Transcript DAA Therapies: What Do The Data Show?

Optimizing Outcomes:
Balancing Disease-Modifying
and Symptomatic Therapy in
Multiple Sclerosis
James D. Bowen, MD
Medical Director
Multiple Sclerosis Center
Swedish Neuroscience Institute
Seattle, Washington
1
Introduction and
Case Presentation
2
Case—History

52-year-old male

1996 at age 36
– Right-hand numbness and weakness spreading
to entire right body over 2 days
– Told it was a “demyelinating event” but no other
diagnosis or treatment given
– Mild residual right tingling/heaviness

Early 2000s
– Diplopia
– Urinary urgency
– Erectile dysfunction
3
Case—History

2007
– Pain/burning in arms/legs
– Diplopia
– Weakness
– Diagnosis uncertain

MRI interpreted as possible strokes
4
Case—History

December 2008
– Brain MRI


Improvement in left cerebral peduncle lesion
New right frontal lesion
– C-spine MRI normal
– Visual evoked potential and lumbar puncture
normal

December 2009
– Saw an MS specialist
– Diagnosed with MS

April 2010
– Started treatment with glatiramer acetate
5
Case—Current Presentation

Patient transfers to our clinic, February 2011

Reports tolerating treatment well

Admits incomplete adherence

Has had occasional MS attacks
6
Efficacy of First-Line
Disease-Modifying Therapies
(DMTs) in Early MS
7
BENEFIT—IFN Beta-1b SC in Early MS

IFN beta-1b 250 µg vs placebo for 2 years
–

468 patients with clinically isolated syndrome and abnormal
MRI
Primary outcome: development of clinically definite
MS (CDMS)
IFN Beta-1b
(n = 292)
Placebo
(n = 176)
P-Value
28%
45%
<.0001
Time to CDMS (25%)
618 days
255 days
––
McDonald at 2 years
69%
85%
<.00001
McDonald at 6 months
28%
51%
––
Outcome
CDMS at 2 years
Kappos L, et al. Neurology. 2006;67:1242-1249.
8
REFLEX—IFN Beta-1a SQ in Early MS

IFN beta-1a SQ 44 µg TIW vs QW vs placebo for 2 years
–

517 patients with CIS and abnormal MRI
Primary outcome: time to MS diagnosis by McDonald
criteria
Outcome at 2 Years
IFN Beta1a TIW
(n = 171)
IFN Beta-1a
QW
(n = 175)
Placebo
(n = 171)
P-Value
2-year probability of MS
(McDonald)
62.5%
75.5%
85.8%
<.0001
TIW
.008 QW
2-year probability of
CDMS
20.6%
21.6%
37.5%
.004 TIW
.0023 QW
0.6
RR 0.19
1.23
RR 0.37
2.70
<.0001
TIW
<.0001 QW
Combined unique active
MRI lesions/person/scan,
mean
Abbreviations: CIS, clinically isolated syndrome; RR, rate ratio.
Comi G, et al. Lancet Neurol. 2012;11:33-41.
9
PreCISe—Glatiramer Acetate
in Early MS

GA 20 mg/day vs placebo for 3 years
– 481 patients with CIS and abnormal MRI

Primary outcome: time to CDMS
Outcome at 3 Years
GA
(n = 243)
Placebo
(n = 238)
P-Value
Time to CDMS (25%)
722 days
336 days
.0005
25%
43%
<.0001
0.7
1.8
<.0001
CDMS
New T2 lesions, last
observed value
Abbreviations: CDMS, clinically definite MS, CIS, clinically isolated syndrome; GA, glatiramer acetate.
Comi G, et al. Lancet. 2009;374:1503-1511.
10
PreCISe Open-Label Extension—
Glatiramer Acetate in Early MS

2-year open-label phase following initial 3-year trial of
GA vs placebo

Early vs delayed GA treatment
 Early cohort = patients initially randomized to GA
 Delayed cohort = patients initially randomized to placebo
Early GA
(n = 243)
Delayed GA
(n = 238)
P-Value
CDMS
33%
49.5%
.0005
Annualized relapse rate
0.22
0.29
NA
-0.99%
-1.27%
.021
Outcome at 5 Years
Brain volume change
Abbreviations: CDMS, clinically definite MS; NA, not available.
Martinelli V, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract PD6.006.
11
FREEDOMS—Fingolimod in
Relapsing-Remitting MS (RRMS)

