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Management of Walking
Impairment and Spasticity
in MS Patients
James D. Bowen, MD
Medical Director, Multiple Sclerosis Center
Swedish Neuroscience Institute
Seattle, Washington
Slide 1of #40)
Spasticity and Walking Impairment
• Symptoms due to involvement of corticospinal
pathways
– Weakness
– Stiffness
– Hyperreflexia/clonus
– Spastic leg jumps
– Babinski sign
• All these symptoms are independent
Slide 2of #40)
Weakness
• In legs, extensors stronger than flexors
• In arms, flexors stronger than extensors
• Some patients use relative extensor strength of
legs to stand
Slide 3of #40)
Stiffness
• Increased resistance to stretch;
more with rapid stretch (clasp knife)
• Extensors legs, flexors arms
• Decreased fine and rapid movements
• May change with activity (gait, transfers)
Slide 4of #40)
Hyperreflexia
• Exaggerated deep tendon reflexes
• Clonus
Slide 5of #40)
Leg Jumps
• Spastic leg jumps
• Extensor spasms
• Flexor spasms
• Differentiate from restless leg syndrome and
nocturnal myoclonus
Slide 6of #40)
Babinski Sign
Spontaneous occurrence may lead to toe trauma
Slide 7of #40)
Upper Limb Spasticity
• Can be severely debilitating and painful
• May result in
– Disfiguring muscle contractions
– Stiff, tight muscles in the elbow, wrist, and
fingers, or a clenched fist
• Affects ability to perform simple tasks, often
leaving the patient dependent on a caregiver
Slide 8of #40)
Spasticity
• Develops slowly in MS and patients may not
mention it until it suddenly becomes problematic
• Developing spasticity may also go unrecognized
by neurologists, particularly in wheelchair-bound
patients
Slide 9of #40)
Factors Worsening Spasticity
• Overheating (fever, environmental)
• Intercurrent illnesses
• Noxious stimuli (pain, bladder, renal, bowel,
cholelithiasis, fracture, skin lesions/injury)
• Position
• Nocturnal
Slide 10of #40)
Nonpharmacologic Interventions
• Range of motion exercises
– Needed to maintain joint mobility
– Particularly important for shoulders, finger
extensors, hip extensors and ankle
dorsiflexion
– Frequency: at least once a day
Slide 11of #40)
Nonpharmacologic Interventions
• Stretching exercises
• Each stretch should be held 30–60 seconds
• Use slow, steady pressure rather than jerks
• Frequency depends on how acute and severe
the spasms—may require hourly
• Back, hip extensors, hamstrings, ankle
dorsiflexors, finger extensors
Slide 12of #40)
Nonpharmacologic Interventions
• Exercise
– Goal-directed activities (walking, biking)
 Strength
 Balance
 Endurance
• Frequency unclear: many recommend
≥20 minutes, ≥3 times a week
Slide 13of #40)
Nonpharmacologic Interventions
• Alternative exercises
– Yoga
– Tai Chi
– Dance therapy
– Massage
– Chiropractic
Slide 14of #40)
FDA-Approved Medications for Spasticity
• Baclofen
• Tizanidine
• Diazepam
• Dantrolene
• OnabotulinumtoxinA
Slide 15of #40)
FDA-Approved Medication for Walking
• Dalfampridine
Slide 16of #40)
Case 1
• 51-year-old male with secondary-progressive
MS (SPMS)
• Onset age 28 with attack of leg sensory
alteration
• Subsequent SPMS course
• Now in electric wheelchair
– Minimal movement of legs
– 4/5 strength in arms
– Spastic leg jumps and clonus
Slide 17of #40)
Case 1
• Treated with baclofen 10 mg QID
• Continues to have leg jumps, interfering with
sleep
• Having spasticity of arms with clawing of fingers,
early contractures, difficulty controlling
wheelchair
Slide 18of #40)
Baclofen
• GABAB agonist1
– Inhibits mono/polysynaptic reflexes at spinal cord
level
• Side effects1,2
– Weakness
– Drowsiness/cognitive slowing
– Nausea
– Vertigo
– Dry mouth
1.
2.
Simon O, Yelnik A. Eur J Phys Rehabil Med. 2010;46:401-410.
Haselkorn JK. J Spinal Cord Med. 2005;28:167-199.
