Adult Epilepsy

8/8/2019 Adult Epilepsy

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Epilepsy is a disorder of the brain characterised by anenduring predisposition to generate epileptic seizures,and epileptogenesis is the development of a neuronalnetwork in which spontaneous seizures occur. Epilepsyaffects the whole age range from neonates to elderlypeople, and has varied causes and manifestations, withmany distinct seizure types, several identiablesyndromes, but also much that is poorly classied. Thereare very many comorbidities that complicate assessmentand treatment planning, including learning disabilities,xed neurological decits, progressive conditions,psychological and psychiatric problems, and, particularlyin the older age group, concomitant medical conditions.

Classication of epileptic seizures and syndromes iscontinually evolving. The present proposed classicationis across ve axes that consider seizure types, focal orgeneralised seizure onset, the syndrome, causation, andassociated decits. 1 Here, we have dened individualsaged 16 years and older as adults. The UK NationalInstitute for Health and Clinical Excellence (NICE) produced in October 2004 detailed evidence-basedguidelines 2 for the clinical management of individualswith epilepsy (panel). Other guidelines include those of

the American Academy of Neurology and the ScottishIntercollegiate Guidelines Network.

Stigma and prejudice mark epilepsy out from otherneurological conditions. The past decade has seenconsiderable progress in epilepsy research, andimprovement in public understanding. Much, however,remains to be done, especially for people for whom drugsare ineffective. An important issue that needs urgentattention is the fact that most people with epilepsy live inresource-poor countries where the management of epilepsy is inconsistent. There is a great diagnostic gap inlarge parts of the world because there are too few trainedpersonnel and medical facilities. The WHO-led GlobalCampaign Against Epilepsy with the active support of theInternational League Against Epilepsy and International

Lancet 2006; 367: 1087100

Department of Clinical andExperimental Epilepsy,Institute of Neurology UCL,Queen Square, LondonWC1N 3BG, UK and TheNational Society for Epilepsy,Chalfont St Peter, UK(J S Duncan FRCP, J W Sander MRCP,S M Sisodiya FRCP,M C Walker MRCP)

Correspondence to:

Prof J S Duncan [email protected]

Adult epilepsy John S Duncan, Josemir W Sander, Sanjay M Sisodiya, Matthew C Walker

The epilepsies are one of the most common serious brain disorders, can occur at all ages, and have many possiblepresentations and causes. Although incidence in childhood has fallen over the past three decades in developedcountries, this reduction is matched by an increase in elderly people. Monogenic Mendelian epilepsies are rare. Aclinical syndrome often has multiple possible genetic causes, and conversely, different mutations in one gene canlead to various epileptic syndromes. Most common epilepsies, however, are probably complex traits withenvironmental effects acting on inherited susceptibility, mediated by common variation in particular genes.Diagnosis of epilepsy remains clinical, and neurophysiological investigations assist with diagnosis of the syndrome.Brain imaging is making great progress in identifying the structural and functional causes and consequences of theepilepsies. Current antiepileptic drugs suppress seizures without inuencing the underlying tendency to generateseizures, and are effective in 6070% of individuals. Pharmacogenetic studies hold the promise of being able tobetter individualise treatment for each patient, with maximum possibility of benet and minimum risk of adverse

effects. For people with refractory focal epilepsy, neurosurgical resection offers the possibility of a life-changingcure. Potential new treatments include precise prediction of seizures and focal therapy with drug delivery, neuralstimulation, and biological grafts.

Search strategy and selection criteria

We searched PubMed for articles from 2002, with thekeywords epilep*, EEG, MRI, seizure prediction,SUDEP, antiepileptic drug, gene*, surgery, andmechanisms. We also cite occasional earlier articles andreviews, where these are particularly relevant.

ForUK National Institute forHealth and Clinical ExcellenceGuidelines see http://www.nice.org.uk

ForAmerican Academy of Neurology guidelines seehttp://www.guideline.gov

ForScottish IntercollegiateGuidelines Network seehttp://www.sign.ac.uk

Forthe Global CampaignAgainst Epilepsy see http://www.who.int/mental_health/

management/globalepilepsycampaign

Panel: NICE epilepsy guidelines key points2

Diagnosis should be made urgently by a specialist with aninterest in epilepsyEEG used to support diagnosis when the clinical historysuggests itMRI should be used in people who develop epilepsy asadults, in whom focal onset is suspected, or in whomseizures persist

