Presentation by Val Stevenson

1. Management of Tremor and Spasticity in
Multiple Sclerosis
Val Stevenson
MS Trust Annual Conference Nov 2015

2. Plan
Tremor
Introduction
Assessment- impact and what type of tremor?
Interventions and team management
Spasticity
What is spasticity?
Impact on the person with MS
Assessment
Interventions and team management
Case studies

3. Tremor
3
An involuntary, rhythmic, muscle movement involving oscillations
of one or more parts of the body
Common in MS- Charcot triad: tremor, nystagmus, dysarthria
•Prevalence- 25-58*% of people with MS
•Titubation (nodding head tremor) ~ 9% of MS clinic patients*
•Presence of tremor associated with greater disability*
•Median latency from disease onset to tremor~ 11 years*
Cause
1)Demyelinating lesions- cerebellar, basal ganglia and connections
2)Coincidental
*Alusi SH et al. Tremor in Multiple Sclerosis. JNNP 1999;66:131-134.

4. Assessment
4
Impact
Measurement difficult as tremor, ataxia and other impairments co-
exist
Impact on daily activities most important
•Washing, dressing
•Feeding, drinking
•Hand-writing, keyboard
Quality of Life
Tremor diagnosis
Observation at rest and in postures
Intention movements
Associated features
•Ataxia- eg. past-pointing, dysarthria, nystagmus
•Dystonia
•Parkinsonism
•Family history

5. Tremor types
5
Intention tremor (cerebellar dysfunction), commonest cause MS
Intensified physiological tremor eg hyperthyroidism, drugs
Essential tremor
Parkinson’s disease
Dystonic tremor
Orthostatic tremor
Holmes (rubral) tremor
Psychogenic tremor
Huntington’s Disease
Hemifacial spasm
Ballismus

6. MS tremor (intention and/or postural)
6
Clinically- usually arms +? head, neck, trunk, vocal
cords
Pathophysiology of tremor in MS is poorly understood
•MS is by definition a multifocal disease; tremor
occurrence cannot easily be linked to a single
neuroanatomical site
•No postmortem studies on the link between lesion site
and the tremor have been undertaken
•Pontine lesion load correlates with
severity of tremor in MS patients

7. MS tremor- cerebellum and connections
7
• The predominance of action tremors (postural and intention) point
to the cerebellum and its connections as the most likely source of
tremor
• Bilateral, asymmetrical involvement indicates that damage to the
cerebellum and its connections is often multifocal
• Animal studies- damage to cerebellar efferents (through lesions of
the dentate nucleus or superior cerebellar peduncle) may cause
disinhibition of thalamic nuclei, which are the main producers of
intention tremor
• Alterations in sensory inputs- afferents, (from muscle spindles via
spinocerebellar pathways) modulate MS tremor
Complex
• The cerebellum contributes to various aspects of motor control-
postural stabilization, coordination, precision and timing of
movements all of which can be affected

8. Management
8
Understand and educate
Target;
Afferent inputs
Cerebellum
Efferents/ thalamic nuclei
Strategies;
Non pharmacological
•Lifestyle changes
•Positioning and Orthotics
•Cooling
Pharmacological
Surgical

9. Non pharmacological
9
Physiotherapy/ Occupational therapy
Exercise-based rehabilitation strategies to improve posture and movement
control
Seating- proximal support and stability
Robotics- practising task to correct movements
Orthotics
Writing, feeding aids relying on postural support
Weighted wrist bands, sensory dynamic splints
Neuroprostheses
•Devices that deliver electrical stimulation to the antagonist muscles in an
out-of phase manner to the EMG signals of the muscles from which tremor
originates eg. spoon (handheld device using active cancellation of tremor
technology).

10. Non pharmacological
10
Lifestyle changes
•Reduce caffeine intake
•Review drugs, other stimulants
•Relaxation techniques
•Computer adaptations to aid mouse control
Cooling
•Cooling affected limb can improve function for ~ 30 mins*
•Task directed eg. ISC, PC use, signing documents
Pulsed Electromagnetic Fields
•Reported in 3 patients
*Feys P, Helsen W, Liu X, Mooren D, Albrecht H, Nuttin B,
Ketelaer P (2005). Effects of peripheral cooling on intention tremor
in multiple sclerosis. J Neurol Neurosurg Psychiatry 76:373–379.

