Acute Therapies: Steroids, IVIG, Plasmaexchange and Cyclophosphamide

Benjamin Greenberg, M.D., M.H.S. Assistant Professor Department of Neurology The Johns Hopkins University School of Medicine Co-Director CoJohns Hopkins Transverse Myelitis Center [Disclosures: none]

Stages of Disease

Chronic Degeneration

Stages of Disease

Stages of Disease

Acute Inflammation

Endogenous Repair

Acute Inflammation
Cytokines: IL-6, TNF alpha, etc.

Immune Mediated Neurologic Disease
TRIGGER

INTERVENTIONS Avoidance Vaccines Anti-inflammatories Neuroprotection Neuroprotection Prevent Recurrence

ACUTE INFLAMMATION

Antibodies, complement

CHRONIC DEGENERATION

ENDOGNEOUS REPAIR

Promote Repair Repair it Iatrogenically

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Acute Therapy
Goals of acute therapy Mechanisms Lessons from transverse myelitis

Drugs/Strategies Used as Acute Therapy and Their Mechanism of Action
Steroids
dampens the inflammatory cytokine cascade 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-helper cell cytokines, Tmetalloproteinase and chemokine production

Goals of Acute Therapy
Limit Inflammation
Preventing more cells from infiltrating blood brain barrier Eliminate members of the immune system that are in inappropriate places

Drugs/Strategies Used as Acute Therapy and Their Mechanism of Action
Plasmaexchange (plasmapheresis/PLEX) plasmapheresis/PLEX)
reduces the amount of circulating antibodies in a patient through filtration

Limit substances that lead to nervous system damage
Directly inhibit substances that are neurotoxic (i.e. Il-6) Il-

Protect components of the nervous system
“neuroprotective” strategies aim to shield neurons from neuroprotective” damage even in the presence of inflammation.

Cyclophosphamide
Alkylating agent, destroys proliferating lymphocytes

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Difficulties Encountered When Designing Acute Strategies
Limited clinical trials Difficulty for designing prospective, blinded trials
Small numbers Difficulty blinding patients and physicians

Measures of Outcome
Delta EDSS

Heterogeneity of disorders obscures data
Lumpers versus splitters

Outcome measures are limited
Subjective and objective data

10 8 6 4 2 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

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Minimal signs
10 9 8 7 6 5 4 3 2 1 0

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Cane

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Wheelchair

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8

Bed

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Death

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Neurology, in press

1. What therapies work? 2. How well do they work? 3. Are there subsets of patients who should have certain therapies?

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Experience from Transverse Myelitis Analysis of 122 Consecutive Patients
IV MP IV MP + PLEX 32 38.6 56 41 9.7 67 61 34 IV MP + IV CP 13 41.6 92 85 38.5 85 100 31 IVMP + PLEX+IV CP 11 41 55 82 36.4 46 80 36

Experience from Transverse Myelitis
10 9 8 7 6 Delta EDSS 5 4 3 2 1 0

Patients Mean Age % Women Recurrent TM % Multifocal CSF Pleo Elev Prot % ASIA A

66 43.9 58 35 9.4 67 67 11

4.1 3 2.1 0.3 IV Steroids 0.5 PLEX

4.9

4.4 2.8

ASIA A NON-ASIA A

IV CP

PLEX + IV CP

Treatment Groups

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

Treatment Groups

Experience from Transverse Myelitis

Diagnostic approach to acute myelopathy

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 Myelitis
Patients with transverse myelitis secondary to systemic autoimmune disease respond best to regimens that include cyclophosphamide Patients who are ASIA A at nadir respond significantly better to regimens with cyclophosphamide, regardless of other factors. Patients who are non-ASIA A and who do not have nonsigns of autoimmune disease do not necessarily have improved outcomes from the addition of cyclophosphamide to their regimen. Time is cord!!

Thank You
Our patients, who face each day with courage and accept our faults and uncertainty with grace. Our patients’ families who advocate for, support patients’ and care for their loved ones.

And most importantly, thank you to

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