There have been recent proposals to revise the concepts, terminology and approaches for classifying seizures and forms of epilepsy (Berg et al., 2010). In this proposal, the so-called natural classes, for example, specific underlying cause, age at onset, associated seizure type; or pragmatic groupings, for example, epileptic encephalopathies, self-limited electroclinical syndromes, serve as the basis for classification.

Diagnosis

Diagnosing epilepsy can be difficult as it is first necessary to demonstrate a tendency to recurrent epileptic seizures. The one feature that distinguishes epilepsy from all other conditions is its unpredictability and transient nature. The diagnosis of epilepsy is clinical and depends on a reliable account of what happened during the attacks, if possible both from the patient and from an eyewitness. Investigations may help and the EEG is usually one of them. These investigations, however, cannot conclusively confirm or refute the diagnosis of epilepsy.

There are other conditions that may cause impairment or loss of consciousness and which can be misdiagnosed as epilepsy; these include syncope, breath-holding attacks, transient ischaemic attacks, psychogenic attacks, etc. In addition, people may present with acute symptomatic seizures or provoked seizures as a result of other problems such as drug intake, metabolic dysfunction, infection, head trauma or flashing lights (photosensitive seizures). These conditions have to be clearly ruled out before a diagnosis of epilepsy is made. Epilepsy must only be diagnosed when seizures occur spontaneously and are recurrent. The diagnosis must be accurate since the label ‘suffering with epilepsy’ carries a social stigma that has tremendous implications for the person.

The EEG is often the only examination required, particularly in generalised epilepsies, and it aims to record abnormal neuronal discharges. EEGs have, however, limitations that should be clearly understood. Up to 5% of people without epilepsy may have non-specific abnormalities in their EEG recording, while up to 40% of people with epilepsy may have a normal EEG recording between seizures. Therefore, the diagnosis of epilepsy should be strongly supported by a bona fide history of epileptic attacks. Nevertheless, the EEG is invaluable in classifying seizures.

The chance of recording the discharges of an actual seizure during a routine EEG, which usually takes 20–30 min, is slight and because of this, ambulatory EEG monitoring and EEG video-telemetry are sometimes required. Ambulatory EEG allows recording in day-to-day circumstances using a small cassette recorder. EEG video-telemetry is useful in the assessment of difficult cases, particularly if surgery is considered. The person is usually admitted to hospital and remains under continuous monitoring. This is only helpful in a very few cases, and it is best suited for people who have frequent seizures.

Neuroimaging with magnetic resonance imaging (MRI) is the most valuable investigation when structural abnormalities such as stroke, tumour, congenital abnormalities or hydrochephalus are suspected. MRI should be carried out in anyone presenting with partial seizures or where a structural lesion on the brain may be responsible for seizures.

Treatment

National Institute for Health and Clinical Excellence (2004a) issued guidance on the diagnosis and treatment of the epilepsies in adults and children in primary and secondary care. The guidance covered issues such as when a person with epilepsy should be referred to a specialist centre, the special considerations concerning the care and treatment of women with epilepsy and the management of people with learning disabilities. The key points of the guidance are summarised in Box 31.1.

Box 31.1 Key points on the diagnosis and management of epilepsy (National Institute for Health and Clinical Excellence, 2004a)

• Diagnosis to be made urgently by a specialist with an interest in epilepsy

• EEG to be used to support diagnosis

• MRI to be used in people who develop epilepsy as adults, in whom focal onset is suspected, or in whom seizures persist

• Seizure type(s) and epilepsy syndrome, aetiology and co-morbidity to be determined

• Initiation of appropriate treatment to be recommended by a specialist

• Treatment individualised according to seizure type, epilepsy syndrome, co-medication and co-morbidity, the individual’s lifestyle and personal preferences

• The individual with epilepsy, and their family and/or carers, to participate in all decisions about care, taking into account any specific need

• Comprehensive care plans to be agreed

• Comprehensive provision of information about all aspects of condition

• Regular structured review at least once a year

• Patient to be referred back to secondary or tertiary care if:

– Epilepsy inadequately controlled

– Pregnancy considered or pregnant

– Antiepileptic drug withdrawal considered

• MRI, magnetic resonance imaging; EEG, electroencephalogram.

Treatment during seizures

Convulsive seizures may look frightening but the person is not in pain, will usually have no recollection of the event afterwards and is usually not seriously injured. Emergency treatment is seldom necessary. People should, however, be made as comfortable as possible, preferably lying down (ease to the floor if sitting), cushioning the head and loosening any tight clothing or neckwear. During seizures, people should not be moved unless they are in a dangerous place, for example, in a road, by a fire or hot radiator, at the top of stairs or by the edge of water. No attempt should be made to open the person’s mouth or force anything between the teeth. This usually results in damage, and broken teeth may be inhaled, causing secondary lung damage. When the seizure stops, people should be turned over into the recovery position and the airway checked for any blockage.

Partial attacks are usually less dramatic. During automatisms, people may behave in a confused fashion and should generally be left undisturbed. Gentle restraint may be necessary if the automatism leads to dangerous wandering. Attempts at firm restraint, however, may increase agitation and confusion. No drinks should be given after an attack, nor should extra antiepileptic drugs (AEDs) be administered. It is commonly felt that seizures may be life-threatening, but this is seldom the case. After a seizure, it is important to stay with the person and offer reassurance until the confused period has completely subsided and the person has recovered fully.

If a seizure persists for more than 10 min, if a series of seizures occur or if the seizure is particularly severe, then intravenous or rectal administration of 10–20 mg diazepam for adults, with lower doses being used in children, is advisable.