11. Pharmacological
11
Very difficult
•Poor evidence- case reports, small open label trials
•Reduction in tremor does not always equate to
functional benefit
•Side effects common
Be clear with goals of treatment
Essential to monitor effect and review goals

12. Evidence
Possibly effective (insufficient
evidence to confirm or refute)
Topiramate
Riluzole
Rituximab, Natalizumab
Isoniazid
Carbamazepine
Gluthetimide
Primidone
SR-Fampridine
Clonazepam
Gabapentin
Botulinum toxin type A
12
Probably ineffective
Levetiracetam
Propanolol
Ondansetron
Canabinoids

13. Botulinum Toxin Type A
Two randomized placebo controlled studies reporting benefit
•Tremor reduction
•Improved writing ability
However
•No improvement in QoL
•Increased weakness
Alusi SH, Worthington J, Glickman S, Findley LJ, Bain PG. Evaluation of three different ways of
assessing tremor in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2000;68:756–60.
Brin MF, Lyons KE, Doucette J, Adler CH, Caviness JN, Comella CL, et al. A randomized, double
masked, controlled trial of botulinum toxin type A in essential hand tremor. Neurology. 2001;56:1523–8.
13

14. Surgery- Deep Brain Stimulation (DBS)
Implantation of electrodes bilaterally or
Unilaterally into a given nucleus
Mechanism of action is not clear, possibly through;
•Stimulation of neuro- transmitter release
•Blockage of local circuits by preventing action potential
generation
•Stimulation of axonal firing in afferent/efferent axons or fibres of
passage
Historically most common target was unilateral or bilateral
stimulation of the thalamic nucleus ventralis intermedius (Vim).
More recently ventralis oralis posterior (Vop) a basal ganglia
outflow nucleus, and zona incerta (ZI), have gained favour.
May help tremor but is not helpful in the management of other
components of the MS movement disorder, such as ataxia
14

15. DBS- Efficacy and side effects
In mixed population studies DBS less effective in MS than
Parkinson’s Disease or Essential Tremor
Majority do improve (~70% at 1 year), 10% do not
•Tremor improvement may not correlate with improved function or
QoL
Side effects common (25%)
•Reported adverse events include seizures, monoparesis,
dysarthria, gait disturbance, intracerebral haemorrhage and
relapse of MS
Given the risks of surgery, careful patient evaluation and selection
is crucial.
•Pure tremor
•Avoid in patients with severe underlying spasticity or sensory
deficits in the tremulous limb, those with a rapidly progressive MS
or in people with severe cognitive impairment
15

16. 1)New or worsening tremor- consider steroids, optimise
DMD’s ?Nataluzimab
2)Maximise physical strategies
•Physio
•OT
•Seating
3) If tremor disabling or embarrassing consider oral therapies
•Carbamazepine- Primidine- Gabapentin- Topirimate-
Clonazepam
4) If drugs ineffective consider;
•Botulinum toxin
•DBS if pure tremor and good cognitive function
16
Pragmatic approach

17. Spasticity
17
Common feature of MS
•84% of 18,727 patients with MS reported at least some symptoms
of spasticity, and 30% reported moderate to severe symptoms*
The impact ranges from minor discomfort to complete immobility
with pressure sores and contractures
•Pain, spasms and sleep disturbance frequently reported
•Reduction in quality of life for patients and caregivers
*Rizzo MA, Hadjimichael OC, Preiningerova J and Vollmer TL. Prevalence and treatment of
spasticity reported by multiple sclerosis patients. Multiple sclerosis . 2004; 10: 589-95.