Seizure types and epilepsy syndrome, cause, andcomorbidity should be determinedInitiation of appropriate treatment recommended by aspecialistTreatment individualised according to the seizure type,epilepsy syndrome, comedication and comorbidity,individuals lifestyle, and personal preferencesIndividual with epilepsy, and their family, carers, or both,participate in all decisions about their care, taking intoaccount any specic needComprehensive care plans agreedComprehensive provision of information about all aspectsof condition

Regular structured review at least once a yearReferral back to secondary or tertiary care if Epilepsy inadequately controlledPregnancy considered or pregnantAntiepileptic drug withdrawal considered

www.thelancet.com Vol 367 April 1, 2006 1087


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1088 www.thelancet.com Vol 367 April 1, 2006

Bureau for Epilepsy (the two major internationalnon-governmental organisations in epilepsy) is seekingto address these issues. 3,4 Additionally, there is a largetreatment gap in resource-poor countries, and worldwide,less than 20% of people with the disorder are estimated tobe treated at any time. 5,6 However, resolving thesediffi culties will require tremendous effort and will taketime to achieve. Most of what we discuss here relates todiagnosis and treatment of epilepsy as seen in thedeveloped world. We hope that before long, the samestandards will be achieved in resource-poor countries.

EpidemiologyThe incidence of epilepsy in developed countries isaround 50 per 100 000 people per year, and is higher in

infants and elderly people. 79 Less wealthy people show ahigher incidence, for unknown reasons. 10 Poor sanitation,inadequate health delivery systems, and a higher risk of brain infections and infestations could contribute to ahigher incidenceusually above 100 per 100 000 peopleper yearin resource-poor countries where most peoplewith epilepsy usually do not receive treatment. 8,11Childhoodincidence has fallen over the past three decades indeveloped countries, which could be a result of adoptionof healthier lifestyles by expectant mothers, improvedperinatal care, and immunisation programmes. A parallelrise in incidence in elderly people could be related toimproved survival in people with cerebrovascular diseaseand cerebral degeneration. 8,12

The prevalence of epilepsy is between 4 and 10 per 1000people per year. 8,9 A few (typically small) studies fromisolated geographical areas with unique genetic orenvironmental factors 8 have shown higher rates. Lifetimeprevalence rates are much higher than rates of activeepilepsy, even in resource-poor countries where mostpeople do not have access to antiepileptics. 8 Thisdifference is mainly explained by the cessation of seizuresin most people who develop the disorder, but also partlyby increased mortality in epilepsy. 13,14

Risk factors vary with age and geographical location.Epilepsy associated with head trauma, central nervoussystem infections, and tumours occurs at any age.

Cerebrovascular disease is the most common risk factorin people older than 60 years. 15 Endemic parasitic diseasessuch as falciparum malaria and neurocysticercosis areprobably the most common preventable risks for epilepsyworldwide.11,1620 Recently, toxocariasis and onchocerciasishave been suggested as important risk factors. 21,22 Susceptibility to epilepsy could be partly geneticallydetermined. The complex interplay between genetic andenvironmental factors might underlie our incompleteunderstanding of the population dynamics of thedisorder. 11 Additionally, some epileptic syndromes evolveover time. Two examples of this evolution are infantilespasms progressing to Lennox-Gastaut syndrome (anespecially severe form of epilepsy), and the occurrence of febrile convulsions in an infant leading to the later

development of medial temporal lobe epilepsy. From anepidemiological or biological point of view, however, themechanisms of progression have not yet been fullyelucidated and genetic factors are likely to have a role.

In developed countries, more than 60% of patientsachieve long-term remission, usually within 5 years of diagnosis; the possibility of remission decreases the longerthe epilepsy is active.8 Predictors of good outcome includeearlier age of onset, fewer early seizures, 23,24 and earlyresponse to drug treatment. 25 In any individual, outcomeand response to treatment can be inherent to either thecondition or to the individual, and seizure control in somecan be diffi cult from the outset. 8,26 In developed countries,the overall good prognosis is often attributed to thewidespread use of antiepileptic drugs. In resource-poor

countries lacking such drugs, however, many patientsenter long-term remission, lending support to thesuggestion that prognosis is dependent on the cause of theepilepsy and not on drug treatment. 26 Up to a third of people having seizures develop chronic epilepsy. 26 However,up to 20% of patients referred to clinics with refractoryepilepsy might have been misdiagnosed, and many morecould be helped by optimum treatment. 27 People withchronic epilepsy also have an increased risk of comorbidconditions, including cardiovascular and cerebrovasculardisorders, gastro intestinal disorders, fractures, pneumonia,chronic lung diseases, and diabetes. 28

