Neurological disorders – epilepsy, Parkinson’s disease and multiple sclerosis

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Chapter 21 Neurological disorders – epilepsy, Parkinson’s disease and multiple sclerosis

Paul Bentley, Pankaj Sharma

Synopsis

• This chapter focuses on several common neurological disorders, each of which has a wide range of therapeutic strategies available. These disorders are: epilepsy, Parkinson’s disease and multiple sclerosis. The treatments of other common neurological disorders are covered in other sections: namely: headaches (Pain section: Ch. 18), stroke (Ch. 24) and dementia (Ch. 20).

• It also touches on the pharmacological principles of other neurological disorders, including: movement disorders other than Parkinson’s disease; spasticity (that is a physical sign characteristic of certain diseases such as stroke or multiple sclerosis); peripheral neuropathy; motor neurone disease; tetanus.

Epilepsy

Definitions

A seizure is a clinical symptom or sign caused by abnormal electrical discharges within the cerebral cortex.1 For example, a tonic–clonic seizure refers to a pattern by which a patient loses consciousness, becomes generally stiff (tonic), and subsequently jerks all limbs (clonus); whereas a complex partial seizure refers to a constellation of impaired consciousness, déjà vu sensations, epigastric rising sensation, olfactory hallucinations and motor automatisms, e.g. lip smacking.2 By contrast, epilepsy refers to the clinical syndrome of recurrent seizures, and implies a pathological state that predisposes to further future seizures. Hence having one, or even a single cluster of seizures (i.e. over a few days) does not in itself qualify as epilepsy, since these seizures may have been due to a febrile illness or drug intoxication that themselves later resolve. By contrast, having at least two seizures, separated by at least a few weeks, is usually sufficient to signify epilepsy. Only one-third of people having seizures develop chronic epilepsy.

Pathology and seizure types

Epilepsy affects 0.5–1% of the general population, while the lifetime risk of having a seizure is 3–5 %. There are both multiple causes and multiple seizure types.3 Approximately half of adult epilepsy is believed to be due to genetic or early developmental causes, although the exact nature of these – e.g. sodium channel mutations or cerebral palsy – are determined in only a small minority. The other half of adult epilepsy is due to acquired causes, such as alcohol, stroke, traumatic head injury or brain tumours.

The cause of epilepsy determines the seizure type. Genetic causes (i.e. ‘primary’) predispose to generalised seizures4 characterised by tonic–clonic or absence seizures (lapses of consciousness lasting seconds), myoclonus (random limb jerk at other times), photosensitivity (seizures triggered by flashing lights), EEG showing a 3-Hz spike-and-wave pattern, and a normal MRI brain. Conversely, where focal brain injury has occurred, e.g. brain tumour or stroke, and the brain scan is abnormal, focal epileptic discharges occur within the brain leading to a partial seizure – i.e. when only a narrow set of brain functions are disturbed, e.g. causing single limb jerking (implying motor cortex involvement). Importantly, partial seizures can propagate very quickly to become a ‘secondary generalised seizure’. Another common cause of adult-onset partial epilepsy is maldevelopment of the medial temporal lobes (‘mesial temporal sclerosis’) believed to be due to injury, e.g. hypoxia or infection, during fetal or early childhood life, and sometimes apparent as atrophic hippocampi and amygdala on high-resolution MRI.

Principles of management

• Identification of underlying cause and treatment of this where possible, e.g. cerebral neoplasm or arteriovenous malformation.

• Educate the patient about the disease, duration of treatment and need for compliance.

• Counselling the patient about avoiding harm from seizures, e.g. driving regulations, swimming or bathing alone and climbing, as well as other dangerous pursuits, to be avoided.

• Avoid precipitating factors, e.g. alcohol, sleep deprivation, stroboscopic light.

• Anticipate natural variation, e.g. fits may occur particularly or exclusively around menstruation in women (catamenial5 epilepsy).

• For most cases with recurrent seizures, an antiepileptic drug is prescribed with subsequent monitoring and adjustment of dosage or drug type (see below).

• Consider surgical therapies in patients with refractory seizures, e.g. vagal nerve stimulation, temporal lobectomy. For childhood refractory epilepsy, a ketogenic diet – i.e. high fat:carbohydrate ratio – is useful, as ketone bodies are antiepileptogenic.

• Acute treatment of generalised convulsive seizures consists of ensuring the patient lies on the floor away from danger, and is postictally manoeuvred into the recovery position. If a seizure continues for more than a few minutes, rectal or buccal diazepam or intranasal midazolam can be given. If convulsive seizures last for more than 5 min, patients should be transferred to hospital for consideration of intravenous benzodiazepine and phenytoin.

Practical guide to antiepilepsy drugs

1. When to initiate. Following a single seizure the chance of a further seizure is approximately 25% over the following 3 years. Furthermore, only 33% of single-seizure patients develop chronic epilepsy. Hence the majority of first seizures are provoked by a reversible, and often recognisable, factor, e.g. infection, drug toxicity, surgery. For these reasons, following a single seizure6 anticonvulsants are not generally prescribed, whereas after two or more distinct seizure episodes (i.e. with more than a few weeks apart between episodes), they generally are prescribed. Immediate treatment of single or infrequent seizures does not affect long-term remission but introduces the potential for adverse effects. Patients need to be made aware that anticonvulsant therapy reduces harm caused by generalised seizures, and may also reduce the risk of sudden death in epilepsy (SUDEP), that usually occurs during sleep.

2. Monotherapy. Although the choice of anticonvulsants is large (approximately 20), first–line therapy is generally restricted to one of only a few drugs that have a good track record and are relatively safe and well-tolerated. Initial therapy is confined to a single drug (i.e. monotherapy) that is usually effective in stopping seizures or at least significantly decreasing their frequency. The majority of epilepsy patients (70%) can remain on monotherapy for adequate control, although sometimes the choice of monotherapy may need to be switched to allow for tolerance or optimisation of seizure control. As the number of single anticonvulsants tried increases, the incremental likelihood that any new one will offer a significant reduction in seizures decreases: from 50% response to a first drug, to an additional 30% to a second drug, to an extra 10% to a third drug, and less than 5% for any subsequent drug tried.

3. What drug to initiate. For older types of anticonvulsants, knowing the seizure type – i.e. whether partial or primary generalised – mattered, because in certain cases the spectrum of seizure efficacy is limited, and, moreover, certain seizure types can be worsened by ill-chosen drugs. For example, carbamazepine is an effective first-line therapy for partial seizures but may worsen primary generalised, absence or myoclonic seizures; similarly phenytoin can worsen absence and myoclonic seizures. Ethosuximide, by contrast, is only effective in primary generalised, and not partial, seizures.

More modern anticonvulsants, by contrast, are in general effective over a much broader range of seizure types allowing for more confidence of use even when seizure type is uncertain. Thus sodium valproate, lamotrigine and levetiracetam are active against both primary and secondary generalised epilepsy, and being relatively well tolerated, account for most first-line prescriptions. In one head-to-head study comparing popular first-line therapies for generalised and partial seizures, lamotrigine was generally tolerated better than other drugs, while valproate was the most efficacious; carbamazepine and topiramate were more likely to cause unwanted effects.7

4. Women of reproductive age and children. These categories of patients prompt selection of particular drugs and avoidance of others (see below for more detail).

5. Polytherapy. If a trial of three or so successive anticonvulsants (i.e. taken as monotherapy at adequate dosage for at least several months) does not control a patient’s epilepsy, it may be worthwhile trying dual therapy. Polytherapy offers the theoretical advantage of controlling neuronal hyperexcitability by more than one mechanism, that can be synergistic. In reality, increasing polytherapy often adheres to the law of diminishing returns, viz. the proportion of uncontrolled patients who show a positive response decreases at each addition of drug number And at the same time, adverse effects become more likely.

6. Abrupt withdrawal. Effective therapy must never be stopped suddenly, as this is a well-recognised trigger for status epilepticus, which may be fatal. But if rapid withdrawal is required by the occurrence of toxicity, e.g. due to a severe rash or significant liver dysfunction, a new drug ought to be started simultaneously. The speed by which the dose of a new drug can be raised varies according to drug type and urgency.

7. Circumstantial seizures. In cases where fits are liable to occur at a particular time, e.g. the menstrual period, adjust the dose to achieve maximal drug effect at this time or confine drug treatment to this time. For example, in catamenial epilepsy, clobazam can be useful given only at period time.

Once treatment is stable, patients should keep to a particular proprietary brand as different brands of the same generic agent (e.g. carbamazepine) may exhibit varying pharmacokinetics.

Dosage and administration

The manner in which drug dosing is initiated depends on: (1) the drug type, and (2) the frequency and severity of the patient’s seizures (i.e. the relative urgency with which therapeutic levels are reached). Phenytoin and phenobarbital allow for a rapid loading (within 24 h); valproate, levetiracetam and oxcarbazepine allow for escalation over days or a few weeks, whilst lamotrigine and carbamazepine require gradual escalations over many weeks. If seizures are infrequent at the time of presentation, e.g. every few weeks, antiepileptics should generally be started at their lowest dose, with small increments made every 1–2 weeks. In this way, the risk of unwanted effects, especially dizziness or ‘feeling drunk’ are minimised. A slow introduction of lamotrigine is also essential to reduce the risk of rash or more severe hypersensitivity reactions, Most drugs have a generally recognised maintenance dose range; the lowest dose within this range that achieves a reasonable degree of seizure control should be established. Monitoring of blood concentrations is helpful in guiding dosage of carbamazepine, phenytoin and phenobarbital, but not other anticonvulsants.

Failure to respond

In patients who continue fitting in spite of the recommended maintenance dose range having been reached, there are numerous possible explanations:

• Non-compliance, diarrhoea and vomiting, patients instructed to be ‘nil by mouth’ (revealed by measuring blood concentrations of drug).

• Inadequate dosing, including the possibility of drug interaction, e.g. another drug reducing the effective dose of the anticonvulsant by hepatic enzyme induction.

• Pregnancy also causes hepatic induction, and reduces the effective dose of lamotrigine.

• Increase in the severity of an underlying disease, e.g. enlargement of a brain tumour, or new disease.

• Drug resistance, e.g. genetic polymorphisms in hepatic cytochromes (such as CYP 2 C9) that metabolise drugs, sodium channel subunit SCN1A, or the P glycoprotein drug transporter (ABCB1 gene) that expels drugs from neurones.

Drug withdrawal

If patients have remained seizure-free for more than a few years, it is reasonable to consider withdrawal of antiepilepsy drug therapy.8,9 The prognosis of a seizure disorder is determined by:

• Type of seizure disorder – benign rolandic epilepsy, solely petit mal or grand mal seizures confer a high chance of full remission, whereas juvenile myoclonic epilepsy, temporal or frontal lobe epilepsies often require lifelong treatment.

• Time to remission – early remission carries a better outlook.

• Number of drugs required to induce remission – rapid remission on a single drug is a favourable indicator for successful withdrawal.

• MRI brain scan findings – presence of an underlying lesion predicts difficult control.

• EEG findings – epileptogenic activity is a predictor of poor outcome for drug withdrawal.

• Associated neurological deficit or learning difficulty – control is often difficult.

• Length of time of seizure freedom on treatment – the longer the period, the better the outlook.

