[1]
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Generalised seizures include tonic-clonic seizures, absences, myoclonic jerks, and, more unusually, atonic and tonic seizures and epileptic spasms [1]. Onset of seizure activity is usually in childhood, adolescence or early adulthood. In 2017, the International League Against Epilepsy (ILAE) published an updated classification of seizures and the epilepsies [2]. In this expert review, we discuss the pharmacological management of the common genetic generalised epilepsy (GGE) syndromes, childhood (CAE) and juvenile absence epilepsies (JAE), juvenile myoclonic epilepsy (JME) and generalised tonic-clonic seizures (GTCS) on awakening. Characteristics of these syndromes are detailed in Table 1.
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The diagnosis of generalised epilepsy is generally clinical; patients with these seizure types typically show generalised spike-wave activity on the electroencephalogram
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Treatment of the genetic generalised epilepsy syndromes involves largely the use of broad-spectrum antiseizure drugs Despite treatment, some patients with genetic generalised epilepsies do not become seizure free or relapse when treatment is discontinued Management of young women with genetic generalised epilepsies can be challenging given the issues surrounding valproate in this population epilepsies include sodium valproate (VPA), phenobarbital (PB), ESM, clobazam (CLB), clonazepam (CLZ), lamotrigine (LTG), levetiracetam (LEV), topiramate (TPM), zonisamide (ZNS) and, more recently, perampanel (PER) and brivaracetam (BRV). We review the practical use of these agents and their adverse effects and drug interactions. Considerations relevant to treating the GGEs, including lifestyle issues, are essential to ensure an optimal outcome for these often young and vulnerable patients.
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Evidence for this expert opinion review has been gathered by searching Ovid (1946Ovid ( -2019) ) and EMBASE (1974EMBASE ( -2019) ) databases and the Cochrane Library via the National Health Service Scotland Knowledge Network for articles published in English using the following MeSH terms 'genetic and generalised and epilepsy', 'idiopathic and generalised and epilepsy', 'genetic and epilepsy', 'idiopathic and epilepsy', 'generalised and epilepsy', 'antiepileptic drug and epilepsy', 'antiepileptic drug and seizures', 'generalised and tonic-clonic', 'absence and seizures' and 'myoclonic and seizures', as well as searching for relevant articles using the antiseizure drugs discussed in the article as search terms.
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Valproate is generally regarded as the most effective treatment for GGE in adults [1,20] and in children [21]. The antiseizure properties of VPA were first recognised by chance in France in 1963, where it was first licensed in 1967. Available as valproic acid, sodium valproate (Fig. 1) and valproate semisodium, it has the broadest spectrum of activity for a range of seizure types, including absences, myoclonic jerks and tonic-clonic seizures. The exact mechanisms of action are unclear, but VPA is thought to have an antiseizure effect through indirectly increasing GABA transmission [22]. It may also have an effect on voltage-gated sodium channels. Dosing is usually twice daily in children and adults, although it can be used once daily in an extended-release formulation or even three times daily in an enzyme-induced patient. The reference range for serum concentration monitoring is 40-100 mg/L.
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Common side effects with VPA include weight gain due to appetite stimulation, tremor, drowsiness, hair loss and gastrointestinal disturbances. Some young women taking VPA complain of menstrual irregularities or even amenorrhoea with associated polycystic ovarian syndrome [23]. Thrombocytopenia can occur at a high dosage. Rare, but serious problems include acute pancreatitis, liver damage and stupor secondary to hyperammonaemia [1]. Valproate use has been restricted in Europe in women of childbearing potential because of concerns of dose-dependent teratogenicity, neural tube defects and neurodevelopmental abnormalities [24].
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Enzyme-inducing drugs, such as PB, phenytoin, carbamazepine and rifampicin, and carbapenem antibiotics reduce VPA concentrations, whereas stiripentol and isoniazid can increase its circulating concentrations. Valproate itself will inhibit the metabolism of a number of drugs, particularly that of PB and LTG [25].
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Lamotrigine, a phenyltriazine derivative (Fig. 1), was originally launched in 1990 and has long been recognised as a broad-spectrum antiseizure drug. Lamotrigine is effective for tonic-clonic seizures, but it is less useful for absences [7]. The situation with myoclonic jerks is also less clear cut with evidence of benefit in some patients with JME [26] and the potential for seizure exacerbation in others [27]. Onceor twice-daily dosing is recommended when LTG is used as monotherapy or together with VPA, a combination for which there is evidence of synergism [28].