Fingolimod 0.5 mg or 1.25 mg vs placebo for 2 years
–
–

N = 1272 with RRMS
Mean EDSS: 2.3, fingolimod 0.5 mg; 2.5, placebo
Primary outcome: annualized relapse rate
Outcome at 2 Years
Fingolimod
0.5 mg
(n = 425)
Placebo
(n = 418)
P-Value
0.18
0.40
<.001
82.3%
75.9%
.03
2.5
9.8
<.001
Annualized relapse rate
Free of sustained
progression
Mean new/enlarging T2
lesions
Kappos L, et al. N Engl J Med. 2010;362:387-401.
12
TRANSFORMS—Fingolimod vs IFN
Beta-1a in RRMS

Fingolimod 0.5 mg or 1.25 mg vs IFN beta-1a 30 µg IM
for 1 year
–
–

N = 1292 with RRMS
Mean EDSS: 2.24, fingolimod 0.5 mg; 2.19, IFN
Primary outcome: annualized relapse rate
Outcome at 1 year
Annualized relapse rate
Fingolimod
IFN
0.5 mg
(n = 431)
(n = 429)
P-Value
0.16
0.33
<.001
Free of sustained progression
94.1%
92.1%
.25
Mean new/enlarging T2 lesions
1.7
2.6
.004
No trials under way for fingolimod in CIS
Cohen JA, et al. N Engl J Med. 2010;362:402-415.
13
TEMSO—Teriflunomide in
Relapsing MS

Teriflunomide (TFN) 7 mg and 14 mg vs placebo
for 2 years
–

N = 1086 with relapsing MS, mean EDSS 2.68
Primary outcome: annualized relapse rate
TFN
7 mg
(n = 365)
TFN
14 mg
(n = 358)
Placebo
(n =363)
Annualized relapse rate
0.37
0.37
0.54
<.001/
<.001
Sustained progression
21.7%
20.2%
27.3%
.08/.03
Change in T2 lesion
volume from baseline
1.31 mL
0.72 mL
2.21 mL
.03/
<.001
Outcome at 2 Years
O'Connor P, et al. N Engl J Med. 2011;365:1293-1303.
P-Value
7 mg/
14 mg
14
TOWER—Teriflunomide Multiple
Sclerosis Oral

Teriflunomide (TFN) 7 mg and 14 mg vs placebo for
48 wks + ≤18 months extension
–

N = 1165 with relapsing MS, mean EDSS 2.7
Primary outcome: annualized relapse rate
TFN
7 mg
(n = 407)
TFN
14 mg
(n = 370)
Placebo
(n = 388)
P-Value
7 mg/
14 mg
Annualized relapse rate
0.389
0.319
0.50
.018/ .0001
Sustained progression
21.0%
22.2%
15.8%
.76/.04
Outcome at 2 Years
CIS trial under way—TOPIC (NCT00622700)
Kappos L, et al. Paper presented at: ECTRIMS 2012; October 10-13, 2012; Lyon, France. Abstract 153.
15
Importance of Early Treatment

Studies of injectable first-line DMTs
(IFN betas and GA) approved for RRMS have
shown benefit in clinically isolated syndrome
(CIS)
– These often have a greater magnitude of benefit
than the RRMS study


Different populations studied, however
No data yet on newer oral first-line DMTs
– No CIS trial under way for fingolimod
– TOPIC trial under way for teriflunomide in CIS
16
Case Continues—Findings at
Presentation

Occasional attacks, adherence poor

Timed 25-Foot Walk – 14.2 sec

Internuclear ophthalmoplegia (INO) on right gaze

Motor: 4/5 throughout, spasticity right > left

Decreased light touch/pin prick all 4 limbs, pain

Gait: right >left hemiparetic

Reflexes: 4+, right >left with clonus

Urinary urgency/frequency, cognitive impairment,
fatigue
17
Case—MRI Findings
T2 FLAIR weighted MRI showing
lesions typical for MS
Graphic courtesy of James D. Bowen, MD.
18
Case—Issues to Address

Issues with greatest impact for this patient
– Nonadherence
– Cognitive impairment
– Mobility impairment

Additional issues
– Urinary urgency
– Fatigue
19
Nonadherence
20
Case Continues—Assessment of
Poor Adherence

First priority = improve adherence

Nurse discussed poor adherence with patient

Identified reasons
– Insurance lapses
– Pharmacy refill interruptions
– Cognitive impairment
21
Barriers to Adherence