MortalityPeople with epilepsy have an increased risk of prematuredeath. 29 Symptomatic epilepsy can reduce life expectancyby up to 18 years.30 Sudden death, trauma, suicide,pneumonia, and status epilepticus are more common inpeople who have epilepsy than those without the disorder. 31 Little is known about mortality in resource-poor countries,although circumstantial evidence suggests that it is higherthan in developed countries, helping to explain thediscrepancy between the higher incidence and lowerprevalence of active epilepsy in poor countries. 8

Sudden unexpected death in epilepsy is thought toaccount for at least 500 deaths per year in the UK, and isnot fully explained. 32 In people with refractory epilepsy

attending specialist clinics, the yearly rate is one per 200.The highest risk is in male teenagers and young adultswith convulsive seizures. 33 High seizure frequency andseverity are risk factors, and in the highest risk group(ie, those who have been considered for surgery butdeclined)the yearly rate is one per 75 individuals. 34 Sleeping unattended is another risk factor. 35,36 Thepathophysiological causes of sudden unexplained deathin epilepsy is unknown, but cardiac arrhythmiasinparticular asystole secondary to seizureshave beennoted in monitoring studies and might only arise withoccasional seizures (gure 1). 37 Further long-termelectrocardiogram (ECG) monitoring studies are neededto identify characteristics that carry a high risk of asystoleand indicate prophylactic cardiac pacing.


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PathophysiologyAn epileptic seizure is a transient occurrence of signs, orsymptoms, or both, due to abnormal excessive orsynchronous neuronal activity in the brain. 38 Brief synchronous activity of a group of neurons leads to theinterictal spike, which has a duration of less than 70 msand is distinct from a seizure. 39 Indeed, the site of interictal spiking can be separate from the zone of seizure onset.

An early view that disruption of the normal balancebetween excitation and inhibition in the brain results inseizure generation is now thought to be an over-simplication. The function of the brain depends oncooperation between disparate networks that is probablymediated through oscillations within these networks.

Cortical networks generate oscillations, for whichinhibitory neurons, 40 neuronal communication (eg,synaptic transmission), and intrinsic neuronal properties(eg, the ability of a neuron to maintain burst ring) arecrucial. The occurrence of epileptic activity might be anemergent property of such oscillatory networks. 41 Transition from normal to epileptiform behaviour isprobably caused by greater spread and neuronalrecruitment secondary to a combination of enhancedconnectivity, enhanced excitatory transmission, a failureof inhibitory mechanisms, and changes in intrinsicneuronal properties. In studies in man the electro-encephalogram (EEG) becomes less chaotic within largeareas of cortex before a seizure, suggesting thatwidespread synchronisation is taking place. 42

In focal epilepsies, focal functional disruptionoftendue to focal pathological changes (eg, tumour), or rarelyto a genetic diathesis (eg , autosomal dominant frontallobe epilepsy)results in seizures beginning in alocalised fashion, which then spread by recruitment of other brain areas. The site of the focus and the speed andextent of spread determine the clinical manifestation of the seizure.

Generalised epilepsies result in seizures occurringthroughout the cortex because of a generalised lowering of seizure threshold, and are usually genetically determined.Absence seizures are a distinct form of generalised seizuregenerated by thalamocortical loops (gure 2). 43 Absenceswere originally believed to be generated subcortically, bythalamic neurons driving recruitment of neocortical

neurons. However, paroxysmal oscillations withinthalamocortical loops in absence seizures in rats seem tooriginate in the somatosensory cortex rather than thethalamus, with synchronisation mediated by rapidintracortical propagation of seizure activity. 44 Together withobservations of subtle cortical structural abnormalities insome patients with absence seizures, 45 and the potential of focal pathological change in the medial frontal lobe togenerate absence-like seizures, the distinction betweenfocal and generalised epilepsies has become blurred.

Genetic basis and contributionGenetic variation can determine the causes, susceptibility,mechanisms, syndrome, treatment response, prognosis,and consequences of the epilepsies to varying degrees.Part of the promise of genetics lies in its power to relatethese characteristics of the overall clinical presentation of the individual patient. There has been considerableprogress in this area. 46,47 Several monogenic Mendelianepilepsies are known, but are generally rare and accountfor few cases. There can be variation in the genetic causesof a clinically homogeneous syndrome, such as juvenilemyoclonic epilepsy, 48,49 and, conversely, different mutationsin a single gene can cause various epilepsy syndromes.

