Motor neurone disease - part two

THE ESSENTIALS
- Average survival is three to five years from symptom onset.
- There is no cure, but riluzole modestly prolongs survival.
- Symptomatic treatment can improve quality of life.
- End-of-life care must be discussed while patients can still
communicate.
- The primary aim in the terminal phase is the patient's comfort.

1. CLINICAL COURSE OF DISEASE

Patients with sporadic amyotrophic lateral sclerosis (ALS) survive for three to five years from symptoms onset. A fifth of patients will survive for five years and 10 per cent for 10 years.

Prognostic factors

Poor prognostic factors include older age at onset, bulbar onset and the presence of respiratory symptoms at presentation. Disease course in familial ALS is due to SOD1 mutations and depends on the mutation present.

Disease progression

Problems due to weakness might be minimal early on, but the progression of limb and bulbar weakness produces extreme disability. Limb weakness progresses to involve all four limbs. Patients become unable to walk, talk or eat. Upper limb weakness means patients become unable to self-care or feed themselves. Involvement of the axial muscles causes head-drop, a flexed trunk posture and difficulty in turning in bed.

Bulbar involvement

Bulbar symptoms develop in most patients with ALS. Speech difficulties can progress to anarthria, with communication difficulties compounded by difficulty writing if there is additional hand weakness. Progressive dysphagia makes maintaining calorie and fluid intake difficult which results in weight loss and accelerated debility.

Respiratory problems

The combination of dysphagia and a weak cough make aspiration pneumonia a risk. Weakness of the diaphragm and accessory muscles of respiration occur in patients with advanced ALS producing shortness of breath. Difficulty in coughing up chest secretions may be distressing. The cause of death is usually respiratory failure.

KEY POINTS
- Ten per cent of patients with ALS might survive for 10 years or more.
- Older age at onset, bulbar onset and respiratory symptoms at
presentation are poor prognostic factors.
- Limb weakness usually progresses to include to all four limbs.
- Difficulties with speech and communication are common.
- Dysphagia can be complicated by malnutrition and aspiration pneumonia.
- Respiratory muscle weakness results in dyspnoea in advanced ALS.
- Cause of death is usually respiratory failure.

2. DISEASE-MODIFYING TREATMENT

There is no cure for ALS and no therapy that dramatically slows disease progression. Riluzole modestly prolongs survival and is approved by NICE for prescription by a neurologist.

Many other potential therapies have been evaluated without success but many clinical trials are ongoing.

So far, statistically significant survival benefits have been found with riluzole alone.

Riluzole

Riluzole is a sodium channel blocker which inhibits the presynaptic release of glutamate among other potentially neuroprotective actions. Two double-blind, placebo-controlled trials have been carried out in a total of more than 1,100 patients with ALS and both trials demonstrated a significant but modest prolongation of survival.

Quality of life was not assessed in these trials, but there was no evidence that riluzole prolonged the late stage of severe disability.

The average survival benefit to be expected is approximately three to four months after 18 months of treatment. Many neurologists suspect that there might be subgroups of patients who benefit much more from riluzole but this suspicion remains unproven.

Riluzole is expensive, at about £3,700 per patient per year, but the number of patients requiring the drug is small and they face a life-threatening disease for which there is no other therapy. Riluzole is contraindicated in hepatic or renal impairment and during pregnancy and breast-feeding. The dose is 50mg twice a day. It is generally well tolerated although nausea, diarrhoea and tiredness might occur.

Monitoring LFTs

Aminotransferase levels (ALT and AST) often increase on riluzole, so LFTs should be checked monthly for the first three months and three-monthly thereafter. If levels exceed five times the normal rate, the drug should be stopped.

Lesser elevations should prompt closer monitoring and if persistent, a reduction in dose or drug withdrawal. In these circumstances, it might be possible carefully to reintroduce riluzole once LFTs have settled. The evidence implicating oxidative stress in the pathogenesis of ALS makes antioxidants of interest as potential treatments.

