Acute Therapies: Steroids, IVIG, Stages of Disease

Plasmaexchange and
Cyclophosphamide
Benjamin Greenberg, M.D., M.H.S.

Assistant Professor
Department of Neurology Chronic Degeneration
The Johns Hopkins University School of Medicine

Co-
Co-Director
Johns Hopkins Transverse Myelitis Center
[Disclosures: none]

Stages of Disease Stages of Disease

Acute Inflammation Endogenous Repair

Immune Mediated Neurologic

Acute Inflammation Disease
INTERVENTIONS

Avoidance
TRIGGER Vaccines
Cytokines: IL-6, TNF alpha, etc.

Anti-inflammatories
ACUTE INFLAMMATION
Neuroprotection

Neuroprotection
Antibodies, complement CHRONIC DEGENERATION Prevent Recurrence

Promote Repair
ENDOGNEOUS REPAIR Repair it Iatrogenically

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 Drugs/Strategies Used as Acute
Acute Therapy Therapy and Their Mechanism of
„ Goals of acute therapy
Action
Mechanisms „ Steroids
„
„ dampens the inflammatory cytokine cascade
„ Lessons from transverse myelitis
„ inhibits the activation of T cells
„ decrease the extravasation of immune cells into the
CNS
„ facilitate the apoptosis of activated immune cells

Drugs/Strategies Used as Acute

Therapy and Their Mechanism of
Action
„ IVIG
„ neutralization of pathogenic autoantibodies
„ suppression of pathogenic autoantibody production
„ acceleration of native IgG degradation
„ inhibition of complement binding
„ blockage of Fc binding mediated phagocytosis
„ interruption of antigen recognition
„ suppression and neutralization of T-
T-helper cell cytokines,
metalloproteinase and chemokine production

Drugs/Strategies Used as Acute

Goals of Acute Therapy Therapy and Their Mechanism of
„ Limit Inflammation Action
„ Preventing more cells from infiltrating blood brain barrier
„ Eliminate members of the immune system that are in „ Plasmaexchange (plasmapheresis/PLEX)
plasmapheresis/PLEX)
inappropriate places
„ reduces the amount of circulating antibodies in a
„ Limit substances that lead to nervous system damage
patient through filtration
„ Directly inhibit substances that are neurotoxic (i.e. Il-
Il-6)
„ Protect components of the nervous system „ Cyclophosphamide
„ “neuroprotective”
neuroprotective” strategies aim to shield neurons from „ Alkylating agent, destroys proliferating lymphocytes
damage even in the presence of inflammation.

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 Difficulties Encountered When
Measures of Outcome
Designing Acute Strategies
„ Limited clinical trials „ Delta EDSS
„ Difficulty for designing prospective, blinded
trials
„ Small numbers
„ Difficulty blinding patients and physicians 10
„ Heterogeneity of disorders obscures data 8
6
„ Lumpers versus splitters
4
„ Outcome measures are limited 2
„ Subjective and objective data 0
Delta EDSS 7-3 = 4

American Spinal Injury Association Measures of Outcome

„ Percent Maximum Expected Improvement

10
8
6
4
2
0
Delta EDSS 7-4 = 3
Percent MEI 7-4/7-3 = 75%

Kurtzke Expanded Disability Status

Scale

1 2 3 4 5 6 7 8 9 10
Minimal Cane Wheelchair Bed Death Neurology, in press
signs

10
9
8
7
1. What therapies work?
6
5
2. How well do they work?
4
3
3. Are there subsets of patients who should have certain therapies?
2
1
0

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 Experience from Transverse Myelitis
Analysis of 122 Consecutive Patients Experience from Transverse Myelitis
IV MP IV MP + IV MP + IV IVMP +
10
PLEX CP PLEX+IV 9
CP 8
7
Patients 66 32 13 11 6
Mean Age 43.9 38.6 41.6 41 Delta EDSS 5 4.9
4.4
4 4.1
ASIA A
% Women 58 56 92 55 3 3 2.8 NON-ASIA A
2 2.1
Recurrent 35 41 85 82
1
TM 0
0.3 0.5

% Multifocal 9.4 9.7 38.5 36.4 IV PLEX IV CP PLEX +

Steroids IV CP
CSF Pleo 67 67 85 46 Treatment Groups
Elev Prot 67 61 100 80
% ASIA A 11 34 31 36

Experience from Transverse Myelitis

100 145.6
90 85.1
80 76.1
70 70.1
60
Percent MEI 50 43.9 47.5
40 ASIA A
30 NON-ASIA A
20 17.4
10
3.01
0
IV PLEX IV CP PLEX +
Steroids IV CP
Treatment Groups

Diagnostic approach to acute myelopathy

Experience from Transverse Myelitis

Transverse Myelitis Consortium Working Group*,

Neurology 2002;59:499-505

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 Thank You
„ Project RESTORE
„ Transverse Myelitis Association
„ The Cody Unser First Step Foundation

Spine Attack Thank You

Conclusions from Transverse

Thank You
Myelitis
„ Patients with transverse myelitis secondary to systemic „ Our patients, who face each day with courage
autoimmune disease respond best to regimens that
include cyclophosphamide and accept our faults and uncertainty with grace.
„ Patients who are ASIA A at nadir respond significantly „ Our patients’
patients’ families who advocate for, support
better to regimens with cyclophosphamide, regardless
of other factors. and care for their loved ones.
„ Patients who are non-
non-ASIA A and who do not have
signs of autoimmune disease do not necessarily have
improved outcomes from the addition of
cyclophosphamide to their regimen.
„ And most importantly, thank you to
„ Time is cord!!

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