Status epilepticus

Initial management of status epilepticus is supportive and may include:

• positioning the person to avoid injury

• supporting respiration

• maintaining blood pressure

• correcting hypoglycaemia

Drugs used include intravenous lorazepam or diazepam. Alternative medicines include midazolam in cases where the person has not responded to first-line drugs. Alternatively, buccal midazolam has been advocated and is increasingly being used, although it is not licensed in the UK. In severe cases, phenytoin, clonazepam or phenobarbital sodium may be required.

Febrile convulsions

Convulsions associated with fever are termed febrile convulsions and may occur in the young. Brief febrile convulsions are managed conservatively with the primary aim of reducing the temperature of the child. Tepid sponging and use of paracetamol is usual. Prolonged febrile convulsions lasting 10–15 min or longer or in a child with risk factors require active management to avoid brain damage. The drug of choice is diazepam by intravenous or rectal (rectal solution) administration. Prophylactic management of febrile convulsions may be required in some children, such as those with pre-existing risk factors or a history of previous prolonged seizures.

Long-term treatment

In most cases, epilepsy can only be treated by long-term, regular drug therapy. The objective of therapy is to suppress epileptic discharges and prevent the development of epileptic seizures. In the majority of cases, full seizure control can be obtained, and in other patients drugs may reduce the frequency or severity of seizures.

Initiating treatment with an AED is a major event in the life of a person, and the diagnosis should be unequivocal. Treatment options must be considered with careful evaluation of all relevant factors, including the number and frequency of attacks, the presence of precipitating factors such as alcohol, drugs or flashing lights, and the presence of other medical conditions (Feely, 1999). Single seizures do not require treatment unless they are associated with a structural abnormality in the brain, a progressive brain disorder or there is a clearly abnormal EEG recording. If there are long intervals between seizures (over 2 years), there is a case for not starting treatment. If there are more than two attacks that are clearly associated with a precipitating factor, fever or alcohol for instance, then treatment may not be necessary.

Therapy is long-term, usually for at least 3 years and, depending on circumstances, sometimes for life. A full explanation of all the implications must be given to the person and they must be involved in all stages of the treatment plan. It is vital that the person understands the implications of treatment and agrees with the treatment goals. Empowerment of the person with epilepsy to be actively involved in the decision-making process will encourage adherence and is essential for effective clinical management. Support for people so that they understand the implications of the condition and why drug therapy is so important is crucial to ensure effective clinical management.

Health professionals have a key role in supporting people with epilepsy to ensure they are able to manage their medicines appropriately. AED treatment will fail unless the patient fully understands the importance of regular therapy and the objectives of treatment. Poor adherence is still a major factor which results in hospital admissions and poor seizure control and leads to the clinical use of multiple AEDs.

General principles of treatment

Therapy aims to control seizures using one drug, with the lowest possible dose that causes the fewest side effects possible. The established AEDs, carbamazepine, ethosuximide and sodium valproate, are still important parts of the antiepileptic armamentarium. Acetazolamide, clobazam, clonazepam, phenobarbital phenytoin and primidone are also still used. In the last two decades, new AEDs such as vigabatrin, lamotrigine, gabapentin, topiramate, tiagabine, oxcarbazepine, levetiracetam, pregabalin, zonisamide, lacosamide and eslicarbazepine acetate have been introduced. The choice of drugs depends largely on the seizure type, and so correct diagnosis and classification are essential. Table 31.1 lists the main indications for the more commonly used AEDs, and Table 31.2 summarises the clinical use of the newer AEDs.

Table 31.1 Antiepileptic drugs for different seizure types

Seizure type	First-linetreatment	Second-line treatment
Partial seizures
	Carbamazepine	Topiramate
	Lamotrigine	Valproate
	Oxcarbazepine	Clobazam
	Levetiracetam	Zonisamide
		Pregabalin
		Phenytoin
		Gabapentin
		Lacosamide
		Eslicarbazepine
Generalised seizures
Tonic clonic	Valproate sodium	Lamotrigine
Tonic	Carbamazepine	Clobazam
Clonic	Lamotrigine	Phenobarbital
Absence	Ethosuximide	Clonazepam
Absence	Sodium valproate	Lamotrigine
Atypical absences	Sodium valproate
Atonic	Clonazepam	Lamotrigine
	Clobazam	Carbamazepine
		Phenytoin
		Acetazolamide
		Topiramate
Myoclonic	Sodium valproate	Levetiracetam
	Clonazepam	Acetazolamide
		Topiramate

Table 31.2 Summary of newer antiepileptic agents

Initiation of therapy in newly diagnosed patients

The first-line AED most suitable for the person’s seizure type should be introduced slowly, starting with a small dose. This is because too rapid an introduction may induce side effects that will lose the person’s confidence. For most drugs, this gradual introduction will produce a therapeutic effect just as fast as a rapid introduction, and the person should be reassured about this.

Maintenance dosage

There is no single optimum dose of any AED that suits all patients. The required dose varies from person to person, and from drug to drug. Drugs should be introduced slowly and then increased incrementally to an initial maintenance dosage. Seizure control should then be assessed, and the dose of drug changed if necessary. For most AEDs, dosage increments are constant over a wide range. More care is, however, needed with phenytoin as the serum level–dose relationship is not linear, and small dose changes may result in considerable serum level changes. Generic prescribing for epilepsy remains controversial. Most specialists would prefer people to remain on the same brand of medication, and this is also preferred by the majority of people with epilepsy. This is obviously important in those people in whom the dosage has been carefully titrated to achieve optimal control.

Altering drug regimens

If the maximal tolerated dose of a drug does not control seizures, or if side effects develop, the first drug can be replaced with another first-line AED. To do this, the second drug should be added gradually to the first. Once a good dose of the new drug is established, the first drug should then slowly be withdrawn.

