Advances in the
Treatment of Autoimmune
Neuromuscular Disease—
From Diagnostic Challenges
to Long-Term Management
Faculty
Chairperson
Gil I. Wolfe, MD
Professor and Chief of the Neuromuscular Section
Department of Neurology
University of Texas Southwestern Medical Center
University of Texas Southwestern Hospital
Dallas, Texas
Erik R. Ensrud, MD
Gregory T. Carter, MD, MS
Board certified in
PM&R/EMG/Neurology/
Neuromuscular Disease
Director, Neuromuscular Center and
EMG Laboratory
VA Boston Healthcare System
Associate Neurologist
Brigham and Women’s Hospital
Boston, Massachusetts
Clinical Professor of Physical Medicine
and Rehabilitation and of
Neuromuscular Medicine
University of California Davis
Sacramento, California
Medical Director
Regional Neuromuscular Center
Providence St. Peter Hospital
Olympia, Washington
Topics
 Diagnostic criteria for autoimmune
neuromuscular diseases (NMD)
 Making treatment decisions—using experience,
exploring the evidence
 Role of rehabilitation in autoimmune NMD
Objectives
On completion of this activity, participants should be
able to:
 Recognize the clinical presentations and key diagnostic
features of autoimmune NMD
 Select appropriate therapies and recognize potential
treatment failures on the basis of patient history and
available clinical evidence
 Determine appropriate timing, dosage, and duration of
therapies used in the treatment of autoimmune NMD
 Recognize the long-term implications of NMD and
become proficient in applying appropriate rehabilitative
strategies
Guillain-Barré Syndrome (GBS)
Acquired Inflammatory Demyelinating Polyneuropathy (AIDP)
 Typical GBS—monophasic immune attack
 +\- Prodromal infection
 Rapidly evolving weakness—variable degree
 Initial paresthesias, sensory loss
 Areflexia
 Pathology-segmental demyelination
arohn RJ, Saperstein DS. Semin Neurol.1998;18:49-61.
Prodromal Aspects
 2/3 of patients report a prodromal event or
symptoms 1 to 4 weeks before onset of
weakness
 28% gastroenteritis
 18% URI
 Surgery
CIDP
Chronic Inflammatory Demyelinating Polyneuropathy
 Dyck at Mayo Clinic, 1975
 Acquired neuropathy that shares a similar pathology and
autoimmune etiology with GBS
 Different from GBS
 Usually, but not always, in the manner of presentation
 Natural history of the disease
 Rarely associated with antecedent infection
 Responds to prednisone
 Peak incidence at 40–60 yrs old
Dyck PJ et al. Mayo Clin Proc. 1975;50:621-637; Burns T, Ensrud E. (Producers). (17 Aug 2007). “Chronic
inflammatory polyradiculoneuropathy with Peter J. Dyck, MD” Available at:
http://beta.aanem.org/Education/Products/PhyPodcasts.aspx?page=3&fileid=355.
Typical CIDP
 Slow onset of progressive symmetric muscle weakness
 Both proximal and distal weakness
 Progresses for >2 months; may be relapsing-remitting
 ~60% slowly progressive course
 ~35% relapsing-remitting
 Sensory loss less prominent than weakness; paresthesias
and numbness, but rarely significant pain
 Large-fiber sensory modalities are more affected
 Diffuse decreased or absent reflexes
 3%–5% have evidence of CNS demyelination
 Pathology
 Multifocal demyelination
 No vasculitic changes
 Sural nerve biopsy is rarely necessary
The Triad of GBS Diagnosis*
 Clinical picture, syndrome
 CSF
 EMG findings
* Preferably 2 of 3 consistent with GBS before
treatment is initiated
Ensrud ER, Krivickas LS. Phys Med Rehabil Clin N Am. 2001:12:321-334.
Electrophysiology
 Dependent on subtype
 Crucial to maintain and record adequate
temperature
 Findings of demyelination, axonal loss, or
both, especially with a prolonged course
Alberti MA et al. J Peripher Nerv Syst. 2011;16:136-142.
