Management of Tremor and Spasticity in Multiple Sclerosis

Val StevensonMS Trust Annual Conference Nov 2015

PlanTremorIntroductionAssessment- impact and what type of tremor?Interventions and team management

SpasticityWhat is spasticity?Impact on the person with MSAssessmentInterventions and team managementCase studies

Tremor

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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*

Cause1)Demyelinating lesions- cerebellar, basal ganglia and connections2)Coincidental

*Alusi SH et al. Tremor in Multiple Sclerosis. JNNP 1999;66:131-134.

Assessment

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ImpactMeasurement difficult as tremor, ataxia and other impairments co-existImpact on daily activities most important•Washing, dressing•Feeding, drinking•Hand-writing, keyboardQuality of Life

Tremor diagnosisObservation at rest and in posturesIntention movementsAssociated features•Ataxia- eg. past-pointing, dysarthria, nystagmus•Dystonia•Parkinsonism•Family history

Tremor types

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Intention tremor (cerebellar dysfunction), commonest cause MS Intensified physiological tremor eg hyperthyroidism, drugsEssential tremorParkinson’s diseaseDystonic tremorOrthostatic tremorHolmes (rubral) tremorPsychogenic tremor

Huntington’s DiseaseHemifacial spasmBallismus

MS tremor (intention and/or postural)

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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

MS tremor- cerebellum and connections

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• 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

Management

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Understand and educate

Target;Afferent inputsCerebellumEfferents/ thalamic nuclei

Strategies;Non pharmacological•Lifestyle changes•Positioning and Orthotics•Cooling

Pharmacological

Surgical

Non pharmacological

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Physiotherapy/ Occupational therapyExercise-based rehabilitation strategies to improve posture and movement controlSeating- proximal support and stabilityRobotics- practising task to correct movements

OrthoticsWriting, feeding aids relying on postural supportWeighted wrist bands, sensory dynamic splintsNeuroprostheses•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).

Non pharmacological

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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.

Pharmacological

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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

Evidence

Possibly effective (insufficient evidence to confirm or refute)TopiramateRiluzoleRituximab, NatalizumabIsoniazidCarbamazepineGluthetimidePrimidoneSR-FampridineClonazepamGabapentinBotulinum toxin type A

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Probably ineffective

LevetiracetamPropanololOndansetronCanabinoids

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.

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Surgery- Deep Brain Stimulation (DBS)

Implantation of electrodes bilaterally or Unilaterally into a given nucleusMechanism 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 passageHistorically 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

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DBS- Efficacy and side effectsIn mixed population studies DBS less effective in MS than Parkinson’s Disease or Essential TremorMajority do improve (~70% at 1 year), 10% do not•Tremor improvement may not correlate with improved function or QoLSide 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

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1)New or worsening tremor- consider steroids, optimise DMD’s ?Nataluzimab2)Maximise physical strategies•Physio•OT•Seating3) If tremor disabling or embarrassing consider oral therapies•Carbamazepine- Primidine- Gabapentin- Topirimate- Clonazepam4) If drugs ineffective consider;•Botulinum toxin•DBS if pure tremor and good cognitive function

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Pragmatic approach

Spasticity

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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.

Spasticity as part of the upper motor neuron syndrome

Positive Features

SpasticitySpasms - Flexor

- Extensor - Adductor

Increase in tendon reflexesExtensor plantar responses

ClonusPositive support reaction

Negative Features

WeaknessFatigueLoss of Dexterity

- develops over time, not a direct or immediate effect of a pyramidal tract or cortical lesion

Abnormal muscle tone

Descendinginhibition

Ascending sensory

excitation

Descendinginhibition

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

Muscle Stiffness

PassiveConnective Tissue

& muscle

Intrinsic

Cross-bridges in active Muscle

ReflexiveNon 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

But.. spasticity does not But.. spasticity does not occur in isolation occur in isolation

WeaknessLoss of dexterity

Fatigue

Pain

Ataxia

Sensory loss

Bladder and bowel impairment

Cognitive impairment

Non-neural changes- contractures

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..

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 appointmentNursing telephone assessment MDT Clinic

Expertise of team- One stop shop’- Sharing and learning for person and team- Good practice for invasive procedures decision making

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?

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?

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

Spasticity management

Oral

Medication

Botulinum

Toxin

Intrathecal

Baclofen

Intrathecal

Phenol

Inpatient

Rehabilitation

Surgical

Options

Individualised treatment plan

Education•What is spasticity?•Contribution of spasticity to current problems/ functionManagement of trigger factors•More education…Physical management programme•Positioning, Seating, Standing, Stretches, StrengtheningPharmacological treatment

Physical intervention

Remove physical trigger factorsDetermine spasticity needed for function and what is notIf needed prevent contracture and overuse of spasticityIf not needed re-educate movement patternsMaximise use of weakened musclesMaintain/improve soft tissue length- splinting, standing, positioning/ posture management