Figure 1:Electrocardiogram showing asystole resulting from temporal lobeseizure 37

Cortex

Thalamus

RT

TC

Figure 2:Possible mechanism of generation of spike-wave discharges (absences)Burst ring of cortical neurons leads to recruitment of reticular thalamic (RT) neuronal network. Activation of low-threshold calcium currents results in burst ring of RT network, releasing aminobutyric acid (GABA) ontothalamocortical (TC) neurons, which are hyperpolarised through activation of GABAB and GABAA receptors. Thishyperpolarisation results in deinactivation of T type calcium channels. On repolarisation, these calcium channelsopen, resulting in a burst of action potentials from TC neurons that then drives the cortical neurons (left). In this

way the cycle continues generating the spike-wave discharges seen on scalp EEG (right).Red=inhibitory GABAergic neurons. Blue=excitatory glutamatergic neurons.


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Thus, different mutations in the gene SCN1A, whichencodes a neuronal sodium channel subunit, underlie arange of epilepsies, from the severe myoclonic epilepsy of infancy to the usually more benign generalised epilepsywith febrile seizures plus, 50,51 which, conversely, mightresult from mutations in other genes. 52,53

The present belief that most common epilepsies arecomplex traits with environmental effects acting on abackground of multigenic or oligogenic susceptibility, mediated by common genetic variationespecially singlenucleotide polymorphismsis largely based on geneticepidemiological studies. 54 Idiopathic generalised epilepsiesare emerging as an example of such complex disease

causation. 55,56 Relevant genetic variation is usually identiedby population genetic association studies of largegroupings of well characterised patients whose genotypesare related to their phenotypes. Many such studies of susceptibility and other phenotypic features have beenpublished, but very few have been replicated. 57,58 Evolvingmethods and larger collaborative studies will reveal singlenucleotide polymorphisms and other common geneticvariants that confer disease susceptibility. 59

Diagnosis and investigationThe diagnosis of epilepsy remains clinical and is based onprobability after assessment of the whole individual.

Interictal spikes over left anterior temporal region

Depth electrode recording at beginning of seizure

Right amygdala

Right hippocampus

Left amygdala

Left hippocampus

Seizure activity over left temporal region

Figure 3:EEG in temporal lobe epilepsyUpper=scalp EEG recordings: left, interictal EEG demonstrating anterior temporal spikes; right, rhythmic activity over left temporal region during seizure. Lower=EEGrecording from intracranial electrodes (placed in right amygdala and hippocampus and left amygdala and hippocampus) showing fast activity in left amygdala andhippocampus at beginning of temporal lobe seizure.


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Misdiagnosis is potentially very damaging. The differentialdiagnosis must therefore always be carefully considered.In some cases the diagnosis of epilepsy syndrome orseizure types is incorrect, or the events are not due toepilepsy at all, but instead have their basis in a cardiac,psychological, psychiatric, or metabolic disturbance. Suchnon-epileptic seizures are important to identify since theyhave distinct causes, treatments, and risks, including theresults of inappropriate use of antiepileptic drugs,especially in an emergency setting, and withholding of appropriate therapy. 27

Sometimes, diagnosis of epilepsy has to be delayed whilewitness accounts are sought. Video recordings lmed outof hospital are increasingly accessible and form a veryuseful adjunct, especially when seizures are infrequent.

Other investigation will only rarely affect the actualdiagnosis of epilepsy, although it can be crucial forestablishing the syndromic diagnosis and cause. Goodpractice is to do an ECG for everyone presenting withpossible seizures, especially if the events include loss of awareness and falls. A proportion of such episodes will bedue to cardiac arrhythmiaindicated, for example, by aprolonged QT interval. In cases of diagnostic uncertainty afull cardiac assessment is appropriate and could reveal aprimary cardiovascular cause. For infrequent events with apossible cardiac cause, an implanted ECG loop recorder isan essential diagnostic aid, often leading to specic andeffective therapy.60

In clinical practice, the hallmark of epilepsy is interictalepileptic activity: spikes, sharp waves, and spike-wavedischarges (gure 3). The integration of the clinicaldescription of the seizures, the age and comorbidities of the patient, the EEG patterns, and brain imaging lead toa syndromic diagnosis that conveys prognosticinformation. Prolonged digital ambulatory and videoEEG provide greater temporal samples than a standard30 min EEG and, if seizures are frequent, the realisticpossibility of direct observation and recording of habitualseizures. Such information is invaluable in the event of diagnostic uncertainty and if surgical treatment isconsidered. 61