Withdrawal of drugs

AEDs should not be withdrawn abruptly. With barbiturates and benzodiazepines, in particular, rebound seizures may occur. Withdrawal of individual AEDs should be carried out in a slow stepwise fashion to avoid the precipitation of withdrawal seizures (e.g. over 2–3 months). This risk is particularly great with barbiturates, for example, phenobarbital and primidone, and benzodiazepines, for example, clobazam and clonazepam. If a drug needs to be withdrawn rapidly, for example, if there are life-threatening side effects, then diazepam or another benzodiazepine can be used to cover the withdrawal phase.

Examples of withdrawal regimens are given below.

• Carbamazepine

100–200 mg every 2 weeks (as part of a drug change)

100–200 mg every 4 weeks (total withdrawal)

• Phenobarbital

15–30 mg every 2 weeks (as part of a drug change)

15–30 mg every 4 weeks (total withdrawal)

• Phenytoin

50. mg every 2 weeks (as part of a drug change)

50. mg every 4 weeks (total withdrawal)

• Sodium valproate

200–400 mg every 2 weeks (as part of a drug change)

200–400 mg every 4 weeks (total withdrawal)

• Ethosuximide

125–250 mg every 2 weeks (as part of a drug change)

125–250 mg every 4 weeks (total withdrawal)

Variations in the above regimens may be used in different settings. People must be monitored closely for any change in seizure frequency. The pace of withdrawal may be slower if the person is within the higher end of the quoted dose range. The pace of withdrawal may be faster if the person is an inpatient.

When to make dose changes

Some AEDs have long half-lives and it may, therefore, take some time, normally five half-lives, before a change in dose results in a stable blood level. For example, phenobarbital has a half-life of up to 6 days and will take more than 4 weeks to produce a stable blood level. For this reason an assessment of the effectiveness of any dose change should be undertaken several weeks after the dose change has been made and be informed by knowledge of the half-life of the drug.

Newer AEDs

The newer AEDs are generally used as second-line drugs when treatment with established first-line drugs has failed. Exceptions to this are lamotrigine, levetiracetam, topiramate and oxcarbazepine, which have indications for first-line use in the UK. Lamotrigine is considered the first-line option in women of child-bearing potential who have idiopathic generalised epilepsy because of the teratogenic profile of sodium valproate, otherwise the first-line drug for this indication. Oxcarbazepine has the same indications as carbamazepine, although the latter is probably more cost-effective.

There is no evidence that the newer AEDs are more effective than the established drugs, although it could be argued that they might be better tolerated. The chronic side effect profile of the new AEDs has not yet been fully established and this is the main reason why use should be reserved for those cases where benefit outweighs risk. Guidance has been issued that covers the use of the newer AEDs in adults (National Institute for Health and Clinical Excellence, 2004b):

• Newer drugs, for example, lamotrigine, oxcarbazepine and topiramate, suitable for the type of epilepsy to be treated can be used in patients where older drugs, for example, sodium valproate or carbamazepine, do not provide effective clinical control or cause untolerable side effects.

• Gabapentin, levetiracetam, tiagabine and vigabatrin are generally used in combination with another drug.

• Newer drugs can be used where older drugs are unsuitable for the person, for example, liver disease, or where unwanted effects cannot be tolerated.

• The aim should be to treat people with just one AED where possible.

The guidance for adults was followed up by advice for use of the newer AEDs in children (National Institute for Health and Clinical Excellence, 2004c). This advice reflected that issued for adults and included:

• Lamotrigine, oxcarbazepine or topiramate can be given to children as sole treatment for epilepsy.

• Gabapentin, tiagabine and vigabatrin are generally used as combination therapy with another drug.

• Vigabatrin is suitable for first-line treatment of young children with a rare type of infantile spasm called West’s syndrome.

• Newer drugs are indicated if older drugs are unsuitable, for example, in liver disease, or if patients cannot tolerate unwanted effects.

• Children should be treated with just one AED where possible.

A third set of national guidance was issued on the diagnoses and management of the epilepsies in adults and children in primary and secondary care (National Institute for Health and Clinical Excellence, 2004a). A recent report on the implementation of this guidance (National Institute for Health and Clinical Excellence, 2009) revealed:

• No major change was noticed in the rate of increase for prescriptions for newer AEDs.

• Use of the newer AEDs had increased at a faster rate than the older drugs.

• Over 70% of patients received mono-therapy for their epilepsy during the period monitored. Of these patients, 60% received an ‘old’ epilepsy drug. Of newly diagnosed patients, 80% received mono-therapy as their treatment.

• 68% of adults received a medication review within 12 months of being prescribed a drug for their epilepsy.

Follow-up and monitoring of treatment

It is essential to follow up patients in whom AED treatment has been started. The reason for this is essentially to monitor the efficacy and side effects of treatment, upon which drug dosage will depend, but also to encourage good adherence to the treatment. This follow-up is particularly important in the early stages of treatment, when an effective maintenance dose may not have been fully established, when the importance of regular adherence may not have been recognised by the person, and when the psychological adjustment to regular treatment may not be resolved.

Chronic epilepsy

The drug treatment of people with established epilepsy that is uncontrolled despite initial attempts is much more difficult than that of newly diagnosed patients. Prognosis is worse, drug resistance may have developed, and there may be additional neurological, psychological or social problems.

Assessment

The diagnosis of epilepsy should be reassessed before assuming seizures are intractable. A significant proportion of patients may have been incorrectly diagnosed. The aetiology of the epilepsy should also be considered, and the question of a progressive neurological condition addressed. A treatment history should be obtained and note made of previous drugs used which were helpful, unhelpful or of uncertain benefit. Serum level measurements should be obtained where appropriate and drugs not previously tried should be identified.

