALITIS Recommendation category-I An acute autoimmune neurological disorder first described by dalmau (2007). It is characterized by IgG antibodies targeting the synaptic GLuN1 (also known as NR1) subunit of the NMDAR.

53. NMDA RECEPTOR ANTIBODY ENCEPHALITIS 50% have an underlying neoplasm; usually ovarian teratoma . Definitive diagnosis -by the detection of NMDAR autoantibodies in the serum, and more specifically in the CSF. Imaging, EEG, and brain biopsy are typically nondiagnostic . Delay in diagnosis is common - often mistaken for psychosis or viral encephalitis.

54. NMDA RECEPTOR ANTIBODY ENCEPHALITIS First-line immunotherapies - IV MPS IVIG, and/or TPE. Approximately 50% of patients respond to these first-line immunotherapies Other 50% require second-line therapies- rituximab or combination of rituximab and cyclophosphamide

55. NMDA RECEPTOR ANTIBODY ENCEPHALITIS 75–80% -recover or improve (50% within 4 weeks of treatment) 20%- substantial deficits or death. Relapses -12–20% Disease activity appears to correlate with antibody levels.

56. NMDA RECEPTOR ANTIBODY ENCEPHALITIS Dalmau (2011) proposed a treatment plan consisting of teratoma removal (if present), corticosteroids and/or IVIG and/or TPE (alone or any combination) as the first-line of treatment), and rituximab and cyclophosphamide as the second-line of treatment for non-responders. The exact order of the treatments (corticosteroids, IVIG, and TPE) was not defined.

57. NMDA RECEPTOR ANTIBODY ENCEPHALITIS Furthermore, systematic comparisons between the three first-line modalities are unavailable ( Titulaer , 2013). Recent case series (Pham, 2011; DeSena , 2015) suggest early initiation of TPE or TPE followed by IVIG provide better outcomes 5–6 TPE procedures on alternate days.

58. Conclusion Removal of immunoglobulins Centrifugation and Plasma filtration Albumin MC used 5 cycles alt. days Good response in GBS,Myasthenia crisis, Autoimmune encephalitis. Good for acute management

59. References Joseph Schwartz et al; Guidelines on the Use of Therapeutic Apheresis in Clinical Practice—Evidence-Based Approach from the Writing Committee of the American Society for Apheresis : The Seventh Special Issue ;.; Journal of Clinical Apheresis 31:149–338 (2016) Update: Plasmapheresis in Neurologic Disorders; Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology; Irene Cortese , MD et al; 2011. American Academy of Neurology (AAN) guideline update (Neurology ® 2011;2011;76:294–300) regarding use of plasmapheresis in treating neurologic disorders Neurology in clinical practice ;Bradley 7 TH edition.