Oxford Handbook of Palliative Care (2 edn)
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Local nerve damage
(
For spinal cord compression see Chapter 15, ‘emergencies in palliative care’.)
Brachial plexopathy
Cause
Invasion or compression by tumour, or fibrosis secondary to radiotherapy.
Clinical features
Shoulder or arm pain (suggestive of tumour), numbness or allodynia in an arm or hand, muscle weakness, atrophy, Horner’s syndrome.
Investigations
CT or MRI scan of the brachial plexus.
Management
Palliative radiotherapy or chemotherapy may reduce the pain if tumour is the cause, but there is rarely an improvement in function. Otherwise, appropriate analgesia, including an agent for neuropathic pain, will be necessary.
Lumbosacral plexopathy
Cause
Invasion or compression by tumour, radiation fibrosis or abscess (rare).
Clinical features
Lumbosacral pain radiating into the legs. Leg weakness is usually unilateral and sensory dysfunction is apparent.
Investigations
CT or MRI scan of the pelvis.
Management
Palliative radiotherapy or chemotherapy, if tumour is the cause, reduces pain and can occasionally improve function.
Paraneoplastic neurological syndromes
These are neurological disorders which occur in up to 7% of patients with cancer
The aetiology is unclear, although the production of a specific antibody may be involved
Syndromes can occur as a presenting feature before the diagnosis of cancer is made
The commonest implicated cancers include small cell lung cancer (SCLC) (30%), breast and ovarian cancer and lymphoma
Symptoms are usually subacute and there may be more than one syndrome in the same patient
Syndromes include:
Peripheral neuropathy involving distal sensory and/or motor or autonomic nerves. Removal of tumour (which is usually SCLC, myeloma, Hodgkin’s disease, breast and gastrointestinal cancers) does not usually produce an improvement in symptoms, which are generally progressive. Steroids may help, but only for short time.
Cerebellar degeneration may present rapidly, sometimes before the primary tumour becomes apparent. Response to treatment, however, is disappointing
Lambert–Eaton myasthenic syndrome is a disorder of neuromuscular transmission occurring in 3% of patients with small cell lung cancer who account for 60–70% of cases. It is seen occasionally with other cancers including thymoma, breast cancer and lymphoma. There is a presynaptic deficit in neuromuscular transmission caused by a reduction in the amount of acetylcholine released at the motor nerve terminal
There is some evidence of an autoimmune aetiology, with the presence of autoantibodies to calcium channels at the neuromuscular junction. Common symptoms include proximal muscle weakness, particularly of the legs, and an associated waddling gait. Fatigue, diplopia, ptosis and dysarthria may also be a problem. Unlike classical myasthenia, weakness may be improved by repetitive activity and there is a poor response to edrophonium. It may improve with treatment of the underlying malignancy
Encephalomyelopathies can affect the limbic system, brainstem and spinal cord
Other clinical presentations include dementia, opsoclonus–myoclonus, limbic encephalitis (presenting rapidly with confusion, memory disturbance and agitation) and necrotizing myelopathy
Corticosteroid-induced proximal myopathy
This can occur within a few weeks of starting dexamethasone, 8–16mg a day
Patients experience difficulty in rising from a sitting position and in climbing stairs
Disabling symptoms may not be readily volunteered and direct questioning may be needed. Management includes reducing the dose of steroid to the minimum possible and considering a change to prednisolone, which may not cause as much muscle wasting (but is associated with more fluid retention)
Weakness should improve in 3–4 weeks of steroid withdrawal
Drug-induced movement disorders
Certain drugs may induce extrapyramidal symptoms and signs
These include akathisia (motor restlessness in which the patient may frequently change position or pace up and down if able), dystonia and parkinsonism.
Implicated drugs are those which block dopamine receptors such as antipsychotics (particularly haloperidol and the phenothiazines) and metoclopramide
Antidepressants and ondansetron may also cause problems
All these drugs should be avoided as far as possible in patients with Parkinson’s disease
Convulsions and seizures
Common causes of seizures in palliative care include:
Brain tumour (primary or secondary)
Biochemical disturbance (e.g. severe hyponatraemia)
Previous cerebrovascular accident
Long-standing epilepsy
Isolated tonic–clonic seizures sometimes occur but rarely last more than a few minutes: treatment should be initiated since they may herald status epilepticus or grand mal seizures.
A grand mal seizure should be treated promptly since it is very distressing and frightening for families to witness. Efficient management is therefore needed.
If a patient develops a grand mal seizure or status epilepticus, give:
Midazolam 5–10mg buccal/SC or slow IV (dilute 10mg with water to 10mL) and repeat after 15 and 30 minutes if not settled. Midazolam is not licensed as an anticonvulsant, but is usually readily available in palliative care units. A number of alternative benzodiazepines can be used:
lorazepam 4–6mg slow IV or sublingually
diazepam solution 10mg p.r. or emulsion 2–10mg slow IV
clonazepam 1mg slow IV (into large vein)
If the patient has not responded to a repeated dose of benzodiazepine or seizures recur, consider:
Phenobarbital 100mg SC or IV after diluting 1 in 10 with water for injection on p. 92.