Discontinuing antiepilepsy medication is associated with about 20% relapse during withdrawal and a further 20% relapse over the following 5 years; after this period relapse is unusual. A general recommendation is to withdraw the antiepilepsy drug over a period of 6 months. If a fit occurs during this time, full therapy must recommence until the patient has been free from seizures for several years.

Driving regulations and epilepsy

Multiple driving regulations exist that relate epilepsy (and neurological conditions predisposing to epilepsy, e.g. brain surgery) to stipulations regarding driving (according to the UK Driving Vehicle Licensing Authority). These rules are based upon statistical data relating specific diagnoses or clinically described events (e.g. blackouts without warning) with the risk of future blackout and/or car accidents. Epileptic patients who wish to continue driving therefore need to contact their national driving licensing body so that each case can be judged on its merits; while waiting for a decision, patients must not drive.

In general in the UK, patients suffering seizures, or blackouts of undetermined cause, are not permitted to drive a car for 1 year from their last attack. Exceptions include: patients who have had exclusively nocturnal seizures for at least 3 years, or patients in whom a single seizure has occurred more than 6 months earlier, providing they have a normal brain scan and EEG; these groups are usually permitted to drive.

Pregnancy and epilepsy

Pregnancy worsens epilepsy in about a third of patients, but also improves epilepsy in another third. One of the main concerns in this patient group is that all anticonvulsants increase the chance of teratogenicity slightly, with valproate, phenytoin and phenobarbital carrying most risk. The toxicological hazard must be weighed against the risk of seizures which themselves can be harmful to mother and unborn baby, and are likely to worsen if anticonvulsants are discontinued. For instance, the risk of major congenital anomalies in the fetus is 1% for healthy mothers, 2% in untreated epileptic mothers (in observational studies, so generally not severe epileptics), and 2–3% in mothers on epilepsy monotherapy. Valproate, by contrast, has been associated with a malformation rate of approximately 10%,10 while 20–30% of children are subsequently found to have mild learning disabilities or require ‘special needs’ education. The UK maintains a national drug monitoring register of all pregnant women taking antiepileptic drugs.

Doctor–patient discussions about what antiepileptic drug, if any, and at what dose, are required pre-conception. Advance planning is preferred because:

• neural tube defects are related to deficiencies in folic acid stores before pregnancy, so that antiepileptic drugs that affect stores, e.g. valproate, can be avoided, and folic acid 5 mg per day given for several months in advance, and

• adjustments in dose and type of drug can be avoided in the early stages of pregnancy as there is a higher risk of toxicity and seizure breakthrough during this critical phase of fetal development. In general, patients having seizures with blackouts should be on an effective dose of an anticonvulsant, because of the risks of anoxia, lactic acidosis and trauma.

During pregnancy, liver enzymes become induced, which has implications in epilepsy. Firstly, patients on lamotrigine before conception require a gradually increased dose during the pregnancy, to cope with enhanced catabolism (lowering lamotrigine plasma concentration). Secondly, enzyme-inducing drugs often aggravate a relative deficiency of vitamin K that occurs in final trimester women, predisposing to postpartum haemorrhage; vitamin K is therefore given by mouth during the last 2 weeks of pregnancy.

Breast feeding

Antiepilepsy drugs pass into breast milk: phenobarbital, primidone and ethosuximide in significant quantities, phenytoin and sodium valproate less so. There is a risk that the baby will become sedated or suckle poorly but provided there is awareness of these effects, the balance of advantage favours breast feeding while taking antiepilepsy drugs.

Epilepsy and oral contraceptives

Many antiepileptic drugs induce steroid-metabolising enzymes and so can cause hormonal contraception to fail. This applies to: carbamazepine, oxcarbazepine, phenytoin, barbiturates, and topiramate. Patients receiving any of these drugs and wishing to remain on the combined contraceptive pill need a higher dose of oestrogen (at least 50 micrograms/day), which they should take back-to-back for three cycles (‘tri-cycling’), before stopping for 3 days, and then repeating the pattern. Even this method offers a suboptimal level of contraception, and a non-oestrogenic form of contraception is preferred. Lamotrigine is not an enzyme inducer but can decrease levonorgestrel plasma concentration through other mechanisms.

Epilepsy in children

Seizures in children tend to arise from different sets of causes (usually genetic or cerebral palsy) from those arising in adults, and can carry either very good long-term outcomes, e.g. spontaneous resolution, or, less commonly, bad outcomes, e.g. gradual deterioration. Treatments are similar to those used in adults, but certain seizure types necessitate drugs that are rarely used in adults, e.g. ethosuximide for absence seizures, or vigabatrin for refractory partial seizures (partly because children may become irritable or more cognitively impaired with drugs such as valproate and phenobarbital).

Febrile convulsions. Seizures triggered by fever due to any cause (typically viral infection) are common in young children (3 months – 5 years old). Two-thirds of such children will have only one attack, and in total only 2% will progress to adult epilepsy. For this reason, continuous prophylaxis is seldom given, except for those cases where atypical febrile seizures occur, e.g. lasting for more than 15 min, have focal features or recur within the same febrile illness. Long-term antiepileptic therapy is avoided where possible in children due to recognised adverse effects of most such drugs on learning and social development. Febrile convulsions may be treated on an ad hoc basis by issuing parents with a specially formulated solution of diazepam for rectal administration (absorption from a suppository is too slow) that allow for easy and early administration. Febrile convulsions may be prevented by treating febrile children with paracetamol and cooling with sponge soaks.

Status epilepticus

Status epilepticus refers to continuous or repeated epileptic seizures for more than 30 min. It often arises in patients already known to have epilepsy, in whom antiepileptic drug therapy has been inappropriately withdrawn or not taken. It can be the first presentation of epilepsy, due to an acquired brain insult, e.g. viral encephalitis.

Status epilepticus is a medical emergency. In the first instance, general resuscitation (airway control, oxygen, intravenous saline, etc.) is required. Treatment of seizures is initially with the intravenous benzodiazepine lorazepam (0.5–4 mg). Lorazepam is preferred to diazepam because it has a longer effective t½ and is less lipophilic and so accumulates less in fat, causing less delayed toxicity (hypotension and respiratory depression). The speed of action of lorazepam and diazepam are both rapid. Phenytoin i.v. may be started simultaneously to suppress further seizures, given as a loading dose (15–20 mg/kg body-weight) over 1 h, while monitoring ECG and blood pressure for arrhythmias and hypotension. Subsequently a maintenance dose of approximately 300 mg/day is given and adjusted according to plasma levels (corrected for albumin). Phenobarbital may be given i.v. as a third-line drug when seizures continue. At this point, the level of sedation (due both to seizures and drugs) is usually sufficiently great to warrant general anaesthesia, e.g. with propofol or thiopental, combined with intubation, mechanical ventilation and intensive care management. Pharmacologically induced sedation is removed periodically to allow for assessment of seizure activity (both from clinical observations and using EEG).

If resuscitation facilities are not immediately available, diazepam by rectal solution is a useful option. In some cases, midazolam (nasally) may be preferred, e.g. in children or those with severe learning disability. Intravenous benzodiazepines should not be used if resuscitation facilities are unavailable as there is risk of respiratory arrest.

Always investigate and treat the cause of a generalised seizure. Give aciclovir i.v. if viral encephalitis is suspected or, if status is triggered by removing an antiepileptic drug, it must be re-instituted. Magnesium sulphate is the treatment of choice for seizures related to eclampsia (see also p. 125).11

Details of further management appear in Table 21.1.

Table 21.1 Treatment of status epilepticus in adults

Status Treatment
Early Lorazepam 4 mg i.v., repeat once after 10 min if necessary, or clonazepam 1 mg i.v. over 30 s, repeat if necessary, or diazepam 10–20 mg over 2–4 min, repeat once after 30 min if necessary
Established Phenytoin 15–18 mg/kg i.v. at a rate of 50 mg/min, and/or phenobarbital 10–20 mg/kg i.v. at a rate of 100 mg/min
Refractory Thiopental or propofol or midazolam with full intensive care support

Pharmacology of individual drugs

Modes of action

Antiepilepsy (anticonvulsant) drugs aim to inhibit epileptogenic neuronal discharges and their propagation, while not interfering significantly with physiological neural activity. They act by one of five different mechanisms given below. It is generally recommended that when more than one drug is needed to control seizures, then drugs chosen should be selected from different classes of action, both to target epileptogenesis at more than one control point (resulting in synergistic effects) and to reduce unwanted effects.

Decreases electrical excitability

Examples: phenytoin, carbamazepine, lamotrigine, lacosamide. These drugs reduce cell membrane permeability to ions, particularly fast, voltage-dependent sodium channels which are responsible for the inward current that generates an action potential. Receptor blockage is typically use-dependent, meaning that only cells firing repetitively at high frequency are blocked, which permits discrimination between epileptic and physiological activity. A further potential avenue for reducing neuronal depolarisation is to use a potassium channel opener, e.g. retigabine.

Decreases synaptic vesicle release

Examples: calcium channel blockers: e.g. gabapentin; levetiracetam. Calcium channel activation is required for synaptic vesicle release and so calcium channel blockers may act by decreasing synaptic transmission, and therefore activity propagation, especially during periods of high burst activity. Calcium channel blockade may also reduce excitoxicity – a pathological process by which repetitive neuronal depolarisation leads to calcium entry into neurones, with resultant cell death. Gabapentin and pregabalin are specific for high-voltage-gated P/Q type calcium channels, whereas ethosuximide is specific for low-voltage-gated T-type calcium channels. Other drugs such as lamotrigine, valproate and topiramate block calcium channels as just one of many cellular actions.

Levetiracetam uniquely inhibits synaptic vesicle protein 2A (SV2A), thereby reducing synaptic vesicle recycling.

Enhancement of gamma-aminobutyric acid (GABA) transmission

Examples: benzodiazepines, phenobarbital, valproate, vigabatrin, tiagabine.12 By enhancing GABA, the principal inhibitory transmitter of the brain, neuronal membrane permeability to chloride ions is increased, which secondarily reduces cell excitability. Benzodiazepines and barbiturates activate the GABA receptor via specific benzodiazepine and barbiturate binding sites.

Inhibition of excitatory neurotransmitters, e.g. glutamate

Examples: topiramate, felbamate. Glutamate inhibition both stops neuronal excitation in the short term, and excitotoxicity and cell death in the long term.

Other actions

Example: lacosamide, which as well as inhibiting sodium channel conductance, also targets a neuronal protein called ‘collapsin-response mediator protein 2’ (CRMP2).

The drugs used in the treatment of various forms of epilepsy are shown in Table 21.2.

Table 21.2 Drugs of choice for the treatment of epilepsy

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Sodium channel blockers

Carbamazepine

Carbamazepine (Tegretol) acts predominantly as a voltage-dependent sodium channel blocker, thereby reducing membrane excitability.

Pharmacokinetics

Carbamazepine is metabolised to an epoxide; both compounds possess antiepileptic activity but the epoxide may cause more adverse effects. The t½ of carbamazepine falls from 35 h to 20 h over the first few weeks of therapy due to autoinduction of hepatic enzymes. For this reason, the dose of carbamazepine is gradually increased, over many weeks, with the expectation that plasma levels will remain within a therapeutic range over this time. Other drugs relying on hepatic metabolism may also have their effective plasma level decreased due to induction secondary to carbamazepine, e.g. glucocorticosteroids, contraceptive pill, theophylline, warfarin, as well as other anticonvulsants, e.g. phenytoin. The metabolism of carbamazepine itself may be inhibited by valproate and to a lesser extent, by lamotrigine and levetiracetam (thereby raising carbamazepine plasma levels).

