Presentation on theme: "Managing Walking Impairment in MS a Step at a Time"— Presentation transcript:
1Managing Walking Impairment in MS a Step at a Time Andrew D. Goodman, MD, FAANProfessor of NeurologyDirector, Multiple Sclerosis CenterChief, Neuroimmunology UnitDepartment of NeurologyUniversity of Rochester Medical CenterRochester, New York
3Case Study—Patient Presentation 40-year-old femaleDiagnosed with MS at age 32 yearsBrain MRI scan at time of diagnosis10 lesions in periventricular and subcortical white matter, several cervical cord lesionsPresents now with slowly progressive worsening of gait, easy fatigability, leg spasticity, and frequent fallsNo longer employedCurrently on a first-line injectable disease-modifying therapy
4Common MS Symptoms Fatigue Motor impairment − spasticity, weakness Gait difficultyCognitive impairmentDepressionPainTremorBladder symptomsBowel symptomsSexual dysfunction4
5Prevalence of Gait Impairment Survey commissioned by the National MS Society1011 people with MS64% experienced trouble walking at least twice weeklyOf these, 70% reported it to be the most challenging aspect of their MSNational MS Society. News. March 25, Accessed 8/22/12 at:
6Underreporting of Gait Impairment A significant proportion of patients with MS and their caregivers rarely or never discuss mobility issues with a physician39% of surveyed MS patients (n = 1100)49% of surveyed caregivers (n = 317)Indicates need for neurologists and other MS care providers to initiate conversations about mobilityNational MS Society. News. March 25, Accessed 8/22/12 at:
7Gait Impairment’s Impact on Quality of Life Loss of independencePhysical appearance of disabilityIncreased unemploymentSutliff MH. Curr Med Res Opin. 2010;26:
8EDSS—Progression to Disability Walking Ability8.0–8.5 = Confined to bed/chair; self-care with help7.0–7.5 = Confined to wheelchair6.0–6.5 = Walking assistance is needed5.0–5.5 = Increasing limitation in ability to walk4.0–4.5 = Disability is moderate3.0–3.5 = Disability is mild to moderate2.0–2.5 = Disability is minimal1.0–1.5 = No disability0 = Normal neurologic exam10.0 = Death due to MS9.0–9.5 = Completely dependentConfined to awheelchair or bedWalks with aid(<5 yards)Walks with assistance(20–100+ yards)Walks unaided(100–200+ yards)Walks unaided(300–500+ yards)Fully ambulatoryKurtzke JF. Neurology. 1983;33: Graphic courtesy of Dr. Andrew D. Goodman.
9Common Gait Abnormalities Foot slap due to mild ankle dorsiflexion weaknessKnee instability with buckling leading to a fallTrendelenburg’s sign secondary to hip abduction weaknessSteppage gait with moderate to severe ankle dorsiflexion weakness
10Common Tools to Measure Gait Impairment Clinical assessment of casual gaitSpasticityAtaxiaFoot dropValidated instruments1Timed 25-foot walkEDSS (distance walked up to 500 m)12-Item Multiple Sclerosis Walking Scale (MSWS-12)Bethoux F, et al. Int J MS Care. 2011;13:4-14.
12Assistive Devices for Ambulation Single-point canesQuad caneForearm crutches4-point folding walkerFront-wheeled walker4-wheeled walker with seat and active braking system4-wheeled walker with seat and passive braking system (U-Step walker)
13Ankle Foot Orthoses Posterior leaf spring Double metal upright Ground reaction forceCarbon fiber
14Functional Electrical Stimulation Devices Commercially availableNess L300™WalkAide®Odstock® Dropped Foot StimulatorGeared toward assisting foot drop through stimulation of the common fibular nerveNational MS Society. Functional Electrical Stimulation (FES). Accessed 8/23/12 at:
15Fall Prevention Strategies Change the environmentInstall heavy-duty grab bars in showers and tubs and beside toilets Avoid “obstacle courses” in the homeMaintain clear pathways inside and outAssistive devices
16Pharmacologic Management—Dalfampridine-ER, Part 1
