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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

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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

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Weakness

• In legs, extensors stronger than flexors• In arms, flexors stronger than extensors• Some patients use relative extensor strength of

legs to stand

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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)

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Hyperreflexia

• Exaggerated deep tendon reflexes• Clonus

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Leg Jumps

• Spastic leg jumps• Extensor spasms• Flexor spasms• Differentiate from restless leg syndrome and

nocturnal myoclonus

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Babinski Sign

Spontaneous occurrence may lead to toe trauma

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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

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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

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Factors Worsening Spasticity

• Overheating (fever, environmental)• Intercurrent illnesses• Noxious stimuli (pain, bladder, renal, bowel,

cholelithiasis, fracture, skin lesions/injury)• Position• Nocturnal

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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

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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

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Nonpharmacologic Interventions

• Exercise– Goal-directed activities (walking, biking)

Strength Balance Endurance

• Frequency unclear: many recommend ≥20 minutes, ≥3 times a week

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Nonpharmacologic Interventions

• Alternative exercises– Yoga– Tai Chi– Dance therapy– Massage– Chiropractic

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FDA-Approved Medications for Spasticity

• Baclofen• Tizanidine• Diazepam • Dantrolene• OnabotulinumtoxinA

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FDA-Approved Medication for Walking

• Dalfampridine

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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

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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

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Baclofen• GABAB agonist1

– Inhibits mono/polysynaptic reflexes at spinal cord level

• Side effects1,2

– Weakness– Drowsiness/cognitive slowing– Nausea– Vertigo– Dry mouth

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.

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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.

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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.

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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.

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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 failure1. 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.

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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.

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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.

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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.

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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;190:62-663. Lapeyre E, et al. NeuroRehabilitation.2010;27:193-200.

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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.

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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

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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

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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

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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

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Case 2

• Continued to have difficulty walking despite– Frequent stretching/range of motion program– Unable to increase baclofen any further due

to weakness

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Dalfampridine (4-Aminopyridine)

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.

K+Na+

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Dalfampridine Phase III TrialsResponder 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.

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Dalfampridine Phase III TrialsTrial

Treatments No. Patients

Treatment Duration

Results (% of Patients Responding)

P value

1 Dalfampridine vs placebo

229

7214 weeks

34.8% 8.3%

Effect maintained over 14 weeks

<.0001

2 Dalfampridine vs placebo

119

120 9 weeks

42.9% 9.3%

Effect maintained over 8 weeks

<.0001

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 1.Goodman A, et al. Lancet. 2009;373:732-738. Goodman A, et al. Ann Neurol. 2010;68:494–502.

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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.

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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.

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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

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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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