Symptom Management in Motor

Neuron Disease

Cathy Ellis Kings College Hospital MND Care &

Research Centre 2016

General principals

• Multidisciplinary clinics: NICE – Fewer hospital admissions

– Independent survival benefit

– Increased use of NIV, gastrostomy

– Earlier access to palliative care

• Evidence base weak – Cochrane reviews

– Consensus on good practise

– Evidence from other conditions (MS, brain injury)

• Symptomatic treatments aim to improve quality of life

• Some treatments extend life

Symptoms commonly reported:

• Spasticity

• Cramps

• Sialorrhoea

• Swallowing

• Breathing

• Communication

• Emotional lability

• Cognitive aspects

Symptoms

• Spasticity

• Cramps

• Sialorrhoea

• Swallowing

• Breathing

• Communication

• Emotional lability

• Cognitive aspects

Spasticity

• Velocity dependent increase in muscle tone

• “Tightness” “stiffness” of muscles

• Voluntary movement increasingly difficult

• Limbs can “jump”, “spasms”

• Limbs hard to position passively

• Cochrane review (Ashworth et al 2012)

• “The single trial performed was too small to determine whether individualized moderate intensity endurance type exercises for the trunk and limbs are beneficial or harmful” (Drory 2001)

Spasticity: oral treatment

• 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)

• Evidence limited

• High occurrence of side effects

Spasticity: medical treatment

– Cannabis Sativa

• One of oldest herbal plants in medicine

• 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

Spasticity: botulinum toxin

• No specific reports in MND

• Fairly extensive evidence in spasticity from ABI, cerebral palsy

• Main concerns:

• Increased weakness

• Potential for adverse effects from spread of botox

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) • 8 patients treated with ITB

• 6/8 had pain improvement

• Improvement predictable from test dose

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

• 20 patients ITB vs 15 conservative tx

• Better spasticity relief/pain control in ITB group

• No difference in progression of hip flexor weakness or in patients becoming non ambulatory

Cramps: natural history (Caress et al 2016)

• Longitudinal data by interview/survey (not validated)

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

• 78% at baseline

• 95% at some point

• 25% >100/12

Cramps: natural history (Caress et al 2016)

• Trend towards cramps reducing over years 1-3

• Unlikely to develop if not present at diagnosis

• 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

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: treatment

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

• Mexiletine: phase 2 study: Cramps as secondary end point. Sig reduction in cramps at 900mg but poor tolerability. Reduction at 300mg. Further study planned 300mg & 600mg

Sialorrhoea

• Unintentional loss of saliva from the mouth

• Occurs in ~50% patients, with poor control in ~ 40% of those

• Abnormal handling of saliva – Tongue weakness/spasticity

– Facial weakness

– Weakness of pharynx

– Loss of oropharyngeal control

– Exacerbated by neck weakness

Secretions

• Serous secretions: – Drooling

– Excoriation of skin

– Sleep disturbance

– Social withdrawal

– Limiting NIV use

– Voice quality

• Mucoidal secretions: – Choking sensation

– panic

Treatment of sialorrhoea

• Aimed at reducing saliva production or removing saliva

• Poor correlation between reduction in saliva and control of symptoms (PD)

• No guidelines to determine optimal management

Treatment of sialorrhoea

• Natural products: • Papaya: enzymes to break up mucous

• Pineapple: similar

• Sage: reduces saliva production

• Red grape juice

• Avoiding milk products

• Suction

• Nebulisers

Treatment of sialorrhoea: systemic medications

• Anti-cholinergics: – Atropine eye drops

– Hyoscine patches

– Glycopyrronium

– Tricyclic anti-depressants

• B blockers: – Propranolol (Newell 1996)

• Mucolytics – carbocysteine

– Urinary retention

– Loss of visual accommodation

– Headaches

– Dry eyes

– confusion

– Bradycardia/hypotension

– dreams

Survey UK practice: Hobson et al 2013

• Surveyed saliva management in 23 clinicians from 21 MND centres

• 42% patients from surveyed clinics had secretion problems

• 46% of those had suboptimal tx (saliva not well controlled)

