MS ECHO Session 9: Mobility

Gary Stobbe, MD Medical Director, MS Project ECHO

Clinical Assistant Professor, UW Neurology

Conflicts of Interest

• Dr. Stobbe has no conflicts of interest to disclose

Objectives • Describe the changing nature of mobility

over MS disease course • Identify strategies to improve mobility • Discuss fall risk and management • Discuss with patients strategies to preserve

function and maximize independence • Describe how to work with physical therapists

and access resources to maximize mobility

Special thanks to…

Katie Deaton, PT, DPT Ashley Dennis, PT, DPT, NCS

…for slide preparation!

Patient AS

• 45 yo F, relapsing-remitting MS since 2012 • Minimal disability • CO: catches L toe and falls at work 2-3x/yr • Fatigue at work

Patient DM

• 49 yo F, 2° progressive MS since 2001 • Moderate disability • CO: 6/10 fatigue in AM, progressed to 8/10 by PM • 2-3 falls/day

What Impacts Mobility NEGATIVE POSITIVE

- Muscular weakness - Spasticity - Changes in tone - Sensory impairment - Coordination impairment - Vision impairment - Cognitive impairment - Fatigue - Pain - Balance dysfunction: multi-system impairment

- Medications - Therapeutic interventions - Wellness program - Durable medical equipment

Variable environmental demands & disease progression will change mobility needs.

Quick Exam for gait problems

• Observe patient’s gate entering room. • Timed 25-ft walk • Any evidence of falls? • Check strength of ankle dorsiflexion. • Check for tight “heel cord.” • Signs of hyperreflexia, spasticity, or +Babinski. • Check toes of shoe for wear.

Kraft, GH. Prevalence and Diagnosis of Walking Impairments in Patients with Multiple Sclerosis. Neuro Review. Dec. 2013, S2-S5.

Balance • 70% fall rate & 86% near-fall rate among

cohort of 150 people with MS • Ask your patients if they have experienced

falls or near-falls & how often • Consider a quick, dual task assessment in the

clinic – Timed Up & Go (TUG) with Cognitive Task

Fatigue

• Ask your patients how fatigue affects their mobility or participation

• Consider a 6 Minute Walk Test in the clinic to assess how fatigue affects walking ability

Medical Approaches

• Weakness/speed – Dalfampridine (Ampyra), 10mg Q12H.

• Spasticity – Baclofen or tizanidine - start with low dose, titrate

up. – Botox block. – Baclofen pump.

Role of Physical Therapy • Involve PT early and often

– GOALS: Regain, Maintain, Compensate

PT Referral Recommendation Ex: Referral to physical therapy for falls assessment (considering cognition and fatigue), education on energy conservation techniques, and gait training to prevent falls. Prescribe AFO, cane, and walker as needed considering hip flexion weakness. Ex: Referral to physical therapy for moderate to high intensity strengthening in functional positions, moderate to high intensity aerobic exercise program, and gait training to decrease falls considering high fatigue and spasticity

More specific recommendations = better outcomes

Therapeutic Intervention • Encourage your patients to participate in a

comprehensive wellness program that includes: – Stretching – Strengthening – Aerobic exercise

• Begin with a referral to PT to build a patient specific program

• Community classes – Yoga, Tai Chi, Pilates

Durable Medical Equipment • DME will be important for preserving

independent function and participation in your patients with MS – “If you feel like your world is shrinking, you need

to use the right mobility aids/adaptive equipment to make your world feel as normal as possible again.”

• Multiple devices should be the norm • Suggest lightweight devices

Patient AS • 45 yo F, relapsing-remitting MS since 2012, minimal disability • CO: catches L toe and falls at work 2-3x/yr, fatigue at work

• Goals: “not fall at work,” “not drag my foot,” “have more energy” • Current DME: none

• Intervention: • Prescribed custom Posterior Leaf Spring (AFO) with 0.75 cm

heel wedge • Education regarding energy conservation to include using a

stool at work, increasing rest breaks during shift

Patient DM • 49 yo F, 2° progressive MS since 2001, moderate disability • CO: 6/10 fatigue in AM, progressed to 8/10 by PM; 2-3 falls/day

• Goals: “not fall as much,” have more energy” • Current DME: 2 scooters, cane, front wheeled walker, bilateral

walk-aids

• Intervention • Prescribed 4 wheeled walker & bilateral AFOs • Education regarding energy conservation strategies • Education to facilitate safety in the home by utilizing cane in the

AM & 4 wheeled walker or 3 wheeled walker in the PM

DME Examples

http://www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Brochure-How-to-Choose-the-Mobility-Device-that-is-Right-for-You.pdf

Final Message 1. Anticipate the changing mobility needs of

persons with MS as you are making referrals and educating patients on preventative strategies.

