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The new antiepileptic drugs
  1. S Macleod,
  2. R E Appleton
  1. Roald Dahl EEG Department, Paediatric Neurosciences Foundation, Royal Liverpool Children’s Hospital (Alder Hey), Liverpool, UK
  1. Dr R E Appleton, Roald Dahl EEG Department, Paediatric Neurosciences Foundation, Royal Liverpool Children’s Hospital (Alder Hey), Liverpool L12 2AP, UK; richard.appleton{at}rlc.nhs.uk

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The aim of this review is to describe the properties and uses of the more recently available anticonvulsant agents. The goal of epilepsy treatment is to achieve total seizure freedom with no side effects. Despite the appropriate use of anticonvulsants approximately 25% of children will continue to experience seizures. The development of new anticonvulsants is therefore imperative. Since the late 1980s there have been a number of new anticonvulsant agents with various modes of action and differing applications in clinical practice. Although this potentially increases the therapeutic options available to clinicians, the increased choice of drugs may also lead to irrational polypharmacy and some agents are recognised to increase seizures in certain epilepsy syndromes.

INTRODUCTION

Epilepsy is a common problem in childhood with an annual incidence of 60/100 000 children.1 The goal of epilepsy treatment is to achieve complete seizure freedom without any adverse side effects. When considering all the childhood epilepsies, approximately 25–30% of children will continue to experience seizures that are resistant to all currently available antiepileptic drugs. The term “antiepileptic” is somewhat of a misnomer because all that the current antiepileptic therapies are able to achieve—with the exception of epilepsy surgery—is to prevent seizures in someone who has epilepsy. Most but not all of these drugs are effective against tonic-clonic convulsions, which is why antiepileptic drugs may also be called “anticonvulsants”. The antiepileptic drugs that are currently available have no effect on the underlying cause of the seizures. Given the current limitations of therapy, it remains important to try and identify new drugs which are not only effective in preventing seizures and are safe, but which may also be able to act directly on the underlying cause of the epilepsy, or at least modify the pathogenesis of the seizures.

Modern epilepsy treatment began in 1857 with the introduction by Locock of bromides. In the following 100 years a number of other compounds with anticonvulsant properties were discovered, usually by chance. These included phenobarbital (1912), phenytoin (1937), sodium valproate (1963) and carbamazepine (1968). By the early 1980s there were seven or eight antiepileptic drugs available for use. However, since the late 1980s, another eight or nine have been introduced (with different licences for use in children), more than doubling the drugs that are currently available to treat the paediatric epilepsies. Although this development is to be welcomed because it provides the clinician with a greater choice of effective and, in many cases, safer drugs, it may pose some difficulties, particularly for those inexperienced in managing epilepsy. The clinician will need to have an understanding of how the drugs work, their safety profile, which drugs are most effective against the different seizure types and importantly, which drugs may exacerbate some seizure types. There is also the danger of irrational and uncontrolled polypharmacy, with the simultaneous use of more than two antiepileptic drugs. It is always easier to add rather than withdraw a drug, and this is facilitated by having a larger number of drugs available.

The aim of this review is to describe the properties and uses of a number of the more recent additions. Throughout, the terms “antiepileptic drugs” and “anticonvulsants” will be used interchangeably.

BASIS OF TREATMENT

Before discussing these new drugs it is necessary to talk about the rationale for treatment. The single most important factor is to ensure that the child has a correct diagnosis of epilepsy, and if the paroxysmal episodes are considered to be epileptic, what is the seizure type (or types if more than one type of paroxysmal episode) and what is the epilepsy syndrome. The final diagnostic question that must be considered is what is the underlying cause. This approach and the question “Is this epilepsy?” must be the mantra that is adopted for every child with paroxysmal episodes, whether referred for the first time from their general practitioner or whose seizures persist despite the use of antiepileptic medication, or for the child with “drug-resistant” or “refractory” epilepsy. Without an accurate and secure diagnosis of epilepsy, any discussion about drug treatment is irrelevant and meaningless. The diagnostic process is also vital in discussing:

  • the prognosis of not just the epilepsy (the likelihood of seizure control and eventual spontaneous seizure remission) but also the child’s likely developmental and cognitive outcome

  • the choice of antiepileptic drug.

