The Role of Therapeutic
Apheresis in Neurological
Disorders
Vishesh Chhibber, MD
November 15, 2013
Disclosure
• I have no actual or potential conflict of
interest in relation to the content of this
presentation
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
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
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
Cortese I et al. Neurology 2011;76:294-300
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;28:145-284
Schwartz J et al. J Clin Apher 2013;28:145-284
Schwartz J et al. J Clin Apher 2013;28:145-284
Disorders that will be discussed
today
Schwartz J et al. J Clin Apher 2013;28:145-284
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
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
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)
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 1-1.5 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;28:145-284
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;76:294-300
Schwartz J et al. J Clin Apher 2013;28:145-284
Neurological Disease Conditions
CNS
PNS
Acute
ADEM
AIDP (Guillain-Barre)
Chronic
MS
NMO
CIDP
MG
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;35:1096 -1104
French Coop. Group on TPE in GBS. Ann Neurol 1987;22:753-761
Therapy
• TPE is considered first line therapy
– 5 or 6 TPE with 1-1.5 volume replacement using 5%
albumin performed every other day
– Exchange 200-250 mL of plasma per Kg over 10-14
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;28:145-284
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;76:294-300
Schwartz J et al. J Clin Apher 2013;28:145-284
Neurological Disease Conditions
CNS
PNS
Acute
ADEM
AIDP (Guillain-Barre)
Chronic
MS
NMO
CIDP
MG
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
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
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;28:145-284
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;76:294-300
Schwartz J et al. J Clin Apher 2013;28:145-284
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
Multiple Sclerosis (MS)
• Presents with sensory deficits, diplopia, optic
neuritis (unilateral), extremity weakness,
bowel/bladder symptoms
• Several patterns of disease: relapsingremitting, chronic progressive (primaryprogressive, secondary-progressive,
progressive-relapsing)
Therapy
• High dose corticosteroids
• In patients with severe acute MS without
response to steroids, consider TPE
– 5 to 7 TPE with 1-1.5 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;28:145-284
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;76:294-300
Schwartz J et al. J Clin Apher 2013;28:145-284
Neurological Disease Conditions
CNS
PNS
Acute
ADEM
AIDP (Guillain-Barre)
Chronic
MS
NMO
CIDP
MG
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
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;202:473-477
NMO Diagnostic Criteria
Wingerchuk et al. Neurology 2006;66:1485-1489
Therapy
• High dose corticosteroids (first line therapy)
• TPE is initiated if no improvement or
progression after steroid administration
– 5 TPE with 1-1.5 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;28:145-284
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;76:294-300
Schwartz J et al. J Clin Apher 2013;28:145-284
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)
Therapy
• Cholinesterase inhibition
– e.g. pyridostigmine
– Stronger action potentials of the muscles
• Corticosteroids and azathioprine for
immunosuppresion
• Surgical thymectomy
– Beneficial if thymoma present
• TPE
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;28:145-284
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;76:294-300
Schwartz J et al. J Clin Apher 2013;28:145-284
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”
http://www.neurology.org/content/76/3/294/reply#neurology_el_42491
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
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;72:402-409
Guidelines
• AAN
– 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;76:294-300
Schwartz J et al. J Clin Apher 2013;28:145-284
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;67:1391-1394
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
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
Questions?