2. Refer to PT early and often to address the changing mobility needs of persons with MS.

3. Facilitate the prescription of all appropriate DME for persons with MS in order to preserve mobility and participation.

Resources • www.resna.org - Resource for finding a seating

specialist in your area. • http://www.apta.org/apta/findapt/index.aspx?na

vID=10737422525 - PT professional association site that allows you to locate PTs in your area and neurologic PT specialists in your area.

• www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Clinical-Bulletin-Physical-Therapy.pdf - Resource to send with patients and medical records when referring patients with MS to PT.

References • Kalb, R. Multiple Sclerosis: A Focus on Rehabilitation. 4th Ed. 2010. • Outcome Measures for Persons with MS

– http://www.neuropt.org/docs/ms-edge-documents/ms-edge_rehab_recs5417E23D4B53.pdf?sfvrsn=2

• National MS Society Webpage – http://www.nationalmssociety.org

• Gunn H, Creanor S, Haas B, Marsden J, Freeman J. Frequency, characteristics, and consequences of falls in multiple sclerosis: findings from a cohort study. Arch Phys Med Rehabil. 2014; 95(3): 538-45.

• Kraft, GH. Prevalence and Diagnosis of Walking Impairments in Patients with Multiple Sclerosis. Neuro Review. Dec. 2013, S2-S5.

• Johnson, SL, Kraft, GH: Multiple Sclerosis Rehabilitation. PM and R Clinics, Nov 2013.

Tecfidera From pivotal Tecfidera trials: *6% of patients lymphocytes < 0.5 at one point during the study *Overall 2% <0.5 for greater than 6 months (in PI) *Beyond PI - 0.6% stayed < 0.5 for 2 and 3 years *Patients dc’d only if <0.2 *Those patient showed improvement in 4 to 8 weeks but not back to baseline

• Currently no data regarding re-challenge with Tecfidera after DC • No data on CD4/CD8 counts (retrospective study in planning) • No data on use of 240mg QD (efficacy/safety) • 1 case of PML/ no other opportunistic infections • 120mg BID and TID not effective during phase 2 trials • 120mg available beyond starter pak but only recommend BID for one

month • Other providers trying decreased dose to improve lymphocytes • Vaccine study – will look at immune response to Tecfidera vs IFN 2 non Biogen sponsored studies mentioned 1. Anne Cross et al http://www.ncbi.nlm.nih.gov/pubmed/25432948 2. Scott Zamvil et al http://www.ncbi.nlm.nih.gov/pubmed/25738172

Tecfidera-associated PML case

• > 130,000 patients exposed • 1st case of PML in an MS patient treated with

Tecfidera in 10/2014 • 4 cases in psoriasis patients taking oral

fumarate (1 was also on Efalizumab)

Tecfidera-associated PML case • 64-year-old European woman • Tecfidera 240 mg BID vs TID since January

2010 and received 4.5 years of Tecfidera • Prior DMT: only Copaxone • No prior immunosuppressive therapy • PMH : reportedly no other than MS

• Onset of lymphopenia 1 year after starting Tecfidera

• Prolonged duration (over 3.5 years) • Count 290 - 580 cells/µL and never below 200. • Onset of PML symptoms 7/2014 • Patient died from aspiration pneumonia on

October 17th.

Recent PML case at UW MS center

• 70-year-old woman, right-handed • Diagnosis of RRMS in 1999 • PMH of depression. No other relevant

comorbidities. • Medication: Tysabri (Infusion # 55 in May

2014), etc. • No prior immunosuppressive therapy.

• Baseline functioning: • EDSS ~ 2-2.5 • Lives independently in her house • Normal cognition

• June 20th 2014: Seen urgently by NP during Tysabri infusion # 56:

• In the last 2 weeks, weakness in her right hand and increased fatigue

• Neurological exam: mild right hand weakness 4/5 and mild dysdiadochokinesia.

• 3-day course IVMP 1g die prescribed and Tysabri antibodies ordered (came back negative)

• JCV antibody on May 22nd was negative (index value 0.19)

• Brain MRI on June 13th, after being stable for several years prior, showed “4 new lesions (subcortical left precentral gyrus, subcortical left insula, punctiform involving the central pons and punctiform involving the posterior left medulla). No enhancement and no evidence of PML”.

• July 7th, 2 weeks after IVMP course and 1 month after onset:

• Follow-up with NP. Right hand weakness worsening. Cannot grip utensils or hold a pen.

• 2nd course IVMP ordered

• July 21th: • Symptoms are stable after 2nd 3-day course of IVMP. • Receives Tysabri infusion # 57

• August 5th: • Follow-up with NP. Weakness continues to worsen.