AIDP
• Prolonged distal motor and F-wave (early)
•
•
•
•
latencies
Absent or impersistent F-waves
Slowing of CV and/or conduction block
Reduction of CMAPs +/- temporal dispersion
Abnormal or absent median SNAP + normal
sural SNAP (AMNS) 39%
Alberti MA et al. J Peripher Nerv Syst. 2011;16:136-142.
Very Early EDX Findings in GBS
(Within 4 Days of Clinical Onset)
•
•
•
•
Abnormally late responses in 77%
Prolonged distal motor latency in 55%
Cranial nerve study abnormality in 44%
Motor nerve conduction velocity slowing in 23%
Alberti MA et al. J Peripher Nerv Syst. 2011;16:136-142.
CIDP—Diagnosis*
 Exam, symptoms
 CSF
 EMG
*At least 2 of 3 before treatment
CIDP—CSF/Serum
 CSF is very important in diagnosis
 Elevated (>45mg/dl) in 94% of patients, average
135
 CSF protein level is very sensitive!
 90% of patients have CSF cell count WBC <5
 ~ 25% with this phenotype have monoclonal
gammopathy; check serum SPEP/IFX for a
monoclonal spike
 Commercial serum antibodies are rarely needed
Barohn RJ et al. Arch Neurol. 1989;46:878-884.
CIDP—Electrophysiology




Complex topic
Need to study multiple nerves, “MS of PNS”
Correct temperature (>32.00C) is crucial
NCS shows electrophysiologic evidence of demyelination
 Distal motor latency >125% normal
 Conduction velocity <70% normal (<80% if CMAP amp
≥80% normal)
 Conduction block
 Temporal dispersion
 Needle EMG tends to show more prominent reinnervation
changes than acute denervation changes, consistent with slow
temporal nature of pathology
 EMG may look axonal because of secondary axonal damage
Barohn RJ, Saperstein DS. Semin Neurol .1998;18:49-61.
GBS—Early Recognition
of Poor Prognosis
 A recent paper looked at 397 GBS patients
 Which patients were unable to walk at 4 weeks,
3 months, and 6 months?
 Three important factors
 Older age (>60)
 Preceding diarrhea
 MRC scores averaged 3 or less when the
following were tested:
•
•
Shoulder abd/elb flexion/wrist ext hip
flexion/knee ext/ankle dorsiflexion
MRC scores were most predictive at 7
days after admission
Walgaard C et al. Neurology. 2011;76:968-975.
CIDP With Acute Onset
(A-CIDP)
 170 patients with GBS
 1-year follow-up
 Treatment–related fluctuation (TRF) in GBS always
occurred within 8 weeks of symptom onset
 Always 1 or at the most 2 TRFs
 Consider A-CIDP when a patient thought to have
AIDP/GBS deteriorates 8 weeks from onset or has 3 or
more TRFs
 Start maintenance therapy for CIDP when A-CIDP is
recognized
Ruts L et al. Neurology. 2010;74:1680-1696; Ensrud E. (Producer). (25 May 2010). “Distinguishing
acute-onset CIDP from fluctuating Guillain-Barré syndrome : a prospective study “ with Dr. Pieter van
Doorn. Available at: http://www.aan.com/rss/?event=feed&channel=1.
A-CIDP—Recommendations for
Identification or Appropriate Treatment
 When a GBS patient is discharged from an acute
hospital, always schedule an 8-week outpatient follow-up
appointment
 In acute rehab, document a full motor and sensory exam
on admission and every week subsequently until the
patient is discharged from rehab
 Consider differential diagnoses in this setting
 Eg, a second condition such as steroid myopathy
 TRF of GBS
 Note: Unrecognized A-CIDP can result in irreversible
axonal loss  permanent loss of function including
quadriplegia
GBS—Rehabilitative Strategies
 ICU setting
• Passive ROM, prevent joint contracture
• Active assisted ROM as tolerated
• Close monitoring
 Medical-surgical setting
• Increase intervention
• Isometric exercises while the patient is
nonambulatory (Delorme technique)
• Physical therapy
CIDP
Evidence-based treatments
 Prednisone: 60–100 mg per day, followed by taper
 IVIG: 2 g/kg as induction therapy
 Plasma exchange 5–6 treatments
Hughes RA et al. Cochrane Database Syst Rev. 2004;(4):CD003280. Mehndiratta MM et al. Cochrane
Database Syst Rev. 2004;(3):CD003906. van Schaik IN et al. Cochrane Database Syst Rev.
