Symptom Management in Motor Neuron Disease

Cathy Ellis

MND Care & Research Centre

Kings Health Partners

Background

• Care approach in MND is palliative – Symptom control – Respiratory & Nutritional support – Use of assistive devices – Psychological & emotional support

• Multidisciplinary care associated with better outcomes – Survival – QOL – Symptom management – Psychological & social domains

Symptoms in MND

Weakness

Spasticity

Pain

Cramps

Fatigue

Immobility

Cognition

Emotional lability

• Sialorrhoea

• Mucus

• Dysarthria/anarthria

• Dysphagia

• Weight loss

Raheja et al 2016

Mean Non-Bulbar Symptom Scores Over Time. The symptom scores are a subset of the first 10 items of the ALS Specific Quality of Life Instrument, and range from 0 (no problem) to 10 (tremendous problem).

Raheja et al 2016

Mean Bulbar Symptoms Scores Over Time. . The symptom scores are a subset of the first 10 items of the ALS Specific Quality of Life Instrument, and range from 0 (no problem) to 10 (tremendous problem).

Strength & ability to move

• Aids and equipment

• No medications proven to improve strength available to date – Recent trials focusing on increasing muscle strength (tirasemtiv,

levosimendan)

• Therapeutic exercise for people with ALS or MND (Cochrane review 2013 updated dal Bello-Haas & Florence 2013) – Moderate load endurance exercise (twice daily) & moderate load and

intensity resistive exercise (3x per week)

– Improvement in disability (ALSFRS) but not strength, fatigue, QOL

– No adverse effects

Strength & ability to move

• Repetitive transcranial magnetic stimulation – Uses pulsed magnetic field to excite superficial nerve cells

– Non invasive approach to condition excitability & activity of neurons

– Increasing application with evidence of efficacy in pain, epilepsy, psychiatric disorders

– Small studies in MND for role in disease modification: inconclusive

– Role in symptom management unknown

Spasticity

• Velocity dependent increase in muscle tone

• Neurogenic component: overactive muscle contraction

• Biomechanical component: stiffening & shortening of muscle/tendons

• Voluntary movement increasingly difficult

• Limbs can “jump”, “spasms”

• Limbs hard to position passively

Spasticity: patient experience Milinikis & Young, on behalf

of TONIC study group 2015

• Physical symptoms – ‘When I get out of bed in the morning, my whole body goes

rigid’ ‘My jaw locks when I yawn’

• Bulbar spasms • Modifying factors

– Alleviating: Heat, massage, relaxation and antispasticity medication

– Aggravating: Sudden movements, writing, stretching, cold, fatigue and exercise

• Psychosocial factors: – ‘I get embarrassed when I get spasms’

‘I try not to show that I have stiffness’

Spasticity treatment: maintain length/positioning/prevent soft tissue shortening

• Physiotherapy /orthotics • Baclofen

• 1 small study in ALS no sig benefit (Norris 1979) • Potential for muscle weakness? (Cochrane review

MS 2003) • Tizanidine • Dantrolene • Benzodiazepines • Gabapentin (de Carvalho 2001) • ? L-dopa

• Evidence limited • High occurrence of side effects

Spasticity: medical treatment: Cannabis

– Cannabis Sativa • One of oldest herbal plants in medicine • Cannabinoids are the bioactive compounds • Used for pain & spasticity

– Sativex (oromucosal spray) • Approved as add on tx in MS, licensed • 1/3 reported improvement • Well tolerated • 2014: NICE did not recommend use in MS

– Hemp oil/CBD oil (Holland & Barretts, internet:

Cannabinoids but no THC) – Cannabinoids as disease modifiers (mouse model work)?

Spasticity: botulinum toxin

• No specific reports in MND

• Substantial evidence in spasticity due to other conditions

• Main concern: • Increased weakness

• Reduced dose suggested for MND

• BSRH guidelines: “conditions causing systemic weakness such as in myopathy, myasthenia gravis, motor neurone disease, or neuropathy should provoke extreme caution, but are not absolute contraindications (Moore and Naumann 2003)”

Spasticity: advanced therapies

• Phenol nerve block: focal spasticity

• Intrathecal baclofen

• Intractable spasticity in ALS (Marquardt et al 1999)

• Improved spasticity in PLS (Milano et al 2005)

• Improved pain associated with spasticity (McClellend et al 2008)

• Improved spasticity & pain in UMN predom MND (Bethoux et al 2013)

Cramps

•Sudden onset focal muscle pain with palpable contraction or feeling of contraction of muscle

Cramps: natural history (Caress et al 2016)

• Longitudinal data by interview/survey (not validated)

• 78% at baseline

• 95% at some point

• 25% >100/12

• Trend towards cramps reducing over years 1-3

• Unlikely to develop if not present at diagnosis

Cramps in MND: treatment

• Cochrane review 2012: 20 studies included cramps • 1 assessed cramps as primary end point:

tetrahydrocannabinol (no benefit)

• 13 cramps as secondary end points (including vit E, baclofen, riluzole, memantine, L-threonine

• 6 cramps as adverse event: creatine, gabapentin, dextromethorphan, quinindine, lithium)

• None had sig effect on cramps, but underpowered

• Leviteracetam

• (open label) reduced cramp frequency & severity in MND Bedlack et al 2009

Benign cramps:

• Magnesium not helpful in older adults with benign cramps (Cochrane 2012)

• Quinine (Cochrane 2015)

• may reduce number of cramps (low quality evidence) and severity (moderate quality)

• May rarely be fateful (avoid use in cardiac conduction defects). FDA alert

• Can rarely cause thrombocytopenia

• ?better if combined with theophylline

• Carbamezepine: no evidence

Cramps in MND: treatment

• Mexiletine:

• phase 2 study: Cramps as secondary end point. Sig reduction in cramps at 900mg but poor tolerability. Reduction at 300mg (non stat).

