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Management of epilepsy
EPILEPSY
Management of epilepsy
What’s new?
Yvonne M Hart C
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Abstract A complete diagnosis of epilepsy involves the diagnosis of seizures (based on the clinical history), the epileptic syndrome, and the underlying aetiology. Epilepsy may be genetic or have a structural or metabolic cause (identified or unknown). The most common differential diagnoses are syncope and psychogenic non-epileptic seizures. Seizures may be generalized or focal, and take different forms. All patients developing seizures should have an ECG, and neuroimaging should be undertaken in all patients developing epilepsy in whom a focal cause is suspected, with the exception of genetic focal epilepsies. Antiepileptic medication should be tailored to the specific needs of the patient, with particular reference to the seizure type(s) and epilepsy syndrome. Other needs, such as the likelihood of pregnancy, and the presence of co-morbidities including learning disability and psychiatric disorders also need to be taken into account. Patients not responding to antiepileptic drugs may be candidates for surgery. The need for ongoing medication should be regularly reviewed in patients in long-term remission.
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appear to be without an obvious trigger and may not cause an aura (see chapter on T-LOC). Typically the patient appears pale and clammy. Loss of consciousness results in their falling to the ground: the body may be either stiff or limp. Brief, irregular, multifocal jerking movements may occur, but unless the patient is maintained in the upright position these invariably last less than 15 seconds (which may still seem a long time to an observer)1. Automatisms may also occur. Recovery to the point where the patient can hold a conversation almost invariably occurs within a minute or two, but recurrence of loss of consciousness that occurs on standing upright is a strong pointer
Keywords antiepileptic drug; epilepsy; focal seizure; generalized seizure; seizure; status epilepticus
Diagnosis
Questions for an eyewitness when diagnosing possible seizures
The diagnosis of epilepsy involves not only the diagnosis of seizures, but also an assessment of the nature of the epileptic syndrome and the underlying aetiology. Seizures are diagnosed clinically on the basis of the description of the event. This should include both the patient’s own account and that of an eyewitness, if one was present. Particular points to be noted include any precipitating factors, the nature of any warning symptoms, the features of the event itself, the duration of the event, and the post-ictal period (Table 1). Common differential diagnoses include syncope and psychogenic non-epileptic seizures.
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What was the person doing just before the seizure? What alerted you to the seizure? What time of day did it occur? Describe what you saw during the seizure
Syncope Syncope is usually provoked by an obvious trigger, such as pain, strong emotion, dehydration, and standing for long periods in a hot atmosphere. Usually the patient experiences an aura, which may consist of nausea, greying of the vision, muffled hearing, or a feeling of lightheadedness. If no such warning is experienced or if there is no provoking factor, the diagnosis should be reconsidered, although syncope due to cardiac arrhythmias may
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Yvonne M Hart MA MD FRCP is Consultant Neurologist at the Royal Victoria Infirmary, Newcastle upon Tyne, UK. Competing interests: Over the past 5 years I have received payments for lectures given, advisory work and/or sponsorship to attend epilepsy conferences from UCB Pharma, GlaxoSmithKline, Pfizer, Janssen-Cilag and Eisai.
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Levetiracetam, along with lamotrigine and carbamazepine, appears to have low risk of teratogenicity Women taking enzyme-inducing antiepileptic drugs and requiring emergency contraception should be offered a copperbearing intrauterine device Buccal midazolam is the treatment of choice for prolonged or serial seizures in the community setting Deep brain stimulation may be a treatment option for people with refractory epilepsy who are not candidates for resective surgery
Which parts of the body were affected? Was one side affected more than the other? Did the person go stiff? What type of movements, if any, did the person make? (e.g. twitching, jerking, thrashing) Were there any facial movements? Was the person unconscious or was there a change in awareness? Could they speak to you, and did their speech make sense? Were their eyes open or shut? Did their colour change? Were they flushed, clammy or pale? Did their breathing change? If so, in what way? How long did the seizure last? Did the person injure him or herself? Did you see anything else that you think might be important? How did the person behave after the seizure? Were they sleepy, confused, or alert? How long did they take to recover completely? Did they want to sleep afterwards?
Table 1
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towards syncope. Despite the rapid recovery patients may feel ‘drained’ for some considerable period of time. If the patient is maintained upright (e.g. supported by friends or if seated on a chair) a more prolonged convulsion may occur due to failure of the cerebral circulation to become adequately reestablished. Similarly, if syncope is complicated by a head injury, recovery may be delayed by the occurrence of a concussive convulsion.2 These begin within 2 seconds of the head injury and involve stiffening followed by myoclonic jerking, sometimes asymmetrical, which may last up to 150 seconds. Such convulsions do not lead to epilepsy, and neuroimaging is normal. Both types of seizure are considered to be ‘provoked’ seizures, and do not usually lead to a driving ban.
Differential diagnosis of partial seizures Migraine
TIA
Psychogenic non-epileptic seizures Psychogenic non-epileptic seizures (PNES) (functional seizures, dissociative seizures) are common, particularly in neurology clinics and emergency departments. Clues to the diagnosis in the history may include reference to ‘thrashing’ or ‘flailing’, directed violence, a tendency for the seizure repeatedly to stop and start, pelvic thrusting and opisthotonus, the occurrence of seizures at times of acute stress (although they may also occur when the patient is apparently relaxed) and long duration with rapid recovery. Patients may report such seizures occurring from sleep, although EEG evidence of occurrence from sleep would point to epileptic seizures. At times injury may occur during PNES. Some PNES take the form of ‘swoons’, in which the patient slumps and lies still for a long period of time, ‘as if they are asleep’, while others take the form of absence-like episodes. It may be difficult to identify an underlying cause for PNES, but if they are suspected, every attempt should be made to secure the diagnosis (for example by ambulatory EEG or EEG-videotelemetry if the seizures are sufficiently frequent), and a ‘trial of antiepileptic drugs’ is not indicated. However, it should be remembered that frontal lobe seizures (which commonly occur in the early stages of sleep) may appear bizarre, are often short-lived but repeated, and are often followed by a quick recovery: the differentiation from PNES is made more difficult by the fact that ictal EEG may not demonstrate obvious epileptic activity, or may be obscured by movement artefact. It is also not uncommon for PNES to occur in people who have epilepsy, and if the circumstances of the original diagnosis are not known, for example if it was made elsewhere, any attempt to withdraw antiepileptic drugs should be undertaken with extreme caution.
Panic attacks
Parasomnias
Other conditions mimicking toniceclonic seizures Hypoglycaemic seizures may need to be distinguished from unprovoked seizures, particularly in people with diabetes mellitus, and blood glucose should be measured immediately after the episode to give a reliable indication of this. Breath-holding attacks typically occur in young children who are thwarted or frustrated: the child cries then stops breathing, becoming cyanosed and then limp and unresponsive, often with a few clonic movements. Day-dreaming may sometimes be confused with absence seizures in children but differ in that the child can be alerted out of them. Table 2 lists other diagnoses that may be confused with focal seizures.