Choice of drug and dosage

Treatment should always be started with one AED appropriate for seizure type and suitable for the individual. Only when attempts at monotherapy fail should a combination of two AEDs be tried. In the majority of patients, there is no place for therapy with more than two drugs. The choice of drugs should be made according to seizure type and previous treatment history. Drugs that were helpful in the past or found to be of uncertain benefit, or which have not been used before, should be tried if appropriate to seizure type. The use of sedative AEDs should be minimised where possible.

Intractable epilepsy

It is important to realise that there are limits to AED treatment and that in some people, albeit a small group, seizure control is not possible with the drugs currently available. In such cases, the goal of drug treatment changes, and the objectives are to reduce medication to minimise toxicity while providing partial control. The sedative drugs, for example, barbiturates or benzodiazepines, should be used only where absolutely necessary. In these persons, surgical treatment or the use of experimental antiepileptic agents may be considered. However, only a relatively small number of people with partial epilepsy are suitable for curative surgical treatment.

Stopping treatment

Withdrawing therapy should be considered in people who have been seizure free for a considerable period of time. In no individual case, however, can the safety of drug withdrawal be guaranteed, and the risk of relapse on withdrawal of medication in a person who has been seizure free for more than 2 years is about 40%. The longer the person has been free of seizures, the lower the risk of seizure recurrence when drugs are withdrawn. If a person has a learning disability, partial seizures or symptomatic epilepsy, neurological signs or other evidence of cerebral damage, this risk is much higher and in such cases it may be best to continue drug treatment indefinitely. Drug withdrawal should be carried out only very slowly in staged decrements, and only one drug at a time should be withdrawn.

The risks of drug withdrawal should be clearly explained to the person, and the possible medical and social implications taken into account. There may be serious social or domestic consequences should seizures recur, and the attacks may be subsequently difficult to control, even if the original AED regimen is re-established. In the final analysis, the decision to withdraw therapy is an individual one, and the person should be made aware of the risks and benefits of withdrawal.

Monitoring antiepileptic therapy

Therapeutic drug monitoring (TDM) involves the measurement of serum drug levels and their pharmacokinetic interpretation. It is an integral component in the management of people taking phenytoin and carbamazepine but is less useful in people receiving other AEDs. Indeed, TDM has a very limited use for new AEDs except in people who are acutely unwell, pregnant or elderly. It is also very useful to document AED side effects and in managing drug interactions. Adherence may also be a problem in these patients and hence TDM may be useful to establish adherence with the treatment.

TDM is indicated:

• at the onset of therapy

• if seizure control is poor or sudden changes in seizure control occur

• if toxicity is suspected

• if poor or non-adherence is suspected

• to monitor the time-scale of drug interactions

• when changing AED therapy or making changes to other aspects of a person’s drug regimen that may interact with the AED.

The frequency of undertaking TDM varies. Stabilised patients may require their serum levels to be checked only once or twice a year. TDM may be used more often in some people, for one or more of the above indications. A number of the newer AEDs do not require routine TDM. However, since most are used as adjuvant therapy, it is useful to establish baseline levels of existing drugs before the new agent is introduced. Clinical effects should be monitored and TDM, where appropriate, carried out at 6–12 month intervals.

Drug development and action

The older, more established AEDs were developed in animal models in which the potential drugs were assessed in terms of their ability to raise seizure threshold or prevent spread of seizure discharge. The animals involved in these tests would not have epilepsy but would have seizures induced by, for instance, maximal electroshock or subcutaneous pentylenetetrazole. As a consequence the relevance of these models to epilepsy can be questioned.

Established AEDs such as phenytoin, phenobarbital, sodium valproate, carbamazepine, ethosuximide, clonazepam and diazepam are effective but have poor side effect profiles, are involved in many interactions and have complex pharmacokinetics. Over the past 10–15 years, there has been renewed interest in the development of new AEDs, based on a better understanding of excitatory and inhibitory pathways in the brain. The main mechanisms of current drugs are thought to involve enhancement of the inhibitory GABA-ergic system, for example, benzodiazepines, barbiturates, tiagabine, vigabatrin or use-dependent blockers of sodium channels, for example, carbamazepine, oxcarbazepine, lamotrigine and phenytoin (Fig. 31.1).

Fig. 31.1 Action of antiepileptic drugs

(from Duncan et al., 2006).

New drugs include lamotrigine, pregabalin, levetiracetam, topiramate, felbamate, lacosamide, oxcarbazepine, eslicarbazepine and zonisamide. Unlike most of the older agents, vigabatrin, lamotrigine, levetiracetam, lacosamide, gabapentin, pregabalin and zonisamide are devoid of clinically significant enzyme-inhibiting or enzyme-inducing properties. Oral contraceptives may increase the metabolism of lamotrigine and topiramate, and oxcarbazepine may induce cytochrome P450 CYP3A4 which is responsible for the metabolism of oral contraceptives (Sabers and Gram, 2000).

AED profiles

The maintenance doses for the more widely used AEDs are given in Table 31.3, while their pharmacokinetic profile is presented in Table 31.4. Drug interactions are summarised in Table 31.5, and common side effects in Table 31.6.