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Like all sodium channel blockers, LTG can cause dizziness, diplopia, ataxia, blurred vision, headache and nausea [29]. It can cause both sedation and insomnia. A slow introduction is necessary to reduce the risk of allergic rash. Other severe idiosyncratic reactions with LTG include Stevens-Johnson syndrome and toxic epidermal necrolysis [30]. Agranulocytosis and hepatoxicity are also unusual allergic manifestations associated with its use.
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Different dosing schedules are needed when introducing LTG in patients receiving enzyme-inducing anti-epileptic drugs (AEDs), including PB, phenytoin and carbamazepine.
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Other inducers, such as rifampicin, reduce LTG circulating concentrations by 50%. Lamotrigine concentrations are doubled with VPA coadministration [29]. Lamotrigine circulating concentrations are halved by the administration of oral contraceptives containing ethinylestradiol and levonorgestrel [31].
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Topiramate, a sulfamate-substituted monosaccharide (Fig. 1), has been in everyday use in the UK since 1995 both as antiseizure monotherapy and as an adjunctive treatment. It acts to inhibit excitatory transmission through kainite and AMPA glutamate receptors, as well as acting at sodium and calcium channels and being a carbonic anhydrase inhibitor [32]. Topiramate has a broad spectrum for the seizure types making up the GGEs, including, absences, myoclonic jerks and tonic-clonic seizures.
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Side effects of TPM are usually confined to the nervous system and can include headache, dizziness, nausea, diarrhoea, tiredness, tremor, paraesthesia and ataxia [1]. Reduced appetite and weight loss are common problems. Uniquely, TPM can cause cognitive slowing and word-finding difficulties particularly at higher doses [33]. The drug can have a negative effect on mood and occasionally can cause or worsen aggression and psychosis [34]. Rare adverse events include the development of renal stones and glaucoma [1]. Topiramate is teratogenic, particularly associated with the production of facial clefts [35].
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Circulating TPM concentrations are lowered by the broadspectrum enzyme inducers, PB, phenytoin and carbamazepine [36]. At a high dosage (≥ 200 mg/day), it can decrease the circulating concentration of ethinylestradiol, the oestrogenic component of the oral contraceptive pill [37].
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Levetiracetam, the (s)-enantiomer of the ethyl analogue of piracetam (Fig. 1), was first licensed in 1990 for focal seizures and it took some years before its broader spectrum for CAE, JAE and GGEs with myoclonic jerks was appreciated.
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The drug binds to the synaptic vesicle protein 2A receptor via, which it is thought to exert its antiseizure properties [38].
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Levetiracetam is generally well tolerated, although headache, tiredness, poor appetite, nausea and vomiting have been associated with its introduction [1]. Behavioural and psychiatric symptoms are common complications. Levetiracetam can cause or exacerbate anxiety, depression and psychosis and also irritability, emotional lability, agitation and aggression. All these problems should be anticipated and treated as they can lead to disruption of everyday life and occasional disruptive and violent behaviour [39]. Accordingly, the drug should be avoided in patients with a history of anger management issues, hostility or, even, impulsivity.
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Enzyme-inducing agents, including antiseizure and other drugs, can reduce LEV concentrations by around 20% [40].
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Perampanel, an AMPA glutamate receptor antagonist (Fig. 1), was launched in Europe in 2012 and it was some time later that its use for GGEs was approved following completion of a placebo-controlled adjunctive trial [9]. Efficacy for myoclonic jerks appeared likely, but not for absences [41]. Its very long elimination half-life allows PER to be prescribed once daily, usually in the evening.
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The most common adverse effects with PER reported in the regulatory trials were dizziness, somnolence, fatigue, irritability, nausea and falls [42]. Weight gain may also occur [43]. However, the most problematic issue with the use of PER is its propensity, at doses of 8 mg daily or more, to cause or worsen psychiatric and behavioural adverse events including, in particular, anger, hostility and aggression [44].
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Phenytoin, carbamazepine and oxcarbazepine can increase PER clearance and decrease its circulating concentration by 50% or more [45]. At doses of 12 mg daily or above, PER decreases levonorgestrel exposure in women taking hormonal oral contraceptives [41]. Ketoconazole slightly increases the area under the PER concentration-time curve by 20%, thereby prolonging its elimination half-life by around 15% [41].