18. Spasticity as part of the upper motor neuron syndrome
Positive Features
Spasticity
Spasms - Flexor
- Extensor
- Adductor
Increase in tendon reflexes
Extensor plantar responses
Clonus
Positive support reaction
Negative Features
Weakness
Fatigue
Loss of Dexterity
- develops over time, not a direct or immediate effect of
a pyramidal tract or cortical lesion

19. Abnormal muscle tone
Descending
inhibition
Ascending
sensory
excitation
Descending
inhibition
Ascending
sensory
excitation
Normal muscle tone Abnormal muscle tone
•Loss of descending inhibitory input or reduced spinal cord inhibitory control
may result in spasticity
•Intrinsic changes within the motor neurons causing prolonged plateau
potentials
•Increased ascending sensory excitation can increase spasticity
Changes
in the
motor neuron

20. Muscle Stiffness
Passive
Connective Tissue
& muscle
Intrinsic
Cross-bridges in active
Muscle
Reflexive
Non NeuralNeural
•Exaggerated stretch
reflexes
•Reduced inhibitory
control
•Intrinsic changes
within the motor neuron
•Disinhibited primitive
reflexes
•Co-contraction
•Loss of sarcomeres
•Contracture
•Transition of muscle fibre type
•Thixotrophy

21. But.. spasticity does notBut.. spasticity does not
occur in isolationoccur in isolation
Weakness
Loss of dexterity
Fatigue
Pain
Ataxia
Sensory loss
Bladder and bowel
impairment
Cognitive
impairment
Non-neural changes
- contractures

22. Impact of spasticity and spasms
Feeding
Sexual activity
Safety
Washing
Dressing
Bladder & Bowel
Mood
Relationships
Posture
Maintains muscle bulk
Likes movement
associated with
spasms
Uses spasms to
assist mobility
Maintains vascular
flow, prevent DVT
-ve +ve
Mobility
Transfers
Body Image
Remember spasticity can also be useful..

23. Accurate assessment is key to everything
-Devising management plan and monitoring
interventions
Information gathering
•Effect of spasticity, spasms on daily activities
•Assess patients (and families) expectations
PT appointment
Nursing telephone assessment
MDT Clinic
Expertise of team
- One stop shop’
- Sharing and learning for person and team
- Good practice for invasive procedures decision making

24. Consider
• What is the main problem?
• Hopes/ expectations
• Clarify terminology used
• Are there trigger or aggravating factors?
• Is pain related to spasticity or other cause?
 Neuropathic, musculoskeletal
• Is the spasticity helpful for function?
• Is it focal or generalised?
• What is the individuals level of knowledge about
spasticity?

25. Assessment- Hands on
• Observe-posture, movement
• Feel resistance to passive movement
• Determine biomechanical component
• Define underlying weakness
• Measure; this should be integral to
assessment process
• Combination of qualitative and
quantitative measures, individualised
Does the spasticity need
treating?

26. Primary
Options for spasticity management
Ongoing Medical, Therapy & Nursing
Oral
Medication
Intrathecal
Baclofen
Intrathecal
Phenol
Inpatient
Rehabilitation
MILD
SPASTICITY
SEVERE
SPASTICITY
Surgical
Options
Teamwork
Intermediate
Secondary
Focal
Treatments

27. Spasticity management
Oral
Medication
Botulinum
Toxin
Intrathecal
Baclofen
Intrathecal
Phenol
Inpatient
Rehabilitation
Surgical
Options

28. Individualised treatment plan
Education
•What is spasticity?
•Contribution of spasticity to current problems/ function
Management of trigger factors
•More education…
Physical management programme
•Positioning, Seating, Standing, Stretches,
Strengthening
Pharmacological treatment

29. Physical intervention
Remove physical trigger factors
Determine spasticity needed for function and
what is not
If needed prevent contracture and
overuse of spasticity
If not needed re-educate movement
patterns
Maximise use of weakened muscles
Maintain/improve soft tissue length- splinting,
standing, positioning/ posture management

30. Pharmacological therapies
Generalised
 Baclofen, Tizanidine, Dantrolene, Benzodiazepines,
Gabapentin,
Canabinoids
Focal
 Botulinum toxin
 Regional nerve blocks
Intrathecal
 Baclofen
 Phenol

