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MRC Prion Unit
From fundamental research to prevention and cure
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Symptomatic treatment

Although there is no cure for CJD, treatments are available for a variety of symptoms that occur in patients with CJD.  Often a treatment for a specific symptom is initially effective only to lose its effect over time.  This particularly applies to behavioural disorders, rigidity and hallucinations.  It is unclear why this occurs but a plausible explanation is that there is progressive loss of receptors for the different agents as the disease advances.  Whether this is the explanation or not it is often necessary to change therapy in an attempt to control the breakthrough symptoms and use combinations of different treatments even though some combinations appear to be duplication of therapy. Sometimes it is better to use less specific drugs on the assumption that at least they can bind to multiple receptors some of which may be relatively spared.

Myoclonus

Myoclonus is common in many forms of CJD and is a characteristic feature of sporadic CJD.  Positive myoclonus comprises irregular short duration jerk like episodes involving the somatic musculature. Conversely, negative myoclonus is seen in some neurological diseases, particularly hepatic failure, and is characterised by short lived inhibition of tone in a group of muscles but it is unusual in CJD.  Myoclonus can be generated at several levels in the central nervous system. In the case of CJD it is either cortical or subcortical in origin.  Cortical myoclonus is generated from the cerebral cortex grey matter and is thought to be due to loss of inhibitory gabanergic neurones. Typically cortical myoclonus is multifocal and involves those muscles with the greatest cortical representation i.e. the limbs, especially the digits and face, but no area is immune.  It is stimulus sensitive especially to touch and on eliciting tendon reflexes.  Action triggers the myoclonus.  Proof of cortical origin can be obtained by back averaging the EEG when a discharge consistently precedes the movement by a short interval (10-40ms) this depending on the distance from the cortex to the muscles concerned. In contrast to propriospinal myoclonus there is no sequential progression of the muscles involved.  Somatosensory evoked potentials are enhanced during the discharge. 

Cortical myoclonus is often reduced by gabanergic drugs of which sodium valproate, an agent that increases cortical gamma amino butyric acid (gaba), is the most frequently prescribed.  Most patients respond to 1-2.5G daily.  Levetiracetam in a similar dose is useful but it’s mode of action is unclear.  Benzodiazepines, which act on the gaba receptor complex, are also effective in many cases.  Clonazepam can be dramatically effective in a small dose but many patients only respond to large doses (up to 15mg) which can result in excessive drowsiness.  Combinations of therapy may have to be given and other anticonvulsants such as phenobarbitone are sometimes useful.  Phenytoin, carbamazepine and lamotrigine have also been suggested although exacerbation, rather than improvement, of the myoclonus usually occurs with these drugs.

Subcortical myoclonus also occurs in CJD.  If this arises from the thalamus the drugs used in cortical myoclonus are still effective but if the movement disorder arises from brain stem structures such as the giant reticular cell region of the brainstem as a result of loss of inhibitory input from the cerebellum treatment is more problematic.  Clonazepam is the drug of choice and ethyl alcohol is sometimes beneficial. In general valproate and levetiracetam are not effective.  Having said that, pathology in CJD involves multiple levels of the central nervous system raising the possibility that myoclonus may arise from more than one region so it is always worth trying different agents in combination.

Psychiatric Symptoms

Visual hallucinations occur in various forms of CJD although the true frequency is not known.  They can be relatively benign e.g. seeing furry animals or terrifying ‘Dahliesque’ types.  The pathophysiology of these is obscure although they occur in a wide range of other degenerative conditions and are particularly common in cortical Lewy body disease.  A variety of antipsychotic drugs are used to control them but there are no firm data on efficacy.  Quetiapine, a drug that has marked 5HT1A and 2 blocking activity, together with some activity against D1 and 2 and less against alpha adrenergic and H1 receptors, is most frequently prescribed.  The advantage of this agent over conventional antipsychotic drugs, such as butyrophenones and phenothiazines, is that parkinsonian side effects are much less marked.  This is potentially important in CJD patients who often have signs of basal ganglia dysfunction as part of the disease process.  As with any degenerative disease it is wise to escalate the dose slowly beginning with 25mg daily.  Adverse events are not usually a problem but concern has been raised over the long term use of this agent in elderly demented patients with Alzheimer’s disease whose cognitive impairment can worsen.

Because of the beneficial effect of centrally acting anticholinergic drugs upon visual hallucinations in cortical Lewy body disease it is reasonable to prescribe donepezil or rivastigmine to CJD patients with disturbing hallucinations and the former  does seem to be effective in some patients with intractable visual hallucinations. If the patient has parkinsonian symptoms these do not become more severe. 

Anxiety, Agitation, Insomnia and Depression

Agitation and anxiety are frequent symptoms in patients with CJD.  Often the patient can’t settle and paces around.  They can also become abusive and occasionally physically violent.  Benzodiazepines such as diazepam, which act on benzodiazepine receptors associated with gaba receptors, are effective anxiolytic drugs and can promote sleep (see below).   Dependence can be troublesome if used for long periods.  They can have a paradoxical effect of increasing aggression but dosage adjustment usually ameliorates this.  Olanzapine, which has its maximum receptor blocking activity against 5HT2 receptors, can be helpful although care is needed in the elderly because of an increased risk of stroke and diabetes.  Weight gain is common although not usually a problem with CJD patients.  Mirtazapine is an alternative anxiolytic.  This drug is a potent inhibitor of 5HT2a and H1 receptors.  Risperidone, primarily a D2 antagonist, is also used although there is a risk of exacerbating pre-existing parkinsonism which is also a major problem with the older anti-psychotic drugs such as phenothiazines and haloperidol.  Akathisia and tardive dyskinesias are more common with this latter group of drugs.  Physical symptoms of anxiety such as tremor can respond to beta-blockers which penetrate the blood brain barrier e.g. propranolol (10-120mg).  Anxiety induced sweating is helped by anticholinergic drugs such as oxybutynin (2.5-15mg).