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The aura is typically visual, commonly taking the form of black and white ‘fortification spectra’, and is usually of longer duration than the visual aura of occipital epilepsy (often taking the form of elementary coloured lights). Both migraine and epileptic seizures are associated with a gradual spreading of symptoms Usually of sudden onset, unlike the gradual spread of symptoms in a seizure, and typically causing negative symptoms (weakness, numbness) in contrast to the usual (but not invariable) positive symptoms occurring in seizures (jerking, paraesthesiae) Typically occurring with physical symptoms such as dyspnoea, tachycardia, sweating and tremulousness, sometimes difficult to distinguish from focal seizures of temporal lobe origin. Hyperventilation may also occur, causing dizziness and paraesthesiae in the limbs distally and in a peri-oral distribution Hypnic jerks may be mistaken for myoclonus, but are common in the general population, taking the form of a single jerk in the early stages of sleep, causing a feeling of falling followed by arousal. Other sleep disorders need to be distinguished from partial seizures of frontal or temporal origin. Rapid eye movement (REM) sleep behaviour disorder occurs in elderly people, often in the context of a neurodegenerative condition such as Parkinson’s disease, and takes the form of ‘acting out’ of dreams, sometimes with apparently directed violence. Sleep walking, which involves automatic behaviour occurring during non-REM sleep, is common in children. Narcolepsy is rarely difficult to distinguish from epilepsy, and the typical associated features of sleep paralysis, hypnagogic hallucinations and cataplexy should be sought (though they are not always present). Night terrors typically occur in children, arise from slow-wave sleep, and involve the child suddenly sitting up and crying or screaming, with dilated pupils, as if terrified (although they have amnesia for the attack afterwards). Periodic limb movements of sleep are very common over the age of 50, and involve knee flexion, ankle dorsiflexion and extension of the big toe, lasting a few seconds but occurring every 20e40 seconds for considerable periods of time. Although the patient is unaware of this it may cause concern to their bed partner.
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In patients with frequent ‘funny turns’ in whom there is doubt about the diagnosis of epilepsy, 48-hour ambulatory EEG or EEGvideotelemetry may be helpful if an attack can be recorded (but very minor symptoms, and some frontal lobe seizures, may occur in the absence of obvious EEG change apart from movement artefact).
Table 2 (continued ) Transient global amnesia
Usually occurs in middle-aged to elderly people, and is characterized by amnesia lasting up to several hours, in which the patient may repeatedly ask the same question. Usually TGA occurs as an isolated event, but rarely it may recur (though if it does so more than once, transient epileptic amnesia should be suspected). Sometimes mistaken for a complex partial seizure, particularly if a good eyewitness description cannot be obtained.
Neuroimaging Neuroimaging should be undertaken in all people with epilepsy of focal (or presumed focal) onset, with the exception of children with genetic focal epilepsy. This includes most adults (since genetic generalized epilepsy usually presents in childhood or adolescence). MRI scanning is the imaging modality of choice, as it identifies abnormalities capable of causing epilepsy that are not apparent on CT scanning (such as focal cortical dysplasia, cavernoma, mesial temporal sclerosis) (Figures 1 and 2). However, where MRI scanning is contraindicated (e.g. in people with cardiac pacemakers), it may be necessary to rely on a CT scan. Scanning may not be necessary in people in whom a clear diagnosis of genetic generalized epilepsy has been made, but it should be undertaken if the patient’s seizures fail to respond to first-line antiepileptic medication. CT scanning may be appropriate for initial imaging to aid management in the situation where the patient presents acutely with seizures. Urgent imaging is indicated in those in whom a focal intracranial lesion is suspected, for example those in whom recovery is delayed, people with a recent history of head trauma, those with new or progressive focal neurological signs or those with new focalonset seizures; and in people with persistent altered mental state, malignancy, immunocompromise, HIV infection, fever, alcoholism, or a bleeding diathesis.
Table 2
Examination All patients developing seizures should undergo a full general examination, particular attention being paid to the cardiovascular and neurological systems. Any evidence of conditions that may predispose to epilepsy (such as cutaneous features of tuberous sclerosis or SturgeeWeber syndrome, or hemiatrophy, which might indicate a congenital disorder) should be carefully sought.
Investigation Blood tests are often normal in people developing seizures. However, hyponatraemia, hypoglycaemia, hypocalcaemia, alcohol abuse and hyperthyroidism can all sometimes present with seizures, while anaemia may predispose to syncope. It is therefore appropriate to check full blood count, renal function, blood glucose, calcium, liver function and thyroid function, particularly if antiepileptic drug (AED) treatment is being considered (most AEDs can affect liver function). ECG should be carried out in all people suspected of developing seizures. Cardiac arrhythmias may present as syncope or seizures and may be life threatening, so correct diagnosis is important, particularly since a number of AEDs can affect cardiac conduction. (See Transient loss of consciousness, Medicine 2012; 40(8): 427e430).
Treatment of epilepsy Treatment for epilepsy should not normally be started until the diagnosis is secure, and the decision to treat should be agreed
EEG EEG may be helpful to support a diagnosis of epilepsy in people in whom seizures are considered likely: it may also help in classification of seizures by demonstrating focal or generalized epileptic abnormalities. However, it is of no value in excluding a diagnosis of epilepsy and should not be performed with this in mind. An interictal EEG consistently shows epileptic abnormalities in only about 35% of patients with epilepsy: in another 50%, such abnormalities may sometimes but not always be present, while in 15% of patients with epilepsy interictal epileptiform abnormalities are not seen.3 Up to about a quarter of people without epilepsy may show non-specific slow-wave abnormalities on EEG, but frank epileptic abnormalities are seen in only about 0.5% of people without epilepsy.4 If epileptic abnormalities are present on an EEG carried out after a single seizure, the risk of recurrence is significantly increased.
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Figure 1 MRI scan showing right-sided focal cortical dysplasia.
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considerations to be taken into account in the decision as to whether to start treatment include the nature of the seizures (the need to start treatment for seizures not causing loss of awareness may be less pressing than for other seizures, unless driving is an issue), their timing (toniceclonic seizures in sleep, for example, are associated with an increased risk of sudden unexpected death in epilepsy (SUDEP)), other co-morbidities, the likelihood of pregnancy, and, most importantly, the wishes of the patient.
Counselling for people with epilepsy The development of seizures invariably causes considerable concern and, even when the common fears of an underlying tumour can be allayed, most adults developing seizures go through a period of anxiety and sometimes frank depression, which may require treatment in its own right. Fortunately this usually lessens with time from the last seizure, but many patients find it helpful to learn that this is a common reaction. If patients do require treatment with antidepressants, selective serotonin reuptake inhibitors (SSRIs) are unlikely to cause problems in terms of seizure control (although the patient should always be warned to seek medical help if this does occur). A checklist of information that should be provided is given in Table 4. Particular attention should be paid to the need to be aware of situations posing risk where consciousness is lost without warning (Table 5). However, while people with seizures should be advised to consider the risks of the situations in which they find themselves, it is equally important that, having taken appropriate precautions, they do continue to participate in social activities and do not restrict their lives unnecessarily.
Figure 2 MRI scan showing left temporal cavernoma.