The most widely used diagnostic scheme is the International League Against Epilepsy (ILAE) proposed scheme which looks at five separate axes:2

  • seizure or ictal manifestations

  • seizure type(s)

  • syndrome

  • underlying aetiology

  • associated impairments.

Rational therapy choices can be made according to seizure type—for example, sodium valproate is more effective than carbamazepine for primary generalised seizures (absence, myoclonic and tonic-clonic) and epilepsies. Syndrome diagnosis is also important, not only when choosing the most appropriate drug but also in avoiding worsening of the child’s epilepsy—for example, exacerbation of myoclonic jerks by lamotrigine in severe myoclonic epilepsy in infancy (Dravet syndrome) or inducing absence or myoclonic status with carbamazepine in juvenile absence and juvenile myoclonic epilepsy respectively.

Having established a diagnosis of epilepsy and the seizure type/epilepsy syndrome, the next question is when to treat. A number of the benign idiopathic epilepsy syndromes in childhood only result in a single seizure or small number (<5) of seizures. Examples of these syndromes include benign partial epilepsy with centro-temporal (rolandic) spikes, early-onset benign occipital childhood seizure susceptibility syndrome (also called Panayiotopoulos syndrome) and isolated partial seizures of adolescence. It may not be necessary to treat all children with these well-defined syndromes. However, the majority of children with epilepsy will have recurrent seizures and these seizures may include tonic-clonic seizures and therefore justify the use of antiepileptic medication. The process of choosing which drug to prescribe can be complicated and must be made with the full understanding and cooperation of the child (if they are able to understand the issues) and their carers. This discussion should include providing information (and answering questions) on epilepsy and the epilepsy syndrome, identifying the aims of treatment, written information on the drug in question including side effects and clear, written information on the starting dose and subsequent dose escalation regimes.

The ideal antiepileptic drug or anticonvulsant should have a number of properties as outlined below.

1. It should be effective

Effective can mean different things for different patients and syndromes. Ideally an antiepileptic drug should provide complete seizure freedom. However, in certain situations, as in the severe epileptic encephalopathies, a reduction in seizure frequency may be acceptable. Any anticonvulsant should exert its action rapidly, preferably within a few doses, tolerance should not develop and efficacy should be maintained over a long period of time. Finally, the drug should ideally have a broad spectrum of action, being effective against different seizure types; this would simplify the treatment of, and reduce the possibility of side effects in children with multiple seizure types.

2. Favourable pharmacokinetic properties

Pharmacokinetics refers to the way in which the body handles particular drugs. An ideal anticonvulsant drug should be readily absorbed from the gastrointestinal tract, undergo minimal liver metabolism, have linear pharmacokinetics and be excreted from the kidneys largely unchanged.

3. Favourable pharmacodynamic properties

Pharmacodynamics refers to what the drug does to the body and includes the relation between drug dosage and effects. Examples from anticonvulsant use include the induction of liver enzymes by drugs such as carbamazepine and phenytoin. It also addresses the issue of drug-drug interactions not only with other anticonvulsants, but with all other drugs.

4. Ease of use

Antiepileptic drugs should be available in child-friendly preparations and have easy dosing regimes; three times a day dosing is unattractive because it has implications for either self-medication at school or the child’s school having to take responsibility for administering the medication, which is not always possible. Many anticonvulsants are now available in liquid form or in sprinkle capsules which can be opened and sprinkled on food; unfortunately, not all children like the chosen flavour of these formulations and some of the sprinkles may “fall by the wayside”. A powder formulation that dissolves completely in water without any smell or taste (but that can then be flavoured with milk or the child’s favourite juice) and that is not gritty when swallowed would be the ideal formulation (as with the sachet formulation of vigabatrin).