The mainstay of elective brain imaging is MRI, which

is becoming increasingly available. The quality of MRIhas improved greatly over the past decade. There remainsa gulf between the sensitivity and specicity of optimumimaging as obtained at a centre of excellence, and non-specialised routine brain MRI. 62,63 Widespread adoptionof agreed imaging protocols 64,65 would be an importantstep forward. In resource-poor countries, access to MRIcan be restricted or non-existent. In this situation, CTmight be more accessible and can be used to assess grosspathological changes, but cannot identify most of thesubtle changes that commonly underlie epilepsy. MRI isespecially important in individuals with refractory partialseizures who would be potential candidates for surgicaltreatment, and in those with progressive neurological orpsychological decits.64,65 The sensitivity of MRI in

detection of subtle changes that could underlie refractoryfocal epilepsies, such as focal cortical dysplasia, isimproving with new MRI acquisition sequences (gure 4).Diffusion tensor imaging, 66 magnetisation transferimaging, 67 and T2 mapping 68,69 show promise.Tractography can visualise white-matter tracts includingconnections of eloquent areas 70 and can be used to reducethe risks of surgery 71 (gure 5).

Automated data analysis is becoming an importantadjunct to visual interpretation. 72,73 Voxel-based analysiscan identify subtle changes in the neocortex over time

Figure 5: Tractography outlining the right optic radiation, superimposed on a sagittal MRI scan after rightanterior temporal lobe resection

A superior left quadrantic visual eld defect was noted after surgery, caused by resection affecting anterior part(Meyers loop) of right optic radiation.

Figure 4:Focal cortical dysplasiaArrow=cortical dysplasia in medial left frontal lobe, extending to superior borderof frontal horn (left side of brain is on right side of image).


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Putative modes of action Routes of elimination

and metabolites

Usual starting dose in

adults

Usual daily

maintenance dose inadolescent and adults

Main safety issues or concerns

Acetazolamide (1952) Carbonic anhydrase inhibition Renally excreted 250 mg 5001000 mg Idiosyncrat ic rash; rarely Stevens- Johnson syndrome and toxicepidermal necrolysis; aplasticanaemia

Carbamazepine (1963) Sodium-channel inhibition Hepatic metabolism;active metabolite

100200 mg 4001800 mg Idiosyncratic reactions; rarelyStevens-Johnson syndrome;aplastic anaemia, hepatotoxicity

Clobazam (1986) GABA augmentation Hepatic metabolism;active metabolite

10 mg 1030 mg Rarely idiosyncratic rash

Clonazepam (1975) GABA augmentation Hepatic metabolism 05 mg 16 mg Rarely idiosyncratic rash,thrombocytopenia

Diazepam (1965) GABA augmentation Hepatic metabolism;active metabolite

1020 mg N/A Respiratory depression

Ethosuximide (1953) Calcium-channel modication Hepatic metabolism;

25% excretedunchanged

250 mg 5001500 mg Rarely idiosyncratic rash, Stevens-

Johnson syndrome, aplasticanaemia

Felbamate ( 1993) Glutamate reduction Hepatic metabolism;active metabolites

400 mg 18003600 mg Hepatic failure, aplastic anaemia

Gabapentin (1993) Calcium-channel modulation Not metabolised,urinary excretionunchanged

300 mg 18003600 mg Paradoxical increase in seizures

Lamotrigine (1991) Sodium-channel inhibition;glutamate reduction

Hepatic metabolism byglucuronidation

50 mg(10 mg if takingvalproate)

100400 mg Idiosyncratic rashes, rarelyStevens-Johnson syndrome,Toxic epidermal necrolysis, liverfailure, aplastic anaemia,multiorgan failure

Levetiracetam (1999) Synaptic vesicle proteinmodulation

Urinary excretion 250 mg 7503000 mg Behavioural problems

Lorazepam (1972) GABA augmentation Hepatic metabolism 24 mg N/A Respiratory depression

Phenobarbi tal (1912) GABA augmentat ion Hepat ic metabolism;25% excretedunchanged

30 mg 30180 mg Idisyncratic rash; rarely toxicepidermal necrolysis;hepatotoxicity; osteomalacia;Dupuytrens contracture

Phenytoin (1938) Sodium-channel inhibition Saturable hepaticmetabolism

200 mg 200400 mg Idiosyncratic rash; rarelypseudolymphoma; peripheralneuropathy; Stevens-Johnsonsyndrome; Dupuytrenscontracture; hepatotoxicity;osteomalacia

Pregabalin (2004) Calcium-channel modulation Not metabolised,excreted unchanged

50 mg 100600 mg Weight gain; rarely increasedseizures

Primidone (1952) GABA augmentation Hepatic metabolism 125 mg 5001500 mg Idiosyncratic rash; rarelyagranulocytosis;thrombocytopenia; lupus-likesyndrome