jointly by the patient and the treating clinician. Technically the diagnosis of epilepsy depends on the occurrence of two nonprovoked seizures. However, in some situations where there is a high risk of further seizures, medication may be started after a single seizure. Such circumstances might include the development of epilepsy secondary to a cerebral tumour, or the presence of active epileptic changes on EEG in people with genetic generalized epilepsy. Seizures associated with cavernous haemangiomata also have a high risk of recurrence. Trials of treatment should not normally be undertaken. Rare exceptions occur in which the diagnosis is difficult to confirm, for example in elderly people living alone (provided there is a compatible history and cardiac causes have been ruled out) and in the case of focal seizures without loss of awareness, in which even ictal epileptic activity may not be apparent on scalp electrode EEG recordings. Sometimes specific factors such as alcohol, sleep deprivation and stress are cited by patients as triggers for seizures. Table 3 lists factors that may lower the seizure threshold. However, even where these appear causal, it is often the case that antiepileptic drugs are necessary to stop seizures completely. Other
Drug treatment of epilepsy e general principles Treatment should be started only by a specialist in epilepsy, or after discussion with one.5 Where AED treatment is deemed necessary, initial treatment should be a first-line drug appropriate for their epilepsy syndrome and seizure type(s). The AED should be started at a low dosage and gradually increased until either the patient becomes seizure-free, or they develop adverse effects. If the patient has ongoing seizures despite adequate doses of an appropriate AED for their seizure type or syndrome, the diagnosis should be reconsidered. Is the diagnosis of epilepsy
Counselling people with epilepsy Nature of epilepsy Precipitating factors for seizures C Driving laws C Need to avoid potentially dangerous situations C Sudden unexpected death in epilepsy (SUDEP) C Need (or not) for medication C Adverse effects of medication C Interactions of medication with other drugs including oral contraceptive C Eligibility for free prescriptions/discretionary bus pass, if relevant C Pregnancy and teratogenicity C Employment/leisure C C
Factors that may lower seizure threshold C C C
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Alcohol excess Sleep deprivation Photic stimulation (only relevant in 2e5% of people with epilepsy) Fever/acute systemic illness Hyponatraemia/other metabolic disturbance Abrupt withdrawal of antiepileptic drugs Proconvulsant medication (includes much psychotropic medication as well as some recreational drugs)
Table 4
Table 3
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efficacious than lamotrigine in those randomized, and is the firstline AED for the treatment of generalized epilepsies in men. In girls and women of childbearing age, the risks of teratogenicity and neurodevelopmental delay in children born to mothers taking this drug in pregnancy mean that consideration should be given to the use of other medications, such as levetiracetam or lamotrigine, for generalized seizures. Neither of these drugs is yet licensed in the UK for the treatment of absences or myoclonus, but they are included in the NICE guidelines 2012 as firstline treatments for juvenile myoclonic epilepsy (JME), and as first-line or adjunctive treatments for absences. Lamotrigine has been reported to worsen myoclonus in some people.7 Carbamazepine and oxcarbazepine are effective treatments for generalized toniceclonic seizures but may unmask or worsen absences and myoclonus (as may phenytoin, which is not currently recommended as a first-line drug). Other drugs which may be considered for generalized seizure-types (on specialist recommendation) if these medications are ineffective or not tolerated are topiramate and clobazam (the latter is normally prescribed as an adjunctive therapy, since tachyphylaxis not infrequently develops). Ethosuximide is effective for the treatment of absences but has little effect in other seizure-types. Clonazepam, zonisamide, piracetam (for myoclonus), and rufinamide (for tonic or atonic seizures) are also sometimes used for refractory generalized seizures in tertiary care situations.
Safety precautions in epilepsy (this list is not exhaustive) C C C C
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Avoid unguarded heights Avoid unguarded fires, radiators etc Shower rather than bath where possible Avoid swimming alone: an observer should always be alerted to the possibility of a seizure before swimming When waiting for a train, wait at the back of the platform till the train pulls in Avoid working with unguarded machinery
Table 5
correct? If so, has the seizure type been correctly diagnosed? If the answer is yes, a second first-line drug appropriate for the epilepsy should be added, the dosage being gradually increased as before. Once an appropriate dosage has been reached, the dosage of the AED used initially should be gradually tapered. Only if at least two appropriate first-line drugs have failed independently to control the seizures should two or more drugs be prescribed concurrently. Potential adverse effects of AEDs may be mild or severe and include acute idiosyncratic reaction (such as drug rash); acute toxicity, such as ataxia and blurred vision seen with high plasma concentrations of carbamazepine, lamotrigine or phenytoin; chronic toxic symptoms, such as weight loss with topiramate, weight gain with sodium valproate, and gum hyperplasia with phenytoin; and teratogenicity. The link between the antiepileptic drug and adverse effects may not be immediately obvious, and the occurrence of behavioural or mood changes, the development of psychosis, or worsening of seizure frequency, should lead to a review of medication. People of Han Chinese, Hong Kong Chinese or Thai origin should be tested for HLA-B*1502 before being treated with carbamazepine, since there is a strong association between this allele and the development of StevenseJohnson syndrome. Chronic toxic symptoms are often drug-specific and thus to a certain extent predictable: the choice of medication should be tailored to the individual patient, taking into account potential adverse effects, co-morbidities (including liver or kidney disease, which may affect the pharmacokinetics of the drug) and concomitant medication with potential interactions (such as warfarin, digoxin), as well as suitability for seizure type and syndrome. The potential effect of antiepileptic drugs on bones has been increasingly recognized in recent years. Liver enzyme-inducing drugs affect vitamin D metabolism and may predispose to osteomalacia, but studies suggest that non-enzyme-inducing drugs may also affect bone health. It is recommended that serum vitamin D, calcium and alkaline phosphatase be measured every 2e5 years in people taking hepatic enzyme-inducing drugs; vitamin D supplementation may be necessary.
Focal seizures A second arm of the SANAD study8 randomized patients with partial epilepsy to treatment with carbamazepine, gabapentin, lamotrigine, or topiramate, with oxcarbazepine being added at a later stage (levetiracetam was not included). For time-totreatment failure (withdrawal of therapy because of inadequate seizure control or unacceptable adverse effects) lamotrigine was significantly better than carbamazepine, topiramate or gabapentin, and had a non-significant advantage over oxcarbazepine. This was despite the fact that carbamazepine had a nonsignificant advantage over lamotrigine, topiramate and oxcarbazepine with respect to time-to-12-month remission, and was significantly better than gabapentin. Notwithstanding this, carbamazepine is well tolerated by many people and lamotrigine, carbamazepine, levetiracetam and oxcarbazepine are all effective first-line treatments for focal-onset seizures. Topiramate is also effective but slightly less well tolerated, and sodium valproate may also be used but may be less effective than carbamazepine in simple and complex partial seizures. Other drugs that may be useful in focal epilepsies on specialist recommendation include clobazam, phenytoin, zonisamide, pregabalin, lacosamide, eslicarbazepine, retigabine, tiagabine, phenobarbital, and vigabatrin (the last is used only in particularly refractory cases as it can cause irreversible constriction of visual fields). Most people starting AEDs require them for at least two years. The overall chance of seizure recurrence after drug withdrawal at 2 years is approximately 40%9 over the next 2 years. In people with generalized epilepsies, ongoing epileptic activity on EEG suggests a higher risk of recurrence. However, the risk cannot be predicted with certainty, and the issue of driving (usually a period off driving is required), and risks of injury (and small risk of SUDEP) should be discussed with people wishing to withdraw medication.
First-line AEDs Generalized seizures The SANAD study of Standard And New Antiepileptic Drugs6 randomized patients with generalized or unclassifiable seizures to treatment with sodium valproate, lamotrigine or topiramate. Sodium valproate was better tolerated than topiramate and more
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taking it in pregnancy.13 The MCM rates are not known with accuracy for many antiepileptic drugs, particularly the newer ones, where the confidence intervals remain wide: for example, topiramate (4.8%, 95% CI 1.9e13.3%).14 Most women with epilepsy have uncomplicated pregnancies, and if seizures are well controlled beforehand, they are likely to remain so, although occasionally seizure control is adversely affected. The plasma concentrations of a number of AEDs, particularly lamotrigine and levetiracetam, fall in later pregnancy and an increase in dose may be required if clinically indicated. The infants of women taking liver enzyme-inducing drugs should be given intramuscular vitamin K1 1 mg at birth to prevent haemorrhagic disease of the newborn. Breastfeeding is to be
Women and epilepsy Contraception Hepatic enzyme-inducing antiepileptic drugs, which include carbamazepine, eslicarbazepine, oxcarbazepine, phenytoin, phenobarbital, primidone, and topiramate, may affect the efficacy of the oral contraceptive pill through their enzyme-inducing effect and also by increasing the hepatic synthesis of sex hormone binding globulin, thus decreasing the unbound, active progestagen. Other methods of contraception, such as barrier methods, depot injection of medroxyprogesterone or hormonereleasing intrauterine contraceptive devices, may be suitable alternatives. However, in women wishing to use the combined oral contraceptive pill (COCP), a preparation containing at least 50 mg of oestrogen should be used. It is also recommended that the patient ‘tri-cycles’, which means that she takes the contraceptive preparation without a break for 63 days, followed by a shortened, 4-day, pill-free interval. If breakthrough bleeding occurs it should be assumed that these measures are still ineffective, although its absence does not guarantee effective contraception. Liver enzyme-inducing drugs also affect progesterone-only pills and the progesterone implant, and use of these is not recommended. The copper-bearing intrauterine device is the only method of emergency contraception not affected by liver enzyme-inducing drugs. Patients requiring emergency contraception who elect not to use this should be advised to take a single dose of levonorgestrel 3 mg as soon as possible after unprotected intercourse. Lamotrigine is not thought to induce liver enzymes but may decrease the concentration of levonorgestrel slightly when taken in conjunction with the COCP. The practical effect of this is unknown but is likely to be slight, but women should be warned of the possibility of an interaction. The COCP increases the clearance of lamotrigine and may reduce its plasma concentration by 50%, such that increased dosage of lamotrigine may be necessary. For the same reason, women taking the COCP in addition to lamotrigine may develop symptoms of lamotrigine toxicity when they discontinue the COCP.