Repeat phenobarbital if necessary and set up a syringe driver with phenobarbital 200–600mg SC over 24h
Once seizures have been controlled, review anticonvulsant therapy
General notes
For patients with intracranial tumours, consider starting, or review dose of, corticosteroids
Remember to advise the patient about restrictions on driving and to contact the DVLA
Consider parenteral thiamine if alcohol abuse is suspected
Consider and treat hypoglycaemia in at-risk patients
Consider drug interactions that alter anticonvulsant levels (e.g. steroids)
Initiating anticonvulsant therapy
It is usually appropriate to initiate anticonvulsant therapy after one seizure in patients with terminal illness
Sodium valproate is an appropriate first-line anticonvulsant for almost all types of convulsions or seizures, including focal and partial seizures, and those caused by intracranial tumours
Aim to increase the dose to lower end of quoted ‘usual maintenance dose’ unless side-effects occur, or the patient is frail and elderly (doses given below)
Carbamazepine and phenytoin may be suitable alternatives
Patients unable to take oral medication
Patients who are unable to take oral medication due to dysphagia, vomiting or because they are in the terminal stages may need to be given anticonvulsants by another route
The half-life of most anticonvulsants is quite long (>24h), therefore no parenteral anticonvulsant is usually needed if there is a low risk of seizures, and only a single dose is missed
The risk of seizures is higher if the patient:
has decreased or stopped steroids (intracranial tumours)
has increasing headache, vomiting or other signs suggesting rising intracranial pressure (intracranial tumours)
exhibits myoclonus or other twitching
has a history of poor seizure control or recent seizures
has previously needed more than a single anticonvulsant to achieve control
Because of the long half-life of anticonvulsants, parenteral treatment can be started at any time within 24h after the last oral dose
Choice of non-oral anticonvulsant
Choice may be determined partly by availability (Table 6j.1):
Phenobarbital CSCIor daily SC | Well-proven anticonvulsant for all types of seizures. Experience suggests it is effective in doses of 200mg/24h. Phenobarbital is incompatible with most other drugs in a syringe driver, therefore a second syringe driver may be necessary. Stat doses of 100mg SC or IM can sting |
Midazolam CSCI | Midazolam is more useful as a sedative than as an anticonvulsant. Anticonvulsant efficacy of ‘standard’ doses is unknown, but probably requires 20–30mg/24h minimum. Unlicensed use If low risk of seizures, and midazolam indicated for, e.g. terminal agitation, then additional anticonvulsant probably unnecessary. If higher risk of seizures, use phenobarbital in addition |
Clonazepam CSCI | Main advantage is that clonazepam is compatible with many other drugs used in CSCI. Much less experience supporting its use in this way; doses recommended: 2–4mg/24h (4–8mg/24h if sedation acceptable or desired) |
Carbamazepine orvalproate suppositories | Occasionally suitable for patients well-controlled on one of these drugs who develop a temporary inability to take oral medication (e.g. vomiting and who would find rectal administration acceptable) |
Phenobarbital CSCIor daily SC | Well-proven anticonvulsant for all types of seizures. Experience suggests it is effective in doses of 200mg/24h. Phenobarbital is incompatible with most other drugs in a syringe driver, therefore a second syringe driver may be necessary. Stat doses of 100mg SC or IM can sting |
Midazolam CSCI | Midazolam is more useful as a sedative than as an anticonvulsant. Anticonvulsant efficacy of ‘standard’ doses is unknown, but probably requires 20–30mg/24h minimum. Unlicensed use If low risk of seizures, and midazolam indicated for, e.g. terminal agitation, then additional anticonvulsant probably unnecessary. If higher risk of seizures, use phenobarbital in addition |
Clonazepam CSCI | Main advantage is that clonazepam is compatible with many other drugs used in CSCI. Much less experience supporting its use in this way; doses recommended: 2–4mg/24h (4–8mg/24h if sedation acceptable or desired) |
Carbamazepine orvalproate suppositories | Occasionally suitable for patients well-controlled on one of these drugs who develop a temporary inability to take oral medication (e.g. vomiting and who would find rectal administration acceptable) |
If a patient is dying, and sedation is acceptable, it is better to err on the generous side and give:
phenobarbital 200mg SC stat. as a loading dose
phenobarbital 200mg/24h by CSCI, or
if high risk of seizures—phenobarbital 400mg/24h by CSCI
If needing to minimize sedation, use 100mg SC stat. as a loading dose followed by 100–200mg/24h by CSCI
Phenobarbital is compatible with diamorphine and hyoscine if given by CSCI
Management of seizures at home
Most seizures are self-limiting and require only supportive care. For more prolonged seizures occurring at home, a number of measures can be arranged in anticipation which can avoid inappropriate emergency admission to hospital.
Diazepam rectal solution 10mg p.r.—administered by district nurse or carer
Midazolam 5–10mg SC (or preferably IM)—administered by district nurse
Midazolam buccal 10mg/2mL can be administered by a carer if the rectal route for diazepam is unacceptable: it appears to be as effective and may be quicker-acting than rectal diazepam 10mg. An oral solution is available as a ‘special’ or the injectable preparation can be used
In an inpatient unit, midazolam 5–10mg SC (or preferably IM) may be given first before treating status epilepticus as above.