Financial

Insurance/pharmacy

Perceived lack of benefit

Intolerance of injections

Intolerance of side effects

Laboratory abnormalities

Treatment failure
For more information on adherence, participate in a recent
MS MedImage case by Dr. James D. Bowen:
“Switching Disease-Modifying Therapy Due to Adherence Issues.” Find it at:
http://mic.projectsinknowledge.com/neurology/multiple-sclerosis/SwitchingDisease-Modifying-Therapy-Due-to-Adherence-Issues.cfm?jn=2022.29
22
Financial Support

Manufacturer support programs
– Contact manufacturer for support for individual
medication

National Multiple Sclerosis Society Financial
Assistance Program
– http://www.nationalmssociety.org/living-withmultiple-sclerosis/society-programs-andservices/financial-assistanceprogram/index.aspx
23
Case Continues—Addressing
Nonadherence

Nurse put into place a system to remind
patient about GA injections
– Smart phone alarm

Social worker stabilized insurance and
worked with pharmacy to ensure refills

Patient has remained adherent since
24
Cognitive Impairment
25
Cognitive Impairment in MS

About 60% of MS patients have cognitive
impairment
– About 35% of those with low-disability
relapsing-remitting MS

May be subtle and difficult to recognize in
clinic

Most common − processing speed and
episodic memory
Benedict RH, et al. Nat Rev Neurol. 2011;7:332-342.
26
Cognitive Screening Tests

Paced Auditory Serial Addition Test (PASAT)1
– Takes 2 or 3 minutes
1
5
3
6

7
8
10
Symbol Digit Modality Test (SDMT)2
– Takes about 90 seconds
X ∧
1
2
3
1. National MS Society. Multiple Sclerosis Functional Composite (MSFC) Administration and Scoring
Manual. 2001. Accessed 10/1/12 at: http://www.nationalmssociety.org/forprofessionals/researchers/clinical-study-measures/msfc/index.aspx. 2. Benedict RH, et al. Nat Rev
Neurol. 2011;7:332-342. Graphics courtesy of Dr. James D. Bowen.
27
Medications for Cognitive
Impairment in MS

Disease-modifying therapies

Other1
– Potassium-channel blockers

3,4-diaminopyridine, 4-aminopyridine
– Dopaminergic antiparkinsonism agents

Amantadine
– Stimulants

Modafinil, methylphenidate, L-amphetamine
– Acetylcholinesterase inhibitors

Donepezil, rivastigmine
Benedict RH, et al. Nat Rev Neurol. 2011;7:332-342.
28
DMTs in MS-Related Cognitive
Impairment—Rationale

MS lesions and attacks likely contribute to
cognitive impairment1

Nonlesion damage may also contribute
(atrophy, normal appearing white matter
changes, gray matter changes)1,2

DMTs alter exacerbations, MRI lesion activity,
atrophy, and noncognitive disability
1. Calabrese M, et al. Arch Neurol. 2009;66:1144-1450.
2. Calabrese M, et al. Expert Rev Neurother. 2011;11:425-432.
29
DMTs in MS-Related Cognitive
Impairment—Interferon Betas

IFN beta-1a IM vs placebo for 2 years1
–
–
–
–
–

N = 166 with relapsing MS
Significant benefit for information
processing/memory; P = .036
Trend to benefit for visuospacial/executive;
P = .005, corrected for baseline, P = .085
No effect on verbal ability/attention span; P = .60
Sustained PASAT deterioration: IFN 19.5%, placebo
36.6%; P = .023
IFN beta-1a SQ 22 µg vs 44 µg TWI for 2 years,
open label2
–
–
N = 356 with RRMS
Proportion with ≥3 impaired cognitive tests:
22 µg = 26.5%, 44 µg = 17.0%; P = .034
30
1. Fischer JS, et al. Ann Neurol. 2000;48:885-892. 2. Patti F, et al. Ther Adv Neurol Disord. 2009;2:67-77.
DMTs in MS-Related Cognitive
Impairment—Glatiramer Acetate

GA vs placebo, phase III1
–
–
–
N = 248 with relapsing-remitting MS
5 cognitive domains
No difference between GA and placebo groups

–

However, no measurable decline in cognition in placebo
group
Patients had little baseline impairment
GA for 3 months2
–
–
N = 30 with MS
PASAT improved from 42.16 to 47.76, P <.05, in those
with Gd+ MRI images
1. Weinstein A, et al. Arch Neurol. 1999;56:319-324. 2. Mori F, et al. Neurology. 2012;78:P04.118.
31
DMTs in MS-Related Cognitive
Impairment—Natalizumab, Fingolimod,
and Teriflunomide