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Zonisamide, a sulfonamide (Fig. 1), is thought to exert its antiseizure properties through blockage of the repetitive firing of voltage-sensitive sodium channels and reduction of voltage-sensitive T-type calcium currents without affecting L-type calcium currents [46,47]. It has been shown to inhibit excitatory glutamate-mediated synaptic transmission, as well as to have effects on GABA function. It is also a carbonic anhydrase inhibitor. Despite substantial clinical experience with this broad spectrum antiseizure drug, its efficacy for GGEs has not been formally assessed in randomised placebo-controlled trials.
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Common problems with ZNS include sedation, nausea, vomiting, anorexia and weight loss [12]. It can cause or worsen poor concentration, irritability, agitation, psychosis and depression [48]. Skin rashes are uncommon, but unusual cases of agranulocytosis and aplastic anaemia have been reported. Renal calculi can occur in long-term usage [49] and hypothermia and oligohydrosis have been reported in hot climates [50].
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Circulating ZNS concentrations are lowered by PB, phenytoin and carbamazepine [36].
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Ethosuximide, a succinamide with anticonvulsant activity (Fig. 1), has a narrow spectrum of activity largely confined to absence seizures, for which it has been used since 1956. Its mechanism of action is thought to be via blockade of T-type voltage-sensitive calcium channels [22]. Dosing frequency is two to three times a day.
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The most common problems with ESM include gastrointestinal symptoms, such as anorexia, nausea, vomiting, diarrhoea and abdominal pain [1]. Headache, dizziness, drowsiness and lethargy can also occur. Reported behavioural problems with ESM include euphoria, irritability, aggression and psychiatric disorders. Idiosyncratic reactions such as rash, Stevens-Johnson syndrome, aplastic anaemia, agranulocytosis, hepatotoxicity and a lupus-like syndrome are unusual complications of ESM administration [51].
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Ethosuximide blood concentrations can be reduced by enzyme inducers, such as PB and rifampicin [36]. The drug itself has a low potential for drug interactions.
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Phenobarbital, a long-acting barbituric acid derivative (Fig. 1), was first made available in 1912 for treating epilepsy and is still widely used around the world [52]. The antiseizure effect of phenobarbital is via increasing postsynaptic inhibition at GABA A receptors [52]. Phenobarbital has a broad range of efficacy including for myoclonic jerks and tonic-clonic seizures but is not effective for absences.
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Frequency of dosing is one to two times daily. The reference range for PB serum monitoring is 10-40 mg/L.
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Most adverse effects with PB are dose dependent, including sedation, dizziness and ataxia. Paradoxically, aggression, insomnia and hyperactivity can occur in children. Rashes and other severe idiosyncratic reactions, such as aplastic anaemia, hepatotoxicity and a lupus-like syndrome, are unusual complications of its use [52]. Impotence can occur with PB, and chronic problems include Dupuytren's contracture, retroperitoneal fibrosis and frozen shoulder.
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Phenobarbital is a potent broad-spectrum enzyme inducer that can accelerate the metabolism of a range of lipidsoluble agents, including other antiseizure drugs [53]. The result is around a 50% drop in circulating concentrations of induced agents. Endogenous problems, such as osteomalacia, osteoporosis, sexual dysfunction and vascular diseases, include myocardial infarction and stroke, have been recognised as long-term problems secondary to enzyme induction [36]. Phenobarbital is also teratogenic [24].
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Clobazam, first introduced in 1977, can be used as monotherapy and an adjunctive treatment for a range of generalised epilepsies, including myoclonic jerks and tonic-clonic seizures. The drug is a 1,5-benzodiazepine (Fig. 1) and a partial GABA receptor agonist [54]. It can be taken once or twice daily. Clobazam has less sedative properties than the other benzodiazepines because of a slight difference in its chemical structure [55].
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The most common adverse effects are sedation, dizziness and ataxia [56]. Mood and behavioural changes can also occur [57].
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Clobazam clearance can be increased by enzyme-inducing agents, including other antiseizure drugs [36].
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Clonazepam, a 1,4-benzodiazepine (Fig. 1), has been used since the late 1960s for the treatment of a range of seizure types. It exerts its antiseizure effect through facilitation of GABAergic transmission [22]. It has particular efficacy for myoclonic jerks in GGEs [58]. Clonazepam is also effective against absence, atonic-akinetic, tonic, and tonic-clonic seizures. Once-daily dosing at bedtime is usually preferred.