Hand floppy. Still exhausted. • Exam shows mild proximal weakness of right arm and

plegic wrist and hand • Repeat brain MRI ordered

• Brain MRI August 5th: • “Interval increase in confluent FLAIR signal

abnormality involving the left precentral gyrus, which involves the subcortical U fibers and extends to involve the deep white matter. There is no associated enhancement. Probably represents progression of demyelination, however, early PML is not excluded”.

• Tysabri discontinued • August 7-9th: Hospitalization at UWMC for workup and

PLEX initiation • Total of 5 PLEX (August 9th, 11th, 13th, 15th and 19th) • JCV PCR from CSF (8/8): positive; inconclusive

quantification; Focus Diagnostics recommends repeat • 2nd JCV PCR from CSF (8/21): 70 copies/ml (from NIH);

also found 101 copies/ml for 1st CSF sample • Serum JCV antibody index 2.56 (8/13)

Timeline

IRIS, Regular IVMP

Diagnosis +

PLEX

Onset; IVMP

for relapse

June August September

Slow progression of impairment

Plateau

Late October

Trial Maraviroc

October July May

Worsens; repeat IVMP

-Tysabri # 55 -Doing fine

Introduction • PML is the most feared complication of

natalizumab. • Seropositivity for anti-JCV Ab is an

important risk factor, hence the rationale for periodic testing1.

Our case • 70-yo woman with RRMS

on natalizumab for > 4 years.

• Never received immunosuppressants.

• Developed PML symptoms 2 weeks after last negative anti-JCV Ab testing.

• Periodic testing for anti-JCV Ab every 3 months had always been negative.

• At time of diagnosis, serum anti-JCV Ab was positive with an index of 2.56.

Conclusion • Previously, only 2

natalizumab-related PML cases were anti-JCV Ab negative but testing dated from 8 and 9 months before diagnosis1.

• 2 weeks is the shortest interval ever reported between last negative anti-JCV Ab testing and PML symptoms onset.

• PML is a consideration in any natalizumab-treated patient with new MRI lesions or new symptoms and JCV antibody should be repeated even if recently negative.

References 1: Biogen Idec.Tysabri.

Natalizumab-related PML 2 weeks after negative Gagné anti-JCV antibody

Marie-Sarah Brosseau, MD, Gary Stobbe, MD, Deb Cramer, RN, Hillary Lipe, ARNP, Annette Wundes, MD. University of Washington, Seattle, Washington, USA

May 2014

June July

August

June

Sept.

Oct.

Nov.

Nov.

MS course stable for years. EDSS 2. MS center contacts patient: new mild right hand weakness and increased fatigue. Right hand weakness progression. Right hand now floppy with mild proximal weakness of right arm.

CLINICAL COURSE TREATMENT

-Tysabri infusion #55. -Anti-JCV Ab negative; index 0.19. -Tysabri infusion #56. -3-day course of IVMP 1g die for presumed MS relapse.

MRI

Brain MRI had been stable for years. Routine annual MRI shows 4 new nonenhancing lesions. No evidence of PML.

Dec. - now

Mara- viroc (for IRIS)

IVMP:3-day course every 2 to 4 weeks (for IRIS)

Progressive increase in size of confluent white matter lesion. No enhancement. Minimal enhancement (1st time). PML lesions continue to sprawl. Enhancement at its

zenith. PML lesions worse.

Unchanged. Mild amelioration of language, small non anti-gravity movements in right hemibody.

Rapid progression of neurological impairment: right hemiparesis and speech impairment. Reached nadir: right hemiplegia, global aphasia and severe apraxia.

-Tysabri stopped. -PLEX + PML dx (PCR: 101 copies/mL). -Anti-JCV Ab +; index 2.56. -Trial of mirtazapine (stopped after 2 weeks due to drowsiness).

Increase in non- enhancing FLAIR hyperintense lesion involving left precentral gyrus. Now extending in subcortical U fibers. Early PML not excluded.

2nd 3-day course of IVMP 1g die.

Slight decrease in extent of PML lesions. Enhancement slowly decreases but persists.

Sept.

August

Oct.

Nov.

Nov.

August 25th

Sept 19th; no enhancement

October 15th

Lessons learned and questions raised • The delay between last negative JCV antibody and onset of

symptoms was only 2 weeks. Should we check the antibody index even more often?

• Negative anti-JCV antibody patients are still at risk for the development of PML because of the potential for de novo infection as well as possibly false negative test result, of which the reported rate is 3%.

• Any natalizumab-treated patient with new MRI lesions or new symptoms could have PML and JCV antibody should be repeated even if recently negative. Moreover, in such cases, short-term repeat MRI and/or CSF testing warrants consideration.