31. Optimisation- Getting the most out of the drugs
Timing
 Tablets on waking.. Not with breakfast
 Adjust to activities eg. Car travel, work patterns, therapy, sexual
activity
Drug choice
 Take advantage of other drug actions
 Clonazepam and sedation- for nocturnal spasms
 Gabapentin- for neuropathic pain
 ? Sativex for pain, bladder dysfunction, poor sleep
Mechanism for monitoring effect and adjusting dose
 Patient and carer education, treating therapists, GP
Remember- the aim is to improve function and minimise
complications, not simply to reduce spasticity

32. Oral agents for spasticity
Drug Dose Action Half life (hrs) Side effects
Baclofen 5 – 40mg tds GABA - B ~ 4 Sedation
weakness
Tizanidine
*LFT mon
2 – 12 mg tds α2 adrenergic
agonist
2.5 Sedation, dry
mouth
hypotension
BZPs Drug dependent GABA - A 18 – 50 Sedation
dependence
Dantrolene
*LFT mon
25 – 100mg qds Ca2+
release 8 – 9 Sedation
GI upset
Liver failure
Gabapentin
Pregabalin
100 – 1200mg tds
50 – 300 mg bd
VGCCh
?GABA
5 – 7 Sedation, poor
concentration,
unsteadiness

33. Sativex [Δ9-tetrahydrocannabinol (THC) and
cannabidiol (CBD)]
Combination of the cannabis extracts Δ9-
tetrahydrocannabinol (THC) and cannabidiol
(CBD)
Several studies have shown a small benefit
or trend in reducing spasticity (50%
responder rate)
Generally well-tolerated
 Side effects (mostly psychotropic effects of
cannabis), seem to be dose related
Granted UK license in June 2010 as an
add on therapy for moderate to severe
spasticity in MS

34. Sativex- Eur J Neurol 18:1122-31, 2011
Enriched study design
572 patients underwent 4 week trial
272/572 achieved >20% improvement in
spasticity NRS ‘responders’
241 randomized to double blind placebo
controlled 12 week study
Results show significant differences in
spasticity NRS, spasm and sleep scores
Large placebo effect; (74% active cf 51%
placebo were responders)

35. Combining drugs
Start low and go slow
Start first choice drug
 Increase according to effect or tolerance
 Stop titration when desired effect achieved or
side effects occur
 If no effect at full tolerated dose, withdraw
Add in 2nd
drug
 Repeat process

36. What if the drugs don’t work?
Review trigger factors and physical management
programme before escalating therapy
Other treatment options:
Focal treatments
 Chemical neurolysis or botulinum toxin
Intrathecal baclofen
Intrathecal phenol
Surgery

37. Focal intervention- Botulinum toxin
•Focal spasticity
•Neural component only - Neuromuscular
blockade
•Weakens the targeted muscle
•Usually muscle power recovers by about
3 months; related to axon sprouting
•But period of weakness provides an
opportunity for stretching / splinting
*Without therapy input probably pointless..

38. Concentration of GABA receptors at dorsal horn of
laminae 1- 4
 Intrathecal infusion is therefore delivered direct to site of action
Who is it for?
Severe lower limb spasticity
Oral medication, therapy and nursing
no longer managing spasticity effectively
Responsive to ITB
Realistic, appropriate and achievable goals
Individual/ Carer agrees with treatment goals and to
be responsible for pump follow up
Intrathecal Baclofen

39. ITB therapy
ITB Therapy provides baclofen continually
to the cerebral spinal fluid (CSF), and hence
the receptors, via a pump and catheter
system
Slide courtesy of Medtronic

41. Intrathecal dose is approx. 1% of oral equivalent
60,000
600
0
10,000
20,000
30,000
40,000
50,000
60,000
Oral Intrathecal
1.240
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Oral Intrathecal
µgofbaclofen
µgpermillilitreofCSF
Daily dose Therapeutic dose
Avoids systemic side effects

42. Contraindications to ITB therapy
•Known allergy to baclofen (need to have tried it orally
prior to ITB)
•IV drug user
•Concomitant significant sepsis
•Chronic pressure sores not a contraindication
•Psychological issues
•Needle phobia, lack of commitment, body image
issues
•? Precarious ambulation

43. Not contraindications…
•Pregnancy or potential pregnancy
•MRSA colonisation
•Spinal fusion (cervical approach can be used if
necessary)
•Epilepsy
•LP or VP shunts
•Malnutrition
•Need for MRI scans
•Walking!