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Drowsiness and ataxia are the most common adverse effects with CLZ in adults [1]. Behavioural changes can be problematic in children and adolescents, including irritability and aggression [59]. Treatment with CLZ may cause or worsen depression [60].
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Clonazepam clearance is increased by enzyme-inducing agents, including other antiseizure drugs such as PB, phenytoin and carbamazepine [36].
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Brivaracetam, a racetam derivate of LEV (Fig. 1), is the most recently launched antiseizure drug, which first became available in 2016 [61]. Like LEV it binds to the synaptic vesicle protein 2A receptor, although this molecule undergoes more selective binding with a 15-to 30-fold higher affinity [62]. Brivaracetam is thought to be better tolerated than LEV causing fewer and less severe psychiatric adverse effects [61]. Twice-daily dosing is appropriate for adults and children, although experience with BRV with children is still relatively limited. Switching from LEV to BRV at a ratio of 15:1 is possible [63].
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Common adverse effects with BRV comprise headache, somnolence, dizziness, fatigue and nausea [64]. Irritability, agitation, anxiety, insomnia, aggression and depression have also been reported with BRV, but in less than 3% of patients [61].
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Enzyme-inducing antiseizure drugs decrease BRV concentrations by 30%, while rifampicin drops the circulating concentration by approximately 45% via a similar mechanism [65].
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The diagnosis of absence seizures is often clinical, based on a witnessed history of episodes. There may be a family history of epilepsy. It can be challenging to differentiate ictal episodes from behavioural episodes in some patients and an EEG, with or without a video, can be useful in this respect. Early counselling regarding the diagnosis, management and potential outcomes will give the patient and clinician opportunities to address any issues arising and may help to foster realistic patient expectations. Epilepsy specialist nurses are often best placed to provide counselling. Prior to starting antiseizure treatment, the patient, and where appropriate his/her parents or carers, should understand the benefits of long-term medication and potential outcomes. Low initial dosing and slow titration can maximise the patient's tolerance of a new antiseizure drug. Ethosuximide (250 mg daily or twice daily) is a reasonable first drug with the dose titrated according to efficacy and tolerability. If seizure control is not achieved, switching to an alternative agent such as LEV or VPA (where appropriate) is worthwhile. If control still proves elusive, duotherapy and polytherapy regimens can improve the outlook in some patients [115]. In children, dosing according to weight is often necessary, with appropriate adjustments according to growth (Table 3). The majority of patients with absence seizures will become seizure free with antiseizure monotherapy, but seizures will persist or return after a period of seizure freedom in a minority of patients, requiring the use of higher doses or polytherapy. Some patients, who have been seizure free for a sustained period of time, will be able to discontinue antiseizure treatment. Others will require medication indefinitely [116], particularly if they relapse with a reduction in dosing or antiseizure drug withdrawal, or develop other seizure types. Genetic testing can help identify an underlying cause in some patients.
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In older children, teenagers and young adults, GTCS can manifest as a component of JME or GTCS on awakening. Juvenile myoclonic epilepsy can occur in patients already diagnosed with absence epilepsies [117,118], or can manifest de novo with GTCS and myoclonic jerks with or without absences [119]. Prior to starting antiseizure treatment, discussion regarding potential side effects, optimal adherence and lifestyle factors such as alcohol use and abuse, recreational drugs and sleep deprivation is of prime importance [110]. The impact of the diagnosis on driving, employment and hobbies should also be discussed. Counselling regarding the morbidity and mortality (including sudden unexpected death in epilepsy) associated with seizures helps to inform the patient about the risks associated with epilepsy [120]. If photosensitivity has been demonstrated on the EEG, the importance of avoidance procedures regarding flashing lights should also be raised [27,121]. Data suggest timely initiation of VPA will provide the best outcome for these patients [66,122], but this drug has drawbacks for young women (see below) and thus is often not the drug of first choice. Where VPA is initiated, seizure control can be achieved with daily doses ≤ 750 mg [123]. In patients for whom VPA is not a suitable first antiseizure drug, LEV, LTG, TPM, PER, ZNS, or BRV in low doses are reasonable alternatives. Doses can be increased if further seizures occur. Where appropriate, the synergistic combination of VPA and LTG can be particularly effective [29]. Slow titration of LTG is essential to reduce the risk of rash and other idiosyncratic reactions [30] and the drug may need to be discontinued if these side effects occur. At the Glasgow clinic, patients also achieved seizure freedom when LEV was combined with LTG, TPM or VPA [115].