Uses

Carbamazepine is effective for partial seizures with or without secondary generalisation. It is also first-line treatment for trigeminal neuralgia. It is not recommended for primary generalised seizures (especially myoclonic epilepsy), which can be worsened by it.

Adverse effects

follow from the fact that it depresses electrical excitability. In the central nervous system (CNS) this results in cerebellar and brainstem dysfunction (causing dizziness, diplopia, ataxia, nausea and reversible blurring of vision), as well as drowsiness; in the heart this can result in depression of cardiac atrioventricular (AV) conduction. Rashes, including serious reactions such as Stevens–Johnson syndrome, tend to be more of a problem for this drug than other anticonvulsants. A further set of issues arise from the hepatic induction property of carbamazepine: both osteomalacia and folic acid deficiency may occur due to enhanced metabolism of vitamin D and folic acid, respectively. Elderly patients receiving any enzyme-inducing drug should be screened for osteoporosis with bone-density scanning, and treated with bisphosphonates if necessary. Other unwanted effects can include gastrointestinal symptoms, headache, blood disorders, e.g. leucopenia, syndrome of inappropriate antidiuretic hormone (causing hyponatraemia), liver and thyroid dysfunction. Carbamazepine impairs cognitive function less than phenytoin.

Oxcarbazepine

Oxcarbazepine, like its analogue carbamazepine, acts by blocking voltage-sensitive sodium channels. It is rapidly and extensively metabolised in the liver; the t½ of the parent drug is 2 h, but that of its principal metabolite (which also has therapeutic activity) is 11 h. Unlike carbamazepine, it does not form an epoxide, which may explain its lower frequency of unwanted effects; these include dizziness, headache and hyponatraemia, and selective cytochrome enzyme induction (potentially causing failure of oestrogen contraception). Monitoring of plasma sodium may be necessary in the elderly and patients on diuretics.

Oxcarbazepine is used either as monotherapy or as add-on therapy for partial seizures. The speed with which the dose can be escalated is generally quicker than that for carbamazepine.

Eslicarbazepine

This drug is an enantiomer of a hydroxyl derivative of oxcarbazepine, and has an efficacy spectrum similar to carbamazepine and oxcarbazepine, i.e. it is effective for partial epilepsy with or without secondary generalisation. It appears to have fewer of the unwanted effects of its parent drugs, and its dose can be raised to an effective range more quickly (within 1–2 weeks); only two dose are available.

Phenytoin

Phenytoin (diphenylhydantoin, Epanutin, Dilantin) acts principally by blocking neuronal voltage-dependent sodium ion channels; this action is described as membrane stabilising, and discourages the spread (rather than the initiation) of seizure discharges.

Pharmacokinetics

Phenytoin provides a good example of the application of pharmacokinetics for successful prescribing.

Saturation kinetics. Phenytoin is hydroxylated extensively in the liver, a process that becomes saturated at about the doses needed for therapeutic effect. Thus phenytoin at low doses exhibits first-order kinetics but saturation or zero-order kinetics develop as the therapeutic plasma concentration range (10–20 mg/L) is approached, i.e. dose increments of equal size produce a disproportional rise in steady-state plasma concentration. Thus dose increments should become smaller as the dose increases (which is why there is a 25 mg capsule), and plasma concentration monitoring is advisable. Phenytoin given orally is well absorbed, allowing for achievement of therapeutic range concentrations within 24 h (as may be required in patients with frequent seizures).

Enzyme induction and inhibition. Phenytoin is a potent inducer of hepatic enzymes that metabolise other drugs (carbamazepine, warfarin), dietary and endogenous substances (including vitamin D and folate), and phenytoin itself. This latter causes a slight fall in steady-state phenytoin concentration over the first few weeks of therapy, though this may not be noticeable with progressive dose increments. Drugs that inhibit phenytoin metabolism (causing its plasma concentration to rise) include sodium valproate, isoniazid and certain non-steroidal anti-inflammatory drugs.

Uses

The main role of phenytoin in modern practice is in the emergency control of seizures, including status epilepticus, because of its reliable antiepileptic effect, and because an effective treatment dose can be loaded rapidly. It may also be used to prevent partial seizures with or without secondary generalisation, but is not generally used first line in this regard because of its adverse effect profile (see below). It may worsen primary generalised epilepsies, such as absence or myoclonic seizures, and so is not used for these conditions unless status epilepticus occurs.

Other uses

The membrane-stabilising effect of phenytoin finds use in cardiac arrhythmias, trigeminal neuralgia and myotonic dystrophy (an inherited disorder in which skeletal muscle becomes over-excitable).

Adverse effects

of phenytoin are multitudinous, especially with years of therapy, which fact, together with its narrow therapeutic range, is why phenytoin is not favoured for long-term therapy. Unwanted effects related to the nervous system include cognitive impairment, cerebellar ataxia, dyskinesias, tremor and peripheral neuropathy. Cutaneous reactions include rashes (dose related), coarsening of facial features, hirsutism, lupus-like syndrome, gum hyperplasia (due to inhibition of collagen catabolism), and Dupuytren’s contracture (caused by free-radical formation). Haematological effects include: macrocytic anaemia due to increased folate metabolism (treatable with folate supplementation), IgA hypergammaglobulinaemia, lymphadenopathy and pseudolymphoma. Osteomalacia due to increased metabolism of vitamin D occurs after years of therapy and calls for bone-density scanning.

Intravenous phenytoin is associated with cardiac depression, distal ischemia (‘purple-glove syndrome’) and, if drug extravasation occurs, local but severe ulceration.

Overdose

causes cerebellar symptoms and signs, coma, apnoea or even paradoxically, seizures. The patient may remain unconscious for a long time because of saturation kinetics, but will recover with standard care.

Fosphenytoin,

a prodrug of phenytoin, is soluble in water, and easier and safer to administer. Its conversion in the blood to phenytoin is rapid, and it may be used as an alternative to phenytoin for status epilepticus.

Lamotrigine

Lamotrigine (Lamictal) stabilises pre-synaptic neuronal membranes by blocking voltage-dependent sodium and calcium channels, and reduces the release of excitatory amino acids, such as glutamate and aspartate. The t½ of 24 h allows for a single daily dose.

Lamotrigine is a favoured first-line drug for partial and generalised epilepsy, being both effective and well tolerated. It is also used in bipolar disorder as a mood stabiliser. It has few cognitive or sedating effects relative to other antiepileptic drugs.

It causes rash in about 10% of patients, including, rarely, serious reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis (potentially fatal). The risk of rash lessens if treatment begins with a low dose and escalates slowly, whereas concomitant use of valproate, which inhibits lamotrigine metabolism, adds to the hazard. Carbamazepine, phenytoin and barbiturates accelerate the metabolic breakdown of lamotrigine, thereby prompting an increase in the prescribed lamotrigine dose. Other specific unwanted effects of lamotrigine include insomnia and headache, the latter effect distinguishing it from valproate and topiramate that are used for migraine prevention. Insomnia may respond to lamotrigine taken once daily in the morning.

Lacosamide

Lacosamide (Vimpat) selectively facilitates a ‘slow-inactivating’ component of the voltage-gated sodium channel, which predominates under high-frequency neural activity (e.g. seizures), without affecting ‘fast-inactivating’ sodium channel states that characterise more standard patterns of neural firing frequency. This offers seizure control while reducing common antiepileptic unwanted effects such as sedation or cognitive impairment. Lacosamide also targets a neuronal protein called ‘collapsin-response mediator protein 2’ that is involved in neuronal differentiation, axonal outgrowth and gene expression. Whether this property confers additional disease-modifying properties to lacosamide (as distinct from its antiseizure property) is unknown.

Lacosamide is effective in refractory partial epilepsy, and has the advantage of being available as a syrup and i.v. formulation. The t½ is 13 h, and unwanted effects include dizziness, nausea, headache and prolongation of the PR interval on the ECG.

GABA-potentiators

Sodium valproate

Sodium valproate (valproic acid, Epilim) acts on sodium and calcium channels, as well as GABAA receptors, the latter action by virtue of inhibiting GABA transaminase (thereby increasing GABA levels, and hence neuronal inhibition).

Sodium valproate is metabolised extensively in the liver (t½ 13 h). It is a non-specific metabolic inhibitor, both of its own metabolism, and that of other anticonvulsants including lamotrigine, phenytoin and carbamazepine. To avoid toxicity, patients taking valproate and starting such drugs as second-line therapy should receive lower does of the second anticonvulsant. By contrast, the metabolism of valproate is accelerated by enzyme-inducing drugs, e.g. carbamazepine.

Sodium valproate is effective for both generalised and partial epilepsies, as well as for migraine prevention and mania (for which it acts as a mood stabiliser).

Adverse effects

The main concerns, particularly to women, are weight gain, impaired glucose tolerance, teratogenicity (see p. 119), polycystic ovary syndrome and loss of hair, which grows back curly.13 Nausea and dyspepsia may be a more general problem, ameliorated by using an enteric-coated formulation. Some patients exhibit a rise in liver enzymes, which is usually transient and without sinister import, but patients should be closely monitored until the biochemical tests return to normal as, rarely, liver failure occurs (risk maximal at 2–12 weeks); this is often indicated by anorexia, malaise and a recurrence of seizures. Other reactions include pancreatitis, coagulation disorder due to inhibition of platelet aggregation or thrombocytopenia, and hyperammonaemia that can present with acute confusion.

Barbiturates

Some of the earliest effective antiepileptic drugs came from the barbiturate family: namely, phenobarbital (t½ 100 h), and primidone (Mysoline), the latter being metabolised largely to phenobarbital, i.e. it is a prodrug. The main use of phenobarbital is for status epilepticus because of its potent antiepileptic effect and the ability to give it intravenously. It is also used as an adjunct for long-term control of refractory partial seizures, but suffers from a high level of unwanted effects (especially sedation), including cardiac or respiratory arrest if overdosed, and dependency/addiction, and interactions (enzyme induction). Withdrawal from barbiturates must be performed very slowly (typically over months) because of a high risk of inducing seizures.

Benzodiazepines

Lorazepam and diazepam are first-line drugs for rapid control of acute seizures, but are not recommended for long-term prophylaxis due to unwanted effects: mainly sedation, tolerance and addiction. Clonazepam (Rivotril) (t½ 25 h) is used mainly as an adjunct in myoclonic epilepsy due to its additional effects as a muscle relaxant. Clobazam finds use as an oral method for establishing rapid seizure control, e.g. in patients with a first presentation of frequent symptomatic seizures, and may be effective for drug-resistant partial seizures. Its effectiveness may wane after a few months due to tolerance. Both clonazepam and clobazam should be avoided in patients with anxiety or a history of drug addiction, due to risk of addiction or misuse.

Vigabatrin

Vigabatrin (Sabril) (t½ 6 h) is structurally related to the inhibitory CNS neurotransmitter GABA, and acts by irreversibly inhibiting GABA-transaminase so that GABA accumulates. GABA-transaminase is resynthesised over 6 days. The drug is not metabolised and does not induce hepatic drug-metabolising enzymes.

