Perspectives on Best Practices
for Managing Acute Relapses
in Multiple Sclerosis
Moderator
Barry G. Arnason, MD
Professor of Neurology
University of Chicago
Staff Physician
Department of Neurology
University of Chicago Hospitals and Clinics
Chicago, Illinois
Panelists
Kathleen Costello, RN, MS, CRNP, MSCN
Assistant Professor
Johns Hopkins Medical Institutions
Nurse Practitioner
Johns Hopkins Hospital
Baltimore, Maryland
Saud A. Sadiq, MD
Director and Senior Research Scientist
Tisch Multiple Sclerosis Research Center of New York
Director
International Multiple Sclerosis Management Practice
New York, New York
Disclaimer
This program will include discussion of
treatment options that may deviate from
FDA recommendations.
Program Goals
• Discuss therapeutic options available to
manage acute relapses in patients with MS
• Individualize therapy for acute relapse in MS
• Develop strategies for managing suboptimal
response to acute relapse treatment and
addressing patient tolerability issues
Overview
• Challenge of MS relapse
• Underlying pathophysiology
• Strategies for managing relapse
Definition of Relapse
In clinical trials:
• Neurological deficit lasting > 24-48 hours
• With or without change in EDSS score
In the clinic:
•
•
•
•
•
Change from baseline
Sustained for a period of time (hours, days)
Otherwise unexplained by other medical conditions
Relapse is not usually a medical emergency
Symptoms may resolve over time
Vollmer T. J Neurol Sci. 2007;256:S5-S13.[1]
Relapse Triggers and Associated
Conditions: Cause or Effect?
Infectiona
• Fever can worsen MS symptoms
• Demyelinated nerves are sensitive to temperature changes
• Infection can precipitate MS attacks
Other conditions (pseudorelapse)
•
•
•
•
•
•
Depression
Stress
Sleep issues
Fatigue
Heat intolerance
Headachesb
a. Vollmer T. J Neurol Sci. 2007;256:S5-S13.[1]
b. Mohrke J, et al. PLoS One. 2013;8:e69570.[2]
Patient Assessment
• Response to relapse is highly individualized
• Symptoms may resolve on their own
(pseudorelapse)
• Encourage patients to call to discuss the
situation
• Take a careful history
− MRI may not be necessary
• Consider bringing patient in for clinical evaluation
(especially if motor symptoms are involved)
• In spinal cord disease, MRI is not likely to be
negative
Relapse Treatment: Paradigm
Treatment may be indicated if:
• Patient reports new neurological symptoms and
change in function affecting quality of life
− Sensory, cognitive, mood, or motor
• Associated medical conditions have been ruled out
• MRI shows Gd-enhancing lesion(s)
Acute relapse is not likely present if during
routine evaluation, MRI in an asymptomatic
patient shows new lesion(s) or a Gd-enhancing
lesion since last MRI
• In such cases, consider changing DMT
Myhr KM, et al. Acta Neurol Scand Suppl. 2009;73-80.[4]
Relapse Treatment: Steroids
Steroids: first-line treatmenta,b
• Standard regimen = 1 g/d for 3-5 days
− Treatment for other autoimmune diseases usually
involves lower doses (eg, 5-40 mg/d for RA)
Steroid mechanismc
• At low doses, steroids regulate gene activity
• At high doses, steroids affect cell membranes
(ie, not underlying disease mechanisms)
a. Burton JM, et al. Cochrane Database Syst Rev. 2012;12:CD006921.[3]
b. Myhr KM, et al. Acta Neurol Scand Suppl. 2009;73-80.[4]
c. Arnason BG, et al. Mult Scler. 2013;130-136.[11]
Relapse Treatment: Approaches
Dr Sadiq
• For most patients with relapse:
− 1 g/d IVMP x 3 days for most patients with relapse
− Oral taper not necessary
• If motor symptoms present, consider:
− 5 days
− Oral taper (usually rapid, 2-3 weeks)
• Address steroid adverse effects, eg:
− Sleep issues
− Gastrointestinal upset
Relapse Treatment: Approaches (cont)
Ms Costello
• High-dose oral prednisone (eg, 1250 mg) an
option
− Good efficacy; minimal adverse effectsa
− Some patients experience sleeplessness, may not feel
as well
• IV steroids
− Protocol at Johns Hopkins = IVMP 1 g/d x 5 days or oral
equivalent
− Chart review (N = 50) did not identify a difference in
outcomes with 5 days vs 3 daysb
a. Morrow SA, et al. Can J Neurol Sci. 2012;39:352-354.[5]
b. K. Costello, written communication, September 2013.