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Juvenile myoclonic epilepsy is recognised to have lifelong medical and psychosocial comorbidities. Depression, anxiety, sleep disturbance, impulsiveness, social isolation and unemployment not uncommonly complicate the lives of these patients [124][125][126]. Not infrequently, these factors contribute to inadequate seizure control [110]. Screening for psychiatric conditions should be considered in these patients [110] many of whom may benefit from pharmacological or non-pharmacological treatment [127]. Patients prescribed LEV, BRV, TPM, PER or ZNS should be counselled about the possible negative effects on mood of these antiseizure drugs.
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Anti-epileptic drug treatment is often lifelong in patients with GGEs [150]. Some patients do manage to discontinue medication and remain seizure free, but others relapse [151][152][153][154][155], often requiring antiseizure drugs indefinitely. Achieving positive seizure outcomes in this population is hampered by the limited therapeutic selection available for these syndromes. Given that there are currently no regulatory studies of antiseizure drugs for GGEs planned, this situation is unlikely to alter in the immediate future. While some patients will control on their first agent, others, particularly those prone to side effects, will be switched from drug to drug in the search for a tolerable efficacious medication. Adherence can be an issue in this population, especially for patients who have memory problems, addiction issues, and chaotic lifestyles and for those who have difficulties coming to terms with the diagnosis of epilepsy. Other medical diagnoses are common and, together with comedication, may hamper positive outcomes [156].
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Many patients, particularly those with JME [43], develop, or already have psychiatric comorbidities that worsen the prognosis, both in terms of seizure control and quality of life. Frontal lobe dysfunction, which can present with the diagnosis of JME, can adversely affect the long-term outlook, regardless of the nature of seizure control [43,157]. Ongoing management of GGEs in adolescents and adults requires consideration of psychosocial and behavioural factors that can complicate diagnosis and treatment. Lifestyle issues can also impact significantly on the individual as well as society [158]. For example, physical fitness testing showed children and teenagers with GGEs who had been seizure free for at least 6 months had lower fitness compared with healthy controls [159]. In adults, a questionnaire-based study in the Americas and Europe found that poorly controlled GGE is associated with increased healthcare utilisation, poorer education, lower household income, lower employment and long-term disability [160]. These factors result in direct and indirect financial costs for communities.
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It is important that clinicians managing patients with GGEs are aware of the widespread implications of these syndromes and the detrimental impact the diagnosis can have on quality of life. Neurologists often have long-term relationships with their patients, many of whom will be followed up for years. Liaison with other healthcare professionals, social services and third-sector organisations may be required throughout this time. Consistent, assured support, and a flexible non-judgemental attitude can help build and maintain a positive relationship that will be of benefit over the years to the patient and the clinician. These measures will help to optimise prognosis in these complex and challenging seizure disorders.