Oxcarbazepine (1990) Sodium-channel i nhibition Hepatic metabolism 150300 mg 9002400 mg Idiosyncratic rash; hyponatraemia

Tiagabine (1996) GABA augmentation Hepatic metabolism 5 mg 3045 mg Increased seizures; non-

convulsive statusTopiramate (1995) Glutamate reduction;

sodium-channel modulation;calcium-channel modication

Mostly hepaticmetabolism, with renalexcretion

25 mg 75200 mg Weight loss; kidney stones;impaired cognition

Valproic acid (1968) GABA augmentation Hepatic metaboli sm;active metabolites

200 mg 4002000 mg Teratogenicity; rarely acutepancreatitis; hepatotoxicity;thrombocytopenia;encephalopathy;polycystic ovarian syndrome

Vigabatrin (1989) GABA augmentation Not metabolised 85%excreted unchanged

500 mg 10002000 mg Visual eld defects, increasedseizures

Zoni samide (1990) Calcium channel inhibition Urinary excreti on 50100 mg 200600 mg Rash; rarely blood dyscrasias

GABA= aminobutyric acid.

Table 1:The range of antiepileptic drugs (year of introduction) in present use


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First-line drugs Second-line drugs Other drugs that can be considered Drugs to be avoided (couldworsen seizures)

Seizure type

Generalised tonic-clonic CarbamazepineLamotrigineSodium valproateTopiramate

ClobazamLevetiracetamOxcarbazepineZonisamide

AcetazolamideClonazepamPhenobarbitalPhenytoin

TiagabineVigabatrin

Absence EthosuximideLamotrigineSodium valproate

ClobazamClonazepamTopiramate

.. CarbamazepineGabapentinOxcarbazepineTiagabineVigabatrin

Myoclonic Sodium valproateTopiramate

ClobazamClonazepamLamotrigineLevetiracetamPiracetamZonisamide

.. CarbamazepineGabapentinOxcarbazepinePregabalinTiagabineVigabatrin

Tonic LamotrigineSodium valproate

ClobazamClonazepamTopiramateZonisamide

AcetazolamideFelbamateLevetiracetamPhenobarbitalPhenytoin

CarbamazepineOxcarbazepine

Atonic LamotrigineSodium valproate

ClobazamClonazepamTopiramateZonisamide

ZonisamideFelbamateLevetiracetamPhenobarbital

CarbamazepineOxcarbazepinePhenytoin

Focal with or without secondary generalisation CarbamazepineLamotrigineOxcarbazepineSodium valproateTopiramate

ClobazamGabapentinLevetiracetamPregabalinTiagabineZonisamide

AcetazolamideClonazepamPhenobarbitalPhenytoin

..

Epilepsy syndrome

Juvenile absence epilepsy LamotrigineSodium valproate

LevetiracetamTopiramate

.. CarbamazepineGabapentinOxcarbazepinePhenytoinPregabalinTiagabineVigabatrin

Juvenile myoclonic epilepsy LamotrigineSodium valproateTopiramate

ClobazamClonazepamLevetiracetamZonisamide

Acetazolamide CarbamazepineGabapentinOxcarbazepinePhenytoinPregabalinTiagabineVigabatrin

Generalised tonic-c lonic seizures only CarbamazepineLamotrigineSodium valproateTopiramate

LevetiracetamZonisamide

AcetazolamideClobazamClonazepamOxcarbazepinePhenobarbitalPhenytoin

TiagabineVigabatrin

Focal epilepsies

Cryptogenic, symptomatic CarbamazepineLamotrigineOxcarbazepineSodium valproateTopiramate

ClobazamGabapentinLevetiracetamPhenytoinPregabalinTiagabineZonisamide

AcetazolamideClonazepamPhenobarbital

..

Benign epilepsy with centrotemporal spikes CarbamazepineLamotrigineOxcarbazepineSodium valproate


Sulthiame ..

Benign epilepsy with occipital paroxysms CarbamazepineLamotrigineOxcarbazepineSodium valproate


.. ..

Table 2:Antiepileptic drug options for epileptic seizures and syndromes seen in adults


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specically to a presynaptic vesicular protein that affectsneurotransmitter release. 99 Interest is also growing in thecationic h-channel, which inhibits regenerative dendriticaction potentials, since lamotrigine 100 and possiblygabapentin 101 potentiate this current.