• Further direct study 300mg/900mg. Both reduced cramp frequency and severity. Dose dependent effect. High drop out at higher dose (31%) Weiss et al 2016 Neurology

• Randomised double blind crossover trial effective at 150mg BD. Reduction in frequency & severity. No serious adverse effects. Dizziness main side effect. Oskarsson et al 2018 Muscle & Nerve

• No studies on physical interventions for cramps

Fatigue

Reversible muscle weakness and whole body tiredness brought on by muscular exertion and partially relieved by rest (Gibbons 2013)

Not sleepiness

Fatigue: contributors

• Metabolic changes

• Respiratory impairment

• Medication

• Weakness

• Mood change

• Insomnia

Poor correlation with other factors suggests may be independent factor

Ramirez 2008

Fatigue in MND

• Cochrane review published 2018

• 4 studies included, all low quality with risk of bias

• 1 pharmacological – Modafinil: significant for fatigue, NS for

sleepiness/depression

• 3 non-pharmacological – Resistance exercise: no effect on fatigue but better

physical function

– Respiratory exercise: less fatigue, lower depression

– rTMS: sig effect but not after post hoc adjustments

Secretions: 1-1.5L/day

• Serous secretions (cholinergic control): – Drooling (sialorrhoea)

– Excoriation of skin

– Sleep disturbance

– Social withdrawal

– Limiting NIV use

– Voice quality

• Mucoidal secretions (β adrenergic control): – Choking sensation

– panic

Assessment

• Type of secretion: thick, thin or both

• Severity

• Impact

• Contributing factors eg neck weakness

• Timing of secretions (unstudied)

– Persistent ? Target submandibular

– Related to eating ? target parotids

Conservative measures

Natural products

Anti-cholinergics

Botulinum toxin

Radiotherapy

Management strategies for sialorrhoea

Treatment strategies

• Conservative – Neck collar – Head back wheelchairs – Portable suction

• Natural products: • Papaya: enzymes to break

up mucous • Pineapple: similar • Sage: reduces saliva

production • Red grape juice • Avoiding milk products • Steam nebulisers

Treatment of sialorrhoea: systemic medications

• Anti-cholinergics:

– Atropine eye drops

– Hyoscine patches

– Glycopyrronium

– Tricyclic anti-depressants

Thin secretions

Survey UK practice: Hobson et al 2013

• Most beneficial:

• thin secretions

• Hyoscine, botox, atropine drops, amitriptylline, glcopyrrolate

• Best side effect profile

• Thin secretions

• Atropine drops, glycopyrronium, botox

Botulinum toxin

• Neurotoxin produced by clostridium botulinum

• 7 subtypes

• Types A & B used to treat sialorrhoea

• meta-analysis data supporting efficacy in neurological conditions

• Minimally invasive

• Well tolerated

Botulinum toxin:

• Botox type

• Evidence stronger for type B

• Dosing (in neurological conditions)

• Commonly used doses in trials to date: 100 MU of Botox, 250 MU of Dysport, 2500 MU of NeuroBloc.

• Doses divided between parotids and submandibulars, with parotids receiving higher proportion

• Optimal dosing not established, titrate for effect

VERY LIMITED DATA ON REPEAT INJECTIONS

Botulinum toxin:

• Which glands

• Most inject parotids (but stimulated secretion)

• Some add submandibulars

• Single site or multiple?

• Gland identification

• Landmark: practical, largely considered safe

• EMG (none in survey)

• USS: confirms accurate delivery

McGeachan AJ, McDermott CJ. Pract Neurol 2017;17:96–103. (adapted from Srivanitchapoom et al)

Barriers to Botox use

• From UK Survey (Hobson et al 2013)

– Used in 14/21 MND centres surveyed

– Available to another 6 centres but rarely used

– Availability in non-neurological care centres unknown

• Availability

• Concern about side effects

• Quality of evidence base

Radiotherapy:

• Survey: unavailable or rarely used

• Mounting evidence for use in MND: • Anderson et al 2001; Harriman et al 2001; Stalpers et al 2002; Kasarkis et

al 2011; Guy et al 2011; Bourry et al 2013; Assoulina et al 2014

• Radiation field & dose differed

• Photon or electron beam therapy used

• Electron beam therapy advocated in some recent studies (Guy 2011, Bourry 2013)

• More localised: reducing exposure of mouth, teeth and oral mucosa

• Response rates may be more superior than conventional photon X-irradiation

Radiotherapy:

• Barriers to use

–Availability

–Fear of irreversible effects

–Association with cancer treatment

–Risk of neoplasm (unlikely to be a concern in time course of MND)

Management of thickened secretions

• Conservative methods

– Fluid intake

– Mouth swabs

– Thinning secretions with juice eg papaya/pineapple

– Nebulised saline

• Mucolytics

– carbocysteine

• B Blockers

• Cough assist

Secretion management

• Co-existence of sialorrhoea with thickened tenacious secretions complicates management

• Balanced approach needed, being mindful of worsening one to help the other

• Lack of evidence directing optimal management

• Stepwise approach needed

• Likely to require combination of treatments

• Availablity of treatments may limit use of advanced therapies

Summary

• Symptom management requires MDT approach

• Treatment strategies individualised to patient need & acceptance of treatments

• Personal experience of clinician influences treatment choices

• Availability/experience of advanced treatments

• Research should aim to determine optimal strategies

Thank you