Table 31.3 Commonly used starting and maintenance doses of antiepileptic drugs for adults

Table 31.4 Pharmacokinetic data of antiepileptic drugs

Table 31.5 Examples of drug interactions involving antiepileptic drugs

Table 31.6 Side effect profile of antiepileptic drugs

Drug	Dose related (predictable)	Non-dose related (idiosyncratic)
Carbamazepine	Diplopia, drowsiness, headache, nausea, orofacial dyskinesia, arrhythmias	Photosensitivity, Stevens–Johnson syndrome, agranulocytosis, aplastic anaemia, hepatotoxicity
Clonazepam	Fatigue, drowsiness, ataxia	Rash, thrombocytopenia
Ethosuximide	Nausea, vomiting, drowsiness, headache, lethargy	Rash, erythema multiforme, Stevens–Johnson syndrome
Gabapentin	Drowsiness, diplopia, ataxia, headache	Not reported
Lacosamide	Nausea, vomiting, dizziness, headache, drowsiness, depression, diplopia (double vision), impaired memory, impaired coordination, tremor, fatigue (tiredness), asthenia (muscle weakness), pruritus (itching).	Not reported
Lamotrigine	Headaches, drowsiness, diplopia, ataxia	Liver failure, disseminated intravascular coagulation
Levetiracetam	Dizziness, drowsiness, irritability, behavioural problems, insomnia, ataxia (unsteadiness), tremor, headache, nausea	Not reported
Oxcarbazepine	Diplopia (double vision), ataxia (unsteadiness), headache, nausea, confusion and vomiting	Skin rash
Phenobarbital	Fatigue, listlessness, depression, poor memory, impotence	Maculopapular rash, exfoliation, hepatotoxicity hypocalcaemia, osteomalacia, folate deficiency
Phenytoin	Ataxia, nystagmus, drowsiness, gingival hyperplasia, hirsutism, diplopia, asterixis, orofacial dyskinesia, folate deficiency	Blood dyscrasias, rash, Dupuytren’s contracture, hepatotoxicity
Sodium valproate	Dyspepsia, nausea, vomiting, hair loss, anorexia, drowsiness	Acute pancreatitis, aplastic anaemia, thrombocytopenia, hepatotoxicity
Tigabine		Dizziness, fatigue (tiredness), nervousness, tremor, concentration difficulties, depression of mood, agitation
Topiramate	Dizziness, drowsiness, nervousness, fatigue, weight loss	Not reported
Vigabatrin	Drowsiness, dizziness, weight gain	Behavioural disturbances, severe psychosis
Zonisamide	Ataxia, dizziness, somnolence, anorexia	Hypersensitivity, weight decrease, rash, gastro-intestinal problems

Acetazolamide

Acetazolamide is occasionally used as an AED. It can be prescribed as a second-line drug for most types of seizures, but particularly for partial seizures, absence seizures and myoclonic seizures. Its intermittent use in catamenial seizures has also been suggested. Acetazolamide has only limited use as long-term therapy because of the development of tolerance in the majority of patients. Side effects include skin rashes, weight loss, paraesthesia, drowsiness and depression. Routine TDM is not available for this drug.

Carbamazepine

Carbamazepine is a drug of first choice in tonic clonic and partial seizures, and may be of benefit in all other seizure types except generalised absence seizures and myoclonic seizures. Tolerance to its beneficial effect does not usually develop. Adverse events may occur in up to a third of patients treated with carbamazepine but only about 5% of these events will require drug withdrawal, usually due to skin rash, gastro-intestinal disturbances or hyponatraemia. Dose-related adverse reactions including ataxia, dizziness, blurred vision and diplopia are common. Serious adverse events including hepatic failure and bone marrow depression are extremely uncommon.

Carbamazepine exhibits autoinduction, that is, induces its own metabolism as well as inducing the metabolism of other drugs. It should, therefore, be introduced at low dosage and this should be steadily increased over a period of a month. The target serum concentration therapeutic range is 4–12 μcg/mL. In addition, a number of clinically important pharmacokinetic interactions may occur, and caution should be exercised when co-medication is instituted (see Table 31.5). For patients requiring higher doses, the slow-release preparation of carbamazepine has distinct advantages, allowing twice-daily ingestion and avoiding high peak serum concentrations. A ‘chewtab’ formulation is also available and pharmacokinetic studies have shown that it performs well even if inadvertently swallowed whole. Carbamazepine retard offers paediatric patients in particular a dosage form that reduces fluctuations in the peak to trough serum levels and hence allows a twice-daily regimen, which can assist compliance.

Clobazam

Clobazam is a 1,5-benzodiazepine that is said to be less sedative than 1,4-benzodiazepine drugs such as clonazepam and diazepam. Although the development of tolerance is common, clobazam is used as an adjunctive therapy for patients with partial or generalised seizures who have proved unresponsive to other antiepileptic medication. Its intermittent use in catamenial epilepsy has also been suggested. Clobazam may produce less sedation than other benzodiazepines, but otherwise its adverse effects are similar, including dizziness, behavioural disturbances and dry mouth. Withdrawal may be difficult.

Clonazepam

Clonazepam, a 1,4-benzodiazepine, is a second-line drug for generalised tonic clonic seizures, absences, myoclonic seizures and as adjunctive therapy for partial seizures but, as with clobazam, effectiveness often wears off with time as tolerance develops. Parenteral clonazepam is useful in status epilepticus. It has an adverse effect profile similar to that of clobazam, but may be more sedating.

Diazepam

Diazepam is used mainly in the treatment of status epilepticus, intravenously or in the acute management of febrile convulsions as a rectal solution. Absorption from suppositories or following intramuscular injection is slow and erratic. The rectal solution may also be useful in status epilepticus if it is not possible to give the drug intravenously.

Eslicarbazepine acetate

Eslicarbazepine acetate is a drug which is similar to oxcarbazepine and which is licensed as a second-line treatment for partial seizures. As with oxcarbazepine, its mode of action is thought to be by interacting with voltage-gated sodium channels. Currently it is only available in a 800-mg tablet. It has a long half-life and can be used once per day. Its pharmacokinetics profile and side effects are also similar to those of oxcarbazepine.