Management of status epilepticus 0e10 minutes
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Pregnancy and teratogenicity Pre-conceptual counselling is essential for women with epilepsy, since most if not all antiepileptic drugs carry a risk of teratogenicity. The need for ongoing medication should be reviewed and, if it remains essential, the patient should be treated with a single AED if possible, since the risk of teratogenicity rises considerably with each additional medication. All patients taking AEDs during pregnancy should take folic acid 5 mg daily before pregnancy and for the first trimester, to reduce the risk of teratogenicity. Girls and women of childbearing age should ideally be treated with AEDs carrying a low rate of major congenital malformations (MCMs) from the outset. These include carbamazepine (2.2%, 95% CI 1.4e3.4%)10 compared with a background rate estimated at around 2e3%, lamotrigine (2.8%, 95% CI 1.9e3.9%)11 and levetiracetam (three cases identified in 117 pregnancies in one study, all of whom had taken other AEDs in addition).12 The rate for sodium valproate is considerably higher (6.2%, 95% CI 4.6e8.2%), and in addition there is evidence to suggest that this drug may be associated with neurodevelopmental delay in the infants of women
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Secure airway and assess cardiorespiratory status, administer oxygen Obtain brief history from accompanying persons and carry out general and neurological examination Establish intravenous access in large vein Take blood for full blood count, urea and electrolytes, glucose, calcium, magnesium, liver function tests, anticonvulsant concentration(s), also arterial blood gases Administer 50 ml 50% glucose and thiamine 100 mg intravenously (IV) Monitor ECG, pulse oximetry, pulse and blood pressure Administer lorazepam 2e4 mg (0.1 mg/kg, maximum 4 mg) by bolus IV injection. Repeat dose once if seizures do not stop after 10 minutes. If unavailable treat with diazepam 10 mg IV. Give phenytoin 15e20 mg/kg by slow IV infusion at a rate not greater than 50 mg/minute. If status due to abrupt withdrawal of AEDs, reinstate these unless contraindicated If seizures persist, transfer to intensive care unit and take senior advice; patient may require intubation, ventilation and inotropic support Consider treatment with: propofol 2 mg/kg IV bolus followed by 2e10 mg/kg/hour, or C midazolam 0.2 mg/kg IV followed by 0.1e0.5 mg/kg/hour, or C IV thiopental 3e5 mg/kg followed by boluses of 1e2 mg/kg every 2e3 minutes until seizures controlled, then infusion of 3e7 mg/kg/hour Continuous EEG monitoring should be established Also assess underlying cause of status further: patient may require CT scan and LP C
Table 6
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5 National Clinical Guideline Centre: Pharmacological update of NICE clinical guideline 20 e the epilepsies. The diagnosis and management of the epilepsies in adults and children in primary and secondary care 2012. 6 Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of valproate, lamotrigine or topiramate for generalized and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1016e26. 7 Mantoan L, Walker M. Treatment options in juvenile myoclonic epilepsy. Curr Treat Options Neurol 2011; 13: 355e70. 8 Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1000e15. 9 Medical Research Council Antiepileptic Drug Withdrawal Study Group. Randomised study of antiepileptic drug withdrawal in patients in remission. Lancet 1991; 337: 1175e80. 10 Morrow J, Russell A, Guthrie E, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006; 77: 193e8. 11 Hunt SJ, Irwin B, Russell AJ, et al. Lamotrigine in human pregnancy: updated experience from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2009; 80: 97. 12 Hunt S, Craig J, Russell A, et al. Levetiracetam in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurol 2006; 67: 1876e9. 13 Adab N, Kini U, Ayres J, et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004; 75: 1575e83. 14 Hunt S, Russell A, Smithson WH, et al. Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurol 2008; 71: 272e6. 15 Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000; 342: 314e9.
encouraged in most cases, but if the AEDs include phenobarbital or benzodiazepines, sedation of the baby may be a problem. Sleep deprivation in the post-partum period may increase the risk of seizures, and women should be advised about childcare in the context of epilepsy: for example, they should feed the infant while sitting on a floor cushion, change the infant on a changing mat on the floor, avoid bathing the infant when alone in the house, and use a carrycot if it is necessary to carry the infant upstairs.
Treatment of status epilepticus Status epilepticus is usually defined as ongoing seizure activity lasting 30 minutes or more; it is a medical emergency, with the mortality rate for toniceclonic status epilepticus being of the order of 20e30%. Status epilepticus is often preceded by an increasing frequency of seizures, and in such cases it may be possible to avoid it by the use of protocols for buccal midazolam or rectal diazepam. Significant adverse prognostic factors include the underlying aetiology and the duration of the status. It is therefore of utmost importance to treat ongoing seizure activity early, ideally within 5e10 minutes of onset. The treatment is summarized in Table 6.
Surgery for epilepsy Although seizures can be readily controlled in the majority of people with epilepsy, in approximately 30% they remain refractory to medical treatment (the chance of becoming seizurefree if seizures have failed to respond to treatment with two appropriate antiepileptic drugs is of the order of 4% for treatment with a third AED).15 If medical treatment has failed, the seizures are sufficiently frequent and disabling, the site of onset of the seizures can be identified and the likely benefits outweigh the risks, resective surgery to remove the epileptic focus may be feasible. The likelihood of seizure freedom varies with the type of surgery, but is usually of the order of 50e70%. In patients who are not candidates for resective surgery, vagus nerve stimulation or deep brain stimulation may be helpful. A
Practice points REFERENCES 1 Lempert T, Bauer M, Schmidt D. Syncope: a videometric analysis of 56 episodes of transient cerebral hypoxia. Ann Neurol 1994; 36: 233e7. 2 McCrory PR, Bladin PF, Berkovic SF. Retrospective study of concussive convulsions in elite Australian rules and rugby league footballers: phenomenology, aetiology and outcome. Br Med J 1997; 314: 171e4. 3 Marsan CA, Zivin LS. Factors related to the occurrence of typical paroxysmal abnormalities in the EEG records of epileptic patients. Epilepsia 1970; 11: 361e81. 4 Zivin L, Marsan CA. Incidence and prognostic significance of “epileptiform” activity in the EEG of non-epileptic subjects. Brain 1968; 91: 751e8.
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An accurate history is crucial for diagnosis Investigation for seizures should include ECG Neuroimaging should be undertaken for focal seizures of unknown cause Ambulatory EEG or EEG-videomonitoring may be helpful if diagnosis of ongoing seizures remains unclear Medication should be started on the advice of a specialist Tailor medication to patient, seizure type and syndrome Be aware of drug interactions, particularly with contraceptives and warfarin Consider possibility of surgery in patients failing to respond to medication
Ó 2012 Published by Elsevier Ltd.