More than 20 antiepileptic drugs are licensed worldwide(table 1). These drugs suppress the symptom (seizures)rather than modify disease process (epileptogenesis).There is no evidence that the drugs used at present changelonger-term prognosis for most people. 102 In resource-poor countries, not having a reliable supply of antiepilepticdrugs is a major problem, and can result in abrupttreatment withdrawal and consequent serious exacerbationof seizures. In some circumstances, prescribing a drugthat is usually available (such as phenobarbital) might

therefore be preferable to a newer drug whose supplymight be more erratic. Although phenytoin is widelyavailable, its effective use depends on the ability tomonitor its concentration in serum. If monitoring is notfeasible, the use of this agent is less attractive.

Conventionally, antiepileptic drugs are divided into olddrugs and new drugs, according to whether or not theywere available before the 1990s. Some of these drugs areused as rst-line treatment and are selected mainlyaccording to their clinical effectiveness for the epilepticsyndrome or seizure type, and for tolerability andindividual patients circumstances. 2,96,103,104 Thisindividualised approach to treatment is recommended inall treatment guidelines. 25 Existing NICE guidelinessuggest a range of drugs as potential rst-line treatmentsfor the different seizure types and epilepsy syndromesthat are most likely to be seen in adult practice (table 2).

New antiepileptic drugs have often been promoted ashaving advantages over old drugs. 105107There is, however,no evidence that new drugs are more effective, althoughthey might be better tolerated, than old drugs. Acomparative study of the tolerability and effi cacy of twonewer drugs, lamotrigine and gabapentin, withcarbamazepine, showed no difference in effi cacy inelderly people, but the new drugs were better toleratedthan the old ones in this age group. 108 A major pragmaticclinical trial (SANAD)109 comparing newer and older

antiepileptic drugs is underway and will report withinthe next year.

Despite the fact that several new drugs have beenlicensed in recent times, the principles of epilepsytreatment have not changed much. 96 Antiepileptictreatment is still essentially empirical rather than rational.However, a rational approach to management iswarranted, with a clear individualised management planestablished at the earliest opportunity. For instance,women of childbearing potential should not be startedon drugs that carry an increased risk of detrimentaleffects to a fetus unless there is no other choice. 110 Inelderly people, who might be taking several drugs forother conditions, drugs that are likely to interact withothers should be avoided if possible.

When should treatment should be started in peoplewith few or infrequent seizures? A recurring issue hasbeen whether seizures beget seizures, and thereforewhether failure of early treatment leads to chronicity. 26,111 Recent evidence shows no difference in the long-termoutlook for deferred versus immediate treatment, 104 which justies the practice of waiting for further eventsrather than starting treatment immediately after a singleseizure. Patients perceived to be at high risk of recurrencebecause of a structural abnormality thought to beresponsible for the seizure, an abnormal EEG, a pre-existing neurological decit, or an initial high density of seizures, should, however, still be offered antiepilepticsat the rst opportunity. The same holds true for thosewho, on understanding the risks of recurrence and the

scope and limitations of these drugs wish to takemedication to reduce the risk of a further seizure.

Although randomised clinical trials provide useful datafor guiding drug treatment, they are of little practical use.The studies are generally short term and usually do nottake into account the heterogeneity of patients in termsof epilepsy syndrome, associated comorbidities, andlifestyle factors that direct advice on individual treatmentoptions. 112 This necessity was recognised by the recentNICE guidelines on the management of epilepsy(panel).2,113

Antiepileptic drugs should always be introducedcautiously and the dose stepped up gradually. Titration of the drug is usually symptom-led, and if seizures are stilltaking place, the drug should be titrated up to themaximum tolerated dose. If toxic effects occur at anypoint, the dose should be reduced. If one rst-line drugfails at the maximum tolerated dose, it should besubstituted with another such drug. If all rst-line drugsfail then second-line options should be added (table 2).Monotherapy is preferable because polytherapy increasesthe possibilities of poor compliance, drug interactions,teratogenicity, and long-term toxic effects. There are,however, some individuals for whom polytherapy cannotbe avoided. Consideration has been given to the notion of rational polytherapyie, the use of combinations of drugs with different putative mechanisms of action,

aiming at synergy of effect but not of adverse effects. 114 However, apart from some evidence that lamotrigine andsodium valproate might be better in combination thateither alone, 115 there is no consistent evidence thatsynergisms exist between different drugs, and this areaneeds further investigation.