44. How is it done?
Aspects of ITB service:
•MDT spasticity assessment & measures
 Patient selection
•Trial
•Implant
•Discharge planning
•Long term follow up
 Pump refill and dose titration
 24 hour help-line

45. Trial procedure
Need ITU/ anaesthetic availability
Continue normal oral medication
Define goals of treatment and of trial
Perform outcome measures pre and post
Bolus or continuous infusion
 LP’s or temporary catheter
 Children may have GA for catheter placement
Monitor vital signs every 30 mins

46. Pump implant
Pump Pocket:
Abdominal Incision usually
Intrathecal Catheter: Lumbar
Incision

47. Ongoing follow up

48. Programming
Computer print
out- for medical
notes and
patient hand
held record
Pump- Stores and infuses
prescribed drug. Stores all relevant
patient and system data
Programmer- External device that
allows precise and adjustable dosing
via telemetry

49. Dosing patterns
Time
Increasing
dose

50. Pros and cons of ITB
Pros
Extremely effective
Flexible dosing
No systemic side effects
(particularly CNS)
Consistent treatment
No drug interactions
Allows reduction of oral
medications
Cons
Surgical procedure
Risk of complications
 Catheter issues, infection
Potential risks (can be fatal)
 Overdosing
 Withdrawal (missed refill apt)
Limited battery life
Minimal effect on upper limbs
May compromise walking
Body image issues

51. Case study 1
•59 yr old lady (C), diagnosed with MS in 1986,
now Secondary Progressive
•Using rollator indoors, scooter outside
•Independent personal care, very active
•Difficulty doing ISC due to spasticity
•Oral meds causing side effects
•Poor sleep
•Pain and discomfort

52. Case study 1- Progress
August 2009
On Tizanidine 12mg tds, Clonazepam 1mg nocte,
Amitriptyline 20mg nocte. Previously tried baclofen
(gastric ulcer) and gabapentin (ineffective)
Successful ITB trial at 25mcg
Implanted (dose on discharge 63mcg/day), Tizanidine
stopped and Clonazepam 0.5mcg, Amitriptyline 10mg (to
be weaned as outpatient)
Feb 2010- Present
Off all antispasmodics (remains on; trimethoprim,
movicol, bladder bot tox)
Stable dose of 68.9mcg/day intrathecal baclofen
 Flex pattern with higher dose overnight

53. Outcome measures
Measure Baseline 6 weeks 20 months
Max Ashworth L=3, R=3 L=0, R=0 L=0, R=0
Spasm
frequency
L=4, R=4 L=0, R=0
Provided used T
roll at night
L=0, R=0
Very rare
spasms reported
10m timed walk Rollator
54.8s, 48 steps
2 sticks 20s, 22
steps
1 stick 19.9s, 23
steps
2 sticks 17s, 21
steps
VAS effort of
gait
6/10 4/10
VAS
satisfaction of
gait
8/10

54. Case study 2
• 49 yr old lady presented in 2003, diagnosed
with SPMS in 2005.
• Independent pivot transfers, wheelchair user,
standing in OSF, few steps in parallel bars only
• Drowsy on medication
• Previous Mitoxantrone, currently Copaxone

55. Case study 2- progress
• March 2010 on tizanidine 36mg, clonazepam
0.5mg, gabapentin 300mg
• Implanted with ITB pump 100mcg/ day and meds
weaned
• May 2010 on 117.7mcg/day ITB and no oral
antispasticity drugs. Easier transfers, bed mobility,
burst of physio (Aug-Dec 2010).
• Dec 2010 able to walk short distances with rollator
• June 2011- 15m tolerance with 2 crutches
• Sept 2011 Walking 60m with ease, swimming,
managing stairs
• 10m timed walk; 23 steps in 27 seconds with 2
elbow crutches

56. Case 2
• In August 2011 she returned home to Canada
for a holiday. She walked indoors all the time
there as the house was not wheelchair
accessible. Improved strength and stamina with
this
• When she returned home she put her manual
and powered wheelchairs away in the garage.
She now only uses these for long distances
outdoors.
• She has started swimming once a week. Goes
for walks in the park with family, attends a
regular exercise group and is considering a
return to some sort of voluntary work.