Vigabatrin is effective in partial and secondary generalised seizures that are not satisfactorily controlled by other anticonvulsants, and in infantile spasms, as monotherapy. It worsens absence and myoclonic seizures.

Unwanted effects from drugs sometimes become apparent only following prolonged use, and vigabatrin is a case in point. Vigabatrin had been licensed for a number of years before there were reports of visual field constriction (up to 40% of patients), an effect that is insidious and leads to irreversible tunnel vision. Consequently, it is now indicated only for refractory epilepsy, and patients taking it require 6-monthly visual field monitoring. Other adverse effects include confusion, psychosis and weight gain.

Calcium channel blockers

Gabapentin

Gabapentin (Neurontin) is an analogue of GABA that is sufficiently lipid soluble to cross the blood–brain barrier. Its main action may be through inhibition of voltage-gated calcium channels, especially via interactions with the α2δ subunit. It also facilitates GABAergic transmission, as its name suggests. It is excreted unchanged and, has the advantage of not inducing or inhibiting hepatic metabolism of other drugs.

Gabapentin is effective only for partial seizures and secondary generalised epilepsy. It is also beneficial for neuropathic pain, and anxiety.

Gabapentin may cause somnolence, unsteadiness, dizziness and fatigue, although the likelihood of these decreases if dosing is started very low (e.g. 100 mg three times per day) and increased gradually (e.g. to 900 mg three times per day).

Pregabalin

Pregabalin (Lyrica) acts similarly to gabapentin, and is sometimes used in place of gabapentin when the latter has been ineffective for refractory partial seizures. Its main adverse effects are confusion, dizziness and weight gain. As well as being an antiepileptic it is commonly used against neuropathic pain, and it possesses anxiolytic properties.

Ethosuximide

Ethosuximide (Zarontin) (t½ 55 h) is a member of the succinimide family that differs from other antiepilepsy drugs in that it blocks a particular type of calcium channel that is active in primary generalised epilepsies – especially absence seizures (petit mal) and myoclonic epilepsy. For this reason its main use is among children. Adverse effects include gastric upset, CNS effects, and allergic reactions including eosinophilia and other blood disorders, and lupus erythematosus.

Carbonic anhydrase inhibitors

Carbonic anhydrase inhibition reduces central nervous excitability, and is a property shared by topiramate, zonisamide and acetazolamide. Acetazolamide is rarely used now as an antiepileptic, but the other two find roles as adjuncts in partial epilepsy, as well as migraine. They also share common unwanted effects, namely weakness, anorexia, weight loss, depression, paraesthesia and renal stones (due to alkalosis).

Topiramate

Topiramate (Topamax), acts via various mechanisms, including carbonic anhydrase inhibition, voltage-gated sodium channel blockade, glutamate receptor blockade and enhancement of GABA activity The t½ of 21 h allows once-daily dosing; it is excreted in the urine, mainly as unchanged drug.

Topiramate is used for partial seizures, as well as for migraine prevention (a property it shares with valproate). Unlike valproate, which causes weight gain, topiramate causes weight loss (considered an advantage by many women). Other unwanted effects include cognitive impairment, e.g. naming difficulty, acute myopia and raised intraocular pressure.

Zonisamide

Zonisamide (Zomig) is a sulphonamide analogue that acts as a carboninc anhydrase inhibitor as well as blocking both sodium and T-type calcium channels. Its sodium channel blocking effect increases latency for neuronal recovery following inactivation. It may cause cognitive impairment, and carries a small risk of renal stones (< 1%). It generally finds use as an adjunct for refractory partial epilepsy, and may benefit patients with migraine.

Levetiracetam

Levetiracetam (Keppra) is unique in inhibiting synaptic vesicle protein 2A (SV2A), which secondarily reduces synaptic vesicle recycling. It is effective for both partial and generalised seizures, is relatively well tolerated, and appears not to interact with other drugs. It is also rapidly and completely absorbed after oral administration, and can reach maintenance dose relatively quickly. For these reasons, it has become increasingly popular as a first-line agent for many seizure types. Its therapeutic index appears to be high, with the commonest adverse effects being weakness, dizziness and drowsiness. Relatively specific unwanted effects of levetiracetam are emotional lability, behavioural disturbance and psychosis, and it should be used with caution in patients with prior mood disturbance, learning disability or head injury. It is metabolised predominantly in the kidney, making it a drug of choice in liver disease, but use at lower dose in renal impairment.

Parkinson’s disease and parkinsonism

Definitions

Parkinson’s disease 14 refers to a specific neurodegenerative disease characterised pathologically by intracellular accumulation of Lewy bodies and subsequent neuronal loss, predominantly within the substantia nigra pars compacta (SNpc)15 (see Fig. 20.3, p. 323). This midbrain nucleus normally provides dopaminergic input to the neostriatum (caudate and putamen), a critical aspect to motor control; one cardinal feature of Parkinson’s disease is that motor symptoms are reversible by administration of dopaminergic drugs. By contrast, parkinsonism refers to the clinical symptoms and signs of Parkinson’s disease (tremor, rigidity, bradykinesia and postural imbalance) that may arise either from Parkinson’s disease or one of its mimics; the latter include extensive small-vessel cerebral ischemia due to hypertension, neuroleptic drugs or other neurodegenerative disease such as multiple-systems atrophy (MSA) or Huntington’s disease. Note that parkinsonism due to conditions other than Parkinson’s disease generally responds poorly to dopaminergic therapies. Another distinguishing feature is that symptoms and signs of Parkinson’s disease, but not other causes, are often asymmetric.

Pathophysiology of Parkinson’s disease

Parkinson’s disease16 is the second commonest neurodegenerative disease after Alzheimer’s disease. Both diseases show an exponentially increasing risk with age, with the risk of Parkinson’s disease rising from approximately 0.2% under the age of 60 to 1% over the age of 60 and 4% of people over 85 years old. At the time that a clinical diagnosis first becomes apparent, radioactive dopamine uptake scans (sensitive to dopaminergic neurones) reveal that approximately 70% of the patient’s nigrostriatal dopaminergic neurones have already been lost. The implication of this finding is that treatments which might actually halt neuronal death (‘disease-modifying drugs’ as opposed to ‘symptomatic treatments’) should ideally be used in pre-symptomatic cases, e.g. as identified by dopamine scanning of the elderly, or relatives of affected individuals. In only about 15% of Parkinson’s cases is there a clear family history, and not more than 10% of cases are caused by a recognised gene mutation.17 Furthermore, no current treatment strategies have been shown to prevent disease progression, with the possible exception of rasagiline (see below). Rather, existing drug therapies primarily serve to enhance dopaminergic neurotransmission, whose deficiency underlies the main symptoms of Parkinson’s disease.

The pathophysiology of Parkinson’s disease, and its critical dependency upon dopamine, arises from an imbalance between two striatal–thalamic–cerebral cortical circuits (see Fig. 21.1). To understand this, it is useful to remember that under normal circumstances the globus pallidus INternus (GPi) INhibits thalamic communication with the frontal cortex, thereby braking voluntary movements. Since dopaminergic input to the striatum itself suppresses GPi (via a ‘direct’ pathway), loss of dopaminergic input allows the GPi to be overactive, thereby favouring inhibition of motor cortex, and so causing slowness of movement (bradykinesia) or freezing. Loss of dopamine also encourages an indirect pathway between striatum, subthalamic nucleus and GPi, which has the net effect of increasing GPi braking of movement. Therefore replacing dopamine can increase the relative contribution of the ‘direct’ relative to ‘indirect’ pathway. Furthermore, inducing neurosurgical stereotactic against the globus pallidus or subthalamus can offer a reduction in bradykinesia.18

image

Fig. 21.1 Schematic diagram of principal ‘volitional’ motor pathways, and their interaction with dopaminergic input in health (A) and in Parkinson’s disease (B). In A, normal dopaminergic tone favours the direct pathway which involves two sequential inhibitions, and so overall motor activation (i.e. a ‘−’ and ‘−’ making a ‘+’). In B, inadequate dopaminergic input favours the indirect pathway which involves three sequential inhibitions, and so overall motor inhibition (i.e. a ‘−’ and ‘−’ and ‘−’, making a ‘−’).

Adapted from Hauser RA, Eur Neurol. 2009;62(1):1–8.

Objectives of therapy

The main goal of treatment in Parkinson’s disease is to manage symptoms for as long as possible while minimising treatment-associated complications. The following principles motivate pharmacological strategies:

Enhancement of dopaminergic neurotransmission

This can be achieved by:

• Administering the dopamine precursor levodopa.

• Decreasing endogenous clearance and breakdown of dopamine by inhibiting monoamine oxidase (selegiline, rasagiline) or catechol-O-methyltransferase (entacapone, tolcapone).

• Stimulating dopamine receptors with agonists (ropinirole, pramipexole, cabergoline, rotigotine, apomorphine).

• Increasing pre-synaptic dopamine release (amantadine – this mechanism being only one of many by which this drug may be effective).

• Avoiding dopamine antagonists (especially traditional neuroleptics such as haloperidol, and antiemetics such as prochlorperazine).19

Note that the most seemingly obvious treatment strategy – ingesting or infusing dopamine – is ineffective because dopamine is rapidly metabolised in the gut, blood and liver by monoamine oxidase and catechol-O-methyltransferase. Furthermore, intravenously administered dopamine, or dopamine formed in peripheral tissues, is insufficiently lipid soluble to penetrate the CNS.

Pre-empting and treating levodopa-induced motor complications

Although levodopa is the most effective symptomatic treatment at all stages of the disease, its main drawback is that it usually results in treatment-induced fluctuations in motor control (‘on–off’ phenomena) and dyskinesias (i.e. excessive purposeless movements appearing as restlessness or rocking) by about 5–10 years from treatment initiation. One of the main factors associated with this complication is the total previous exposure to levodopa. Hence, in patients under approximately 70 years old, it is preferable to begin therapy with drugs other than levodopa, typically dopamine agonists or an MAO inhibitor. As the disease progresses, and symptoms become more severe in spite of non-levodopa therapies,20 levodopa is introduced, albeit in small doses, and increasing only very gradually so that only the smallest dose providing reasonable symptom relief is used. In patients over 70 years old, long-term dyskinesias are not so relevant, and moreover alternatives to levodopa, namely dopamine agonists, anticholinergics and amantadine, are more prone to cause confusion in this age group.

One of the theories for why motor fluctuations occur is related to the pulsatile nature by which levodopa is traditionally administered, which results in brain concentrations of levodopa (and dopamine) that rise and fall several times over a typical day. This is in contrast to the ‘physiological mode’ of dopamine release that is to a large extent tonic. Pulsatile, rather than smooth, administration of levodopa or dopamine agonists has been found in animal models to result in a gradual shortening of treatment response and dyskinesias. Consequently, methods which ‘smooth’ circulating levodopa concentrations may protect against eventual development of motor complications. Furthermore, a more sustained and steady supply of levodopa compared to conventional levodopa preparations can be achieved by using catechol-O-methyltransferase (COMT) inhibitors (entacapone or tolcapone) taken at the same time as levodopa, which has the effect of inhibiting dopamine catabolism, and so increasing dopamine availability. Using this strategy from the outset of Parkinson’s disease is controversial, with one study21 showing that levodopa-COMT inhibitors started as first-line therapy result in the sooner development of dyskinesias relative to standard levodopa therapy, possibly due to the fact that patients are exposed to higher effective concentrations of levodopa from early on.

