1. Impairment and Spasticity
Management of Walking
Impairment and Spasticity
in MS Patients
James D. Bowen, MD
Medical Director, Multiple Sclerosis Center
Swedish Neuroscience Institute
Seattle, Washington

2. 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

3. Weakness In legs, extensors stronger than flexors
In arms, flexors stronger than extensors
Some patients use relative extensor strength of legs to stand

4. 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)

5. Hyperreflexia
Exaggerated deep tendon reflexes
Clonus

6. Leg Jumps Spastic leg jumps Extensor spasms Flexor spasms
Differentiate from restless leg syndrome and nocturnal myoclonus

7. Babinski Sign
Spontaneous occurrence may lead to toe trauma

8. 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

9. 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

10. Factors Worsening Spasticity
Overheating (fever, environmental)
Intercurrent illnesses
Noxious stimuli (pain, bladder, renal, bowel, cholelithiasis, fracture, skin lesions/injury)
Position
Nocturnal

11. 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

12. 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

13. Nonpharmacologic Interventions
Exercise
Goal-directed activities (walking, biking)
Strength
Balance
Endurance
Frequency unclear: many recommend ≥20 minutes, ≥3 times a week

14. Nonpharmacologic Interventions
Alternative exercises
Yoga
Tai Chi
Dance therapy
Massage
Chiropractic

15. FDA-Approved Medications for Spasticity
Baclofen
Tizanidine
Diazepam
Dantrolene
OnabotulinumtoxinA

16. FDA-Approved Medication for Walking
Dalfampridine

17. 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

18. 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

19. Baclofen GABAB agonist1 Side effects1,2
Inhibits mono/polysynaptic reflexes at spinal cord level
Side effects1,2
Weakness
Drowsiness/cognitive slowing
Nausea
Vertigo
Dry mouth
Simon O, Yelnik A. Eur J Phys Rehabil Med. 2010;46:
Haselkorn JK. J Spinal Cord Med. 2005;28:

20. 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:
2. Baclofen [PI]. Corona, CA: Watson Laboratories; 2004.

21. 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
Beard S, et al. Health Technol Assess. 2003;7:1-124.

22. 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:
2. Haselkorn JK J Spinal Cord Med. 2005;28:

23. 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:
2. Simon O, Yelnik A. Eur J Phys Rehabil Med. 2010;46:
3. Tizanidine [PI]. Hawthorne, NY: Acorda Therapeutics; 2006.

24. Diazepam Suppresses GABA-mediated spinal reflexes1
Better on flexor than extensor reflexes1
Dosage: 5−10 mg TID1
Side effects1
Drowsiness
Weakness
Lapeyre E, et al. NeuroRehabilitation. 2010;27:

25. 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:
2. Dantrolene [PI]. Rochester, MI: JHP Pharmaceuticals; 2008.

26. 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:
2. Dantrolene [PI]. Rochester, MI: JHP Pharmaceuticals; 2008.

27. 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:

28. OnabotulinumtoxinA Dosage1 Side effects1,2,3
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; Lapeyre E, et al. NeuroRehabilitation.2010;27: Habek M, et al. Clin Neurol Neurosurg. 2010;112:

29. 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

30. 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

31. 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

32. 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

33. Case 2 Continued to have difficulty walking despite
Frequent stretching/range of motion program
Unable to increase baclofen any further due to weakness

34. 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:
Slide courtesy of Dr. J. Bowen.

35. 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:
Goodman A, et al. Ann Neurol. 2010;68:494–502.

36. Dalfampridine Phase III Trials
Treatments
No.
Patients
Treatment Duration
Results (% of
Responding)
P value 1
Dalfampridine vs
placebo
229 72
14 weeks
34.8%
8.3%
Effect maintained
over 14 weeks
<.0001 2
119
120
9 weeks
42.9%
9.3%
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
Goodman A, et al. Lancet. 2009;373: Goodman A, et al. Ann Neurol. 2010;68:494–502.

37. 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.

38. 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 P Goodman A. . 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract P

39. 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

40. Summary Selecting treatments Encourage physical treatments
Use medications in adequate doses
Use local treatment selectively
Advance to more invasive/aggressive treatments if needed

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