5. A recognised mode of action

Current anticonvulsants have three main modes of action. They can influence voltage gated ion channels, increase inhibitory neurotransmitter levels and/or action (usually gamma amino butyric acid (GABA)) or decrease the effect of excitatory neurotransmitters (specifically, glutamate). Some of the anticonvulsants have effects on a number of these mechanisms. Vigabatrin was the first of the “designer” antiepileptic drugs, and it does appear to work through its “designed” mechanism of action (as a suicidal inhibitor of the enzyme, GABA aminotransaminase). Conversely, gabapentin does not (as might be expected from its name) exert any significant effect on the GABA system. Of the newer anticonvulsants, levetiracetam appears to have a novel mode of action.3

6. It should be safe

The anticonvulsant should have no or minimal side effects and if side effects do occur they should be predictable and reversible. All of the older anticonvulsants have significant side effects. Particularly distressing are those that affect body habitus (specifically, hirsuitism and gingival hyperplasia with phenytoin and weight gain with sodium valproate), hormonal effects with sodium valproate and potential teratogenicity for adolescent females of child-bearing age with a number of antiepileptic drugs. Recent data from the British pregnancy register have shown a significant increase in the rate of major congenital malformations in infants born to mothers taking anticonvulsants including sodium valproate, carbamazepine and lamotrigine in higher doses.4 Less common but equally worrying are idiosyncratic reactions including anticonvulsant hypersensitivity reactions. These can include potentially fatal Stevens-Johnson type reactions or valproate-induced hepatotoxicity, particularly in children under 3 years of age with a difficult-to-control epilepsy and developmental delay.

There may also be effects on cognition and learning, an area which is particularly important in school age children. Most of the older anticonvulsants have effects on cognition. In general, drugs acting via GABA potentiation (phenobarbital, benzodiazpines) result in decreased levels of alertness and slowing of mental processes.5 As yet the effects of many of the newer anticonvulsants remain unquantified. Reports of significant mental slowing with topiramate only became apparent in the post-marketing period. Further studies are required to determine the effect of anticonvulsants on cognition at this crucial period of a child’s development.

Finally, in the UK, at least two antiepileptic drugs are now only rarely prescribed, particularly in older children and adults, because of their side effects. These include felbamate, because of its reported fatal aplastic anaemia and hepatitis effects and vigabatrin, because of its reported bilateral constriction of peripheral visual fields.

Obviously, none of the currently available drugs fulfils all these criteria and can be regarded as the “ideal” anticonvulsant. It is also very unlikely (if not certain), that any of the emerging or embryonic drugs will ever achieve the ideal. Therefore, the current and future antiepileptic drugs are likely to function as what could usefully be termed a “therapeutic compromise”. Pragmatically, this means that there will be a compromise or trade-off between the drug’s effectiveness and its safety profile. A number of the newer anticonvulsants introduced over the past decade do represent definite improvements over most of the older drugs, particularly in the area of safety and adverse side effects.

Table 1 Drugs of first, second and third choice in the treatment of seizure types and epilepsy syndromes

THE NEWER OR “SECOND-LINE” ANTICONVULSANTS

These anticonvulsants have been approved for use in the last 15 years and probably many should no longer be described as new, specifically: vigabatrin (1989), lamotrigine (1992), gabapentin (1993) and possibly topiramate (1996). As is common with most pharmaceuticals, these anticonvulsants were first licensed for use in adults with drug-resistant seizures, before obtaining a paediatric licence. In addition, a number of the drugs described below do not yet have a licence in this age group and their use needs to be even more carefully discussed with families and their general practitioner (who may not agree to continue prescribing an off-label drug despite the fact that the drug was initially prescribed by a specialist in paediatric epilepsy). The drugs are discussed chronologically, in the order that they became available in the UK.