Use of cholinergic drugs

One model of Parkinson’s disease conceptualises its pharmacology in terms of a relative imbalance between dopamine levels (too low) and acetylcholine levels (too high). This model explains the fact that cholinergic (muscarinic-type receptor) antagonists are also effective for tremor and rigidity (but not bradykinesia). More recently, cholinesterase inhibitors (especially rivastigmine) that increase acetylcholine levels have been used successfully for psychosis and dementia in Parkinson’s disease, without generally worsening the patient’s motor symptoms. This observation challenges any simplistic relationship between acetylcholine excess and Parkinson’s disease symptomatology.

Treatment of non-motor symptoms of Parkinson’s disease

Consultations with patients should include enquiry into non-motor symptoms that are associated with Parkinson’s disease, and, if present, treatments prescribed appropriately. These include: antidepressants for depression; laxatives for constipation; NSAIDs for pain (especially frozen shoulder); benzodiazepines for REM-sleep disorder; fludrocortisone for postural hypotension; cholinesterase inhibitors for psychosis or dementia; and salivary gland injections of botulinum toxin for sialorrhoea.

Recognition of conservative, surgical and co-morbidity therapies

Patients should be encouraged to keep mobile and exercise within their capabilities. Patients may need to be offered physiotherapy, speech therapy and occupational therapy, the latter of which will involve evaluation of potential risks in the environment, e.g. loose carpet, stairs. Patients with advanced disease who are not demented but suffer severe fluctuations may benefit from functional neurosurgery, the commonest procedure of which is bilateral deep brain electrical stimulation (DBS) of the subthalamic nucleus. Finally, coexisting morbidities, such as hypertension, diabetes and stroke, should be treated optimally, e.g. with antihypertensives, aspirin and statins, so as to reduce cerebral vascular injury, itself a cause of parkinsonism and dementia.

Drugs for Parkinson’s disease

Dopaminergic drugs

Levodopa and dopa decarboxylase inhibitors

Levodopa (‘dopa’ stands for dihydroxyphenylalanine) is the natural amino acid precursor of dopamine.22,23 It is readily absorbed from the upper small intestine24 by active amino acid transport, and traverses the blood–brain barrier by a similar active transport mechanism. Within the brain levodopa is decarboxylated (by dopa decarboxylase) to dopamine.

A major disadvantage is that levodopa is also extensively decarboxylated to dopamine in peripheral tissues, such that only 1–5% of an oral dose of levodopa reaches the brain. This means that large quantities of administered levodopa would be required for a meaningful antiparkinsonian effect. Such high doses cause a high rate of adverse effects caused by peripheral actions of levodopa and dopamine, notably nausea, cardiac arrhythmia and postural hypotension. Furthermore, high-dose levodopa inhibits gastric emptying and results in erratic delivery to the absorption site and fluctuations in plasma concentration. This problem has been largely circumvented by the development of peripheral decarboxylase inhibitors, which do not enter the CNS, and so selectively prevent peripheral conversion of levodopa to dopamine. Thus by combining levodopa with a peripheral decarboxylase inhibitor, unwanted effects due to peripheral dopamine production are minimised,25 while the proportion of ingested levodopa available for export into the CNS is maximised. Decarboxylase inhibitors are given in combination with levodopa in one of several formulations:

• Co-careldopa (carbidopa + levodopa in respective proportions 12.5/50, 25/100 and 50 mg/200 mg26) (Sinemet).

• Co-beneldopa (benserazide + levodopa in proportions 12.5/50, 25/100, 50 mg/200 mg) (Madopar).

• Co-careldopa with entacapone (carbidopa + levodopa + entacapone in same proportions as co-careldopa plus entacapone 200 mg with each tablet) (Stalevo).

These combinations produce similar brain concentrations of dopamine as achievable by levodopa alone, but with only 25% of the levodopa dose given.

The half-life of levodopa given with a decarboxylase inhibitor is 90 min, but its acute motor benefit lasts for 6 h or so, while there is also a lesser effect that lasts for approximately 2 weeks. The acute motor response to levodopa gradually reduces with long-term therapy, which may be related to a progressively diminishing reserve of healthy dopaminergic neurones which store levodopa and allow gradual conversion to dopamine.

Dose management

Levodopa preparations are introduced gradually and titrated according to individual response. Compliance is important. Abrupt discontinuation of therapy can lead to relapse, that when extreme can resemble the neuroleptic malignant syndrome. A controlled-release preparation of levodopa/carbidopa is occasionally used for patients with nocturnal symptoms or akinesia on awakening, when it is prescribed for use before bedtime. This preparation has not proven to be useful for daytime fluctuations, as it increases levodopa levels slowly, and so either controls symptoms too slowly to be useful, or increases the likelihood of end-of-dose dyskinesias. A soluble form of co-beneldopa is also available which can help provide rapid relief of akinesia, e.g. on awakening, and may be more appropriate in patients with dysphagia.

Adverse effects

As mentioned above, the main drawback to levodopa use is the eventual development of motor complications, with about 50% of treated patients developing them within 5 years (although they can occur after only a few months with high doses, especially in young patients), and nearly all patients developing some by 10 years. These take the form of motor fluctuations, e.g. ‘wearing off’, when the duration of clinical response shortens with chronicity of treatment, or ‘on–off fluctuations’, when the patient’s response to each levodopa dose consists of swinging abruptly between violent dyskinesias (during which the patient can move to a degree voluntarily, and so is ‘on’) and freezing (i.e. ‘off’). Dyskinesias typically take the form of continual writhing, rocking or fidgeting movements (also termed ‘chorea’) of the limb, trunk, neck, lips or tongue. These are believed to arise from both pre-synaptic (e.g. diminution of dopa decarboxylase reserves) and post-synaptic (e.g. receptor down-regulation) mechanisms. Dyskinesias can occur coincident with both the peak levodopa blood concentration (e.g. mid-dose), or at the onset and offset of each dose’s clinical effect (i.e. biphasic pattern).

Levodopa-induced dyskinesias are dose-related, so that in general the lowest dose of levodopa is used that achieves a reasonable degree of symptom relief. Further strategies that can be used against motor fluctuations/dyskinesias include: avoiding taking levdopa with meals;27 using small doses more often; slow-release levodopa preparations taken before sleep,28 and use of adjunctive medications such as dopamine agonists;29 amantadine,30 and COMT inhibitors (taken together with levodopa). In advanced cases, a nasoduodenal feeding tube can be placed that allows for continuous enteric infusion of levodopa gel (Duodopa), or patients can be offered deep brain stimulation. All these methods, in enhancing the effectiveness of dopamine or providing alternative antiparkinsonian methods, enable a reduction in levodopa dose, and so provide strategies in cases where dyskinesias are prominent.

In the short term, the main unwanted effect is nausea, which can be minimised by increasing dosage gradually, and offering patients a safe antiemetic such as domperidone (a peripherally confined dopamine antagonist) or cyclizine (an antihistamine), taken half an hour before levodopa. This is usually only required for the first few weeks. Postural hypotension may occur,31 although this can develop as a feature of advanced Parkinson’s disease due to degeneration of noradrenergic nuclei within the brainstem and cord. Agitation and confusion, including visual hallucinations, may occur but it may be difficult to decide whether these are due to drug or to disease. Mental changes are particularly likely in the elderly, especially when there is pre-existing dementia. If acute confusion occurs, other Parkinson’s drugs that cause confusion – antimuscarinics, amantadine or dopamine agonists should be progressively withdrawn before levodopa. Alternatively, the anticholinesterase rivastigmine, or atypical neuroleptics such as quetiapine or clozapine, may be of benefit.

Interactions

With non-selective monoamine oxidase inhibitors (MAOIs), the monoamine dopamine formed from levodopa is protected from destruction; it accumulates and also follows the normal path of conversion to noradrenaline/norepinephrine, by dopamine β-hydroxylase; severe hypertension results. This is not generally seen with the selective MAO-B inhibitors, selegiline or rasagiline, used as adjuncts in Parkinson’s disease.

Levodopa antagonises the effects of antipsychotics (dopamine receptor blockers). Tricyclic antidepressants are safe.

Dopamine agonists

These mimic the effects of dopamine, the endogenous agonist, which stimulates both of the main types of dopamine receptor, D1 and D2 (coupled respectively to adenylyl cyclase stimulation and inhibition). The D2 receptor is the principal target in Parkinson’s disease, although chronic D1-receptor stimulation potentiates response to the D2 receptor. The main advantage of dopamine agonists relative to levodopa is that they do not result in significant motor fluctuations or dyskinesias, which may relate to their longer t½, and to the fact that they are not dependent upon pre-synaptic conversion. Whether they also protect dopaminergic neurones by sparing the levodopa dose, and therefore reducing levodopa-induced oxidative damage, has been theorised but not proven. Conversely, dopamine agonists are not as effective as levodopa, and are limited by a higher rate of confusion and psychosis in the elderly. On the other hand, the problems of developing synthetic alternatives are:

• Reproducing the right balance of D1 and D2 stimulation (dopamine itself is slightly D1 selective, in test systems, but its net effect in vivo is determined also by the relative amounts and locations of receptors – which differ in parkinsonian patients from normal).

• Avoiding the undesired effects of peripheral, mainly gastric, D2 receptors.

• Synthesising a full, not partial, agonist.

Ergot derivatives (cabergoline, pergolide, lisuride, bromocriptine)

These first-generation dopamine agonists are now not preferred because of their high rate of unwanted effects. In particular, the ergotamine component can cause fibrosis of internal organs after chronic exposure, leading to serious complications (below).

Cabergoline and pergolide are the best known drugs of this class; the former has the advantage of being very long acting (a t½ of more than 80 h), allowing a once-daily (or even twice-weekly) administration. The t½ of pergolide is 6 h, longer than that of levodopa. Both drugs therefore allow for a more enduring ‘on’ phase, and can relieve parkinsonian symptoms through the night and on awakening. The ergotamine property of these drugs can cause Raynaud’s phenomenon (painful cold extremities due to vasospasm), while their additional properties as 5-hydroxytryptamine (5HT) type 2 receptor agonists can cause pleural effusions, pulmonary or retroperitoneal fibrosis (the latter causing renal failure due to ureteric obstruction). Additionally, cardiac valve fibrosis may result in valvular incompetency, e.g. aortic regurgitation or pulmonary valve regurgitation (the latter a very rare valvular abnormality otherwise). These effects are also seen with chronic amfetamine use, e.g. dexfenfluramine (antiobesity drugs), possibly through effects on similar receptors. Consequently, patients who previously received ergot derivatives are now treated with non-ergot derivatives. In those patients who require ergotamine dopamine agonists (because non-ergotamine equivalents may be less effective), screening for potential complications is required, e.g. by measuring plasma creatinine and performing echocardiograms 6-monthly.

Bromocriptine

is a D2-receptor agonist and a weak α-adrenoceptor antagonist. It is commonly used to suppress the production of prolactin in patients with prolactinomas (pituitary tumours) but now only rarely for Parkinson’s disease because nausea, vomiting and postural hypotension are more prominent than with more modern dopamine agonists. Pleural effusions and retroperitoneal fibrosis may also occur with prolonged use.