Management of epilepsy
What’s new?
Yvonne M Hart C
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Abstract A complete diagnosis of epilepsy involves the diagnosis of seizures (based on the clinical history), the epileptic syndrome, and the underlying aetiology. Epilepsy may be genetic or have a structural or metabolic cause (identified or unknown). The most common differential diagnoses are syncope and psychogenic non-epileptic seizures. Seizures may be generalized or focal, and take different forms. All patients developing seizures should have an ECG, and neuroimaging should be undertaken in all patients developing epilepsy in whom a focal cause is suspected, with the exception of genetic focal epilepsies. Antiepileptic medication should be tailored to the specific needs of the patient, with particular reference to the seizure type(s) and epilepsy syndrome. Other needs, such as the likelihood of pregnancy, and the presence of co-morbidities including learning disability and psychiatric disorders also need to be taken into account. Patients not responding to antiepileptic drugs may be candidates for surgery. The need for ongoing medication should be regularly reviewed in patients in long-term remission.
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appear to be without an obvious trigger and may not cause an aura (see chapter on T-LOC). Typically the patient appears pale and clammy. Loss of consciousness results in their falling to the ground: the body may be either stiff or limp. Brief, irregular, multifocal jerking movements may occur, but unless the patient is maintained in the upright position these invariably last less than 15 seconds (which may still seem a long time to an observer)1. Automatisms may also occur. Recovery to the point where the patient can hold a conversation almost invariably occurs within a minute or two, but recurrence of loss of consciousness that occurs on standing upright is a strong pointer
Keywords antiepileptic drug; epilepsy; focal seizure; generalized seizure; seizure; status epilepticus
Diagnosis
Questions for an eyewitness when diagnosing possible seizures
The diagnosis of epilepsy involves not only the diagnosis of seizures, but also an assessment of the nature of the epileptic syndrome and the underlying aetiology. Seizures are diagnosed clinically on the basis of the description of the event. This should include both the patient’s own account and that of an eyewitness, if one was present. Particular points to be noted include any precipitating factors, the nature of any warning symptoms, the features of the event itself, the duration of the event, and the post-ictal period (Table 1). Common differential diagnoses include syncope and psychogenic non-epileptic seizures.
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What was the person doing just before the seizure? What alerted you to the seizure? What time of day did it occur? Describe what you saw during the seizure
Syncope Syncope is usually provoked by an obvious trigger, such as pain, strong emotion, dehydration, and standing for long periods in a hot atmosphere. Usually the patient experiences an aura, which may consist of nausea, greying of the vision, muffled hearing, or a feeling of lightheadedness. If no such warning is experienced or if there is no provoking factor, the diagnosis should be reconsidered, although syncope due to cardiac arrhythmias may
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Yvonne M Hart MA MD FRCP is Consultant Neurologist at the Royal Victoria Infirmary, Newcastle upon Tyne, UK. Competing interests: Over the past 5 years I have received payments for lectures given, advisory work and/or sponsorship to attend epilepsy conferences from UCB Pharma, GlaxoSmithKline, Pfizer, Janssen-Cilag and Eisai.
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Levetiracetam, along with lamotrigine and carbamazepine, appears to have low risk of teratogenicity Women taking enzyme-inducing antiepileptic drugs and requiring emergency contraception should be offered a copperbearing intrauterine device Buccal midazolam is the treatment of choice for prolonged or serial seizures in the community setting Deep brain stimulation may be a treatment option for people with refractory epilepsy who are not candidates for resective surgery
Which parts of the body were affected? Was one side affected more than the other? Did the person go stiff? What type of movements, if any, did the person make? (e.g. twitching, jerking, thrashing) Were there any facial movements? Was the person unconscious or was there a change in awareness? Could they speak to you, and did their speech make sense? Were their eyes open or shut? Did their colour change? Were they flushed, clammy or pale? Did their breathing change? If so, in what way? How long did the seizure last? Did the person injure him or herself? Did you see anything else that you think might be important? How did the person behave after the seizure? Were they sleepy, confused, or alert? How long did they take to recover completely? Did they want to sleep afterwards?
Table 1
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towards syncope. Despite the rapid recovery patients may feel ‘drained’ for some considerable period of time. If the patient is maintained upright (e.g. supported by friends or if seated on a chair) a more prolonged convulsion may occur due to failure of the cerebral circulation to become adequately reestablished. Similarly, if syncope is complicated by a head injury, recovery may be delayed by the occurrence of a concussive convulsion.2 These begin within 2 seconds of the head injury and involve stiffening followed by myoclonic jerking, sometimes asymmetrical, which may last up to 150 seconds. Such convulsions do not lead to epilepsy, and neuroimaging is normal. Both types of seizure are considered to be ‘provoked’ seizures, and do not usually lead to a driving ban.
Differential diagnosis of partial seizures Migraine
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Psychogenic non-epileptic seizures Psychogenic non-epileptic seizures (PNES) (functional seizures, dissociative seizures) are common, particularly in neurology clinics and emergency departments. Clues to the diagnosis in the history may include reference to ‘thrashing’ or ‘flailing’, directed violence, a tendency for the seizure repeatedly to stop and start, pelvic thrusting and opisthotonus, the occurrence of seizures at times of acute stress (although they may also occur when the patient is apparently relaxed) and long duration with rapid recovery. Patients may report such seizures occurring from sleep, although EEG evidence of occurrence from sleep would point to epileptic seizures. At times injury may occur during PNES. Some PNES take the form of ‘swoons’, in which the patient slumps and lies still for a long period of time, ‘as if they are asleep’, while others take the form of absence-like episodes. It may be difficult to identify an underlying cause for PNES, but if they are suspected, every attempt should be made to secure the diagnosis (for example by ambulatory EEG or EEG-videotelemetry if the seizures are sufficiently frequent), and a ‘trial of antiepileptic drugs’ is not indicated. However, it should be remembered that frontal lobe seizures (which commonly occur in the early stages of sleep) may appear bizarre, are often short-lived but repeated, and are often followed by a quick recovery: the differentiation from PNES is made more difficult by the fact that ictal EEG may not demonstrate obvious epileptic activity, or may be obscured by movement artefact. It is also not uncommon for PNES to occur in people who have epilepsy, and if the circumstances of the original diagnosis are not known, for example if it was made elsewhere, any attempt to withdraw antiepileptic drugs should be undertaken with extreme caution.
Panic attacks
Parasomnias
Other conditions mimicking toniceclonic seizures Hypoglycaemic seizures may need to be distinguished from unprovoked seizures, particularly in people with diabetes mellitus, and blood glucose should be measured immediately after the episode to give a reliable indication of this. Breath-holding attacks typically occur in young children who are thwarted or frustrated: the child cries then stops breathing, becoming cyanosed and then limp and unresponsive, often with a few clonic movements. Day-dreaming may sometimes be confused with absence seizures in children but differ in that the child can be alerted out of them. Table 2 lists other diagnoses that may be confused with focal seizures.