A recent one-year trial of vitamin E in nearly 300 ALS patients on riluzole showed no effect on survival, but treated patients were less likely to progress from a mild to a more severe clinical state. Many ALS patients are empirically prescribed vitamin E (100mg daily) and vitamin C (500-1,000mg daily).

KEY POINTS
- NICE has approved the use of riluzole in ALS when prescribed by a
neurologist.
- On average, survival is increased by three or four months.
- The cost is about £3,700 per patient per year.
- LFTs need to be checked regularly on riluzole therapy.
- The antioxidant vitamins E and C are often prescribed empirically.

3. SYMPTOMATIC TREATMENT

Patients with ALS should be managed by a neurologist and GP in partnership, with input from a multidisciplinary team as required. Occupational therapists, physiotherapists, specialist nurses, dietitians, speech therapists, social workers and orthotists may all be needed.

Financial allowances and input from other voluntary organisations can also help families to cope. The GP should help co-ordinate these. Because most patients with ALS remain cognitively intact, doctor and patient together must make informed decisions about symptomatic therapies and, more importantly, end-of-life decisions.

Enteral feeding and respiratory support should be discussed while the patient is able to communicate and before a clinical crisis arises.

Painful cramps respond well to quinine bisulphate. Little can be done to alleviate weakness in ALS pharmacologically, but ankle splints, walking aids, wheelchairs, mobile arm supports and head-supporting neck collars can help to maximise useful function.

Physiotherapy

Physiotherapy, which can be taught to the carer, helps prevent painful joint contractures in immobile limbs, while muscle relaxants such as baclofen or diazepam can help patients with prominent spasticity.

Drooling due to excess saliva can be socially disabling. It can be reduced with amitriptyline, atropine or hyoscine hydrobromide skin patches. Portable suction devices are helpful for use at home. If these measures are inadequate, good control can usually be obtained by botulinum toxin injection into the salivary glands.

ALS patients often struggle to clear thick secretions. Beta-blockers such as propranolol or a mucolytic agent such as carbocisteine can help, as can manually assisted coughing techniques taught by a physiotherapist.

Up to half of ALS patients experience embarrassing and inappropriate laughing and crying. This represents an abnormal emotional display rather than a mood disorder. It may respond to amitriptyline or imipramine.

Speech therapy and communication aids may help the dysarthric ALS patient but need to be tailored to each patient's needs. Lightwriters, for example, are very useful for bulbar-onset patients but of little use to dysarthric patients who have also lost the use of their hands. Constipation can aggravate compromised respiratory function by causing abdominal distension and splinting of the diaphragm. The usual measures used to combat constipation can be applied.

Anxiety and depression

Anxiety and depression are common in ALS. If quality of life is adversely affected, anti-depressants or anxiolytic therapy should be offered.

Sleep disturbance and pain are common in the later stages. Identifying the underlying reason is essential. Non-opioid analgesics can be used to manage pain initially, but in the later stages opiates should be provided as necessary.

KEY POINTS
- Patients with ALS should be managed by a neurologist and GP in
partnership.
- Painful cramps respond well to quinine bisulphate.
- Drooling due to excess saliva can be reduced with amitriptyline,
atropine or hyoscine hydrobromide skin patches.
- Speech therapy and communication aids may help the dysarthric ALS
patient.

4. MANAGEMENT OF DYSPHAGIA AND WEIGHT LOSS

There is evidence that maintenance of a good nutritional status in ALS prolongs survival. Dysphagia is managed in stages. Regular weighing is mandatory for the effective management of dysphagia. Advice from a dietitian about the maintenance of calorie intake and the use of nutritional supplements is the first step. This input should be combined with that of a speech therapist, who can help with advice on food consistency for safe swallowing. Initially, this may be all that is required.

Careful timing of the discussion of enteral feeding is important. It must be considered while the patient is still able to communicate and while they are still relatively well but not so early as to cause undue alarm to a too-well patient.

PEG feeding

A percutaneous endoscopic gastrostomy (PEG) tube should be considered when there is continuing weight loss (more than 20 per cent body weight), despite implementation of the measures discussed above; dehydration; frequent choking spells making oral intake intolerable or recurrent chest infections due to aspiration.