57. Intrathecal Phenol
• Protein coagulation & necrosis
• Axonal degeneration
• Indiscriminate destruction of motor and
sensory fibres
• Irreversible… but may need to be repeated
Service requirements
• Spasticity assessment & measures
• Expert injector
• Local anaesthetic trial as inpatient
• Nursing, physio and wheelchair service
follow up

58. Selection criteria
• Severe lower limb spasticity
• Oral medication, physiotherapy, nursing no
longer effective
• ITB not appropriate or Phenol preferred
• Bladder & bowel dysfunction with effective
management programme in place
• Aware of potential sexual dysfunction
• Sensory impairment of lower limbs
• Patient aware of irreversibility (stem cell
treatment…)

59. Lumbar spinal anatomy
Cerebrospinal fluid
Front
Motor nerves
Sensory nerves

60. Right lateral position
Front
90o
Motor nerves
Sensory nerves

61. Lumbar puncture
Front

62. Modified right lateral position
Front
30o

63. Insertion of Phenol
Front

64. End result
Damaged
motor nerve

65. Case Study
• 51 year old lady with secondary progressive MS
• Essentially bed bound although manages to sit
out about once every few weeks in a
customised chair for a short period of time
• Pain is the most troublesome symptom
• Unable to change position in the bed and any
care tasks are painful and extremely difficult to
perform

66. Outcome MeasuresOutcome Measures Pre trial AssessmentPre trial Assessment
10/ 0910/ 09//20122012
Left RightLeft Right
Post Trial InjectionPost Trial Injection
11/09/201211/09/2012
Left RightLeft Right
Post phenol injectionsPost phenol injections
14/ 09 /201214/ 09 /2012
Left RightLeft Right
Tone (Ashworth)Tone (Ashworth)
• Hip flexorsHip flexors
• Knee extensorsKnee extensors
• Hip extensorsHip extensors
• Knee flexorsKnee flexors
• Hip adductorsHip adductors
• Ankle plantar-flexorsAnkle plantar-flexors
Unable toUnable to
formallyformally
assess due toassess due to
lack of passivelack of passive
range andrange and
frequentfrequent
spasmsspasms
Unable toUnable to
formally assessformally assess
due to lack ofdue to lack of
passive rangepassive range
and frequentand frequent
spasmsspasms
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
Spasms (Frequency scale)Spasms (Frequency scale) 44 44 00 00 00 22
Spasm descriptionSpasm description Flexor,Flexor,
adductor andadductor and
internal rotatorinternal rotator
Mainly flexor inMainly flexor in
naturenature
No spasms observedNo spasms observed Occasional short lived spasmsOccasional short lived spasms
affecting the foot onlyaffecting the foot only
Passive range of movementPassive range of movement
(Goniometry)(Goniometry)
Hip flexHip flex –– extext
Knee flexKnee flex –– extext
70/60/070/60/0
110/75/0110/75/0
110/90/0110/90/0
145/100/0145/100/0
105/35/0105/35/0
`45/65/0`45/65/0
120/75/0120/75/0
145/85/0145/85/0
100/40/0100/40/0
145/65/0145/65/0
110/60/0110/60/0
145/90/0145/90/0
Numeric Rating ScalesNumeric Rating Scales
Visual Analogue Score (VAS)Visual Analogue Score (VAS)
• PainPain
• ComfortComfort
in bedin bed
99
66
00
00
00
00

67. Acknowledgements
To all of the patients who consented to their
photos and videos being used to help with
education and training of health
professionals
To you all for listening….
Any questions?