1. The Role of Therapeutic Apheresis in Neurological Disorders
Vishesh Chhibber, MD
November 15, 2013

2. Disclosure
I have no actual or potential conflict of interest in relation to the content of this presentation

3. The Role of Apheresis
Several autoimmune neurological disorders can be treated with TA
Usually a protein in the plasma (often an autoantibody) is being removed
Most common procedure performed is TPE
Immunoadsorption (IA) is also utilized
In some disease indications, it is not clear why TPE is beneficial

4. Evidence Based Guidelines
The American Academy of Neurology (AAN) published updated evidence-based guidelines in 2011
ASFA published the 6th edition of their evidence based guidelines in 2013

5. AAN Guidelines Previous AAN assessment was in 1996
Controlled clinical trials (in humans)
Data from observational studies and case reports was not included in the analysis as this was considered class IV evidence

6. Cortese I et al. Neurology 2011;76:294-300

7. ASFA Previous ASFA guidelines were published in 2010
Considered all published evidence (including observational studies and case reports)
Assigned a category and a recommendation grade for each indication
Schwartz J et al. J Clin Apher 2013;28:

8. Schwartz J et al. J Clin Apher 2013;28:145-284

9. Schwartz J et al. J Clin Apher 2013;28:145-284

10. Disorders that will be discussed today
Schwartz J et al. J Clin Apher 2013;28:

11. Technical Details of TPE
1-1.5 Plasma volumes
Albumin (5%) used as the replacement fluid
Donor plasma added as a portion of the replacement fluid if patient at risk of coagulopathy/bleeding (e.g. daily TPE)
Number and frequency of TA procedures will depend on the disease/indication

12. Acute Disseminated Encephalomyelitis (ADEM)
Acute inflammatory demyelinating disease of the CNS
Immune response to myelin (or other autoantigens)
Presents with acute encephalopathy
altered mental status, hemiparesis, ataxia, motor deficits, may progress to coma

13. Acute Disseminated Encephalomyelitis
Usually
monophasic
seen in children and young adults
lasts 2-4 weeks
follows a viral infection or a vaccine
Lesions in subcortical region with sparing of periventricular areas
Resolution of lesions on repeat MRI (complete or partial)

14. Therapy Corticosteroids (first line therapy)
1/3 fail
In patients that do not respond to steroids, TPE or IVIG can be used
3 to 6 TPE with volume replacement using 5% albumin performed daily or every other day
In patients that respond to TPE, improvement is noted soon after initiation of TPE
Schwartz J et al. J Clin Apher 2013;28:

15. Guidelines
AAN: Possibly effective in acute CNS demyelination (includes MS, ADEM, and NMO) if steroid therapy fails
ASFA: Category II with a recommendation of 2C
Cortese I et al. Neurology 2011;76:
Schwartz J et al. J Clin Apher 2013;28:

16. Neurological Disease Conditions
CNS
PNS
Acute
ADEM
AIDP (Guillain-Barre)
Chronic MS
NMO
CIDP MG

17. Acute Inflammatory Demyelinating Polyneuropathy (Guillain-Barre Syndrome)
Most common general paralytic disorder
Acute motor and sensory deficiency involving the peripheral nerves
Caused by a complement binding IgM antibody to peripheral nerve myelin
RCT’s have shown
Less time to recovery
Greater extent of neurological recovery
The GBS Study Group. Neurology 1985;35:
French Coop. Group on TPE in GBS. Ann Neurol 1987;22:

18. Therapy TPE is considered first line therapy
5 or 6 TPE with volume replacement using 5% albumin performed every other day
Exchange mL of plasma per Kg over days
Alternatively IVIg may be used with similar efficacy
higher cost
may not be as effective in patients with axonal involvement
Schwartz J et al. J Clin Apher 2013;28:

19. Guidelines
AAN: TPE is effective in severe AIDP (impaired ability to walk, requirement of mechanical ventilation) and should be offered to these patients. In milder disease, it is probably effective and should be considered.
ASFA: Category I with recommendation grade of 1A
Category III with a recommendation grade of 2C has been assigned for TPE post IVIG
Cortese I et al. Neurology 2011;76:
Schwartz J et al. J Clin Apher 2013;28:

20. Neurological Disease Conditions
CNS
PNS
Acute
ADEM
AIDP (Guillain-Barre)
Chronic MS
NMO
CIDP MG

21. Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
Chronic autoimmune demyelinating disease of the peripheral nervous system
Symmetric sensory loss and muscle weakness
Progressive or Relapsing course
Believed to be an autoimmune disorder but the pathogenesis is not fully understood

22. Therapy
Improvement seen with immunomodulating and immunosuppressive therapy
Corticosteroids, TPE and IVIg have been used
60-80% respond to initial therapy
Response to therapy is short lived (improvement often wanes after about 2 weeks)
Therapy should be initiated early to prevent inflammatory demyelination and axonal degeneration

23. Therapy TPE performed 2-3 times per week until improvement is noted
1-1.5 volumes using 5% albumin
Taper TPE as tolerated to a maintenance schedule
Maintenance frequency varies between patients (weekly to monthly)
Alternatively IVIg may be used with similar efficacy
Corticosteroids may be used for maintenance (after initial therapy with TPE)
Schwartz J et al. J Clin Apher 2013;28:

24. Guidelines
AAN: TPE is effective in CIDP and should be offered as short-term therapy
ASFA: Category I with recommendation grade of 1B
Cortese I et al. Neurology 2011;76:
Schwartz J et al. J Clin Apher 2013;28:

25. Multiple Sclerosis (MS)
Relapsing/progressive CNS disorder that presents in early adulthood
Pathogenesis not fully understood
believed to be an autoimmune disorder that involves both the cellular and humoral immune systems and results in white matter demyelination
oligoclonal bands in the CSF
Heterogenous with variable prognosis

26. Multiple Sclerosis (MS)
Presents with sensory deficits, diplopia, optic neuritis (unilateral), extremity weakness, bowel/bladder symptoms
Several patterns of disease: relapsing-remitting, chronic progressive (primary-progressive, secondary-progressive, progressive-relapsing)

27. Therapy High dose corticosteroids
In patients with severe acute MS without response to steroids, consider TPE
5 to 7 TPE with volume replacement using 5% albumin performed over 14 days
Other disease modifying therapies include: interferon beta-1a, glatiramer acetate, IVIG, rituximab, cyclophosphamide, azathioprine, mitoxantrone, natalizumab
Schwartz J et al. J Clin Apher 2013;28:

28. Guidelines
AAN: Possibly effective in acute CNS demyelination (includes MS, ADEM, and NMO) if steroid therapy fails
ASFA: Category II with a recommendation of 1B in acute CNS demyelination
Category III with a recommendation grade of 2B has been assigned for chronic progressive MS
Cortese I et al. Neurology 2011;76:
Schwartz J et al. J Clin Apher 2013;28:

29. Neurological Disease Conditions
CNS
PNS
Acute
ADEM
AIDP (Guillain-Barre)
Chronic MS
NMO
CIDP MG

30. Neuromyelitis Optica (NMO)
Aka Devic’s disease (Previously considered a form of MS)
Women are affected more commonly
Typically, patients are in their 30’s but seen at all ages
Autoimmune disorder that results in inflammatory demyelination of the CNS
Primarily involves the spinal cord & optic nerve

31. Neuromyelitis Optica Progressive disease
Incomplete recovery after each relapse leads to residual deficits
5 years: 30% mortality and 50% are wheelchair bound or have severe visual deficits
Recently associated with an IgG autoantibody to aquaporin-4 (a water channel found on the foot processes of astrocytes)
aka NMO-IgG
Lennon et al. J Exp Med 2005;202:

32. NMO Diagnostic Criteria
Wingerchuk et al. Neurology 2006;66:

33. Therapy High dose corticosteroids (first line therapy)
TPE is initiated if no improvement or progression after steroid administration
5 TPE with volume replacement using 5% albumin performed daily or every other day
More likely to see benefit if TPE is initiated early in the course
Schwartz J et al. J Clin Apher 2013;28:

34. Guidelines
AAN: Possibly effective in acute CNS demyelination (includes MS, ADEM, and NMO) if steroid therapy fails
ASFA: Category II with recommendation grade of 1B in acute NMO
Category III with a recommendation grade of 2C has been assigned for maintenance therapy
Cortese I et al. Neurology 2011;76:
Schwartz J et al. J Clin Apher 2013;28:

35. Myasthenia Gravis
Autoimmune disorder that results in disruption of neuromuscular transmission
Antibody to the acetylcholine receptor on the post synaptic motor end plate
Results in muscle weakness
Extraocular and bulbar
Generalized (trunk and extremities)

36. Therapy Cholinesterase inhibition
e.g. pyridostigmine
Stronger action potentials of the muscles
Corticosteroids and azathioprine for immunosuppresion
Surgical thymectomy
Beneficial if thymoma present
TPE

37. TPE TPE used in moderate/severe cases or prior to thymectomy
1-1.5 volumes with replacement using 5% albumin
The number and frequency of TPE depends on the patient’s disease
Induction with 225 mL/kg over 1-2 weeks
Long-term maintenance may be required
Schwartz J et al. J Clin Apher 2013;28:

38. Guidelines
AAN
“There is insufficient evidence to support or refute the use of plasmapheresis for myasthenia gravis”
ASFA:
Moderate-severe disease: Category I with a recommendation grade of 1B
Prethymectomy: Category I with a recommendation grade of 1C
Cortese I et al. Neurology 2011;76:
Schwartz J et al. J Clin Apher 2013;28:

39. Discrepancy between AAN and ASFA
ASFA reviewed all of the published evidence
AAN did not consider evidence from observational studies or case reports
“…reexamination of the methodologies may be warranted due to the failure, in some cases, to account for overwhelming anecdotal evidence or evidence from uncontrolled studies. Thus it may be the case that Class IV evidence should be considered when it is both abundant and consistent, especially when higher standards of evidence cannot feasibly be obtained for either ethical or other reasons”

40. Natalizumab Used to treat relapsing-remitting MS
Monoclonal antibody against α4-integrin
Entry of WBC into the CNS
PML is a life threatening complication of natalizumab therapy
Opportunistic CNS infection by the JC virus

41. Natalizumab Clearance
Natalizumab has a long half life & may be detectable >12 weeks after the last dose
TPE has been used to hasten the removal
May provide significant benefit by restoring ability of WBCs to enter the CNS
TPE decreases the drug levels and T ½
Shorter time to immune reconstitution
Clinical improvement
Khatri et al. Neurology 2009;72:

42. Guidelines AAN ASFA: Category III with a recommendation grade of 2C
Initial data suggests TPE may be useful in restoring leukocyte function by removal of natalizumab
Additional studies are necessary to see whether this results in any benefit in patients with infectious complications
ASFA: Category III with a recommendation grade of 2C
Cortese I et al. Neurology 2011;76:
Schwartz J et al. J Clin Apher 2013;28:

43. Adverse Consequences of TPE
Immune Reconstitution Inflammatory Syndrome (IRIS)
Inflammatory response
Symptom exacerbation
Enlargement of MS lesions
IV Corticosteroid therapy may be of benefit
Schroder et al. Arch Neurol 2010;67:

44. Additional Use of TPE in Natalizumab Clearance
Natalizumab is usually used as monotherapy
Alternate therapy may be necessary if MS patient is not responsive to natalizumab
Adding a second immunosuppressive therapy may place patient at increased risk of infection
Neurologists may request TPE to hasten clearance prior to initiating another drug

45. Summary
TPE plays an important role in the treatment of several autoimmune neurological disorders
Therapy should be based on evidence based review of the literature
The AAN and ASFA have published evidence based guidelines regarding the use of TA
Additional studies are necessary to determine the optimal role of TA in several neurological disease conditions

46. Questions?