Non-ergot dopamine agonists

(ropinirole, pramipexole, rotigotine). These drugs are currently preferred as first-line therapy in newly diagnosed patients under the age of 70 years old. Beyond this age group, the long-term complications of levodopa are not felt to be so relevant (and are milder in older-onset Parkinson’s patients) allowing for levodopa use from the outset. Furthermore, psychosis32 or confusion (unwanted effects of all dopamine agonists) are more likely in elderly patients taking these drugs.

Both ropinirole and pramipexole are relatively selective dopamine 2 receptor agonists, and are generally more effective against tremor than other symptoms. Both drugs are started at low dose and increased over weeks or months, to a maintenance dose (e.g. ropinirole starts at 0.75 mg/day and typically is increased to 9 mg/day over 9 weeks). The relatively short t½ of these drugs necessitates thrice daily administration but formulations that allow once-daily administration are available. The dopamine agonist rotigotine can be used daily as a transdermal patch, and is particularly convenient in Parkinson’s patients with dysphagia.

Apart from psychosis in elderly patients, the other notable unwanted effects of the non-ergot dopamine agonists are: postural hypotension, ankle oedema, daytime somnolence (including sudden sleep attacks in a minority of patients33), and impulse-control disorders in about 15%, including punding,34 hypersexuality, gambling, eating binges and compulsive shopping. Some of these behaviours may be more likely in Parkinson’s disease patients, independent of a treatment effect, due to a dysregulated dopamine-prefrontal reward system. Where obsessionality develops on dopamine agonist therapy, this usually occurs in patients already taking a high daily levodopa dose, and indeed can lead to addiction and patient-initiated escalation of drug doses. The approach in these cases is gradually to withdraw the dopamine agonist.

Apomorphine

is a derivative of morphine with structural similarities to dopamine; it is a full agonist at D1 and D2 receptors, as well as having ergotamine-like properties. Its main use is in patients with advanced disease under 70 years old, who have severe motor fluctuations (i.e. on–off cycles), especially when freezing is common or levodopa provides little benefit, or in patients with severe dyskinesias, in whom reducing the levodopa dose is the aim. The rapid onset of action by the subcutaneous route avoids the ‘off’ component without the patient waiting for 45–60 min to absorb another oral dose of levodopa. Patients can be taught to inject themselves, but because the need is greatest during ‘off’ periods it is more convenient for a carer to administer injections. Alternatively, patients can receive apomorphine by continuous subcutaneous infusion from a portable syringe driver in a pouch. Continuous infusion is also the preferred administration method for dyskinetic patients.

Adverse effects of apomorphine follow from the fact that it is both a dopamine agonist and a morphine derivative. An antiemetic, e.g. domperidone,35 should accompany initial dosing as nausea is almost a universal accompaniment, at least initially. Overdose causes respiratory depression, while naloxone antagonises its action. Apomorphine can also cause confusion, psychosis and dysphoria, induce penile erection (without causing sexual excitement36), Raynaud’s phenomenon and yawning. Autoimmune-mediated haemolytic anaemia is a rare complication in patients taking concurrent levodopa, and their blood counts should be monitored.

Inhibition of dopamine metabolism: MAO-inhibitors and COMT inhibitors

Monoamine oxidase (MAO) enzymes have an important function in modulating the intraneuronal content of neurotransmitters. The enzymes exist in two principal forms, A and B, defined by specific substrates, some of which cannot be metabolised by the other form (Table 21.3). The therapeutic importance of recognising these two forms arises because they are to some extent present in different tissues, and the enzyme at these different locations can be selectively inhibited by the individual inhibitors: moclobemide for MAO-A (used for depression, see p. 311) and selegiline or rasagiline for MAO-B (used in Parkinson’s disease; Table 21.3).

Table 21.3 Isoforms of monoamine oxidase: MAO-A and MAO-B, an explanation

image

Selegiline

is a selective, irreversible inhibitor of MAO type B. The problem with non-selective MAO inhibitors is that they prevent degradation of dietary amines, especially tyramine, which may then act systemically as sympathomimetics (causing the so-called hypertensive ‘cheese reaction’37). Selegiline does not cause the cheese reaction, because MAO-A in the liver and sympathetic nerve endings is unaffected, allowing tyramine to be metabolised. In the CNS, selegiline reduces intraneuronal degradation of dopamine, but has no effect on synaptic cleft concentrations of other neuromodulatory amines, such as serotonin and noradrenaline/norepinephrine. The effects of these amines can be enhanced by MAO-A inhibitors used as antidepressants. Rasagiline38 is another MAO type B inhibitor, but has an advantage over selegiline in not producing amfetamine metabolites, which are believed to be part of the reason for confusion in susceptible patients. Furthermore, two trials39 of rasagiline have suggested that patients who take this early in their disease course show an enduring benefit (of up to 6 years), relative both to patients on placebo, and to those who are treated with rasagiline only after a delay of 9 months. While potentially evidence for a ‘disease-modifying’, rather than merely a symptomatic treatment effect, longer-term follow-up of these patients, and further independent trials will be required to confirm this.

Entacapone

inhibits catechol-O-methyltransferase (COMT), one of the principal enzymes responsible for the metabolism of dopamine, and so prolongs the action of levodopa. It is most effective for patients who experience only short-lived ‘on’ periods with levodopa, and in whom frequent levodopa doses are used (typically at 3–4-hourly intervals), by providing a more predictable and stable response. It is taken at the same time as levodopa, usually as part of the same drug formulation (Stalevo). Entacapone is preferred to long-acting preparations of levodopa, whose main disadvantage is their slow onset of action. The adverse effects of entacapone include increased dyskinesias (by increasing the effective brain levodopa concentration), bodily fluids e.g. urine, turning orange, and diarrhoea.

Tolcapone

is a COMT inhibitor that can be more effective than entacapone; it is taken three times per day, not necessarily at the same time as levodopa. Its main drawback is hepatotoxicity, resulting in liver failure in approximately 1 in 13 000 cases, thereby necessitating fortnightly screening blood tests.

Antimuscarinic (anticholinergic) drugs (see also p. 379)

Antimuscarinic drugs benefit parkinsonism by blocking acetylcholine receptors in the CNS, thereby partially redressing the imbalance created by decreased dopaminergic activity. Their use originated when hyoscine was given to parkinsonian patients in an attempt to reduce sialorrhoea by peripheral effect, and it then became apparent that they had other beneficial effects in this disease. Synthetic derivatives are now used orally. These include benzhexol (trihexyphenidyl), orphenadrine, benzatropine, procyclidine, biperiden. There is little to choose between these. Antimuscarinics produce modest improvements in tremor, rigidity, sialorrhoea, muscular stiffness and leg cramps, but do not generally help with bradykinesia. They are also effective intramuscularly or intravenously in acute drug-induced dystonias.

Unwanted effects include dry mouth, blurred vision, constipation, urine retention, acute glaucoma, hallucinations, memory defects and acute confusional states (which, once again, are more likely in elderly patients).

Amantadine

Amantadine

antedates the discovery of dopamine receptor subtypes, and its discovery as an antiparkinsonian drug was an example of serendipity. It is an antiviral drug which, given for influenza to a parkinsonian patient, was noticed to be beneficial. The two effects are probably unrelated. It appears to act by increasing synthesis and release of dopamine, and by diminishing neuronal reuptake. It also has a slight antimuscarinic effect. The drug is much less effective than levodopa, whose action it enhances slightly, but it has the advantage of reducing levodopa-induced dyskinesias. It is more effective than the standard antimuscarinic drugs, with which it has an additive effect. Amantadine is relatively free from adverse effects but there do occur ankle oedema (probably a local effect on blood vessels), postural hypotension, livedo reticularis and CNS disturbances, e.g. insomnia, hallucinations and, rarely, fits. It is more likely to cause confusion in the elderly and so is preferred for younger patients.

Drug-induced parkinsonism

The classical antipsychotic drugs (see p. 328) block dopamine receptors, and their antipsychotic activity relates closely to this action, which notably involves the D2 receptor, the principal target in Parkinson’s disease. It comes as no surprise, therefore, that these drugs, as well as certain calcium antagonists, e.g. flunarizine (used for migraine) and valproate, can induce a state with clinical features very similar to those of idiopathic Parkinson’s disease. An important distinguishing measure between drug-induced parkinsonism and Parkinson’s disease is that the former shows a normal dopamine-transporter binding using a DAT scan, since the nigrostriatal terminals (on which the transporter is located) are intact; in Parkinson’s disease there is typically a (asymmetric) reduction in transporter binding. The piperazine phenothiazines, e.g. trifluoperazine, and the butyrophenones, e.g. haloperidol, are most commonly involved, whereas neuroleptics with high antimuscarinic blocking activity, e.g. thioridazine, are less likely to cause this.

Treatment of drug-induced parkinsonism firstly involves consideration of whether the offending drug can be withdrawn, or replaced, e.g. by an atypical antipsychotic such as quetiapine, olanzapine or clozapine, that provokes fewer extrapyramidal effects (see p. 325). After withdrawal of the offending drug, most cases resolve completely within 7 weeks. When drug-induced parkinsonism is troublesome, an antimuscarinic drug, e.g. trihexyphenidyl, is beneficial, while levodopa and dopamine agonists are not (and risk provoking psychosis).

Tardive dyskinesias, such as repetitive orofacial or lingual movements, that come on after neuroleptics have been withdrawn, are distinct from drug-induced parkinsonism, can be worsened by anticholinergics, and so are instead treated with reinstatement of the offending drug if appropriate, switching to an atypical neuroleptic, e.g. quetiapine, and addition of either tetrabenazine (which depletes pre-synaptic dopamine) or clonazepam.

Other movement disorders

Essential tremor

is often, and with justice, called benign, but a few individuals may be incapacitated by it. Alcohol, through a central action, helps about 50% of patients but is plainly unsuitable for long-term use and a non-selective β-adrenoceptor blocker, e.g. propranolol 120 mg/day, will benefit about 50%; clonazepam or the barbiturate primidone are sometimes beneficial but predispose to sedation. Botulinum toxin injected into affected muscle groups can also provide benefit in certain circumstances, e.g. injection into forearm flexors and extensors for primary writing tremor, but may cause weakness of the affected part (see below).

Drug-induced dystonic reactions are seen:

• As an acute reaction, often of the torsion type, and occur following administration of dopamine receptor-blocking antipsychotics, e.g. haloperidol, and antiemetics, e.g. metoclopramide. An antimuscarinic drug, e.g. biperiden or benzatropine, given i.m. or i.v. and repeated as necessary, provides relief.

• In some patients who are receiving levodopa for Parkinson’s disease.

• In younger patients on long-term antipsychotic treatment, who develop tardive dyskinesia (see p. 325).

Wilson’s disease

Here, there is a genetic failure to eliminate copper absorbed from food so that it accumulates in the liver, brain, cornea and kidneys. Chelating copper in the gut with penicillamine or trientine can establish a negative copper balance (with some clinical improvement if treatment is started early). The patients may also develop cirrhosis, and the best treatment for both may be liver transplantation.

Chorea

of any cause may be alleviated by dopamine receptor-blocking antipsychotics, and also by tetrabenazine, which inhibits neuronal storage of dopamine and serotonin.

Dystonia

The term covers a variety of clinical syndromes characterised by abnormal postures, or tremor, due to abnormal muscle tone. Examples include cervical dystonia (e.g. torticollis), blepharospasm, hemifacial spasm, or genetic disorders such as primary generalised dystonia. Parkinson’s disease, especially with young onset, Huntington’s disease or Wilson’s disease can also present with dystonia. The mainstay of treatment for these disorders is botulinum toxin (below), although anticholinergics or benzodiazepines can be effective.