Ethosuximide

Ethosuximide is a drug of first choice for generalised absence seizures, and has no useful effect against any other seizure type. Tolerance does not seem to be a problem. The most commonly encountered adverse effects are gastro-intestinal symptoms, which occur frequently at the beginning of therapy. Behaviour disorders, anorexia, fatigue, sleep disturbances and headaches may also occur. The therapeutic range commonly quoted is 40–100 μcg/mL, but some patients may require higher concentrations, sometimes as high as 150 μcg/mL. The absorption of ethosuximide is complete, the bioavailability of the syrup and capsule formulations being equivalent. An increase in daily dose may lead to disproportionately higher increases in average serum concentrations; therefore, careful monitoring is indicated at high doses.

Felbamate

Felbamate may be used as a drug of last resort in people with intractable epilepsy. It is licensed in the USA and most countries of the European Union but not in the UK. Its mechanism of action is unknown. The usual dose is between 1200 and 3600 mg/day. Felbamate exhibits significant pharmacokinetic interactions with phenytoin, carbamazepine and valproic acid. Side effects of felbamate include diplopia, insomnia, dizziness, headache, ataxia, anorexia, nausea and vomiting. A major limiting problem is its potential to cause aplastic anaemia and liver failure, affecting up to 1 in 4000 patients exposed to the drug. It, therefore, seems prudent to limit use to specialist centres and severe intractable cases.

Gabapentin

Gabapentin is occasionally used as a second-line treatment of partial seizures. Although initially developed as an AED, its main use currently is for the treatment of neuropathic pain. In view of its pharmacokinetic profile, a three times daily dosage must be used. To date, no clinically significant interactions with other AEDs, or other drugs, have been reported. The most frequently reported side effects are drowsiness, dizziness, diplopia, ataxia and headache.

Lacosamide

Lacosamide, a functionalised amino acid, is a second-line drug for partial epilepsy in patients over the age of 16 years. Its putative mode of action is not shared with any other currently available AEDs. It is said to enhance the slow inactivation of sodium channels and to modulate collapsing response mediator protein-2 (CRMP-2), although it is not known how this contributes to its antiepileptic action. The recommended doses are between 200 and 400 mg/day divided in two doses. It should be started at 50–100 mg/day and increased by 50 mg/day every 1 or 2 weeks. No drug–drug interactions are known. Its commonest side effects are dizziness, headaches, nausea and diplopia. No idiosyncratic side effects have yet been associated with this drug. The drug should be used with caution in patients with a history of cardiac conduction problems as it is know to increase the PR interval in some patients.

Lamotrigine

Lamotrigine may be used as a first-line drug in patients with partial seizures, with or without secondary generalisation, and in tonic clonic convulsions. The recommended starting dose is 50 mg when used as monotherapy, and 25 mg when used as an add-on therapy; the latter dose is given on alternate days in patients receiving concomitant sodium valproate and daily in patients receiving other AEDs, with a maximum recommended dose of 400 mg/day in two divided doses. It should be slowly titrated as too rapid a titration may be associated with an increased incidence of skin rash. Lamotrigine does not seem to interact with other concomitantly administered AEDs. However, hepatic enzyme inducers increase the metabolism of lamotrigine, reducing its half-life. Therefore, higher doses of lamotrigine need to be administered if it is used in conjunction with enzyme inducers such as phenytoin and carbamazepine. Inhibitors of hepatic enzymes such as sodium valproate block the metabolism of lamotrigine and reduced doses of lamotrigine need to be used if both drugs are given in combination.

Headaches, drowsiness, ataxia and diplopia, usually transient, are the most commonly reported acute adverse effects, particularly during dose escalation. A skin rash is the commonest idiosyncratic side effect of lamotrigine and affects up to 3% of patients.

Levetiracetam

Levetiracetam is indicated for the treatment of refractory partial epilepsy. Placebo-controlled trials in refractory partial epilepsy have shown a 50% seizure reduction in up to 40% of patients. In these trials, 8% of participants became seizure free compared to none on placebo. The usual dose is between 1500 and 3000 mg a day. It is usually started at 500 mg a day and the dose titrated upwards in incremental steps of 500 mg every 1 or 2 weeks. It is well tolerated and the most frequent central nervous system adverse events are dizziness, irritability, asthenia and somnolence. No idiosyncratic adverse events have yet been reported.

Oxcarbazepine

Oxcarbazepine is an analogue of carbamazepine. It is an inactive pro-drug that is converted in the liver to the active 10-hydroxy metabolite and bypasses the 10,11-epoxide, the primary metabolite of carbamazepine. The usual dose is between 900 and 2400 mg/day. The spectrum of efficacy and side effects is broadly comparable to carbamazepine. The principal advantage of oxcarbazepine over carbamazepine is the lack of induction of hepatic enzymes, with the consequence that there is no auto-induction of the metabolism of the drug and fewer pharmacokinetic interactions. In addition, two-thirds of patients who are allergic to carbamazepine can tolerate oxcarbazepine.

Phenobarbital

Phenobarbital, a barbiturate, may be used for the treatment of tonic clonic, tonic and partial seizures. It may also be used in other seizure types. Its antiepileptic efficacy is similar to that of phenytoin or carbamazepine. Adverse effects on cognitive function, the propensity to produce tolerance and the risk of serious seizure exacerbation on withdrawal make it an unattractive option, and it should be used only as a last resort. In addition to cognitive effects, barbiturates may cause skin rashes, ataxia, folate deficiency, osteomalacia, behavioural disturbances (particularly in children) and an increased risk of connective tissue disorders such as Dupuytren’s contracture and frozen shoulder. Phenobarbital is a potent enzyme inducer and is implicated in several clinically important drug interactions (see Table 31.5).