Natalizumab
– AFFIRM phase III trial – natalizumab vs placebo
– 43% reduction in risk of PASAT-3 worsening,
P = .013

Fingolimod
– Little data

Teriflunomide
– Little data
Weinstock-Guttman B, et al. J Neurol. 2012;259:898-905.
32
3,4-Diaminopyridine (DAP)

3,4-DAP up to 100 mg/day vs nicotinic acid (NA) 10 mg/day
 N = 36 with MS
–
Randomized, double-blind, crossover design
Outcome
3,4-DAP
NA
P-Value
Improvement in defined deficit*
22
2
.0005
Selective Reminding Test, mean
37.5
36.9
NS
10/36 Spatial Recall, mean
18.8
17.2
NS
Symbol Digit Modality Test, mean
34.2
34.5
NS
PASAT, mean
66.6
65.4
NS
Word List Generation, mean
28.6
27.7
NS
*Primary outcome – leg weakness in 34 patients, arm ataxia in 2.
Bever CT, et al. Neurology. 1996;47:1457-1462.
33
L-Amphetamine


4 doses: L-amphetamine 15, 30, and 45 mg or placebo
–
N = 19 with MS, suspected cognitive deficit
–
Counterbalanced within-subjects design
Outcome: neuropsychological testing 2 h after dose
Test
Outcome
PASAT
Significant only for 45 mg
SDMT
Significant only for 45 mg,
trend 30 mg
TMT, Part A
Significant only for 45 mg
TMT, Part B; RAVLT; BVMTR
Not significant
Abbreviations: BVMTR, Brief Visuospatial Memory Test – Revised; PASAT, Paced Auditory Serial Addition
Test; RAVLT, Rey Auditory Verbal Learning Test; SDMT, Symbol Digit Modalities Test; TMT, Trail Making
Test.
34
Benedict RH, et al. J Neurol. 2008;255:848-852.
L-Amphetamine

L-amphetamine 30 mg vs placebo for 29 days
–
N = 151 with MS, cognitive deficit
–
Randomized, double-blind, controlled trial
Test
Outcome
SDMT (primary outcome)
No significant difference
CVLT2-TL
No significant difference
CVLT2-DR
Significantly better
BVMTR-TL
Significantly better
BVMTR-DR
Significantly better
PASAT
No significant difference
Abbreviations: Brief Visual Memory Test-Revised-Total Learning (BVMTR-TL); Brief Visual Memory TestRevised-Delayed Recall (BVMTR-DR); California Verbal Learning Test, second edition-Delayed Recall
(CVLT2-DR); California Verbal Learning Test, second edition-Total Learning (CVLT2-TL); Paced Auditory
Serial Addition Test (PASAT); Symbol Digit Modalities Test (SDMT).
35
Morrow SA, et al. J Neurol. 2009;256:1095-1102.
Donepezil

Donepezil 10 mg/day vs placebo for 24 weeks
–
N = 120 with MS, memory deficit
–
Multi-center, double-blind, randomized trial
Donepezil
(n = 61)
Placebo
(n = 59)
P-Value
SRT (primary outcome)
1.6
1.7
NS
10/36 Spatial Recall
-0.4
1.6
NS
SDMT
0.6
2.0
NS
PASAT 2 + 3
3.8
3.5
NS
COWA
1.0
0.6
NS
D-KEFS Sort
0.6
0.5
NS
JOLO
0.6
0.6
NS
Outcome, Mean
Abbreviations: COWA, Controlled Oral Word Association; D-KEFS Sort, Delis-Kaplan Executive Function System Sorting;
JOLO, Judgment of Line Orientation; PASAT, Paced Auditory Serial Addition Test; SDMT, Symbol Digit Modalities Test; SRT,
Selective Reminding Test.
36
Krupp LB, et al. Neurology. 2011;76:1500-1507.
Methylphenidate

Single dose: methylphenidate 10 mg vs placebo
–
N = 26 with MS, attention deficit (PASAT score <25th
percentile)
–
Double-blind, placebo-controlled
–
All patients treated with IFN beta-1a ≥6 months
Test
Methylphenidate
(n = 14)
Placebo
(n = 12)
Baseline
1 Hour
After
Baseline
1 Hour
After
PASAT 3
33.3
40.9*
37.8
39.5†
PASAT 2
24.6
30.9*
28.0
28.3†
*P = <.001; †P = NS.
Harel Y, et al. J Neurol Sci. 2009;276:38-40.
37
Modafinil