Slide 19of #40)
Baclofen
• T1/2 = 2−6 hours1
• Dose should be slowly tapered to avoid side
effects2
– Start 5−10 mg/day
– Increase 5−10 mg every 3rd day, divide
TID/QID
– Increase to effectiveness or side effects
• Underdosing a common cause of failure
1. Simon O, Yelnik A. Eur J Phys Rehabil Med. 2010;46:401-410.
2. Baclofen [PI]. Corona, CA: Watson Laboratories; 2004.
Slide 20of #40)
Baclofen Pump
• Delivers baclofen directly to spinal fluid
• Best for patients
– For whom oral baclofen works
– But who have intolerable side effects
• Limitations
– Pump complications
– Intrathecal baclofen complications
– Withdrawal
Slide 21of #40)
Beard S, et al. Health Technol Assess. 2003;7:1-124.
Tizanidine
• Centrally acting α2 adrenergic agonist,
presynaptic inhibition of motorneurons1
• Side effects1,2
– Drowsiness (useful at bedtime)
– Dizziness
– Dry mouth
– Fatigue
– Hypotension
1. Simon O, Yelnik A. Eur J Phys Rehabil Med. 2010;46:401-410.
2. Haselkorn JK J Spinal Cord Med. 2005;28:167-199.
Slide 22of #40)
Tizanidine
• Doses in studies ranged to 36 mg/day1
• PDR max of 36 mg/day commonly exceeded
• T½ = 2.5 hours2
• Dose should be slowly tapered to avoid
sedation3
– Start 2−4 mg/day
– Increase 2−4 mg/week
– Increase to effectiveness or side effects
• Underdosing a common cause of failure
1. Haselkorn JK. J Spinal Cord Med. 2005;28:167-199.
2. Simon O, Yelnik A. Eur J Phys Rehabil Med. 2010;46:401-410.
3. Tizanidine [PI]. Hawthorne, NY: Acorda Therapeutics; 2006.
Slide 23of #40)
Diazepam
• Suppresses GABA-mediated spinal reflexes1
• Better on flexor than extensor reflexes1
• Dosage: 5−10 mg TID1
• Side effects1
– Drowsiness
– Weakness
1.
Lapeyre E, et al. NeuroRehabilitation. 2010;27:193-200.
Slide 24of #40)
Dantrolene
• Decreases intracellular calcium by blockage of
skeletal muscle ryanodine receptor1
• T1/2 = 8.7 hours2
• Side effects1,2
– Hepatitis (unclear if true)
– Weakness
– Lightheadedness/drowsiness
– Nausea
– Diarrhea
1. Lapeyre E, et al. NeuroRehabilitation. 2010;27:193-200.
2. Dantrolene [PI]. Rochester, MI: JHP Pharmaceuticals; 2008.
Slide 25of #40)
Dantrolene
• Dosage should be slowly tapered1,2
– Start 25 mg/day
– After 7 day, increase to 25 mg TID
– Increase weekly by 25 mg TID up to max
100 mg TID
• Monitor liver function tests1
1. Lapeyre E, et al. NeuroRehabilitation. 2010;27:193-200.
2. Dantrolene [PI]. Rochester, MI: JHP Pharmaceuticals; 2008.
Slide 26of #40)
OnabotulinumtoxinA
• Blocks neuromuscular transmission by binding
to acceptor sites on motor or sympathetic nerve
terminals, inhibiting the release of acetylcholine1
• Recently approved for upper limb spasticity1
• Onset 4−7 days, maximum effect
2 months2
• Lasts about 3 months3
1. OnabotulinumtoxinA [PI]. Irvine, CA: Allergan Inc; 2011.
2. Rekand T. Acta Neurol Scand Suppl. 2010;190:62-66
3. Lapeyre E, et al. NeuroRehabilitation.2010;27:193-200.
Slide 27of #40)
OnabotulinumtoxinA
• Dosage1
– Based on the muscles affected, severity of
the spasticity in those muscles, location of affected
muscles, patient’s prior response to treatment,
and previous adverse events or complications1
• Side effects1,2,3
– Weakness
– Worsened spasticity, often in other muscles
– Antibody formation − wait 3 months to redose
1. OnabotulinumtoxinA [PI]. Irvine, CA: Allergan Inc; 2011. 2. Lapeyre E, et al.
NeuroRehabilitation.2010;27:193-200. 3. Habek M, et al. Clin Neurol Neurosurg.