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The aura is typically visual, commonly taking the form of black and white ‘fortification spectra’, and is usually of longer duration than the visual aura of occipital epilepsy (often taking the form of elementary coloured lights). Both migraine and epileptic seizures are associated with a gradual spreading of symptoms Usually of sudden onset, unlike the gradual spread of symptoms in a seizure, and typically causing negative symptoms (weakness, numbness) in contrast to the usual (but not invariable) positive symptoms occurring in seizures (jerking, paraesthesiae) Typically occurring with physical symptoms such as dyspnoea, tachycardia, sweating and tremulousness, sometimes difficult to distinguish from focal seizures of temporal lobe origin. Hyperventilation may also occur, causing dizziness and paraesthesiae in the limbs distally and in a peri-oral distribution Hypnic jerks may be mistaken for myoclonus, but are common in the general population, taking the form of a single jerk in the early stages of sleep, causing a feeling of falling followed by arousal. Other sleep disorders need to be distinguished from partial seizures of frontal or temporal origin. Rapid eye movement (REM) sleep behaviour disorder occurs in elderly people, often in the context of a neurodegenerative condition such as Parkinson’s disease, and takes the form of ‘acting out’ of dreams, sometimes with apparently directed violence. Sleep walking, which involves automatic behaviour occurring during non-REM sleep, is common in children. Narcolepsy is rarely difficult to distinguish from epilepsy, and the typical associated features of sleep paralysis, hypnagogic hallucinations and cataplexy should be sought (though they are not always present). Night terrors typically occur in children, arise from slow-wave sleep, and involve the child suddenly sitting up and crying or screaming, with dilated pupils, as if terrified (although they have amnesia for the attack afterwards). Periodic limb movements of sleep are very common over the age of 50, and involve knee flexion, ankle dorsiflexion and extension of the big toe, lasting a few seconds but occurring every 20e40 seconds for considerable periods of time. Although the patient is unaware of this it may cause concern to their bed partner.
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In patients with frequent ‘funny turns’ in whom there is doubt about the diagnosis of epilepsy, 48-hour ambulatory EEG or EEGvideotelemetry may be helpful if an attack can be recorded (but very minor symptoms, and some frontal lobe seizures, may occur in the absence of obvious EEG change apart from movement artefact).
Table 2 (continued ) Transient global amnesia
Usually occurs in middle-aged to elderly people, and is characterized by amnesia lasting up to several hours, in which the patient may repeatedly ask the same question. Usually TGA occurs as an isolated event, but rarely it may recur (though if it does so more than once, transient epileptic amnesia should be suspected). Sometimes mistaken for a complex partial seizure, particularly if a good eyewitness description cannot be obtained.
Neuroimaging Neuroimaging should be undertaken in all people with epilepsy of focal (or presumed focal) onset, with the exception of children with genetic focal epilepsy. This includes most adults (since genetic generalized epilepsy usually presents in childhood or adolescence). MRI scanning is the imaging modality of choice, as it identifies abnormalities capable of causing epilepsy that are not apparent on CT scanning (such as focal cortical dysplasia, cavernoma, mesial temporal sclerosis) (Figures 1 and 2). However, where MRI scanning is contraindicated (e.g. in people with cardiac pacemakers), it may be necessary to rely on a CT scan. Scanning may not be necessary in people in whom a clear diagnosis of genetic generalized epilepsy has been made, but it should be undertaken if the patient’s seizures fail to respond to first-line antiepileptic medication. CT scanning may be appropriate for initial imaging to aid management in the situation where the patient presents acutely with seizures. Urgent imaging is indicated in those in whom a focal intracranial lesion is suspected, for example those in whom recovery is delayed, people with a recent history of head trauma, those with new or progressive focal neurological signs or those with new focalonset seizures; and in people with persistent altered mental state, malignancy, immunocompromise, HIV infection, fever, alcoholism, or a bleeding diathesis.
Table 2
Examination All patients developing seizures should undergo a full general examination, particular attention being paid to the cardiovascular and neurological systems. Any evidence of conditions that may predispose to epilepsy (such as cutaneous features of tuberous sclerosis or SturgeeWeber syndrome, or hemiatrophy, which might indicate a congenital disorder) should be carefully sought.
Investigation Blood tests are often normal in people developing seizures. However, hyponatraemia, hypoglycaemia, hypocalcaemia, alcohol abuse and hyperthyroidism can all sometimes present with seizures, while anaemia may predispose to syncope. It is therefore appropriate to check full blood count, renal function, blood glucose, calcium, liver function and thyroid function, particularly if antiepileptic drug (AED) treatment is being considered (most AEDs can affect liver function). ECG should be carried out in all people suspected of developing seizures. Cardiac arrhythmias may present as syncope or seizures and may be life threatening, so correct diagnosis is important, particularly since a number of AEDs can affect cardiac conduction. (See Transient loss of consciousness, Medicine 2012; 40(8): 427e430).
Treatment of epilepsy Treatment for epilepsy should not normally be started until the diagnosis is secure, and the decision to treat should be agreed
EEG EEG may be helpful to support a diagnosis of epilepsy in people in whom seizures are considered likely: it may also help in classification of seizures by demonstrating focal or generalized epileptic abnormalities. However, it is of no value in excluding a diagnosis of epilepsy and should not be performed with this in mind. An interictal EEG consistently shows epileptic abnormalities in only about 35% of patients with epilepsy: in another 50%, such abnormalities may sometimes but not always be present, while in 15% of patients with epilepsy interictal epileptiform abnormalities are not seen.3 Up to about a quarter of people without epilepsy may show non-specific slow-wave abnormalities on EEG, but frank epileptic abnormalities are seen in only about 0.5% of people without epilepsy.4 If epileptic abnormalities are present on an EEG carried out after a single seizure, the risk of recurrence is significantly increased.
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Figure 1 MRI scan showing right-sided focal cortical dysplasia.
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considerations to be taken into account in the decision as to whether to start treatment include the nature of the seizures (the need to start treatment for seizures not causing loss of awareness may be less pressing than for other seizures, unless driving is an issue), their timing (toniceclonic seizures in sleep, for example, are associated with an increased risk of sudden unexpected death in epilepsy (SUDEP)), other co-morbidities, the likelihood of pregnancy, and, most importantly, the wishes of the patient.
Counselling for people with epilepsy The development of seizures invariably causes considerable concern and, even when the common fears of an underlying tumour can be allayed, most adults developing seizures go through a period of anxiety and sometimes frank depression, which may require treatment in its own right. Fortunately this usually lessens with time from the last seizure, but many patients find it helpful to learn that this is a common reaction. If patients do require treatment with antidepressants, selective serotonin reuptake inhibitors (SSRIs) are unlikely to cause problems in terms of seizure control (although the patient should always be warned to seek medical help if this does occur). A checklist of information that should be provided is given in Table 4. Particular attention should be paid to the need to be aware of situations posing risk where consciousness is lost without warning (Table 5). However, while people with seizures should be advised to consider the risks of the situations in which they find themselves, it is equally important that, having taken appropriate precautions, they do continue to participate in social activities and do not restrict their lives unnecessarily.
Figure 2 MRI scan showing left temporal cavernoma.