17Dalfampridine Fampridine (formerly) Dalfampridine AcordaDalfampridineFampridine (formerly)Name used in published studiesDalfampridineUS Adopted Name (USAN) to eliminate confusion with other drugsFDA-approved as a treatment to improve walking in patients with MS
18Dalfampridine—Clinical Research in MS 1992: crossover study (N = 70)1,2Broad effects on disability (EDSS)1Dose and serum level related to efficacy and safety2Plasma levels difficult to control with immediate-release formulation; need for extended-release formulation21994: concentration-controlled, crossover study (N = 8)3Improvements in contrast sensitivity, limb strength, neurologic examNo benefit on EDSSSeizure, acute confusional episode at serum levels >100 ng/mL1. van Diemen HA, et al. Ann Neurol. 1992;32: van Diemen HA, et al. Clin Neuropharmacol. 1993;16: Bever CT Jr, et al. Neurology. 1994;44:
19Rationale for Extended-Release (ER) Formulation Immediate-release formulations are limited byRapid rise in plasma level associated with adverse effectsDizziness, nausea, parasthesiasShort half-life, requiring frequent dosingSubstantial effect of food on pharmacokinetics“Extended release (ER)” = “sustained release (SR)”SR – term used in phase IIIa trial publicationER – term used in phase IIIb trial publication and product label
20“Sustained-Release Oral Fampridine in Multiple Sclerosis: A Randomised, Double-Blind, Controlled Trial”Andrew D. Goodman, Theodore R. Brown, Lauren B. Krupp, Randall T. Schapiro, Steven R. Schwid, Ron Cohen, Lawrence N. Marinucci, Andrew R. Blight; on behalf of the Fampridine MS-F203 InvestigatorsGoodman AD, et al. Lancet. 2009;373:
21Dalfampridine-SR—Phase IIIa Study Design Fampridine-SR* (n = 229)VVVVScreeningRVPlacebo (n = 72)Placebo for 2 weeks14 weeksFollow-up for 4 weeks*10 mg BID.Abbreviations: R, randomization; V, clinic visit.Goodman AD, et al. Lancet. 2009;373:
22Dalfampridine Phase III Trials—Responder Analysis Phase IIIa1 and IIIb2 trialsBlinded placebo-controlled randomized trialsClass I evidenceTraditional data analysis in clinical trialsCompare mean differences between the placebo and active treatment groups"Responder analysis” in dalfampridine phase III trialsCompare percentage of patients in each group who respondedUsed to evaluate primary outcome1. Goodman AD, et al. Lancet. 2009;373: Goodman AD, et al. Ann Neurol. 2010;68:
23Responder Analysis—Rationale Best means of evaluating highly variable responsesIntrapatient variability of MS patientsInterpatient variabilitySome patients responded briefly or not at allOther patients responded very wellResponder analysis allows assessment on individual basisConsistent with individualized approach to patient care
24Dalfampridine-SR—Phase IIIa Primary Outcome Primary outcome = proportion of “timed walk responders”Measured by change in walking speed as measured by timed 25-foot walkTimed walk responder = a subject whose walking speed on at least 3 of the 4 “on-drug” visits is faster than the fastest speed during any of the 5 “off-drug” visits
25Dalfampridine-SR—Timed Walk Responders, Phase IIb and IIIa (ITT Population)Phase IIIa2P <.0001Placebo (n = 47)Dalfampridine-SR* (n = 158)Placebo (n = 72)Dalfampridine-SR† (n = 224)*Pooled doses: 10, 15, and 20 mg BID; †10 mg BID.1. Goodman AD, et al. Neurology. 2008;71: Goodman AD, et al. Lancet. 2009;373:
26Dalfampridine-SR—Consistent Improvement in Walking Speed, Phase IIIa Consistent improvement in walking speed among dalfampridine respondersOver the course of 14 weeksDifference in magnitude of change in walking speed from baselineChange in walking speed was sustainedGoodman AD, et al. Lancet. 2009;373:
27Dalfampridine-SR—Change in MSWS-12 Score, Phase IIIa Change in MSWS-12 from Baseline-12-10-8-6-4-21Nonresponders(n = 212)Responders(n = 84)P = .0002Phase IIIa2(ITT Population)-6.84+0.05Abbreviations: MSWS, multiple sclerosis walking scale.Goodman AD, et al. Lancet. 2009;373: Graphic courtesy of Dr. Andrew D. Goodman.