VIGABATRIN

Vigabatrin was developed as a rational anticonvulsant. It is an irreversible inhibitor of the enzyme, GABA aminotransaminase, which facilitates the catalysation of GABA. Inhibition of the enzyme increases concentrations of GABA in the pre-synaptic terminal. Vigabatrin is primarily used in the treatment of infantile spasms and occasionally for refractory partial (focal) seizures.6 It appears to be well tolerated (somnolence and headache in 10%, weight gain and an increased incidence of depression in adults) and the only known interaction with other anticonvulsants is with phenytoin, with serum levels of this latter drug being reduced by approximately 25% in one third of patients. As described earlier, vigabatrin is available as tablets and also as a powder (in a sachet) which can be dissolved in water for ease of administration in children. The drug has been shown to be effective in partial seizures, with or without secondary generalisation, and particularly when the underlying cause of the seizures is an underlying structural lesion including focal cortical dysplasia and benign brain tumours. Importantly, the drug’s efficacy seems to be maintained. It is particularly effective in the management of infantile spasms as reported in a blinded, randomised, placebo-controlled trial where 42% of patients became spasm-free and 78% demonstrated a reduction in spasms.7 It is more effective than hydrocortisone and is better tolerated than ACTH. Vigabatrin is particularly effective (and superior to both prednisolone and hydrocortisone) in suppressing spasms due to tuberous sclerosis. A more recent, unblinded and randomised study demonstrated that vigabatrin was not as effective as oral prednisolone or intramuscular tetracosactide (the synthetic form of ACTH) in the suppression of spasms due to non-tuberous sclerosis causes.8 Vigabatrin has the additional advantage that it can be continued for six months whereas ACTH has to be withdrawn, usually after a few weeks of therapy.

The predominant problem with vigabatrin is asymptomatic and bilateral visual field constriction, which only emerged some eight years after its introduction. The field defect occurs in up to 40% of adult patients and appears to be irreversible. The incidence is thought to be lower in children (20–25%) and anecdotal reports have suggested that in some children the defect may be reversible. The visual fields are constricted most prominently in the nasal fields with relative sparing of the temporal fields. Detection of visual field constriction can be easily missed with the bedside confrontation test and is best undertaken using formal Goldman perimetry. Unfortunately, this test requires significant cooperation, which can be difficult in young children and in those with learning disability; a cognitive age of 10 years is considered necessary to obtain reliable (and reproducible) visual field measurements. Consequently, the risk of developing visual field deficits has therefore limited the use of vigabatrin9 and its continuing use must be on a considered risk:benefit basis.10 The other significant problem with vigabatrin is that it can induce absence status epilepticus if used in some of the idiopathic epilepsies, particularly in childhood and juvenile onset absence epilepsy, and the drug may also exacerbate myoclonic seizures. This again emphasises the importance of correctly identifying the child’s seizure types and also having a good pragmatic knowledge about the drug.

LAMOTRIGINE

Its mechanism of action is via inhibition of voltage activated sodium channels, and possibly calcium channels, thereby preventing release of excitatory neurotransmitters, particularly glutamate. It is a broad-spectrum anticonvulsant used in both partial and generalised epilepsies. It is available in tablet and dispersible tablet form.11

Lamotrigine has a number of important advantages over many of the older anticonvulsants. Its broad spectrum of action makes it an effective choice in all focal or generalised epilepsy syndromes in childhood, data recently supported by the SANAD (Standard And New Antiepileptic Drugs) study.12 It appears to be well tolerated by children with no major cognitive or behavioural adverse effects. The combination of sodium valproate and lamotrigine may be effective in some children with the idiopathic generalised epilepsies whose seizures are not completely controlled with valproate monotherapy. Ethosuximide and lamotrigine may also be a useful combination for childhood-onset absence epilepsy.

Lamotrigine must be introduced and titrated slowly; the drug is usually started once daily, or even once every other day, with subsequent dose increases every two weeks to avoid developing the measles-like rash that may develop into Stevens-Johnson syndrome. The rash, which appears to be both idiosyncratic and dose-related, occurs in 4–7% of patients and one in 100 children will develop an acute anticonvulsant hypersensitivity reaction. This risk is reduced by a slow titration of lamotrigine and is increased with the concomitant administration of sodium valproate, which inhibits the metabolism of lamotrigine. There is some evidence that lamotrigine can be re-introduced even after the development of a rash, albeit in small doses and with a very gradual period of dose escalation, over months rather than weeks.13 Lamotrigine may also increase myoclonic seizures in severe myoclonic epilepsy in infancy (Dravet syndrome) and occasionally, juvenile myoclonic epilepsy.

GABAPENTIN

Gabapentin, a GABA analogue but whose mechanism of action appears to involve calcium channels, is licensed for use in partial (focal) epilepsies with or without secondary generalisation.