Spasticity

results from disruption of the corticospinal tract, which causes disinhibition of local spinal reflex circuits. Spasticity limited to well-defined muscle groups is best treated with botulinum toxin. Otherwise, systemic drugs can be given, including the GABA agonist baclofen, diazepam and tizanidine (an α2-adrenoceptor agonist).

Myotonia,

in which voluntary muscle fails to relax after contraction, may be symptomatically benefited by drugs that increase muscle refractory period, e.g. procainamide, phenytoin, quinidine.

Restless legs syndrome

(RLS) is a condition in which the patient has an urge to move their legs because of an unpleasant sensation, especially in the evening. Movement of the legs can provide temporary relief; some claim that it occurs in 5–10% of the general population. The disorder occurs from a deficiency in descending dopaminergic input to the spinal cord (as opposed to the deficiency of ascending dopaminergic fibres in Parkinson’s disease); the descending opioidergic neuromodulatory system is also affected. Most cases are primary (i.e. with no associated disease) but it may also accompany iron deficiency (because of low brain ferritin levels), pregnancy, peripheral neuropathy and dopamine antagonists. Treatment consists of a dopamine agonist, e.g. pramipexole or ropinirole, either taken an hour or two before symptoms develop, or taken as a long-acting preparation, e.g. rotigotine patch, in patients who experience symptoms throughout the day. Levodopa is also effective but can aggravate symptoms with chronic use. Opioids or valproate provide alternative therapies.

Botulinum toxin (Botox)

Botulinum toxin benefits many clinical states characterised by muscle overactivity, especially dystonia and spasticity, from various causes, e.g. stroke, multiple sclerosis. It is also effective for bladder overactivity (injected intravesically), achalasia (injected endoscopically), anal fissure, spasmodic dysphonia, excessive saliva production (parotid injection), and even migraine (multiple scalp and face injections). The toxin consists of metalloproteinases that prevent docking of acetylcholine vesicles at the pre-synaptic membrane, and hence effectively block the neuromuscular junction or autonomic ganglia. Type A Botox cleaves synaptosome-associated protein (SNAP-25), whereas Type B Botox cleaves a vesicle-associated membrane protein (VAMP), also called synaptobrevin.

Although the enzymes within Botox act irreversibly, new enzymes are produced by the neurones and transported gradually from cell body to pre-synaptic membrane. Thus the effect of Botox is limited typically to no more than 3 months, at which time further injections are needed. Neverthless, Botox is at least partially effective in up to 90% of patients with dystonia or spasticity, and unwanted effects are generally limited to discomfort or weakness at the site of injection (as compared to systemic antidystonia or antispasticity drugs that typically will have central nervous system effects such as sedation). Injections in the anterior neck, e.g. for torticollis, run a small risk of dysphagia, while periorbital injections for blepharospasm may cause ptosis. If Botox is used to excess, generalised weakness (similar to myasthenia gravis) may occur temporarily, as may antimuscarinic effects, due to its action on postganglionic parasympathetic nerve endings, e.g. dry mouth, dizziness.

Multiple sclerosis

Multiple sclerosis (MS) is the archetypal neuroinflammatory disease and the commonest cause of neurodisability in young adults. In recent years there has been a rapid expansion in the number of available disease-modifying immunomodulatory therapies, all of which are normally given by a specialist MS centre. It is important to distinguish the inflammatory component of MS, which usually manifests itself as self-terminating relapses, from a more insidious neurodegenerative component that is the cause of long-term ‘progressive’ disability. Most drug therapies target the former process without appearing to have significant impact on the latter.

First-line injectable disease-modifying drugs

Interferon (IFN) β

was the first treatment consistently to show a reduction in the number of symptomatic relapses, and demyelinating lesions observable on MRI. IFNβ also delays disability by 12–18 months in relapsing/remitting disease, probably by reducing relapses (rather than because of an effect on progression). Clinical trials show that in ambulant MS patients with relapsing/remitting disease, IFNβ produces a relative reduction in risk of relapse of approximately one-third. Furthermore, in previously healthy patients who present with a ‘clinically isolated syndrome’, i.e. a single episode of neurological disturbance associated with MRI white matter lesions, IFNβ delays the occurrence of a second episode. Thus the drug may suppress the onset of multiple sclerosis (taken as the point at which more than one neurological episode has occurred).

IFNβ is a polypeptide, normally produced by fibroblasts, whose natural purpose is probably as an effector of an antiviral response. It has multiple immunological effects, including suppression of antibody production, cytokine modulation (e.g. increasing interleukin-10 while decreasing tumour necrosis factor-α and interleukin-1), and inhibition of antigen presentation, T-cell proliferation, differentiation and migration into the brain. As a therapy it is produced as a human recombinant product within either mammalian cells (type 1a; Avonex or Rebif) or modified E. coli bacteria (type 1b: Betaferon or Betaseron) formulations, with only the Rebif formulation available in more than one dose. It is not indicated for patients with purely progressive forms of disease, although it may still be effective at reducing relapses in patients who have entered a relapsing, progressive phase (i.e. continuous disability progression with superimposed temporary exacerbations).

IFNβ is usually self-injected either subcutaneously three times per week, or i.m. once per week. Unwanted effects of IFNβ are usually minor, with some patients experiencing ’flu-like symptoms, nausea, mildly deranged liver or thyroid function tests, mood disturbance (it is thus relatively contraindicated in patients with a history of depression or suicidal thoughts) and less commonly, seizures. With IFNβ, especially type 1b preparations, some patients develop neutralising antibodies, resulting in a clear decrease in therapeutic efficacy in approximately one-third of patients. The finding of raised antibody levels may prompt change in therapy.

Glatiramer acetate

(co-polymer) is an oligopeptide that suppresses various components of the MS-immune response. Like IFNβ, it is self-administered, albeit in daily subcutaneous injections, and has the advantage of not inducing neutralising antibodies. The range of patients in which it is effective, and its level of efficacy, matches that of IFNβ.

Oral disease-modifying drugs

The development of oral disease-modifying therapies for multiple sclerosis promises to transform patient experience by offering patients a considerably more practical and painless therapy compared to the previous mainstay of treatment – IFNβ. Furthermore, preliminary trials suggest that the effectiveness of these therapies is superior to that of IFNβ, with relative reductions in relapse rate approaching 50% and relative reductions in new MRI lesions of 50–80%.

Sphingolipid (also called fingolimod) is high-affinity agonist at the sphingosine-1-phosphate receptor, causing receptor down-regulation. This receptor is normally required to allow lymphocyte egress from lymph nodes, and so the drug suppresses trafficking of autoreactive T cells into the blood. ECG monitoring is required as it can cause heart block. Laquinimod shifts the immunophenotype of T-helper lymphocytes to a Th2 pattern (characterised by IL-4 secretion), and away from a Th1 pattern (characterised by interferon-γ secretion), the latter of which is believed to be contributory to ongoing relapses. Fumarate is a citric acid cycle intermediate that acts in a similar way to laquinimod, but may also act to up-regulate antioxidant enzymes via the Nrf2 signalling pathway. It can cause flushing, pruritus and abdominal pain. Cladribine acts as a purine nucleotide antagonist that suppresses DNA replication necessary for lymphocyte and monocyte division (indeed its original use was for the treatment of leukaemia). It has the advantage that only two 5-day courses per year need be taken to produce a significant MS-treatment effect. Thus adverse effects seen with high doses of this drug used for cancer, e.g. nephrotoxicity and neuropathy, can mostly be avoided in MS treatment. A small excess of bone marrow suppression and opportunistic infection is still observed. Finally, teriflunomide is the active metabolite of leflunomide (used in rheumatoid arthritis) that blocks pyrimidine, and consequently, DNA synthesis. Similar to cladribine, it is associated with mild myelosuppression and upper respiratory tract infection.

Intravenous therapies

Monoclonal antibodies targeted against critical steps of the cell-mediated immune reactions that underlie MS are among the most effective immunomodulatory therapies in MS. But these drugs also carry the potential for serious unwanted effects (notably opportunistic infections) and are therefore reserved for patients with rapid deterioration who have failed to respond to less intensive immunomodulatory therapies such as IFNβ.

Natalizumab (Tysabri) targets the alpha4-beta1-integrin receptor VCAM-1 (vascular cell adhesion molecule) that is required for T lymphocytes to enter the central nervous system from the blood. Typically administered every 4 weeks, it decreases relapse rate by up to 70%. A real concern is that approximately 1 in 1000 treated patients (predominantly those taking additional immunosuppressants) develop progressive multifocal leukoencephalopathy (PML). This is an aggressive cerebral white-matter disease caused by reactivation of the Jakob–Creutzfeldt virus, previously seen only in diseases characterised by immunocompromise, such as advanced HIV infection or lymphoma. Unlike PML in these diseases which are nearly always fatal, PML associated with natalizumab can be reversed if therapy discontinues soon after its development (MRI scans are necessary every few months while on treatment).

Alemtuzumab (MabCampath or Campath) comprises monoclonal antibodies against CD52 – a marker of mature lymphocytes. In certain patients with frequent relapses it has been able to completely suppress their future occurrence. This occurs at the risk of provoking new organ-based autoimmune diseases, especially thyroid disease (in 40%), immune thrombocytopenic purpura (ITP) and Goodpasture’s disease(that can cause life-threatening bleeding and renal failure, respectively).

Other intravenous therapies used in advanced cases of MS include mitoxantrone, a cytotoxic drug that decreases interleukin-10 production, but which can cause infertility, cardiomyopathy and promyelocytic leukaemia, rituximab (anti-CD20 monoclonal antibody), i.v. immunoglobulin, cyclophosphamide and bone-marrow ablation with subsequent autologous stem-cell transplantation.

Symptomatic therapies

Corticosteroid

therapy is often used for acute, disabling attacks of MS. The drugs decrease the length of an attack but do not reduce the number of recurrent attacks or the final disability. Methylprednisolone (0.5–1 g) is given i.v. or by mouth over a 3–5-day period. Intravenous treatment appears to benefit relapses of optic neuritis more than do oral steroids but usually requires hospital admission.40

Urinary frequency and urgency (spastic bladder) is common, for which the antimuscarinics propantheline or oxybutynin can be useful by acting as a detrusor relaxant. Constipation is treated with laxatives, while impotence may respond to sildenafil. In progressive disease, muscle spasticity can be severe and disabling. Oral baclofen or tizanidine, or locally injected botulinum toxin can reduce spasticity, but over-treatment may lead to flaccid weakness. Intranasal cannabinoid is a more recent treatment for spasticity. Very occasionally, baclofen given intrathecally by an implanted pump can relieve severe spasticity. Fatigue is common in MS and may respond to amantadine or modafinil. Depression or psychosis, features of MS, require specific treatments. Finally, the role of general supportive measures, such as ramps, wheelchairs, stairlifts, prevention of bedsores, cannot be overstated.

Miscellaneous neurological disorders

Peripheral neuropathies

A large number of disease processes affect peripheral nerves causing one of several clinical syndromes. For example, such diseases can be classified according to whether sensory, motor or both types of nerve fibre are affected, or divided, depending upon whether it is the myelin sheath that is damaged primarily (peripheral demyelination) or the axon (axonopathy).