Steroid Treatment: Risks and Benefits
• Variable patient response
− Some patients feel energetic; others feel jittery, sleepless
• Adverse effects can occur and should be managed
− Common AEs: Flushing, acne, dyspepsia, metallic taste
− Severe AEs: avascular necrosis, osteoporosis, hypertension,
glucose intolerancea-c
• Goal: Accelerated recovery; restore function in short term
• Steroids per se do not delay disease progressiond…
− …But treating acute relapse and optimizing ongoing therapy may
affect progression
• Frequent use (pulsing) should be avoided
− Consider switching DMT
a. Sahraian MA, et al. Neurol Sci. 2012;33:1443-1446.[6]; b. Ce P, et al. Eur J Neurol. 2006;13:857861.[7] ; c. Ciccone A, et al. Cochrane Database Syst Rev. 2008:CD006264.[8] ; d. Andersson PB, et
al. J Neurol Sci. 1998;160:16-25.[9]
ACTH
• Only FDA-approved drug for managing acute MS attacks
• Induces production of glucocorticoids, mineralocorticoids
• Binds to 5 different melanocortin receptors
(1 of which regulates steroids)a,b
a. Arnason BG, et al. Mult Scler. 2013;19:130-136.[11]; b. Catania A. J Leukoc Biol. 2007;81:383-392.[12]
ACTH (cont)
Option for selected patients
• Intolerant to IVMP
• History of response to ACTH
Drawbacks
• Cost, insurance barriers
• Adverse effects related to increase in steroids
(eg, bloating, anxiety, appetite changesa)
Advantages
• Bone-sparing (avoids osteoporosis; aseptic
necrosisb)
a. H. P. Acthar Gel (repository corticotropin injection) [package insert].[15]
b. Arnason BG, et al. Mult Scler. 2013;19:130-136.[11]
Other Options for Managing Relapse
Plasma exchange (plasmapheresis)
• Often used in transverse myelitis, NMOa
• Consider for patients with spinal cord disease who
are still plegic after initial steroid therapy
• Typical regimen: 5 exchanges over 10 days
• Potential risk of infected lines
IVIG
• Option for pregnant patients reluctant to use
steroids
• May provide more complete recovery in optic
neuritis compared with steroidsb
a. Bonnan M, Cabre P. Mult Scler Int. 2012;2012:787630.[14]
b. Magraner MJ, et al. Neurologia. 2013;28:65-72.[15]
Comprehensive MS Management
Relapse provides opportunity to reassess
patients, review treatment strategy, and
make adjustments as needed
• Evaluate and treat symptoms (eg, mood, fatigue,
functional loss)
A team approach is valuable
• Physical therapy
• Occupational therapy
• Speech therapy
Treat the whole patient
Adjusting MS Treatment
Acute relapse may be a signal that
treatment is not optimal
• Has the DMT had time to work?
• Are other medical conditions involved (eg, cancer,
heart disease)?
• Is a switch in DMT indicated?
Summary and Key Points
• High-dose steroids (IVMP, oral prednisone)
are standard treatments for MS relapse
− Other options include ACTH, plasma exchange,
IVIG
• Overuse of steroids may cause serious
adverse effects
• Manage the whole patient, not just the
immediate symptom
− Assess and address other medical issues
(eg, depression, headache)
Abbreviations
ACTH = adrenocorticotropic hormone
AE = adverse event
DMT = disease-modifying therapy
EDSS = Expanded Disability Status Score
FDA = US Food and Drug Administration
IV = intravenous
IVIG = intravenous immunoglobulin G
IVMP = intravenous methylprednisolone
MRI = magnetic resonance imaging
MS = multiple sclerosis
NMO = neuromyelitis optica
RA = rheumatoid arthritis
RRMS = relapsing-remitting multiple sclerosis
References
1. Vollmer T. The natural history of relapses in multiple sclerosis. J Neurol Sci.
2007;256 Suppl 1:S5-13.
2. Möhrke J, Kropp P, Zettl UK. Headaches in multiple sclerosis might imply an
inflammatorial process. PLoS One. 2013;8:e69570.
3. Burton JM, O'Connor P, Hohol M, Beyene J. Oral versus intravenous steroids for
treatment of relapses in multiple sclerosis. Cochrane Database Syst Rev.
2012;12:CD006921.
4. Myhr KM, Mellgren SI. Corticosteroids in the treatment of multiple sclerosis. Acta
Neurol Scand Suppl. 2009;73-80.
5. Morrow SA, McEwan L, Alikhani K, Kremenschutzky M. MS patients report excellent
compliance with oral prednisone for acute relapses. Can J Neurol Sci. 2012;39:352354.
6. Sahraian MA, Yadegari S, Azarpajouh R, Forughipour M. Avascular necrosis of the
femoral head in multiple sclerosis: a report of five patients. Neurol Sci. 2012;33:14431446.
References (cont)
7. Ce P, Gedizlioglu M, Gelal F, Coban P, Ozbek G. Avascular necrosis of the bones:
an overlooked complication of pulse steroid treatment of multiple sclerosis. Eur J
Neurol. 2006;13:857-861.
8. Ciccone A, Beretta S, Brusaferri F, Galea I, Protti A, Spreafico C. Corticosteroids for
the long-term treatment in multiple sclerosis. Cochrane Database Syst Rev.
2008:CD006264.
9. Andersson PB, Goodkin DE. Glucocorticosteroid therapy for multiple sclerosis: a
critical review. J Neurol Sci. 1998;160:16-25.
10. Glaser GH, Merritt HH. Effects of ACTH and cortisone in multiple sclerosis. Trans
Am Neurol Assoc. 1951;56:130-133.
11. Arnason BG, Berkovich R, Catania A, Lisak RP, Zaidi M. Mechanisms of action of
adrenocorticotropic hormone and other melanocortins relevant to the clinical
management of patients with multiple sclerosis. Mult Scler. 2013;19:130-136.
12. Catania A. The melanocortin system in leukocyte biology. J Leukoc Biol.
2007;81:383-392.
References (cont)
13. H. P. Acthar Gel (repository corticotropin injection) [package insert]. Hayward,
CA: Questcor Pharmaceuticals, Inc; 2012.
14. Bonnan M, Cabre P. Plasma exchange in severe attacks of neuromyelitis optica.
Mult Scler Int. 2012;2012:787630.
15. Magraner MJ, Coret F, Casanova B. The effect of intravenous immunoglobulin on
neuromyelitis optica. Neurologia. 2013;28:65-72.