Pharmacological therapies

Generalised Baclofen, Tizanidine, Dantrolene, Benzodiazepines,

Gabapentin, Canabinoids

Focal Botulinum toxin Regional nerve blocks

Intrathecal Baclofen Phenol

Optimisation- Getting the most out of the drugsTiming

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

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 Sedationdependence

Dantrolene*LFT mon

25 – 100mg qds Ca2+ release 8 – 9 SedationGI upset

Liver failure

GabapentinPregabalin

100 – 1200mg tds50 – 300 mg bd

VGCCh?GABA

5 – 7 Sedation, poor concentration, unsteadiness

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

Sativex- Eur J Neurol 18:1122-31, 2011

Enriched study design572 patients underwent 4 week trial272/572 achieved >20% improvement in spasticity NRS ‘responders’241 randomized to double blind placebo controlled 12 week studyResults show significant differences in spasticity NRS, spasm and sleep scoresLarge placebo effect; (74% active cf 51% placebo were responders)

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, withdrawAdd in 2nd drug

Repeat process

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 toxinIntrathecal baclofenIntrathecal phenolSurgery

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..

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 spasticityOral medication, therapy and nursing no longer managing spasticity effectivelyResponsive to ITB Realistic, appropriate and achievable goalsIndividual/ Carer agrees with treatment goals and to be responsible for pump follow up

Intrathecal Baclofen

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

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

µg o

f bac

lofe

n

µg p

er m

illili

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of C

SF

Daily dose Therapeutic dose

Avoids systemic side effects

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

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!

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

Trial procedure

Need ITU/ anaesthetic availabilityContinue normal oral medicationDefine goals of treatment and of trialPerform outcome measures pre and postBolus or continuous infusion LP’s or temporary catheter Children may have GA for catheter placementMonitor vital signs every 30 mins

Pump implant

Pump Pocket:Abdominal Incision usually

Intrathecal Catheter: Lumbar Incision

Ongoing follow up

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

Dosing patterns

Time

Increasing dose

Pros and cons of ITB

ProsExtremely effectiveFlexible dosingNo systemic side effects (particularly CNS)Consistent treatmentNo drug interactionsAllows reduction of oral medications

ConsSurgical procedureRisk of complications Catheter issues, infectionPotential risks (can be fatal) Overdosing Withdrawal (missed refill apt)Limited battery lifeMinimal effect on upper limbsMay compromise walkingBody image issues

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

Case study 1- Progress

August 2009On Tizanidine 12mg tds, Clonazepam 1mg nocte, Amitriptyline 20mg nocte. Previously tried baclofen (gastric ulcer) and gabapentin (ineffective)Successful ITB trial at 25mcgImplanted (dose on discharge 63mcg/day), Tizanidine stopped and Clonazepam 0.5mcg, Amitriptyline 10mg (to be weaned as outpatient)

Feb 2010- PresentOff all antispasmodics (remains on; trimethoprim, movicol, bladder bot tox)Stable dose of 68.9mcg/day intrathecal baclofen

Flex pattern with higher dose overnight

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=0Provided used T roll at night

L=0, R=0Very rare spasms reported

10m timed walk Rollator 54.8s, 48 steps

2 sticks 20s, 22 steps1 stick 19.9s, 23 steps

2 sticks 17s, 21 steps

VAS effort of gait

6/10 4/10

VAS satisfaction of gait

8/10

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

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

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.

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

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…)

Lumbar spinal anatomy

Cerebrospinal fluid

FrontMotor nerves

Sensory nerves

Right lateral position

Front

90o

Motor nerves

Sensory nerves

Lumbar puncture

Front

Modified right lateral position

Front

30o

Insertion of Phenol

Front

End result

Damaged motor nerve

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

Outcome MeasuresOutcome Measures Pre trial AssessmentPre trial Assessment10/ 0910/ 09//20122012

Left RightLeft Right

Post Trial InjectionPost Trial Injection11/09/201211/09/2012

Left RightLeft Right

Post phenol injectionsPost phenol injections14/ 09 /201214/ 09 /2012

Left Right Left 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 to Unable to formally formally assess due to assess due to lack of passive lack of passive range and range and frequent frequent spasmsspasms

Unable to Unable to formally assess formally assess due to lack of due to lack of passive range passive range and frequent and frequent spasmsspasms

0000000000

0000000000

0000000000

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Spasms (Frequency scale)Spasms (Frequency scale) 44 44 00 00 00 22

Spasm descriptionSpasm description Flexor, Flexor, adductor and adductor and internal rotatorinternal rotator

Mainly flexor in Mainly flexor in naturenature

No spasms observedNo spasms observed Occasional short lived spasms Occasional short lived spasms affecting the foot onlyaffecting the foot only

Passive range of movement Passive range of movement (Goniometry)(Goniometry)

Hip flex Hip flex –– ext extKnee flex Knee flex –– ext ext

70/60/070/60/0110/75/0110/75/0

110/90/0110/90/0145/100/0145/100/0

105/35/0105/35/0`45/65/0`45/65/0

120/75/0120/75/0145/85/0145/85/0

100/40/0100/40/0145/65/0145/65/0

110/60/0110/60/0145/90/0145/90/0

Numeric Rating ScalesNumeric Rating ScalesVisual Analogue Score (VAS)Visual Analogue Score (VAS) PainPain Comfort Comfort in bedin bed

9966

0000

0000

Acknowledgements

To all of the patients who consented to their photos and videos being used to help with education and training of health professionalsTo you all for listening….

Any questions?