Phenytoin

In current practice, phenytoin is now a second-line drug for partial seizures, tonic clonic seizures as well atonic seizures and atypical absences. It is not effective in typical generalised absences and myoclonic seizures. Tolerance to its antiepileptic action does not usually occur. Phenytoin has non-linear kinetics and a low therapeutic index, and in some patients frequent drug serum level measurements may be necessary. Drug interactions (see Table 31.5) are common as phenytoin metabolism is very susceptible to inhibition by some drugs, while it may enhance the metabolism of others. Caution should be exercised when other medication is introduced or withdrawn.

Adverse events may occur in up to a half of patients treated with phenytoin, but only about 10% will necessitate drug withdrawal, most commonly due to skin rash. Dose-related adverse reactions including nystagmus, ataxia and lethargy are common. Cosmetic effects such as gum hypertrophy, hirsutism and acne are well-recognised adverse effects, and should be taken into account when prescribing for children and young women. Chronic adverse effects include folate deficiency, osteomalacia, Dupuytren’s contractures and cerebellar atrophy. Serious idiosyncratic adverse events, including hepatic failure and bone marrow depression, are extremely uncommon.

Pregabalin

This drug has been licensed for the adjunctive treatment of refractory partial epilepsy. It is closely related to gabapentin and a structural analogue of the neurotransmitter GABA but does not seem to affect transmitter response. It modulates calcium channels by binding to a subunit of Ca²⁺ and this action is thought to be the basis of its antiepileptic mechanism. The recommended doses for pregabalin are between 150 and 600 mg divided into two doses, although some people may respond to doses outside this range. Pregabalin would normally be started at 50 or 75 mg twice daily and increased in incremental steps of 50 mg every 2 weeks up to 600 mg according to clinical need. Pregabalin is available in 25, 50, 75, 100, 150, 200 and 300 mg tablets.

Overall, pregabalin is well tolerated and so far no idiosyncratic side effects have been described. Dizziness, drowsiness, ataxia, tremor and diplopia are the most common side effects. Weight gain, particularly with higher doses, seems to be a chronic side effect of this medication. No pharmacokinetic interactions have yet been identified. In addition to its use in epilepsy, pregabalin has also been indicated for neuropathic pain and there are studies to suggest that it might be useful in generalised anxiety disorders.

Primidone

Primidone is principally metabolised to phenobarbital in vivo and has similar effects but a more severe side effect profile than phenobarbital. There is nothing to recommend primidone as an AED over phenobarbital.

Rufinamide

Rufinamide is licensed as an orphan drug for the adjunctive treatment of seizures in Lennox-Gastaut syndrome. It is a triazole derivative and is structurally unrelated to any other AED. Its mode of action is unknown. A serious hypersensitivity syndrome that may include rash, fever, lymphadenopathy, hepatic dysfunction, haematuria and multi-organ dysfunction has been reported upon initiation of therapy. Individuals should be warned to seek immediate medical assistance if signs or symptoms of hypersensitivity develop.

Sodium valproate

Sodium valproate is a drug of first choice for the treatment of generalised absence seizures, myoclonic seizures and generalised tonic clonic seizures, especially if these occur as part of the syndrome of primary generalised epilepsy. Tolerance to its anti-epileptic action does not usually occur. Drug interactions with other AEDs may be problematic. Phenobarbital levels increase following co-medication with valproate, and a combination of these two drugs may result in severe sedation. Sodium valproate may also inhibit the metabolism of lamotrigine, phenytoin and carbamazepine. Enzyme-inducing drugs enhance the metabolism of sodium valproate, so caution should be exercised when other AEDs are introduced or withdrawn.

Up to a third of patients may experience adverse effects, but fewer than 5% will require the drug to be stopped. Adverse effects include anorexia, nausea, diarrhoea, weight gain, alopecia, skin rash and thrombocytopenia. Confusion, stupor, tremor and hyper-ammonaemia are usually dose related. Serious adverse events, including fatal pancreatic and hepatic failure, are extremely uncommon. In children under 2 years, on other AEDs and with pre-existing neurological deficit, the risk of this is 1/500. In adults on valproate monotherapy, the risk is 1/37,000.

The usual therapeutic range quoted is 50–100 μcg/mL, although because of the lack of a good correlation between total valproate concentrations and effect, serum level monitoring of the drug has limited use. TDM should only be performed in cases of suspected toxicity, deterioration in seizure control, to check adherence or to monitor drug interactions. Routine monitoring of this drug is not necessary. Sodium valproate is more teratogenic than other commonly used AEDs and should be used cautiously in women of child-bearing age.

Stiripentol

Stiripentol is licensed as an orphan drug for severe myoclonic epilepsy of infancy (SMEI) when used in conjunction with sodium valproate and clobazam. It is an aromatic alcohol and is unrelated to any other AED. Its mode of action is unknown.

Tiagabine

Tiagabine is a drug with mild efficacy in seizure control. It is used as a second-line drug in partial seizures with or without secondary generalisation. The usual dose is between 30 and 45 mg a day, and it is normally started at 10 mg/day in two divided doses, with incremental steps of 5 mg every 2 weeks. The most common adverse events are on the central nervous system and consist of sedation, tremor, headache, mental slowing, tiredness and dizziness. Confusion, irritability and depression may occur. Increases in seizure frequency and episodes of non-convulsive status have also been reported.

So far, no life-threatening idiosyncratic reactions have been reported. Use in pregnancy is not recommended, although no teratogenicity has been reported in humans.