jointly by the patient and the treating clinician. Technically the diagnosis of epilepsy depends on the occurrence of two nonprovoked seizures. However, in some situations where there is a high risk of further seizures, medication may be started after a single seizure. Such circumstances might include the development of epilepsy secondary to a cerebral tumour, or the presence of active epileptic changes on EEG in people with genetic generalized epilepsy. Seizures associated with cavernous haemangiomata also have a high risk of recurrence. Trials of treatment should not normally be undertaken. Rare exceptions occur in which the diagnosis is difficult to confirm, for example in elderly people living alone (provided there is a compatible history and cardiac causes have been ruled out) and in the case of focal seizures without loss of awareness, in which even ictal epileptic activity may not be apparent on scalp electrode EEG recordings. Sometimes specific factors such as alcohol, sleep deprivation and stress are cited by patients as triggers for seizures. Table 3 lists factors that may lower the seizure threshold. However, even where these appear causal, it is often the case that antiepileptic drugs are necessary to stop seizures completely. Other
Drug treatment of epilepsy e general principles Treatment should be started only by a specialist in epilepsy, or after discussion with one.5 Where AED treatment is deemed necessary, initial treatment should be a first-line drug appropriate for their epilepsy syndrome and seizure type(s). The AED should be started at a low dosage and gradually increased until either the patient becomes seizure-free, or they develop adverse effects. If the patient has ongoing seizures despite adequate doses of an appropriate AED for their seizure type or syndrome, the diagnosis should be reconsidered. Is the diagnosis of epilepsy
Counselling people with epilepsy Nature of epilepsy Precipitating factors for seizures C Driving laws C Need to avoid potentially dangerous situations C Sudden unexpected death in epilepsy (SUDEP) C Need (or not) for medication C Adverse effects of medication C Interactions of medication with other drugs including oral contraceptive C Eligibility for free prescriptions/discretionary bus pass, if relevant C Pregnancy and teratogenicity C Employment/leisure C C
Factors that may lower seizure threshold C C C
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Alcohol excess Sleep deprivation Photic stimulation (only relevant in 2e5% of people with epilepsy) Fever/acute systemic illness Hyponatraemia/other metabolic disturbance Abrupt withdrawal of antiepileptic drugs Proconvulsant medication (includes much psychotropic medication as well as some recreational drugs)
Table 4
Table 3
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efficacious than lamotrigine in those randomized, and is the firstline AED for the treatment of generalized epilepsies in men. In girls and women of childbearing age, the risks of teratogenicity and neurodevelopmental delay in children born to mothers taking this drug in pregnancy mean that consideration should be given to the use of other medications, such as levetiracetam or lamotrigine, for generalized seizures. Neither of these drugs is yet licensed in the UK for the treatment of absences or myoclonus, but they are included in the NICE guidelines 2012 as firstline treatments for juvenile myoclonic epilepsy (JME), and as first-line or adjunctive treatments for absences. Lamotrigine has been reported to worsen myoclonus in some people.7 Carbamazepine and oxcarbazepine are effective treatments for generalized toniceclonic seizures but may unmask or worsen absences and myoclonus (as may phenytoin, which is not currently recommended as a first-line drug). Other drugs which may be considered for generalized seizure-types (on specialist recommendation) if these medications are ineffective or not tolerated are topiramate and clobazam (the latter is normally prescribed as an adjunctive therapy, since tachyphylaxis not infrequently develops). Ethosuximide is effective for the treatment of absences but has little effect in other seizure-types. Clonazepam, zonisamide, piracetam (for myoclonus), and rufinamide (for tonic or atonic seizures) are also sometimes used for refractory generalized seizures in tertiary care situations.
Safety precautions in epilepsy (this list is not exhaustive) C C C C
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Avoid unguarded heights Avoid unguarded fires, radiators etc Shower rather than bath where possible Avoid swimming alone: an observer should always be alerted to the possibility of a seizure before swimming When waiting for a train, wait at the back of the platform till the train pulls in Avoid working with unguarded machinery
Table 5
correct? If so, has the seizure type been correctly diagnosed? If the answer is yes, a second first-line drug appropriate for the epilepsy should be added, the dosage being gradually increased as before. Once an appropriate dosage has been reached, the dosage of the AED used initially should be gradually tapered. Only if at least two appropriate first-line drugs have failed independently to control the seizures should two or more drugs be prescribed concurrently. Potential adverse effects of AEDs may be mild or severe and include acute idiosyncratic reaction (such as drug rash); acute toxicity, such as ataxia and blurred vision seen with high plasma concentrations of carbamazepine, lamotrigine or phenytoin; chronic toxic symptoms, such as weight loss with topiramate, weight gain with sodium valproate, and gum hyperplasia with phenytoin; and teratogenicity. The link between the antiepileptic drug and adverse effects may not be immediately obvious, and the occurrence of behavioural or mood changes, the development of psychosis, or worsening of seizure frequency, should lead to a review of medication. People of Han Chinese, Hong Kong Chinese or Thai origin should be tested for HLA-B*1502 before being treated with carbamazepine, since there is a strong association between this allele and the development of StevenseJohnson syndrome. Chronic toxic symptoms are often drug-specific and thus to a certain extent predictable: the choice of medication should be tailored to the individual patient, taking into account potential adverse effects, co-morbidities (including liver or kidney disease, which may affect the pharmacokinetics of the drug) and concomitant medication with potential interactions (such as warfarin, digoxin), as well as suitability for seizure type and syndrome. The potential effect of antiepileptic drugs on bones has been increasingly recognized in recent years. Liver enzyme-inducing drugs affect vitamin D metabolism and may predispose to osteomalacia, but studies suggest that non-enzyme-inducing drugs may also affect bone health. It is recommended that serum vitamin D, calcium and alkaline phosphatase be measured every 2e5 years in people taking hepatic enzyme-inducing drugs; vitamin D supplementation may be necessary.
Focal seizures A second arm of the SANAD study8 randomized patients with partial epilepsy to treatment with carbamazepine, gabapentin, lamotrigine, or topiramate, with oxcarbazepine being added at a later stage (levetiracetam was not included). For time-totreatment failure (withdrawal of therapy because of inadequate seizure control or unacceptable adverse effects) lamotrigine was significantly better than carbamazepine, topiramate or gabapentin, and had a non-significant advantage over oxcarbazepine. This was despite the fact that carbamazepine had a nonsignificant advantage over lamotrigine, topiramate and oxcarbazepine with respect to time-to-12-month remission, and was significantly better than gabapentin. Notwithstanding this, carbamazepine is well tolerated by many people and lamotrigine, carbamazepine, levetiracetam and oxcarbazepine are all effective first-line treatments for focal-onset seizures. Topiramate is also effective but slightly less well tolerated, and sodium valproate may also be used but may be less effective than carbamazepine in simple and complex partial seizures. Other drugs that may be useful in focal epilepsies on specialist recommendation include clobazam, phenytoin, zonisamide, pregabalin, lacosamide, eslicarbazepine, retigabine, tiagabine, phenobarbital, and vigabatrin (the last is used only in particularly refractory cases as it can cause irreversible constriction of visual fields). Most people starting AEDs require them for at least two years. The overall chance of seizure recurrence after drug withdrawal at 2 years is approximately 40%9 over the next 2 years. In people with generalized epilepsies, ongoing epileptic activity on EEG suggests a higher risk of recurrence. However, the risk cannot be predicted with certainty, and the issue of driving (usually a period off driving is required), and risks of injury (and small risk of SUDEP) should be discussed with people wishing to withdraw medication.
First-line AEDs Generalized seizures The SANAD study of Standard And New Antiepileptic Drugs6 randomized patients with generalized or unclassifiable seizures to treatment with sodium valproate, lamotrigine or topiramate. Sodium valproate was better tolerated than topiramate and more
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taking it in pregnancy.13 The MCM rates are not known with accuracy for many antiepileptic drugs, particularly the newer ones, where the confidence intervals remain wide: for example, topiramate (4.8%, 95% CI 1.9e13.3%).14 Most women with epilepsy have uncomplicated pregnancies, and if seizures are well controlled beforehand, they are likely to remain so, although occasionally seizure control is adversely affected. The plasma concentrations of a number of AEDs, particularly lamotrigine and levetiracetam, fall in later pregnancy and an increase in dose may be required if clinically indicated. The infants of women taking liver enzyme-inducing drugs should be given intramuscular vitamin K1 1 mg at birth to prevent haemorrhagic disease of the newborn. Breastfeeding is to be
Women and epilepsy Contraception Hepatic enzyme-inducing antiepileptic drugs, which include carbamazepine, eslicarbazepine, oxcarbazepine, phenytoin, phenobarbital, primidone, and topiramate, may affect the efficacy of the oral contraceptive pill through their enzyme-inducing effect and also by increasing the hepatic synthesis of sex hormone binding globulin, thus decreasing the unbound, active progestagen. Other methods of contraception, such as barrier methods, depot injection of medroxyprogesterone or hormonereleasing intrauterine contraceptive devices, may be suitable alternatives. However, in women wishing to use the combined oral contraceptive pill (COCP), a preparation containing at least 50 mg of oestrogen should be used. It is also recommended that the patient ‘tri-cycles’, which means that she takes the contraceptive preparation without a break for 63 days, followed by a shortened, 4-day, pill-free interval. If breakthrough bleeding occurs it should be assumed that these measures are still ineffective, although its absence does not guarantee effective contraception. Liver enzyme-inducing drugs also affect progesterone-only pills and the progesterone implant, and use of these is not recommended. The copper-bearing intrauterine device is the only method of emergency contraception not affected by liver enzyme-inducing drugs. Patients requiring emergency contraception who elect not to use this should be advised to take a single dose of levonorgestrel 3 mg as soon as possible after unprotected intercourse. Lamotrigine is not thought to induce liver enzymes but may decrease the concentration of levonorgestrel slightly when taken in conjunction with the COCP. The practical effect of this is unknown but is likely to be slight, but women should be warned of the possibility of an interaction. The COCP increases the clearance of lamotrigine and may reduce its plasma concentration by 50%, such that increased dosage of lamotrigine may be necessary. For the same reason, women taking the COCP in addition to lamotrigine may develop symptoms of lamotrigine toxicity when they discontinue the COCP.