Gabapentin has a number of important advantages over the older anticonvulsants. It does not bind appreciably to plasma proteins and is excreted unchanged in the urine, it does not therefore interfere with the metabolism of other anticonvulsants. Side effects are uncommon and include somnolence, dizziness and ataxia. Behavioural changes (hyperactivity and aggression) have been reported and occur most commonly in children with pre-existing behavioural and learning difficulties. Gabapentin is available in tablets, capsules and (in the USA) as a fruit-flavoured suspension. The capsules can be opened and sprinkled on food; the bitter taste of the contents can also be partly masked with strong flavours, including blackcurrant or cola.14 15 The final problem with gabapentin is that it may have to be given three times a day, with potential concordance problems (both at home and school).

Unfortunately, despite its relatively impressive safety profile and good pharmacodynamic/pharmacokinetic properties, gabapentin appears to be less effective than most other anticonvulsants in paediatric focal epilepsies.12 Its use in children is therefore limited and currently it is being prescribed more for neuropathic pain syndromes (for example, Guillain-Barré syndrome) than epilepsy.

TOPIRAMATE

Topiramate is a broad-spectrum anticonvulsant and is licensed for use in children aged 2 years and above. It has multiple mechanisms of action, including the blockade of voltage dependent sodium channels, potentiation of GABA and by antagonism of glutamate; it is also a weak carbonic anhydrase inhibitor (weaker than acetazolamide), but this is unlikely to contribute significantly to any anticonvulsant action. It is effective in treating partial (focal), generalised tonic-clonic and some myoclonic seizures but is ineffective in treating absence seizures in childhood and juvenile-onset absence epilepsy. Largely anecdotal reports suggest that topiramate may also be useful in the treatment of some of the more severe epileptic encephalopathies, including refractory infantile spasms, Lennox-Gastaut syndrome and severe myoclonic epilepsy, particularly when used in combination with sodium valproate. Topiramate is currently available in tablet and “sprinkle” capsule form. It requires slow dose escalation (every two weeks) to avoid sedation and some of its adverse effects on the central nervous system.16 17

The two most commonly encountered side effects, both of which occur in approximately 10% of patients, are anorexia (and consequent weight loss) and behavioural changes (aggression, hostility but also depression). These appear to be largely idiosyncratic but may also be dose-related and usually occur within the first few months of starting the drug. Their persistence usually necessitates withdrawing topiramate. Other relatively common adverse effects include impaired speech and language processing (manifesting as word-finding and speech fluency) difficulties, sleep difficulties (insomnia and drowsiness) and headache. Due to its inhibition of carbonic anhydrase it can also cause nephrolithiasis (renal calculi) and glaucoma, although these appear to occur more commonly in adults than children.

LEVETIRACETAM

Levetiracetam is another broad-spectrum anticonvulsant with what appears to be a novel mode of action, binding to and modulating a synaptic vesicle (SV2A), possibly enhancing the release of inhibitory neurotransmitters such as GABA. There is also the suggestion that it might also prevent epileptogenesis which, if confirmed, would suggest that it might be the first antiepileptic drug to influence the pathogenesis of epilepsy. For similar reasons, levetiracetam is also being considered as a potential neuroprotective drug. The drug is licensed for use as an adjunctive drug in the treatment of partial epilepsies in children aged 4 years and above. Most recently it has achieved a license for treating myoclonic seizures in patients aged 12 years and above with juvenile myoclonic epilepsy. It is effective in both partial and generalised epilepsies and for treatment of epilepsy in some of the progressive myoclonic epilepsies.1820 Levetiracetam is available in tablet and liquid form. An intravenous preparation has recently been introduced which may be used when children are unable to take medications orally (for example, in the perioperative period). The manufacturer does not appear to have considered the possibility that the intravenous preparation could be used in the treatment of status epilepticus (convulsive or partial) and therefore represents a useful alternative to phenytoin, phenobarbital or sodium valproate. It will be interesting to evaluate intravenous levetiracetam in the treatment of acute, repeated seizure clusters and status epilepticus.