Topiramate

Topiramate is chemically unrelated to other AEDs and is used as a second-line drug for patients with partial seizures. Usual doses are between 200 and 600 mg/day. It has to be titrated slowly, and the recommended starting dose is 25 mg once daily, titrating upwards in 25 mg/day increments every 2 weeks up to 200 mg/day in two divided doses. After that the dose should be increased by 50 mg every 2 weeks until seizure control is achieved or side effects develop. It has no clinically significant interactions with other AEDs, although hepatic enzyme inducers accelerate its metabolism and topiramate doses need to be adjusted downwards if patients are coming off carbamazepine or phenytoin.

Side effects of topiramate include dizziness, drowsiness, nervousness, impaired concentration, paraesthesias, nephrolithiasis and fatigue. Patients starting topiramate should increase their fluid intake to reduce the risk of kidney stones. Weight loss is seen in up to 30% of patients receiving topiramate.

Vigabatrin

Vigabatrin is an inhibitor of GABA transaminase but because of a poor safety profile, it is a last resort drug for partial seizures. Vigabatrin may also be useful in West’s syndrome, particularly if associated with tuberous sclerosis. Vigabatrin does not interact with other drugs apart from decreasing phenytoin levels, probably by blocking its absorption. The most common adverse events associated with vigabatrin are behavioural disturbances, ranging from agitation and confusion to frank psychosis and visual field defects. Other known adverse effects include drowsiness, headaches, ataxia, weight gain, depression and tremor. Careful monitoring for side effects, particularly ophthalmological, on initiation of therapy is essential. Routine TDM is not available for this drug.

Zonisamide

Zonisamide, a sulphonamide analogue which inhibits carbonic anhydrase, is a potent blocker of the spread of epileptic discharges. This effect is believed to be mediated through action at voltage-sensitive sodium channels.

It is used as a second-line drug for patients with partial seizures with or without secondary generalisation. Anecdotal reports of its efficacy in other seizure types, particularly myoclonic seizures, need to be formally tested. Recommended doses are between 200 and 500 mg/day, although some patients may derive benefit from doses outside this range. The recommended starting dose for most patients is 100 mg once daily, titrating upwards every 2 weeks in 100 mg/day increments until seizure control is achieved or side effects develop. Its long elimination half-life allows once-daily dosing.

Zonisamide does not affect levels of carbamazepine, barbiturates or valproate, but may increase the serum concentration of phenytoin by about 10–15%. Zonisamide metabolism is, however, induced by carbamazepine, barbiturates and phenytoin and higher zonisamide doses may be necessary during co-administration with these AEDs.

Side effects of zonisamide include dizziness, drowsiness, headaches, hyporexia, nausea and vomiting, weight loss, skin rashes, irritability, impaired concentration and fatigue. These are mostly transient and seem to be related to the dose and rate of titration. Nephrolithiasis has also been reported, particularly in caucasians. It is not recommended for women of child-bearing age as there are issues about its teratogenic potential (Table 31.7).

Table 31.7 Common therapeutic problems in epilepsy

Problem	Comment
Hepatic enzyme induction	Enzyme induction occurs with carbamazepine, phenytoin, phenobarbital, primidone and topiramate
Hepatic enzyme induction	Interactions occur with a large number of drugs including oral contraceptives
Use of progesterone-only contraceptives with enzyme-inducing antiepileptic drug	Best avoided. If no acceptable alternative, patient should take at least double usual dose of progesterone-only pill
Use of combined oral contraceptive with enzyme-inducing antiepileptic drug	Preparations containing 50 μcg of oestrogen should be used
Continuation of antiepileptic drug during pregnancy	Ideally review before attempting pregnancy to determine if reducing or discontinuing treatment is possible
Use of phenytoin as monotherapy	Less frequently considered first-line monotherapy due to poor side effect profile, narrow therapeutic index and saturation pharmacokinetics
Prescribing of branded antiepileptic drugs	Debate continues about whether significant differences exist between generic and branded antiepileptic drugs

Evidence for clinical use of newer drugs

The evidence for the efficacy, tolerability, and safety of seven new AEDs (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam and zonisamide) in the treatment of children and adults with refractory partial and generalised epilepsies was assessed by French et al. (2004). All drugs demonstrated efficacy as add-on therapy in patients with refractory partial epilepsy. The relative efficacy of the various agents could not, however, be determined due to the differing populations and dose ranges employed in the various studies. The analysis did, however, show that for all drugs, efficacy and side effects increased with increasing dose. A slower titration of dosage improved tolerability and hence the guidance remains to start with a low dose and increase slowly until side effects occur. For efficacy it appears useful to push to maximal tolerated dose.

Wilby et al. (2005) evaluated the clinical effectiveness, tolerability and cost-effectiveness of gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate and vigabatrin for epilepsy in adults. They included randomised controlled trials (RCTs) and systematic reviews for the newer AEDs when used in the treatment of adults with newly diagnosed or refractory epilepsy and relevant comparator studies which employed older AEDs, other newer AEDs and placebo. The overall findings revealed the following:

• Minimal good-quality evidence exists to support the use of newer AEDs as part of monotherapy or adjunctive therapy over older AEDs, or to support the use of one new AED in preference to another.

• Data relating to clinical effectiveness, safety and tolerability failed to demonstrate consistent and statistically significant differences between the newer and older drugs. The exception being comparisons between newer adjunctive AEDs and placebo, where a significant difference favoured use of the newer AEDs.

• Newer AEDs used as monotherapy may be cost-effective for the treatment of patients who have experienced adverse events with older AEDs, who have failed to respond to the older drugs, or where such drugs are contraindicated.

• An integrated economic analysis suggested that newer AEDs used as adjunctive therapy were cost-effective when compared with continuing current treatment alone.

Case studies