Management of status epilepticus 0e10 minutes
10e30 minutes
Pregnancy and teratogenicity Pre-conceptual counselling is essential for women with epilepsy, since most if not all antiepileptic drugs carry a risk of teratogenicity. The need for ongoing medication should be reviewed and, if it remains essential, the patient should be treated with a single AED if possible, since the risk of teratogenicity rises considerably with each additional medication. All patients taking AEDs during pregnancy should take folic acid 5 mg daily before pregnancy and for the first trimester, to reduce the risk of teratogenicity. Girls and women of childbearing age should ideally be treated with AEDs carrying a low rate of major congenital malformations (MCMs) from the outset. These include carbamazepine (2.2%, 95% CI 1.4e3.4%)10 compared with a background rate estimated at around 2e3%, lamotrigine (2.8%, 95% CI 1.9e3.9%)11 and levetiracetam (three cases identified in 117 pregnancies in one study, all of whom had taken other AEDs in addition).12 The rate for sodium valproate is considerably higher (6.2%, 95% CI 4.6e8.2%), and in addition there is evidence to suggest that this drug may be associated with neurodevelopmental delay in the infants of women
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Secure airway and assess cardiorespiratory status, administer oxygen Obtain brief history from accompanying persons and carry out general and neurological examination Establish intravenous access in large vein Take blood for full blood count, urea and electrolytes, glucose, calcium, magnesium, liver function tests, anticonvulsant concentration(s), also arterial blood gases Administer 50 ml 50% glucose and thiamine 100 mg intravenously (IV) Monitor ECG, pulse oximetry, pulse and blood pressure Administer lorazepam 2e4 mg (0.1 mg/kg, maximum 4 mg) by bolus IV injection. Repeat dose once if seizures do not stop after 10 minutes. If unavailable treat with diazepam 10 mg IV. Give phenytoin 15e20 mg/kg by slow IV infusion at a rate not greater than 50 mg/minute. If status due to abrupt withdrawal of AEDs, reinstate these unless contraindicated If seizures persist, transfer to intensive care unit and take senior advice; patient may require intubation, ventilation and inotropic support Consider treatment with: propofol 2 mg/kg IV bolus followed by 2e10 mg/kg/hour, or C midazolam 0.2 mg/kg IV followed by 0.1e0.5 mg/kg/hour, or C IV thiopental 3e5 mg/kg followed by boluses of 1e2 mg/kg every 2e3 minutes until seizures controlled, then infusion of 3e7 mg/kg/hour Continuous EEG monitoring should be established Also assess underlying cause of status further: patient may require CT scan and LP C
Table 6
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5 National Clinical Guideline Centre: Pharmacological update of NICE clinical guideline 20 e the epilepsies. The diagnosis and management of the epilepsies in adults and children in primary and secondary care 2012. 6 Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of valproate, lamotrigine or topiramate for generalized and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1016e26. 7 Mantoan L, Walker M. Treatment options in juvenile myoclonic epilepsy. Curr Treat Options Neurol 2011; 13: 355e70. 8 Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1000e15. 9 Medical Research Council Antiepileptic Drug Withdrawal Study Group. Randomised study of antiepileptic drug withdrawal in patients in remission. Lancet 1991; 337: 1175e80. 10 Morrow J, Russell A, Guthrie E, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006; 77: 193e8. 11 Hunt SJ, Irwin B, Russell AJ, et al. Lamotrigine in human pregnancy: updated experience from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2009; 80: 97. 12 Hunt S, Craig J, Russell A, et al. Levetiracetam in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurol 2006; 67: 1876e9. 13 Adab N, Kini U, Ayres J, et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004; 75: 1575e83. 14 Hunt S, Russell A, Smithson WH, et al. Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurol 2008; 71: 272e6. 15 Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000; 342: 314e9.
encouraged in most cases, but if the AEDs include phenobarbital or benzodiazepines, sedation of the baby may be a problem. Sleep deprivation in the post-partum period may increase the risk of seizures, and women should be advised about childcare in the context of epilepsy: for example, they should feed the infant while sitting on a floor cushion, change the infant on a changing mat on the floor, avoid bathing the infant when alone in the house, and use a carrycot if it is necessary to carry the infant upstairs.
Treatment of status epilepticus Status epilepticus is usually defined as ongoing seizure activity lasting 30 minutes or more; it is a medical emergency, with the mortality rate for toniceclonic status epilepticus being of the order of 20e30%. Status epilepticus is often preceded by an increasing frequency of seizures, and in such cases it may be possible to avoid it by the use of protocols for buccal midazolam or rectal diazepam. Significant adverse prognostic factors include the underlying aetiology and the duration of the status. It is therefore of utmost importance to treat ongoing seizure activity early, ideally within 5e10 minutes of onset. The treatment is summarized in Table 6.
Surgery for epilepsy Although seizures can be readily controlled in the majority of people with epilepsy, in approximately 30% they remain refractory to medical treatment (the chance of becoming seizurefree if seizures have failed to respond to treatment with two appropriate antiepileptic drugs is of the order of 4% for treatment with a third AED).15 If medical treatment has failed, the seizures are sufficiently frequent and disabling, the site of onset of the seizures can be identified and the likely benefits outweigh the risks, resective surgery to remove the epileptic focus may be feasible. The likelihood of seizure freedom varies with the type of surgery, but is usually of the order of 50e70%. In patients who are not candidates for resective surgery, vagus nerve stimulation or deep brain stimulation may be helpful. A
Practice points REFERENCES 1 Lempert T, Bauer M, Schmidt D. Syncope: a videometric analysis of 56 episodes of transient cerebral hypoxia. Ann Neurol 1994; 36: 233e7. 2 McCrory PR, Bladin PF, Berkovic SF. Retrospective study of concussive convulsions in elite Australian rules and rugby league footballers: phenomenology, aetiology and outcome. Br Med J 1997; 314: 171e4. 3 Marsan CA, Zivin LS. Factors related to the occurrence of typical paroxysmal abnormalities in the EEG records of epileptic patients. Epilepsia 1970; 11: 361e81. 4 Zivin L, Marsan CA. Incidence and prognostic significance of “epileptiform” activity in the EEG of non-epileptic subjects. Brain 1968; 91: 751e8.
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An accurate history is crucial for diagnosis Investigation for seizures should include ECG Neuroimaging should be undertaken for focal seizures of unknown cause Ambulatory EEG or EEG-videomonitoring may be helpful if diagnosis of ongoing seizures remains unclear Medication should be started on the advice of a specialist Tailor medication to patient, seizure type and syndrome Be aware of drug interactions, particularly with contraceptives and warfarin Consider possibility of surgery in patients failing to respond to medication
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