2002;(2):CD001797.
MG—Routine Diagnostic Work-up
 Repetitive nerve testing (3 Hz)
 U-shaped decrement
 Reproducible
 Partially repairable
 Anti-acetylcholine receptor antibodies (IgG)
 Anti–muscle-specific tyrosine kinase (anti-MUSK)
antibodies
 Chest CT to look for thymoma
Autoimmune NMD—
Rehabilitative Strategies
 MG patients who are adequately medicated may
have minimal rehabilitative needs
 During an acute crisis, passive limb exercises
lower the risk of deep vein thrombosis (DVT)
 DVT prophylaxis is recommended
 Bulbar dysfunction increases the risk of aspiration
MG—Treatment
 Anticholinesterase agents (pyridostigmine) for symptomatic
relief
 Corticosteroids
 Immunosuppressants for steroid-sparing effect (azathioprine,
mycophenolate mofetil, cyclosporine, tacrolimus, rituximab)
 Plasma exchange or IVIG for a crisis; before thymectomy; for
severe exacerbations; or in refractory patients
 IVIG is more accessible
 Plasma exchange may work faster
 Thymectomy
 Removal of thymoma
 Thymectomy is a treatment option in nonthymomatous MG1
1. Gronseth GS, Barohn RJ. Neurology. 2000;55:7-15.
Summary of Consensus Statements
IVIG
• Myasthenia gravis—Level A
 Acute exacerbations1,2
 Short-term Rx for severe disease1
Plasmapheresis
• Myasthenia gravis—Level U
 Myasthenic crisis3
 Prethymectomy
 “Plasmapheresis is used at many medical centers for
these indications”3
Corticosteroids
• Myasthenia gravis4,5—Experience-based
1. Elovaara I et al. Eur J Neurol. 2008;15:893-908. 2. Donofrio PD et al. Muscle Nerve. 2009;40:890-900.
3. Cortese et al. Neurology. 2011;76:294-300. 4. Evoli A et al. Eur Neurol. 1992;32:37-43. 5. Pascuzzi RM et al.
Ann Neurol. 1984;15:291-298.
MG─Long-Term
Azathioprine Treatment
 n=23
 Outcomes
 All improved
 Clinical grade 3 or 4 initially (moderate to severe
weakness)
 Clinical grade 1 or 2 at last observation (no or mild
weakness)
 2 patients discontinued azathioprine after full remission
 Mean prednisolone dose fell to 5 mg/d
 Side effects
 No patients with WBC <2.5
 No opportunistic infections
Fonseca V et al. Postgrad Med J. 1990;66:102-105.
MG─Long-Term Use of Cyclosporine
 N=39, randomized to cyclosporine (5 mg/kg per body weight in
divided doses) or placebo
 After 6 months

Treatment group had significantly greater improvement in strength (p=0.004)
and a reduction in anti-Ach receptor antibody titer (p=0.01)

Percentage reduction of steroid medication was greater in the cyclosporine
group, although the difference was not statistically significant (p=0.12)

No significant nephrotoxicity was noted at this dosage during the first 6
months
 55% of patients no longer on cyclosporine at 36 months





Nephrotoxicity
Headache
Psychiatric symptoms
GI intolerance
Infection
Tindall RSA et al. Ann NY Acad Sci. 1993;681:539-551.