One important set of causes are the inflammatory demyelinating polyneuropathies, which can be either acute (AIDP, also called Guillain–Barré syndrome) or chronic (CIDP). Both diseases are treated with intravenous immunoglobulin or plasma exchange, so as to suppress production of antibodies against gangliosides, a glycosphingolipid present in the lipid membrane. CIDP is also responsive to glucocorticoids; this is not the case for Guillain–Barré syndrome. Other types of inflammatory demyelinating polyneuropathy associated with plasma cell dyscrasia and paraproteinaemia, must be sought. These are treated in similar ways, although increasingly use is also made of the monoclonal anti-CD20 drug rituximab. Autoimmune mechanisms can also cause an axonopathy pattern of neuropathy, usually in association with a systemic vasculitis, e.g. Churg–Strauss syndrome. These conditions require corticosteroid, and often, immunosuppressants such as azathioprine, mycophenolate or cyclophosphamide.

A separate group of polyneuropathies arise from metabolic derangements, commonly diabetes mellitus (which can improve or at least stabilise with rigorous glycaemic control) and alcoholism (which can respond partially to high-dose parenteral niacin, vitamin B1). Others in this category include deficiency of vitamin B12, or vitamin B6 (the latter may arise as an unwanted effect of the antituberculous drug isoniazid). Multiple other types of polyneuropathy exist, a fraction of which will have their specific treatments, e.g. HIV infection (HAART therapy); Lyme disease (ceftriaxone or doxycycline); diphtheria (antitoxin, penicillin); acute intermittent porphyria (heme arginate and high-carbohydrate diet); amyloidosis (chemotherapy, e.g. melphalan); Fabry’s disease (α-galactosidase gene replacement).

Motor neurone disease

The cause of the progressive destruction of upper and lower motor neurones is unknown. The only drug available, riluzole, acts by inhibiting accumulation of the neurotransmitter, glutamate. Riluzole prolongs survival time from 13 to 16 months, with no effect on motor function.41 It may cause neutropenia. Its use in the UK is limited to neurologists.

Tetanus

Tetanus remains a potentially fatal disease among underprivileged people in parts of the world where immunisation programmes are inadequate. Management involves:

• Immediate neutralisation of any toxin that has not yet become attached irreversibly to the CNS. Human tetanus immunoglobulin 150 units/kg is given intramuscularly at multiple sites to neutralise unbound toxin.

• Wound debridement and destruction of Clostridium tetani with metronidazole.

• Control of convulsions while maintaining respiratory function. Midazolam or diazepam is given for spasms and rigidity, and tracheal intubation and mechanical ventilation for prolonged spasms with respiratory dysfunction (in severe cases, a neuromuscular blocking drug, e.g. intermittent doses of pancuronium, may be required).

• Control of cardiovascular function (tetanus toxin often causes disturbances in autonomic control, with sympathetic overactivity). First-line treatment is by sedation with a benzodiazepine and opioid; infusion of the short-acting β-blocker esmolol, or the α2-adrenergic agonist clonidine, helps to control episodes of hypertension.

• Severe cases generally require admission to an intensive care unit for fluid and electrolyte management; enteral nutrition (weight loss is universal in tetanus); and monitoring for infection (usually aspiration pneumonia), thromboembolism, and pressure sores.

Guide to further reading

Baker G.A., Lane S., Benn E.K., et al. Adverse antiepileptic drug effects in new-onset seizures: a case-control study. Neurology. 2011;76:273–279.

Drivers Medical Group, At a glance guide to the current medical standards of fitness to drive. DVLA, Swansea. Available online at: http://www.dft.gov.uk/dvla/medical/ataglance.aspx (accessed February 2011).

Fahn S., Oakes D., Shoulson I., Parkinson Study Group. Levodopa and the progression of Parkinson’s disease. N. Engl. J. Med.. 2004;351:2498–2508.

Marson A.G., Al-Kharusi A.M., Alwaidh M., et alSANAD Study Group. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet. 2007;369:1016–1026.

Marson A.G., Al-Kharusi A.M., Alwaidh M., et alThe SANAD Study Group. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, xcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet. 2007;369:1000–1015.

Meador K.J., Baker G.A., Browning N., et alThe NEAD Study Group. Effects of breastfeeding in children of women taking antiepileptic drugs. Neurology. 2010;75:1954–1960.

Rascol O., Fitzer-Attas C.J., Hauser R., et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes. Lancet Neurol.. 2011;10:415–423.

Rudzinski L.A., Meador K.J. Epilepsy: five new things. Neurology. 2011;76(Suppl. 2):S20–S25.

Siddiqui A., Kerb R., Weale M.E., et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N. Engl. J. Med.. 2003;348:1442–1448.

1 Epilepsy has been recognised since early times. A Babylonian medical text dated about 650 BC gives the following description: ‘while he is sitting down, his left eye moves to the right, a lip puckers, saliva flows from his mouth, and his hand, leg and trunk on the left side jerk like a slaughtered sheep …’. Because of its unusual manifestations epilepsy was known as the ‘sacred disease’. Wilson J V K, Reynolds E H 1990 Medical History 34:192.

2 For a first-hand description of what it is like to experience a seizure, the reader is referred to many passages in the works of a lifelong epilepsy sufferer, Fyodor Dostoevsky, e.g. in The Idiot (1869): ‘all at once everything seemed to open up before him: an extraordinary inner light flooded his soul. That lasted half a second … he clearly remembered the beginning, the first sound of a dreadful scream which burst from his chest of its own accord and which no effort of his could have suppressed.’

3 Some people with epilepsy make pilgrimages to Terni (Italy) to seek intercession from Saint Valentine to relieve their condition. There was more than one Saint Valentine and it is unclear whether he was also the patron saint of lovers.

4 So-called ‘primary’ or ‘idiopathic’ generalised epilepsies that reflect the fact that the specific cause is usually undetermined, although presumed to be developmental (e.g. in utero) or genetic.

5 Greek katamenios, monthly.

6 Or single cluster of seizures, i.e. if they all occurred on one day or over a few consecutive days, without any recurrence.

7 SANAD Study.

8 Medical Research Council 1991 Antiepileptic Drug Withdrawal Study Group. Lancet 337:1175–1180.

9 Medical Research Council 1993 Antiepileptic Drug Withdrawal Study Group. British Medical Journal 306:1374–1378.

10 As well as spina bifida, cleft palates, cardiac and urogenital anomalies in the fetus, valproate during early pregnancy or pre-conception is associated with a particular dysmorphic appearance of the newborn (‘fetal valpraote syndrome’) characterised by wide, flat nasal bridge, long philtrum, thin lip, widely spaced eyes (hypertelorism) and epicanthic folds.

11 Eclampsia Trial Collaborative Group 1995 Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 345:1455–1463.

12 The last two of these examples have names that help to recall their mechanisms: vigabatrin (as well as valproate) being a GABA TRansamine INhibitor, and TiaGABINe being an INhibitor of GABA Transporter.

13 ‘We thought the change might be welcomed by the patients, but one girl preferred her hair to be long and straight, and one boy was mortified by his curls and insisted on a short hair cut’ (Jeavons P M, Clark J E, Harding G F 1977 Valproate and curly hair. Lancet i:359).

14 Sometimes referred to as idiopathic Parkinson’s disease (IPD) – a name that is likely to move out of favour as its pathophysiology becomes increasingly elucidated.

15 Substantia nigra is (Latin) black substance. A coronal section at this point in the brain shows the distinctive black areas, visible with the naked eye in the normal brain, but absent from the brains of patients with Parkinson’s disease.

16 James Parkinson (1755–1824), physician; he described paralysis agitans in 1817.

17 The commonest mutations associated with Parkinson’s disease (including sporadic disease – i.e. not apparently inherited) are leucine-rich repeat kinase (LRRK) and glucocerebrosidase (GBA), the latter of which in homozygous form causes the severe childhood disorder Gaucher’s disease.

18 Deep brain stimulation, a more popular neurosurgical technique, causes functional inactivity (i.e. ‘virtual lesion’) of either of these same target brain regions.

19 Atypical neuroleptics such as quetiapine or olanzapine, and antiemetics that only minimally cross the blood–brain barrier, such as domperidone, can be used relatively safely.

20 The CALM-PD study, for example, randomised 300 early PD patients to levodopa or pramipexole, where either group could subsequently have the other drug added in if clinically required. At 6 years the pramipexole group had less wearing off and dyskinesias than the levodopa group, but more oedema and sleepiness. Overall quality of life was no different between groups.

21 STRIDE-PD.

22 Levodopa is derived from the fava bean (Vicia faba); compare this with the prototypical drug for Alzheimer’s disease, physostigmine, which is derived from the calabar bean. The discoverer of natural levodopa, Marcus Guggenheim, explored its physiological effects by ingesting 2.5 g of the compound. He subsequently became violently ill with vomiting – a fact not too surprising given that the recommended starting dose now is one-tenth this amount.

23 The reason why the levo form of dopa is used is because racemic (d/l) mixtures of dopa were found to cause agranulocytosis in up to 25% of patients.

24 Explaining why nasoduodenal tube insertion for continuous levodopa instillation (Duodopa) can be effective.

25 For example, nausea frequency is reduced from 80% with levodopa alone to less than 15% with a decarboxylase inhibitor, for the same dopamine brain concentration achieved.

26 The dosage commonly referred to is the sum of both drugs: hence: 62.5 mg, 125 mg and 250 mg.

27 Amino acids compete for levodopa uptake and so absorption may vary depending on meal size and type.

28 Slow-release preparations are not preferable during the day as they are generally insufficient in achieving peak levels required for normal motor activity.

29 Dopamine agonists enable a reduction in the total levodopa dose, and in the cases of long-acting formulations, e.g. rotigotine, provide a relatively continuous and smooth level of dopaminergic stimulation.

30 Which has an independent antidyskinesia effect.

31 Note that dopamine causes hypotension, whereas further metabolism of levodopa to adrenaline/epinephrine and noradrenaline/norepinephrine causes hypertension – that is not seen with levodopa therapy.

32 This unwanted effect can be predicted from the fact that dopamine antagonists are used as antipsychotics.

33 Patients who drive, or engage in other potentially dangerous pursuits, need to be warned about this (and to stop driving etc. if they were to experience this).

34 Punding refers to behaviours such as sorting or hoarding objects to an extreme degree; the phrase was first coined to describe similar behaviour in chronic amfetamine abusers.

35 Domperidone is preferred as it does not cross the blood–brain barrier, unlike metoclopramide or prochlorperazine.

36 It also enhances the penile response to visual erotic stimulation, allegedly.

37 Tyramine is an indirectly acting amine which displaces noradrenaline/norepinephrine from nerve terminals.

38 This drug is unique in PD for having a very easy dosing schedule: 1 mg per day with no titration upwards necessary.

39 TEMPO and ADAGIO trials with approximately 400 and 1100 mild PD patients enrolled, respectively.

40 Some MS centres have arrangements in place for patients to receive intravenous corticosteroids in their own home, e.g. by employing community nurses who can monitor the hourly infusion. This is often preferred by patients, and reduces overall medical costs.

41 Lacomblez L, Bensimon G, Leigh P N et al 1996 A controlled trial of riluzole in ALS. Lancet 347:1425–1431.

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