IM IFN beta-1a vs IM IFN beta-1a + modafinil
– N = 60 with RRMS, attention deficit
– 49 completed study

Improvement in multiple cognitive outcomes

However:
– No placebo control
– High dropout
– Multiple comparisons
Wilken JA, et al. Int J MS Care. 2008;10:1-10.
38
Drugs with No Significant
Cognitive Effects

4-aminopyridine (AP) vs placebo1
 N = 20 with MS; randomized, double-blind, crossover

4-AP 32 mg/d vs placebo for 6 mo2
 N = 54 with progressive MS; randomized, doubleblind, crossover design

Amantadine vs pemoline vs placebo for 6 wk3
–
–

N = 45 with MS and severe fatigue
Only written Symbol Digit Modalities Test showed
significance for amantadine
Rivastigmine 3 mg BID vs placebo for 12 wk4
–
N = 60 with MS and cognitive impairment; doubleblind, randomized, controlled trial
1. Smits RC, et al. Neurology. 1994;44:1701-1705. 2. Rossini PM, et al. Mult Scler. 2001;7:354-358.
3. Geisler MW, et al. Arch Neurol. 1996;53:185-188. 4. Shaygannejad V, et al. Can J Neurol Sci.
2008;35:476-481.
39
Medications for Cognition in MS

None proven effective

Stimulants may have some benefit
– Perhaps nonspecific due to increased alertness,
decreased fatigue
40
Cognitive Rehabilitation

Few studies

Psychology for stress reduction

Neuropsychology for identification of
specific areas of deficit

Speech therapy for help with organizational
skills

Occupational or physical therapy for energy
conservation

Assistive technology
41
Case Continues—Addressing
Cognitive Impairment

Neuropsychological testing offered to patient, but
refused

Family recognized that cognitive loss was due to MS

Reminders put in place

–
Cell phone, memory book
–
With these, patient and family believe he is functioning
adequately
If reminders fail, will consider further testing or
cognitive rehabilitation with speech/language
pathology and neuropsychology
42
Mobility Impairment
43
Contributors to MS-Related
Mobility Loss

Spasticity

Proprioceptive deficits

Balance deficit

Psychological contributors
44
Spasticity

Weakness

Stiffness (clasp knife)

Spastic leg jumps

Hyperreflexia (clonus)

Babinski response
45
Balance Deficit

Loss of position sense

Visual loss

Vestibular loss

Ataxia
46
Oral Medications for Spasticity

Baclofen

Tizanidine

Benzodiazepines

Dantrolene

Cannabis
47
Physical Therapy for Mobility

Stretching

Strengthening

Cardiovascular

Balance
48
Botulinum Toxin

Prevents acetylcholine release at
neuromuscular junction1

Typically lasts about 3 months1

Ideal for relatively localized muscle groups
(eg, footdrop, hand flexors)
Hyman N, et al. J Neurol Neurosurg Psychiatry. 2000;68:707-712.
49
Intrathecal Baclofen

Ideal patient is one in whom oral baclofen works
but sedation is excessive1
–
Also for patients with severe spasticity who require
higher dose than can be delivered orally

Delivered directly into CSF by lumbar catheter1

Typically, a test dose is given first1

Complications/adverse effects2
–
Mechanical pump/catheter failure, infection,
sedation, dizziness, impaired vision, slurred speech
1. National MS Society. Intrathecal baclofen. Accessed 10/2/12 at:
http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-aboutms/treatments/medications/baclofen-intrahecal/index.aspx. 2. Beard S, et al. Health Technol Assess.
2003;7:1-111.
50
Surgical Options

Nerve blocks – phenol

Neurectomy

Rhizotomy

Tenotomy
51
Dalfampridine—Mechanism of Action

Demyelinated axons have excessive
potassium channels that lead to
– Potassium leakage out of the cell
– Signal failure

Dalfampridine blocks these channels
– Improving signal conduction
Jeffery DR, et al. Core Evid. 2010;5:107-112.
52
Dalfampridine Phase III Trials—
Responder Analysis

Responder analysis = percentage of patients
in each group who respond
– Not mean differences between groups

Best means of capturing response when
some individuals have a high level of
response, while others have little or no
response

Facilitates assessing patient-perceived value
of response
53
Dalfampridine-Extended
Release (ER) Phase IIIb Trial