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A number of antiseizure drugs are available for the treatment of the GGEs. Licensing details are discussed below, together with the characteristics of different drugs. Comparative and other antiseizure drug clinical trial data in patients with GGEs are outlined. Childhood absence epilepsy [81] Typical absence seizures (12-60% also have GTCS) < 5 2-5:1 Bilateral, synchronous, symmetrical 3-Hz spike wave discharges on a normal background Photoparozysmal response in 18% Juvenile absence epilepsy [81] Typical absence seizures (80-83% also have GTCS) (20% also have myoclonic seizures) 9-13 1:1 Bilateral, synchronous, symmetrical 3-Hz (can be 3.5-4 Hz) spike wave discharges on a normal background Photoparoxysmal response in 7.5% Juvenile myoclonic epilepsy [81,151] GTCS, absence, myoclonic seizures 11-13 1:1 Rapid, generalised (irregular) spike waves and polyspike wave Photoparoxysmal response in 14-75% GTCS alone [119,161] GTCS 20-30
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1.2:1 Generalised spike wave discharges (most commonly 4-6 Hz) and polyspikes Photoparoxysmal response in 13-62.5%
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(EEG) [2]. However, some patients can have clinical seizure activity with a normal EEG [2]. Genetic generalised epilepsy syndromes are also referred to as idiopathic generalised epilepsies. The word 'idiopathic' is derived from the Greek term 'idios', which means 'one's own' or 'belonging to', and eludes to the premise that a genetic aetiology can play a part in these syndromes. The 2017 ILAE Classification Commission therefore proposed that it would be more meaningful to refer to these syndromes as GGEs where there is sufficient evidence for this classification [2]. Although genetic components have been revealed in some patients with these syndromes, these are rarely straightforward and tend to be heterogeneous [3]. Treatment of GGE syndromes involves largely the use of broad-spectrum antiseizure drugs. The exception is ethosuximide (ESM), which has specific efficacy for absence seizures [4], although it may be useful as an adjunct to treat myoclonic seizures [5,6]. Drugs effective for the generalised Current licensing regulations based on class III and class IV evidence support the use of VPA, LTG and TPM as initial monotherapy in GTCS in patients with GGEs [7]. Having proved superior to placebo, LEV is licensed as adjunctive therapy for the treatment of GTCS and myoclonic seizures [8]. The use of PER as add-on therapy for GGEs was approved following positive efficacy outcomes from a placebo-controlled adjunctive trial [9]. Although encouraging results have been achieved with adjunctive ZNS in observational studies of GGEs [10][11][12][13], there are no regulatory trial efficacy data and therefore the drug is not licensed for this indication. Ethosuximide is licensed for use as monotherapy for absence and myoclonic seizures and as adjunctive therapy for atypical absence seizures [5,6]. Prior to the introduction of VPA, PB and primidone were documented to control seizures in 80% of patients with JME [14]. These drugs were used widely in epilepsy prior to the introduction of other antiseizure medications, but are still prescribed in countries with limited resources [15]. Like CLB [16] and CLZ, also prescribed in GGEs and ESM, prescribed mainly in CAE and JAE, there are no placebo-controlled studies of these drugs, but licenses have been granted on a grandfather clause [15]. Brivaracetam is not licensed in GGEs and there are no regulatory trial data of the drug in this setting although preclinical studies and clinical regulatory data suggest BRV may have broad-spectrum efficacy [17][18][19]. The characteristics of these antiseizure drugs are discussed in detail below. Pharmacological properties and dosing are detailed in Tables 2 and 3. Other antiseizure drugs, namely lacosamide and acetazolamide, which do not have a license for use in GGEs, but for which few supportive data exist, are mentioned in the epilepsy syndrome discussions.
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When selecting an antiseizure drug for patients with GGEs, comparative outcome data for different syndromes can help inform choices. For GGEs in general, results from two multicentre randomised studies of antiseizure drugs are available [66,67]. The SANAD study randomised adult patients with newly diagnosed epilepsy in equal proportions to receive VPA, LTG and TPM [66]. In the 272 patients classified as having GGEs, VPA was significantly better for time to treatment failure than LTG (95% CI 1.55 [1.07-2.24]) and TPM (95% CI 1.89 [1.32-2.70]), and for time to 12-month remission, VPA was better than LTG (95% CI 0.68 [0.53-0.89]), but was not significantly different to TPM [66]. In this study, 42 patients had GTCS and a review of evidence suggests VPA should be the antiseizure drug of first choice in this setting [68].
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In a multicentre randomised open-label study comparing outcomes with LTG and LEV in adolescents and adults with newly diagnosed epilepsy, no differences in efficacy were found between the two drugs in the patients with GGEs (LTG, n = 73; LEV, n = 71) [67]. Results from the SANAD 2 multicentre randomised study comparing LEV with VPA for GGEs are imminent, with preliminary outcomes suggesting VPA is more effective than LEV in this setting.
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A variety of studies employing different designs have explored outcomes with antiseizure drugs in absence epilepsies [4]. A large randomised double-blind study in 453 children with new-onset CAE compared outcomes with ESM, VPA and LTG [4]. Over a 16-week treatment period, 156 children were randomised to receive ESM, with 149 receiving LTG and 148 VPA. Dose titration continued until freedom from absence and GTCS occurred or side effects limited further dose increases. Ethosuximide and VPA were found to be more effective than LTG (p < 0.001 for both), and ESM was associated with fewer adverse effects [4]. These effects were still present at the 12-month follow-up [69]. A meta-analysis of eight small studies in 691 patients concluded that for patients with absence seizures, ESM was the most effective drug; VPA was the drug of choice for patients with absence and tonic-clonic seizures [70]. Levetiracetam can be useful in patients with absence epilepsies, with one quarter of 72 children becoming seizure free over 5 years taking the drug [71]. Lamotrigine and LEV are less efficacious alternatives [70,71]. Some patients with myoclonus also responded well with LEV [72,73].