Survey UK practice: Hobson et al 2013

• First line agents: • Thin secretions: Hyoscine, amitriptylline, atropine

drops

• Thick secretions: carbocysteine

• Second line agents: • Glycopyrrolate, botox, amitriptylline

• carbocysteine,

• Third line treatment • Botox, radiotherapy, subcut glycopyrrolate, atropine

tablets, hyoscine

Survey UK practice: Hobson et al 2013

• Most beneficial: • thin secretions

• Hyoscine, botox, atropine drops, amitriptylline, glcopyrrolate

• thick secretions • Carbocysteine, steam, nebulisers

• Best side effect profile • Thin secretions

• Atropine drops, glycopyrronium, botox

• Thick secretions, • carbocysteine, steam,

Botulinum toxin

• Second or third line agent

• Used in 14 MND centres from survey

• Available in further 6 but rarely used

• RCTs most robust evidence

• Recent review of botox in MND identified 12 studies

• Only 1 dedicated RCT

Botulinum toxin: Jackson et al 2009

• Double blind, placebo controlled trial of botox B in MND

• 20 patients randomised

• 18 included: treatment n=9, placebo n=9.

• Botox B 2500U to submandibulars & parotids under EMG control

• Showed effect of botox

• 90% guessed correctly if they received active drug

Botulinum toxin:

• Botox type? • Evidence stronger for type B (survey 11 used Botox A, 5

Botox B

• But injected parotids & submandibulars

• Gland identification? • Landmark

• EMG (none in survey)

• USS

• Which glands? • Most inject parotids

• Some add submandibulars

• Single site or multiple?

VERY LIMITED DATA ON REPEAT INJECTIONS

Radiotherapy:

• Survey: unavailable or rarely used

• Recent review identified 7 open label studies published: • 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: Assoulini et al 2014

• Largest study 50 MND patients

• Prospective study

• Used photon 3D therapy

• Both submandibulars and 2/3 parotids

• Assessed saliva using sialorrhoea scoring scale

• 2 regimes: – 10Gy over 2 fractions (days 1 & 3)

– 20Gy over 4 fractions (days 1, 3, 8 7 10)

Radiotherapy: Assoulini et al 2014

• All patients improved

• 46/50 complete response, 4/50 partial response

• At 6 months 71% complete response, 26% partial

• 9 patients re-treated (8/9 from 10Gy group)

• No difference in toxicity between low and high dose groups (taste modification, mild pain, xerostomia, saliva thickening)

• Radiotherapy induced neoplasia risk is low

20Gy safe and effective treatment in 4 doses. 10Gy may be proposed in patients with poorer medical condition

Sialorrhoea summary

• Evidence based treatment guidelines for saliva management in MND don’t exist

• Consider type of saliva to determine treatment options

• Anti-cholinergics effective in many patients, hyoscine most commonly used. Glycopyrronium may have better side effect profile

• If sialorrhoea is intractible botulinum toxin should be considered depending on local availability

• Radiotherapy could be considered as an alternative treatment with emerging evidence base

Pseudobulbar emotional lability

• Pathological crying, laughing, yawning

• 50% MND patients

• Can occur without bulbar motor signs

• Not a sign of mood disorder

• Anti-depressants helpful in other neurological conditions

• RCT dextromethorphan & quinidine improved symptoms and QOL in MND. 4 trials in pseudobulbar affect. Licensed in USA (Nuedexta)

Pseudobulbar emotional lability: Nuedexta

• RCT dextromethorphan & quinidine improved symptoms and QOL in MND.

• Initial trials had high side effect profile

• Improved on reduced dosing

• 4 trials in pseudobulbar affect.

• Licensed in USA (Nuedexta)

• Licensed in Europe

• 2016: European medicines agency withdrew marketing authorisation at request of Avinar pharmaceuticals inc (commercial reasons).

Pseudobulbar emotional lability

• Education

• citalopram

Conclusions

• Multi-disciplinary care improves symptom control and outlook

• Symptom management can be complex

• Lack of evidence base prevents optimal pathways of care being devised

• Consensus guidelines can improve care, and management surveys help us to see what others do