Levetiracetam appears to demonstrate a number of the characteristics for a new “ideal” anticonvulsant as discussed above. These include, firstly, that it is often effective at the initial dose (an important factor if the patient is experiencing frequent seizures); secondly, dose-escalation can be fairly rapid, with, if necessary, increments every five or seven days; thirdly, it is not known to interact with any other anticonvulsants (an important point in children with difficult-to-treat epilepsy). Finally, it has a good safety profile and appears to be well tolerated. The predominant side effects reported in early clinical trials include somnolence, aggressive or hostile behaviour and headache. Retention rates in clinical trials (patients leaving the trials because of adverse reactions), are approximately 10%, which compares favourably with other anticonvulsants.

OXCARBAZEPINE

Oxcarbazepine is structurally related to carbamazepine and its mechanism of actions are twofold, including blockade of both voltage gated sodium channels and voltage activated calcium channels, the latter resulting in inhibition of the release of excitatory neurotransmitters. The drug is licensed for use as monotherapy or adjunctive therapy in focal epilepsies in children age 6 years and upwards. One important advantage over carbamazepine is that it is not metabolised by the hepatic cytochrome-P450 system and therefore lacks the enzyme-inducing effects of carbamazepine. Oxcarbazepine is available in a tablet and liquid preparation.21

Plasma levels of the active metabolite are reduced by one third by phenytoin, but there do not appear to be any significant interactions with other anticonvulsants. Twenty five per cent of patients who develop a rash with carbamazepine will also develop a rash with oxcarbazepine. More severe reactions including Stevens-Johnson syndrome have also been reported. Its predominant side effects include somnolence and dizziness (most common at the instigation of therapy and thereafter subside), ataxia and diplopia. Hyponatraemia is reported more commonly than with carbamazepine and occurs in 3% of adults; it is usually asymptomatic except in those taking other drugs causing a naturesis, including diuretics and non-steroidal anti-inflammatory drugs. The most important, but uncommon, side effect is agranulocytosis leading to leucopenia, which is reversible on withdrawal of the drug. Pancytopaenia occurs very rarely.

PREGABALIN

Pregabalin is structurally related to gabapentin and has an uncertain mechanism of action. Although it is an analogue of GABA, it is inactive at the GABAA and GABAB receptors. It appears to reduce the release of excitatory neurotransmitters by binding to voltage gated calcium channels. The drug has a licence for the adjunctive (add-on) treatment of refractory focal seizures with or without secondary generalisation in patients aged 18 years and above. There are as yet no data in the literature regarding the use of pregabalin in the paediatric epilepsies. It can exaggerate myoclonic seizures limiting its use in generalised epilepsies. There are no known interactions with other anticonvulsants and it is eliminated largely unchanged through the kidneys. The most commonly reported side effects include somnolence, dizziness and weight gain in up to 6% of patients

ZONISAMIDE

Zonisamide belongs to the sulphonamide group of drugs with mechanisms of action that include blockade of sodium channels, reduction of voltage dependent T-type calcium currents (like ethosuximide) and reduction of glutamate-induced synaptic transmission. In the UK it is licensed for use in focal seizures with and without secondary generalisation in patients aged 18 years and above. The drug has been prescribed in Japan and the USA for over a decade and considerable, mostly anecdotal, data in both children and adults from these countries suggest that it might be effective in treating a number of different seizure types in a number of epilepsy syndromes, including West syndrome (infantile spasms), Lennox Gastaut syndrome and Ohtahara syndrome.22 23 There are few reports that it might be effective in treating refractory absences in the idiopathic generalised epilepsies. Clearly, confirmation of these data would suggest that the drug may have a relatively broad spectrum of action.

Zonisamide is metabolised in the liver and its metabolism is therefore increased by the concomitant use of enzyme-inducing drugs such as carbamazepine. Significant side effects occur in between 26% and 36% of patients, including sedation, somnolence, fatigue and irritability. Because of its carbonic anhydrase inhibiting properties nephrolithiaisis occurs in 4% of adults on long-term zonisamide therapy; the incidence is much lower in children.