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Five of 13 patients with difficult-to-control JAE became seizure free with adjunctive ZNS over a mean period of 34 months [74]. All three patients with absence seizures in a multicentre observational study who were treated with BRV for 3-12 months experienced an improvement in seizures [75]. Successes have also been reported for patients with absence seizures in case studies [76]. A handful of patients with CAE and two patients with absence status epilepticus did not improve with BRV [77]. More robust studies are also needed to examine whether BRV is useful for absence epilepsies. There are a handful of case reports to suggest that lacosamide may be useful in some patients with absence status epilepticus [78].
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Despite JME accounting for 5-10% of all epilepsies and around 18% of GGEs [79], there are no double-blind randomised placebo-controlled or double-dummy trials comparing antiseizure drugs [80]. However, data from the SANAD open-label, randomised study supported the superior efficacy of VPA compared with LTG or TPM [67]. A number of observational studies have also found VPA to have efficacy for myoclonic seizures in patients with GGEs [81][82][83]. In a selected cohort of Indian patients with JME, 80.6% remained seizure free for 15 years on VPA monotherapy [84]. In 186 patients with JME in the Glasgow Epilepsy Unit, 73% achieved remission with a median VPA dose of 1000 mg daily (range 400-2500 mg daily) [85]. Women tended to have a worse prognosis than men in this study, as they were increasingly less likely to receive VPA as a first or second drug choice. Co-existing psychiatric disorders have been significantly associated with a lack of response to VPA [86,87].
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The EpiPGX consortium retrospective database study of 305 patients participating in 688 trials of antiseizure drugs for JME, namely VPA, carbamazepine, LTG, LEV and TPM, found that VPA was most likely to produce ≥ 12 months' seizure freedom (42.7%), but together with TPM, was associated with the highest side effect rate [88]. Two short openlabel randomised studies comparing VPA with TPM in a small number of patients with JME showed no significant difference between the drugs [89,90]. A recent meta-analysis of three studies in 83 patients with JME concluded that TPM seemed to be better tolerated than VPA, but had no clear benefits in terms of efficacy [91].
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Levetiracetam also has efficacy for seizures associated with JME. Two large placebo-controlled studies of adjunctive LEV in patients with drug-resistant GGEs found reductions of 62.8% vs 24.7% and 58.3% vs 23.3%, respectively, against placebo for number of seizure days per week [8,92]. A sub-analysis of both studies combined confirmed a significantly better response rate for LEV vs placebo in patients with JME [93]. Further observational data support the efficacy of LEV in patients with newly diagnosed JME [85,94,95].
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Some patients with JME will improve with TPM. An analysis of outcomes from a placebo-controlled study of adjunctive TPM in 22 patients with JME and uncontrolled GTCS found the AED reduced the frequency of all seizure types associated with JME [96]. In an open-label observational study of 23 patients with JME randomised to VPA or TPM over 24 weeks, efficacy outcomes were similar for the two AEDs and adverse effects associated with TPM were less severe [90]. However, others have found TPM to be more often linked to neuropsychological dysfunction than VPA in patients with JME [97]. In the Glasgow prospective observational study of adjunctive TPM in 36 patients with GGEs, 11 became seizure free for at least 6 months, nine with GTCS and two with JME [98].
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Zonisamide can benefit patients with JME [11,12,99]. In a prospective observational study of adjunctive ZNS, of 60 patients with difficult-to-control GGEs, nine became seizure free for a 6-month period of seizures comprising GTCS, absence and myoclonic seizures [12]. In a multicentre randomised placebo-controlled study of adjunctive PER for GTCS in patients with GGEs, patients receiving PER reported a reduction in the frequency of other seizure types, including absence and myoclonic seizures [9].