PEG feeding allows adequate calorie and fluid intake, weight stabilisation and a secure route for oral medication. It does not prevent aspiration pneumonia. Even with a PEG tube in place, some patients may be able to take small amounts of food by mouth for pleasure.

The placement of a PEG tube is not without risk and should not be lightly attempted once vital capacity has fallen below 50 per cent of predicted. If bulbar symptoms make swallowing the endoscope impossible, a gastrostomy tube may be placed under ultrasound guidance.

Careful consideration of the likely risk of the procedure, the ability of the patient and carers to manage the feeding tube and the likely quality of life of the patient should be made before the decision to place a PEG tube is made. Patients already severely disabled by motor weakness by the time significant dysphagia develops may not be best served by the placement of a tube. Provided the doctor is happy that PEG placement is safe, the patient must have the final say.

Management of respiratory insufficiency Once vital capacity has fallen to 50 per cent of predicted, most patients will begin to experience respiratory symptoms. When vital capacity approaches 30-40 per cent, there is a risk of sudden deterioration and life-threatening respiratory failure. Enabling the patient to sleep semi-upright with back-rest support can help, and prevention, prompt diagnosis and treatment of aspiration pneumonia is important.

Ventilation

In selected patients, non-invasive, intermittent positive pressure ventilation (NIPPV) not only improves quality of life but can also prolong it. Overnight NIPPV provides a better night's sleep and relieves symptoms associated with respiratory failure during the day. Unfortunately, patients with significant bulbar weakness do not tolerate NIPPV well.

KEY POINTS
- The GP and neurologist should work together and involve other relevant
agencies.
- Symptomatic treatment can considerably improve quality of life.
- Dietitians and speech therapists can help with dysphagia.
- PEG feeding can be used when dehydration, weight loss and choking
become significant.
- Assisted ventilation with NIPPV can be of benefit in carefully
selected patients.

5. PALLIATIVE CARE AND SPECIALIST HELP

The sole aim of medical intervention in the terminal phase of the disease is to ensure that the patient is comfortable.

The patient's wishes regarding where and with what level of medical intervention they die must be respected as far as is possible. This is only possible if end-of-life issues have been discussed in advance of the terminal phase of the illness.

Symptom control Good symptom control is essential if a peaceful and dignified death is to be achieved. Sublingual lorazepam (0.5-2mg) or nebulised morphine can be useful for bouts of severe dyspnoea accompanied by anxiety.

Nebulised morphine or oral diamorphine are helpful if constant breathlessness causes distress in the terminal phase. Intravenous opiates should be used if terminal dyspnoea is resistant to these measures.

Opiates should also be used as needed to relieve pain unresponsive to non-opiate analgesia. Sedatives such as diazepam or chlorpromazine help relieve anxiety and restlessness.

There are many neurologists in the UK who have a specialist interest in the management of motor neurone diseases.

These specialists often participate in therapeutic trials in ALS and some have set up specialist regional clinics that are integrated with their research programmes.

A complete list of these specialists can be obtained from the authors.

The Motor Neurone Disease Association provides support for a number of specialist centres and a network of regional care advisers (www.mnsassociation.org).

KEY POINTS
- End-of-life issues should be discussed ahead of time while patients
can still communicate.
- Good symptom control is essential if a dignified death is to be
achieved.
- Benzodiazepines and opiates are helpful if breathlessness causes
distress.
- There is increasing expertise within hospices in the management of
terminally ill ALS patients.
- Many patients will wish to die at home and if so necessary support
should be provided.

FURTHER RESOURCES

Further reading

Amyotrophic Lateral Sclerosis, edited by R H Brown Jr, V Meininger and M Swash. Published by Taylor & Francis 1999.

Palliative Care in Amyotrophic Lateral Sclerosis (Motor Neurone Disease), edited by D Oliver, G Domenico Borasio and D Walsh. Oxford University Press 2000.

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