Symptom Management in Motor Neuron Disease. Cathy Ellis MND Care & Research Centre Kings Health Partners

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1 Symptom Management in Motor Neuron Disease Cathy Ellis MND Care & Research Centre Kings Health Partners

2 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

3 Symptoms in MND Weakness Spasticity Pain Cramps Fatigue Immobility Cognition Emotional lability Sialorrhoea Mucus Dysarthria/anarthria Dysphagia Weight loss

4 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

5 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). Raheja et al 2016

6 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

7 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

8 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

9 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

10 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

11 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)?

12 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)

13 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)

14 Cramps Sudden onset focal muscle pain with palpable contraction or feeling of contraction of muscle

15 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

16 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

17 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

18 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

19 Fatigue Reversible muscle weakness and whole body tiredness brought on by muscular exertion and partially relieved by rest (Gibbons 2013) Not sleepiness

20 Fatigue: contributors Metabolic changes Respiratory impairment Medication Weakness Mood change Insomnia Poor correlation with other factors suggests may be independent factor Ramirez 2008

21 Fatigue in MND Cochrane review published 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

23 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

24 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

25 Management strategies for sialorrhoea Conservative measures Natural products Anticholinergics Botulinum toxin Radiotherapy

26 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

27 Treatment of sialorrhoea: systemic medications Anti-cholinergics: Atropine eye drops Hyoscine patches Glycopyrronium Tricyclic anti-depressants Thin secretions

28 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

29 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

30 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

31 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

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

33 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

34 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

35 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)

36 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

37 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

38 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

39 Thank you

Symptom Control and End of Life Care

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