MG─Long-Term Use of Tacrolimus
 MGFA PIS
25
Total (n=212)
Without thymoma (n=149)
Average Value
20
With thymoma (n=63)
15
 13.7% complete, stable
remission
 73.8% pharmacologic
remission
 5.4% minimal manifestation
 Prednisone withdrawn in 95%
10
5
1.9 *
0.6 *
0.4 *
0
0.3 *
Baseline Month 3 Month 6 Month 9 Month 12
QMG scores over time
*p<0.05
0.2 *
Final
 Favorable response
irrespective of thymectomy or
thymoma
 4.9% discontinued because of
AEs
Adapted from: Ponseti JM et al. Ann NY Acad Sci. 2008;1132:254.
MG─Treatment and Outcomes
n=470, 19 tertiary centers
90
80
70
% percent
60
50
40
30
20
10
0
Thymectomy
Steroids
Other IS
Anti-AchE
Outcomes (mean follow-up 8 years; minimum 1 yr)
• Remission 30%
• Ocular 35%
• Generalized 35% (only 4% with moderate-to-severe disability)
• MGFA 0-II increased from 78.7% to 96.7% (p<0.01)
IS=immunosuppressant; Anti-AchE=cholinesterase inhibitor; MGFA=Myasthenia Gravis Foundation of America.
Adapted from Kawaguchi N et al. J Neurol Sci 2004;224:43.
MG─Treatment and Outcomes (cont)
Adapted from Grob D et al. Muscle Nerve. 2008;37:141.
MG—Selection of Steroid–Sparing
Agents
 Azathioprine (may be used in conjunction
with prednisone)
 At least 1 year to see a full effect
 Often seen—an increase of at least 10 from
baseline MCV in CBC in responders
 Mycophenolate
 Tacrolimus
GBS—Treatment of Pain
• Almost 90% of GBS patients experience pain
• 66% have very severe pain
• Gabapentin or pregabalin
• Tricyclic antidepressants
• Opioid analgesics
GBS—BiPAP for Respiratory Support
 Respiratory failure is a significant cause of
morbidity and mortality in GBS
 33% of GBS patients require intubation
 Average time to intubation is 7 days after
symptom onset
 Little clinical experience with BiPAP in GBS
(used more commonly in MG)
GBS—Rehabilitative Approach
to Pain Management
 Topical agents (capsaicin, lidocaine gel)
 Desensitization techniques (pressure garment)
 Transcutaneous electrical nerve stimulation
(TENS)
NMD—Rehabilitative Strategies
 Isotonic exercise
 Isokinetic exercise
 Occupational therapy—address activities of
daily living (ADLs), functional concerns
 Speech therapy if necessary
 Assistive devices (walker, canes, etc)
NMD—Challenges in Investigations
of Strength Training
 Weakness is progressive
 Slow progression of weakness?
 Increased strength?
 Variable progression
 Relative rarity of individual NMD
 Problem of combining disorders, even those with
a similar clinical picture (LGMDS)
Limitations of Past Studies
 Few study subjects with more than one
type of NMD
 Variable control groups—opposite limb,
able-bodied, NMD
 Method of strength measurement
 Study protocol and duration
 Effect on function
NMD—Exercise as a Precautionary
Step
 Watch for weakness as a sign of overwork
 Exercise level should be submaximal
 Higher repetition, lower weight
 Endurance training—water exercise for uniform
resistance
 Monitor serum creatine kinase; monitor for
myoglobinurea; watch for delayed-onset muscle
soreness or pain
Considerations for Future Studies
 Subjects with more than one type of
NMD need to be studied separately—
multicenter?
 Compare to matched controls with the
same NMD
 Matching should consider the severity of
weakness and the relative level of activity
 Conduct quantitative measures of
strength
Resistance Exercise—
Recommendations
 May be beneficial if weakness is not severe
and the rate of progression is relatively slow
 High-intensity may have no advantage over
moderate resistance
Key Points—Summary
 Autoimmune NMD
 Diagnostic criteria
 Treatment decisions
 Role of rehabilitation
 Diagnostic approach—typical presentations of GBS
and CIDP
 Acute presentation of CIDP with treatment–related
fluctuations; timing could lead to diagnosis of acuteonset CIDP
 Diagnostic elements of MG; long-term management
and outcomes
 Role of physical medicine and rehabilitative
strategies in autoimmune NMD in the acute and
chronic setting
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