Non-convulsive status epilepticus
Non-convulsive status epilepticus (NCSE) is a possible cause of confusion or delirium in terminally ill patients. The clinical presentation varies from altered mental status to comatose patients, without visible convulsions. In comatose patients unilateral tonic head and eye-movement is often observed. Other symptoms include myoclonic contractions of the angle of the mouth, mild clonus of an extremity or rarely epileptic nystagmus. EEG is the most important diagnostic tool to identify epileptiform activity. Treatment should be initiated following a step-wise model (e.g. phenytoin, sodium valproate, levetiracetam together with benzodiazepines), avoiding intubation and transfer to the intensive care unit. Although mortality rates are high, in some patients NCSE can be reversed by treatment.
Anticonvulsants ( see Chapter 4, ‘Principles of drug use in palliative care’)
Carbamazepine and phenytoin levels are decreased (risk of fits) by corticosteroids. Carbamazepine, phenytoin and phenobarbital can reduce the efficacy of corticosteroids.
This two-way interaction is common when managing patients with cerebral tumours. Carbamazepine, phenytoin or phenobarbital plasma levels are also reduced by St John’s Wort (risk of fits).
Sodium valproate
Tabs: 200mg, 500mg; chewable tabs: 100mg; syrup: 200mg/5mL
Dose: 200mg t.d.s. p.o.
Increase 200mg/day at three-day intervals. Usual maintenance dose, 1–2g/24h. Max. 2.5g/24h in divided doses. Suppositories are available as special orders
Carbamazepine
Tabs: 100mg, 200mg, 400mg; liquid: 100mg/5mL; supps: 125mg, 250mg
Dose: 100mg b.d. p.o.
Increase from initial dose by increments of 200mg every week. Usual maintenance dose 0.8–1.2g/24h in two divided doses. Max. 1.6–2g/24h. Equivalent rectal dosage: 125mg p.r. ≅ 100mg p.o.
Carbamazepine levels are increased (risk of toxicity) by clarithromycin, erythromycin, fluoxetine and fluvoxamine
Phenytoin
250 mg b.d. increasing step-wise by 250mg b.d. to a maximum dose 1.5mg b.d.
Caps: 50mg, 100mg, 300mg: chewable tabs: 50mg; susp.: 30mg/5mL, 90mg/5mL
Dose: 90mg b.d. p.o.
Start 150–300mg daily. Usual maintenance dose: 300–400mg daily. Max. 600mg/24h. Single or two divided doses
Phenytoin levels are increased (risk of toxicity) by clarithromycin, metronidazole, trimethoprim, fluconazole, miconazole, omeprazole, fluoxetine, fluvoxamine, aspirin, diltiazem, nifedipine and amiodarone
Because phenytoin has a very long and variable half-life, it can take several days and even up to 3–4 weeks for changes in dosage to take complete effect: this should be borne in mind in determining the interval after dosage is altered before measuring the plasma phenytoin concentration again
Levetiracetam
Tabs: 250mg, 500mg, 750mg, 1000mg; susp.: 100mg/mL
Dose: 500mg b.d. p.o.
Start 250 mg b.d. increasing step-wise by 250mg b.d. to a maximum dose 1.5mg b.d.
Levetiracetam is widely used in addition to phenytoin or sodium valproate, but it may also be used alone. No interaction with other antiepileptic drugs or other drugs have been reported
Barbiturates
Phenobarbital (phenobarbitone)
Inj.: 60mg/1mL, 200mg/1mL; tabs: 15mg, 30mg, 60mg; elixir: 15mg/5mL
Elixir in various strengths can be made to order, e.g. 10mg/mL
Phenobarbital is a barbiturate with both sedative and anticonvulsant effects. It is rarely used nowadays as a first-line anticonvulsant, as it is too sedative. It can be given by CSCI, but usually needs to be given in a separate syringe driver. It can be given by daily SC or IM injection, but the preparation is very viscous and stings on injection. Doses: see above
Benzodiazepines
Midazolam
Inj.: 1mg/1mL, 2mg/1mL, 5mg/1mL. Caution is needed.
Dose: 30mg/24h CSCI
Oral solution available as special order, or use injection for buccal use
Sedative effect markedly enhanced by itraconazole, ketoconazole and possibly fluconazole
Lorazepam
Tabs: 1mg, 2.5mg; inj.: 4mg/1mL
Dilute inj. with an equal volume of water or saline for IM use
Diazepam
Tabs: 2mg, 5mg, 10mg; oral solution: 2mg/5mL, 5mg/5mL
Rectal tubes: 5mg/2.5mL, 10mg/2.5mL; supps.: 10mg
Inj: (emulsion) 10mg/2mL (Diazemuls)—IV use only
Inj: (solution) 10mg/2mL— IM use
Clonazepam
Tabs: 500mcg, 2mg; inj.: 1mg/1mL
Starting dose: 1mg nocte
Increase gradually to usual maintenance dose of 4–8mg/24h. Oral solutions in various strengths are available from several sources