[13]
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One small retrospective study of adjunctive BRV in 61 patients, of whom 16 had JME and four had childhood absence epilepsy, found 40% of those with JME became free of all seizures, with a 50% responder rate in 60% [77]. There are case reports of patients with JME and other GGEs improving with the addition of lacosamide [100,101]. In an open-label pilot safety study of adjunctive lacosamide in 49 patients with GGEs and GTCS, the drug was well tolerated and did not worsen myoclonic or absence seizures [102]. Lacosamide has been used successfully to treat absence status epilepticus in a handful of patients [103,104]. Other drugs with likely efficacy in patients with GGEs include CLZ [105] and acetazolamide [106]. As a last resort, vagal nerve stimulation might be an option for some patients with GGEs refractory to AED treatment-a few small observational reports suggesting similar or greater efficacy of vagal nerve stimulation in refractory GGEs compared to focal epilepsies [107,108].
[14]
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Lamotrigine [109], carbamazepine, phenytoin, oxcarbazepine, eslicarbazepine, gabapentin, pregabalin, tiagabine and vigabatrin have the disadvantage of worsening myoclonic and absence seizures in some patients [110,111]. For example, carbamazepine can both aggravate and induce new seizure types in patients with absence epilepsy, JME and other GGEs, as well as causing new or more severe generalised EEG abnormalities [112]. High-dose phenobarbital has been associated with the aggravation or production of absence seizures [113,114].
[15]
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Although VPA has been shown to be an effective antiseizure drug in many patients with GGEs [66,80], evidence of its teratogenic potential has grown over the years. This has resulted in restrictions on VPA use in women with epilepsy of childbearing potential, issued by the US Food and Drug Administration [128] and the European Medicines Agency [129]. Valproate is the antiseizure drug associated with the highest major congenital malformation risk [24,[130][131][132][133][134].
[16]
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The risk is dose related, increasing from 500 to 750 mg daily [24,130,131]. Genetic factors or individual susceptibility may also be implicated [135]. Valproate use during pregnancy has also been associated with poorer neurodevelopmental outcomes in offspring [132,136], with more children experiencing cognitive, psychomotor or language developmental delay, compared with children of untreated women with epilepsy [134]. Furthermore, VPA exposure in utero was associated with an increased risk of autism spectrum disorder, dyspraxia, learning disability and attention-deficit hyperactivity disorder in offspring [130,134,[137][138][139][140][141]. It is therefore advised that VPA should be avoided, when possible, in women of childbearing potential and women in Europe taking VPA are recommended to fulfil European Medicines Agency pregnancy prevention programme requirements [129]. The programme requires the assessment of pregnancy potential, pregnancy testing prior to and during VPA treatment if required, counselling about the risks of VPA and effective contraception, completion of a risk acknowledgement form by the patient and prescriber, and an annual review of the need for VPA. However, because VPA continues to show superior efficacy for GGEs compared with other antiseizure drugs [66,88], these restrictions create a dilemma for clinicians and patients [23]. For example, following the EpiPGX consortium study that concluded VPA was associated with a longer treatment duration than TPM, carbamazepine, LTG and LEV in 688 patients with JME, authors recommended that VPA should remain in place as an antiseizure drug, including for women of childbearing potential whose seizures are not controlled with other antiseizure medications [88]. For these women, a comprehensive assessment and discussion of treatment options can aid decision making [142].
[17]
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Levetiracetam and LTG have safer teratogenic profiles than VPA [24,130,131] and are generally preferred as first-line treatment options in young women with GGEs, though studies with LEV have been small and it is therefore difficult to draw meaningful comparisons [143,144]. Lamotrigine can worsen myoclonic jerks and concentrations can be halved via induction of glucuronidation by oral contraceptives containing ethinyloestradiol [31]. No increased risk of teratogenicity has been identified with ZNS, or BRV, though few meaningful data are available [144]. Topiramate and PER are other options, but TPM has teratogenic potential [144] and although no teratogenicity was observed in animal models, PER is not recommended for women of childbearing potential without contraception [145]. Ethosuximide and PB also can have teratogenic effects [144] and PB can induce the oestrogenic component of the combined oral contraceptive pill [146].
[18]
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All women of childbearing potential starting antiseizure therapy for GGEs should have preconceptual counselling that should be repeated at regular intervals [144,146,147]. For women trying to conceive, the use of folic acid, at least 400 µg daily and usually 5 mg daily preconceptually and for at least the first trimester is recommended [110,111]. During pregnancy, circulating concentrations of LTG, LEV, TPM and ZNS can fall [148], with LTG concentrations decreasing by as much as 50% [149]. This may jeopardise seizure control and dose adjustments may be necessary.