Oral dalfampridine 10 mg BID vs placebo for 9 weeks
–
N = 239, MS-related gait impairment
–
Relapsing-remitting MS, primary-progressive MS,
secondary-progressive MS, progressive-relapsing MS
–
Double-blind, randomized, controlled trial
Primary outcome = proportion of “timed walk
responders”
–

Timed 25-Foot Walk
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
Goodman AD, et al. Ann Neurol. 2010;68:494-502.
54
Dalfampridine-ER Phase IIIb
Trial Outcomes

Proportion of Timed Walk Responder (TWR)
– Dalfampridine 42.9% vs placebo 9.3%; P <.0001

Walking speed, change from baseline
– Dalfampridine TWRs 24.7% vs placebo 7.7%

12-Item MS Walking Scale, change from
baseline
– TWRs -6.04 vs nonresponders 0.85; P <.001

Leg strength improvement
– Dalfampridine TWRs 0.145 U vs placebo 0.042 U;
P = .028
Goodman AD, et al. Ann Neurol. 2010;68:494-502.
55
Dalfampridine-ER in Clinical Practice

Approved to improve walking in MS patients1
–


Benefit is seen in patients with progressive MS,
as well as RRMS2
Contraindication1
–

Renal failure or seizure history
Adverse effects3,4
–

Only drug approved for this indication
Urinary tract infection, insomnia, dizziness, headache,
nausea, asthenia, fatigue, back pain
In those patients who respond, dalfampridine
results in a significant improvement in walking
and quality of life
1. Jeffery DR, et al. Core Evid. 2010;5:107-112. 2. Pozzilli C, et al. Neurology. 2011;76(suppl 4):A73.
56
3. Goodman AD, et al. Lancet. 2009;373:732-738. 4. Goodman AD, et al. Ann Neurol. 2010;68:494-502.
Gait Aids

Canes, staffs, trekking poles

Forearm crutches

Walkers

Orthoses
– Ankle-foot orthoses, knee, Hip Flexion Assist
Device

Functional electrical stimulation
– Tibialis, quadricep
57
Dalfampridine ER + Walking Aids

Dalfampridine improved walking speeds in
phase III trials in patients already requiring
walking aids (EDSS 6.0+)1-3

Clinical experience suggests synergy
between physical therapy, exercise, walking
devices, and pharmacotherapy with
dalfampridine
1. Goodman AD, et al. Lancet. 2009;373:732-738. 2. Goodman AD, et al. Ann Neurol. 2010;68:494-502.
58
3. Brown T, et al. 62nd AAN; April 10–17, 2010; Toronto, Ontario, Canada. Abstract P07.164.
Case Continues
and Conclusion
59
Case Continues—Addressing
Mobility Impairment

Spasticity identified as a major source of
symptoms

Physical therapy
– Patient started doing leg stretching at home with
therapist oversight

Gait aids
– Single point cane recommended

Pathogenesis of imbalance due to sensory loss
described

Patient resistant in past, but now will consider
– Ankle-foot orthoses recommended but patient
refused
60
Case Continues—Addressing
Mobility Impairment

Botulinum toxin
– Injected into gastrocnemius with excellent results

Baclofen
– Started baclofen 10 mg TID, but continued
marked hyperreflexia
– Dose gradually increased to 20 mg TID with
marked improvement in spasticity
61
Case—Mobility Issue Follow-Up

Spasticity under much better control

Still having falls due to decreased balance
– Most likely due to sensory loss in legs

After other issues addressed, patient still had
gait dysfunction

Dalfampridine Extended Release trial
– Improvement in Timed 25-Foot Walk from 14.2
seconds to 10.1 seconds
– Patient reports that this led to an improvement in
his daily function with better gait
62
Case Continues—Other Issues

Now that the issues with greatest impact on
patient have been addressed, focus can turn
to other issues
– Urinary urgency
– Fatigue

Management strategies for each
63
Practical Considerations of Balancing
DMTs and Symptomatic Therapies

Generally add 1 medication at a time

Increase dose to effectiveness or tolerability
limit

Discontinue medications that fail

Try to dose as few times a day as possible

Use PRN when possible (fatigue, bladder)

Review medications at each visit

Emphasize nonmedical therapy (exercise)
64
Conclusions

Optimal patient care requires balance
between DMTs and symptomatic therapy
– Patients often more concerned about symptoms
than disease modification
– Must address both symptoms and DMT

Often intertwined: optimal DMT use requires
that symptoms be addressed
– Symptoms and DMT adherence often
interconnected
– Prioritize those symptoms that interfere with
DMT adherence
65