STIRIPENTOL

Stiripentol is a relatively new anticonvulsant drug which as yet, is not routinely available in the UK but can be imported from France. Its mechanism of action is not yet clear although a recent study demonstrated enhanced GABA release and prolongation of GABAA mediated currents, possibly at the same locus as barbiturates. The drug inhibits several cytochrome P450 enzymes, thereby reducing oxidative degradation of a number of anticonvulsants. This initially led to stiripentol being used in conjunction with sodium valproate and clobazam in SMEI. However, the drug also appears to have independent anticonvulsant properties.

Stiripentol is used primarily in focal epilepsies and in severe myoclonic epilepsy in infancy (SMEI; Dravet syndrome). Adverse effects occur relatively frequently with stiripentol, particularly when administered with other anticonvulsants. Commonly reported neurological side effects include somnolence, ataxia, diplopia and hypotonia. Many of these side effects appear to be reduced with reduction in co-medications. Gastrointestinal side effects include anorexia and weight loss.24 25

RE-EMERGENCE OF OLDER ANTICONVULSANT AGENTS

Within the past few years there has been a re-emergence of two older anticonvulsant agents—bromide salts and sulthiame. Bromide salts were the first of the modern anticonvulsant agents but were rapidly replaced by phenobarbital and phenytoin in the first part of the 20th century. Some reports have suggested its efficacy in a number of different epilepsy types, in particular refractory generalised tonic-clonic seizures and in malignant migrating partial epilepsy in infancy. Bromide salts have a significant side-effect profile and require careful monitoring of plasma bromide levels. Because of the side-effect profile the role of bromide salts in childhood epilepsy seems to be confined to severe refractory epilepsies.26

Table 2 Paediatric maintenance dosages of antiepileptic drugs

Sulthiame, structurally related to acetazolamide, is a central carbonic anhydrase inhibitor introduced in the 1960s. It was initially thought to exert its antiepileptic properties only as an adjunctive medication and concerns about its toxicity resulted in it being abandoned by epileptologists in the UK; reported toxicity included hyperpnoea, dyspnoea, poor coordination and, rarely, psychosis. Recent data, mainly from mainland Europe and the Middle East, have seen resurgence in the use of sulthiame particularly in the treatment of benign partial epilepsy with centro-temporal (rolandic) spikes.27 However, the drug has also been reported to be effective in some patients with myoclonic-astatic epilepsy (Doose syndrome), refractory absence seizures and electrical status epilepticus of slow-wave sleep.28

THE FUTURE

There are a large number of new anticonvulsants in various stages of development. Some of these exert their antiepileptic or anticonvulsant effect by known mechanisms and are “updates” on the established agents. Examples include remacemide, rufinamide, valrocemide (valproate-like) and selereracetam and brivaracetam (levetiracetam derivatives). Others, including lacosamide, a functionalised amino-acid, are completely novel antiepileptics with an as yet unknown mechanism of action.29

Not surprisingly, but perhaps somewhat belatedly, there is now intense interest in antiepileptogenic or disease modifying agents, drugs that might prevent the development of established epilepsy or, by acting through neuroprotective mechanisms, prevent the development of epilepsy in the first place (for example, following traumatic brain injury or neonatal hypoxic ischaemic encephalopathy).30

SUMMARY

There are a large number of new anticonvulsant agents available to the clinician. Many of these agents have a significant advantage over older drugs in terms of their side-effect profile and pharmacokinetic/dynamic properties. The improvement in efficacy is less impressive and one in three to one in four children still have refractory, drug-resistant epilepsy. Further research is certainly needed to assess the efficacy of new antiepileptic/anticonvulsant drugs but these newer agents must offer significant advantages over the currently available drugs to justify the costs of both their development and their prescribing within the National Health Service. Drugs should be developed that have clear antiepileptogenic properties that could actually prevent the development of epilepsy itself. Comparative “head-to-head” trials (such as the SANAD study), and preferably in specific epilepsy syndromes, should facilitate a more individual approach when treating the paediatric epilepsies.

REFERENCES

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Footnotes

  • Competing interests: Dr Appleton has in the past received honoraria and consultancy fees from the following: Hoechst Marion Roussel, Glaxo-Wellcome, Parke-Davis, Sanofi-Winthrop, Janssen Cilag, UCB Pharma and Eisai.

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