29Pharmacologic Management—Dalfampridine-ER, Part 2
30“A Phase 3 Trial of Extended Release Oral Dalfampridine in Multiple Sclerosis” Andrew D. Goodman, Theodore R. Brown, Keith R. Edwards, Lauren B. Krupp, Randall T. Schapiro, Ron Cohen, Lawrence N. Marinucci, Andrew R. Blight; on behalf of the MSF204 InvestigatorsGoodman AD, et al. Ann Neurol. 2010;68:
31Dalfampridine-ER—Phase IIIb Study Design Dalfampridine-ER* (n = 120)VVVVScreeningRVPlacebo (n = 119)Placebo for 2 weeks9 weeksFollow-up for 2 weeksPrimary outcome = proportion of “timed walk responders”Timed walk responder = subject whose walking speed on at least 3 of the 4 “on-drug” visits is faster than the fastest speed during any of the 5 “off-drug” visits*10 mg BID.Abbreviations: R, randomization; V, clinic visit.Goodman AD, et al. Ann Neurol. 2010;68:
32Dalfampridine-ER—Timed Walk Responders, Phase IIIb Placebo (n = 118)Dalfampridine-ER* (n = 119)*10 mg BID.Goodman AD, et al. Ann Neurol. 2010;68:
33Dalfampridine-ER—Change in MSWS-12 Score, Phase IIIa and IIIb (ITT Population)Phase IIIb2Change in MSWS-12 from Baseline-12-10-8-6-4-21Nonresponders(n = 212)Responders(n = 84)P = .0002-6.84+0.05Nonresponders (n = 175)Responders(n = 62)-12-10-8-6-4-2P <.0011Change in MSWS-12 from Baseline+.85-6.04Abbreviations: MSWS, multiple sclerosis walking scale.1. Goodman AD, et al. Lancet. 2009;373: Goodman AD, et al. Ann Neurol. 2010;68: Graphics courtesy of Dr. Andrew D. Goodman.
34Dalfampridine-ER—Efficacy in Walking Speed Over Time, Phase IIIb (ITT Population)Mean Change (%)51015202530Week 2Week 4Week 6Week 83540Placebo (n = 118)Dalfampridine-ER Responders (n = 51)With permission from Goodman AD, et al. Ann Neurol. 2010;68:
35FDA NEWS RELEASE January 22, 2010 FDA Approves Dalfampridine to Improve Walking in Adults with Multiple Sclerosis“In clinical trials, patients treated with [dalfampridine extended release] had faster walking speeds than those treated with an inactive pill (placebo). This is the first drug approved for this use.”FDA. News Release. January 22, Accessed 8/22/12 at:
36Dalfampridine-ER—Post-Hoc Analyses Abstracts “Response…Is Independent of Baseline Patient Characteristics and Concomitant Immunomodulator Therapy”1“Dalfampridine Extended Release Tablets Improve Walking Speed Across A Wide Range of Baseline Deficits”2“Patients With Progressive Forms of Multiple Sclerosis Benefit From Treatment With Dalfampridine Extended Release Tablets”31. Brown T, et al. 62nd AAN; April 10–17, 2010; Toronto, Ontario, Canada. Abstract P Edwards K, et al. 62nd AAN; April 10–17, 2010; Toronto, Ontario, Canada. Abstraact P Pozzilli C, et al. Neurology. 2011;76(suppl 4):A73.
37Dalfampridine-ER + Walking Aids Dalfampridine improved walking speeds in phase III trials in patients already requiring walking aids (EDSS 6.0+)1-3Clinical experience suggests synergy between physical therapy, exercise, walking devices, and pharmacotherapy with dalfampridine1. Goodman AD, et al. Lancet. 2009;373: Goodman AD, et al. Ann Neurol. 2010;68: Brown T, et al. 62nd AAN; April 10–17, 2010; Toronto, Ontario, Canada. Abstract P
38Future Research Can we improve responsiveness? Better understanding of distribution and pharmacology of channelopathyCan we use similar trial methodology for novel restorative or regenerative experimental therapeutics?Anti-LINGO, cell-based therapy
40My Clinical Experience Trial of 10-mg dalfampridine-ER tablets BID for 2−4 weeksExclude patients withHistory of seizure, orRenal insufficiency (creatinine clearance <50 mL/min )Clinical evaluationTimed 25-foot walkSymptom assessment, including gait quality and fatigability, stair climbing, distanceAdverse effect assessment: insomnia, nausea, tingling, etcContinue on therapy with favorable benefit/risk assessment
41Dalfampridine-ER—Individual Benefit:Risk Ratio Objective measures20% improvement in timed 25-foot walk considered clinically meaningful change1,2Subjective measuresPatient-reported functional improvements in distance, stair climbing, an dependence on walk aids1. van Winsen LM, et al. Mult Scler. 2010;16: Coleman CI, et al. Curr Med Res Opin. 2012;28:49-56.
42Case Study—Continued Gait assessment: foot drop leading to instability Timed 25-foot walk: 10 secondsTherapeutic approachPhysical therapy for ankle-foot orthosis (AFO)-aided gait trainingDalfampridine-ER 10 mg twice dailyFollow-up at 4 weeksTimed 25-foot walk: 7 secondsGait stability improved with AFO
43Conclusions Gait problems are common in MS and not always addressed Optimal individualized approach includesPhysical therapyWalking aids when appropriatePharmacotherapy for spasticityConsideration of dalfampridineDalfampridine may improve speed by 20% or more, which may be clinically meaningfulBenefit:risk easily assessed with patient input