Sleep disturbance is characteristic of the fatal insomnias and some of the thalamic variants of CJD; it is also found in other forms of CJD and is often associated with anxiety.  Unfortunately hypnotic agents are usually ineffective.  Indeed these patients may seem to be excessively sleepy during the daytime which any long acting hypnotic could theoretically worsen. It is worth trying one of the benzodiazepines starting with agents that have a short duration of action such as temazepam (10-40mg) before using longer duration drugs such as nitrazepam (5-10mg).  Non benzodiazepine hypnotics such as zopiclone (3.75-7.5mg), which act on the diazepine receptor, are also worth trying as is mirtazapine (15-40mg).

Depression occurs in some patients with CJD, particularly those with a family history, early in the evolution of the disorder. Cognitive behavioural therapy can be useful in these patients and SSRI’s are of value.  If depression is accompanied by anxiety and agitation one of the sedating antidepressants are useful such as mirtazapine.

Pain

Pain is not usually a problem in patients with most types of CJD. However vCJD is an exception. These patients characteristically have pain, probably of thalamic origin, in the limbs and hyperaesthesia.  Gabapentin and amitriptyline are often effective and can be given in combination.  Most analgesic drugs do not have a beneficial effect.  The pain sometimes resolves as the disease progresses.

Patients with any type of CJD, but particularly vCJD and kuru, appear to have headache. This sometimes responds to conventional analgesics.

Seizures

Epileptic fits are not that frequent in patients with CJD with the exception of patients with E220K mutation.  Occasional epilepsia partialis continua (EPC) can occur.  Levetiracetam (500-3000mg) and sodium valproate (500-3000mg) are useful for generalised tonic clonic seizures and is effective for seizures with myoclonus.  Complex partial seizures are best treated with carbamazepine (400-2000mg) or lamotrigine (25mg-300mg) but these drugs can exacerbate myoclonus.  Older anticonvulsants such as phenobarbitone (30-120mg) are of value for generalised attacks and the side effects of drowsiness can be useful for the agitated patient and insomnia. Similarly, clobazam (10-40mg) is effective for many seizure types and can help anxiety or insomnia. EPC is resistant to therapy.

Increased Muscle Tone

Increased tone is generally extrapyramidal. The rigidity can be severe making nursing difficult particularly late in the course of the disease.  There is no experience of the best management of this rigidity.  Theoretically dopamine replacement with agents such as sinemet might help but as behavioural disturbance is often a problem this might be contraindicated.  Dantrolene (75-225mg) acts directly upon the muscle membrane and can relieve rigidity even though the tone increase is centrally generated.  At higher dose liver function may become deranged. Spasticity develops in many patients but is not usually a prominent feature. If troublesome baclofen (10-90mg), tizanidine (8-24mg) or diazepam (5-15mg) can help as can dantrolene. Intramuscular botulinum toxin is effective in localised rigidity or spasticity although these symptoms are often too generalised to make this a feasible option.  Further, botulinum toxin can exacerbate swallowing difficulties, frequent in the later stages of CJD, if given in large dosage.

Bladder Dysfunction

Incontinence occurs in most patients with CJD late in the course of the disease probably as a result of frontal disturbance.  Retention rarely occurs.  In general use of pads or catheterisation is required. Anticholinergic drugs such as tolterodine XL (4mg) are helpful for frequency in some patients or if the bladder is irritable causing catheter extrusion.  Bladder neck obstruction is not usually a problem but  if it occurs can be treated with alpha adrenergic receptor blocking drugs (internal sphincter) such as prazosin (max 4mg) and baclofen 10-60mg(external sphincter).

Bowel Dysfunction

Terminally incontinence of stool occur requiring routine hygiene.  Spurious diarrhoea with liquid motions is best treated with enemas.  Constipating agents are not indicated in general.

Salivation Control

Occasionally patients who have severe swallowing problems require anticholinergic drugs such as atropine (subcutaneous injection 0.6-1.2mg, or orally), hyoscine patches or oxybutynin tablets (5-15mg) to reduce salivary flow.  Blurring of vision and increase in mucus viscosity can be a problem.

Glycopyrronium bromide is effective in excessive salivation and can be administered orally or subcutaneously.  It has a relativevly long duration of action and is said not to cross the blood brain barrier. Subcutaneous dosage ranges from 0.6-1.2 mg per day and oral adminstration from 1-3 mg per day in divided dosage.

Dysphagia

Difficulty in swallowing is a major problem with the severely disabled patient and a decision has to be made when nutritional intake is critical.  Initially pureed food may help but ultimately this fails to maintain an adequate intake.  If the patient is expected to survive for only a few days hydration can be maintained by nasal tube or subcutaneous administration of fluid.  If the patient is likely to survive for a significant time or cannot tolerate a nasal tube, a gastrostomy will be necessary either by insertion of a tube parenterally (PEG) or radiologically (RIG).  There are no trials to determine criteria for which technique is best suited to a particular patient.  Invasive treatments should always be a mutual decision between the clinician and the patient or their relatives

Terminal Care

Patients should be on appropriate sedatives such as opiates. Nursing input and involvement of palliative care specialists is vital at this stage.

 

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