2010;112:592-596.
Slide 28of #40)
Case 1
• Leg jumps/clonus successfully treated with
increasing baclofen to 30 mg TID
• Tizanidine added at bedtime, eventually
reaching 4 mg. Improved sleep
• Aggressive physical therapy for stretching/range
of motion
Slide 29of #40)
Case 1
• Continued hand clawing despite physical
therapy and splinting
• OnabotulinumtoxinA administered to forearm
flexors
• Combination of onabotulinumtoxinA +
stretching/range of motion improved hand
clawing, allowing him to continue to control his
chair
Slide 30of #40)
Case 2
• 58-year-old female
• Onset age 24 with optic neuritis
• Initial relapsing course treated with interferon
beta-1b since 1995
• Stable for past few years
Slide 31of #40)
Case 2
• Most bothersome symptom is leg spasticity
– Bilateral, left worse than right
– Uses single-point cane
– 25-foot timed walk = 6.4 seconds
– Limited distance of about 4 blocks walking
without rest
• On baclofen 20 mg TID
Slide 32of #40)
Case 2
• Continued to have difficulty walking despite
– Frequent stretching/range of motion program
– Unable to increase baclofen any further due
to weakness
Slide 33of #40)
Dalfampridine (4-Aminopyridine)
Na+
K+
Voltage-gated K+ channels
4-AP
• Hyperpolarizes resting membrane
• Prolongs action potential, increasing likelihood of transmission
(increased area under the curve, increases safety factor)
• Increases release of neurotransmitters at synapse
Nashmi R, Fehlings M. Brain Res Rev. 2001;38:165-191.
Slide courtesy of Dr. J. Bowen.
Slide 34of #40)
Dalfampridine Phase III Trials
Responder Analysis
• Responder analysis = % of patients in each
group who respond, not mean differences
between groups
• Best means of capturing response when some
individuals have high levels of response, while
others have little or no response
Goodman A, et al. Lancet. 2009;373:732-738.
Goodman A, et al. Ann Neurol. 2010;68:494–502.
Slide 35of #40)
Dalfampridine Phase III Trials
Trial
Treatments
1
Dalfampridine
vs
placebo
No.
Treatment
Patients Duration
229
14 weeks
Results (% of
Patients
Responding)
34.8%
8.3%
P value
<.0001
72
Effect maintained
over 14 weeks
2
Dalfampridine
vs
placebo
119
9 weeks
42.9%
9.3%
<.0001
120
Effect maintained
over 8 weeks
For both trials:
•Responder: 25-foot timed walk (25-FTW) faster for 3 out of 4 on-treatment trials
compared with any of 5 off-treatment measures
•Inclusion criterion: 25-FTW 8−45 seconds
Slide 36of #40)
1.Goodman A, et al. Lancet. 2009;373:732-738. Goodman A, et al. Ann Neurol. 2010;68:494–502.
Dalfampridine
• 0.25% seizures
• Urinary tract infections: 12% vs 8%
• Insomnia: 9% vs 4%
• Other side effects may include increased
paresthesias, spasticity, dizziness, headaches
Slide courtesy of Dr. J. Bowen.
Slide 37of #40)
Dalfampridine
• New data show that even patients with lower
Expanded Disability Status Scale scores benefit1
− 20%−35% of patients were responders across all
levels of disability
• In transition to open label extension2
− Responders declined when off medication
− Then recovered on restart of medication (28%
increase in 25-foot timed walk on blinded trial, 24%
after 2 weeks on restart)
− Nonresponders unchanged after restart
1. Brown T. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract P07.164.
2. Goodman A. . 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract P07.165.
Slide 38of #40)
Case 2
• Started on dalfampridine 10 mg BID
– Started week before vacation to Italy; when
walking on vacation, she had to wait for her
husband to catch up to her
– 25-foot timed walk improved to 5.6 seconds
Slide 39of #40)
Summary
Selecting treatments
• Encourage physical treatments
• Use medications in adequate doses
• Use local treatment selectively
• Advance to more invasive/aggressive treatments
if needed
Slide 40of #40)
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Slide 41of #40)