Despite the existence of many antiepileptic drugs, a thirdof people who develop epilepsy continue to experienceseizures unabated. 26 For most of these individuals, inparticular those who are not candidates for curativeepilepsy surgery, the only hope for improved seizurecontrol lies with drugs to which they have not beenpreviously exposed. New agents are rapidly being developedand efforts are being directed at disease modication inaddition to symptom control. 116


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Adverse drug effectsOccasionally, seizures can be aggravated by antiepilepticdrugs. 117120Before attributing exacerbation of seizures to adrug, alternative explanations need to be excluded, such asnatural uctuation of seizure occurrence, irregularadherence to the prescription, comorbid illness, anddevelopment of tolerance. 120 Most information onaggravation of seizures is based on anecdotal case reportsor case series and should be interpreted cautiously. Inpractice, the possibility of seizure aggravation should beconsideredin particular when treating idiopathicgeneralised epilepsy with drugs that modulate sodiumchannels and certain GABAergic drugsand conse-quently, these drugs are best avoided in the initialmanagement of this disorder (table 2). 120

The potential clinical implications of the well establishedadverse effects of older antiepileptic drugs on bonemetabolism and density 121124 have generated studiesinvestigating the extent of these problems and associatedrisk factors. Whether or not this problem is also associatedwith the newer drugs is yet to be proven. There have beenrenewed concerns about the potential teratogenicity of sodium valproate. 125132 Another issue is that sodiumvalproate exposure in utero might impair neuro-psychological development, even in children without overtphysical malformation. 133,134 Prospective studies are beingdone in both the UK and the USA to address this issue,and are of great importance because sodium valproate isstill one of the most effective drugs, especially for someforms of idiopathic generalised epilepsy. 135

Antiepileptic drugs that interact with hormonal contra-ceptives usually do so by enhancing clearance of theoestrogen component. 136 This potential for contraceptive

failure is an important issue in the treatment of womenwith epilepsy. A different form of interaction with oralcontraceptive steroids has been described: levels of lamotrigine are substantially reduced by the oestrogencomponent of oral contraceptives, 137 which has clinicalimplications because initiation of oestrogen contraceptioncould therefore result in recurrence or exacerbation of seizures.

Pharmacogenetics and drug resistancePharmacogenetics addresses the effect of genetic variationon drug response and adverse effects. Environmentalfactors (eg, alcohol abuse) can partly account for resistanceto drugs, but are poorly understood. Major advances ingenetic biotechnology make understanding the genetic

contribution to varying drug responses a realisticpossibility. Little is known of epilepsy pharmacogenetics,apart from the acknowledged effect on phenytoin dosingof variation in the gene encoding the metabolising enzymeCYP2C9, although pretreatment genotyping of suchvariation has not found a place in clinical practice.Pharmacogenetics holds the promise of therapy that moreclosely suits an individuals prole and type of epilepsy.Pharmacogenetics will support, and not supplant, thetreating physician, who can place the cost-effectiveinterpretation of data in the individuals clinical andenvironmental context.

Common variation in the gene SCN1A affects themaximum dose of phenytoin or carbamazepine, which acton the sodium channel subunit encoded by this gene. 138 Although the recorded genotypic variation explained onlyaround 5% of the dose variation seen, the implementationof dosing pharmacogenetics could lead to more effectiveuse of existing specic antiepileptic drugs in patients whoare constitutionally suited to them. However, much moreresearch is needed to make use of data on individualgenetic variation, to guide drug choice, and to predictdosing and response.

Pharmacoresistance per se has received freshattention: 139 two key hypotheses that are not mutuallyexclusive have emerged for the underlying mechanisms.The target hypothesis postulates alteration in drug targets

at some stage, leading to poor response to drugtreatment. 140 The transporter theory posits that certainmultidrug transporters expressed in the brain couldreduce antiepileptic drug concentration around neuronsin the seizure focus by active export away from neurons,back into capillary lumina (gure 7). Variation in the geneABCB1 encoding one such transporter, P glycoprotein,was shown to associate with a phenotype of broad drugresistance. 141 However, a formal replication did not lendsupport to the original nding. 142 Replication andfunctional explanation of reported associations areessential before therapy or prognostication can depend onsuch reports. However, the potential of pharmacogeneticsmakes such investment worthwhile, since resultsgenerated in this way could lead to improved management

BCRP

MVP

?

MRP1

MRP2

Capillary

Interstitial uid

P-gp

Glial cell

AED diffusion

Neuron

Figure 7:Schematic illustration of drug transporter hypothesis of antiepileptic drug resistance

Small circles=multidrug transporters. MRP1, MRP2=multidrug-resistance associated proteins 1 and 2. BCRP=breastcancer resistance protein. MVP=major vault protein.


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more quickly than through an understanding of diseasesusceptibility genetics.

SurgeryIn view of the rapidly diminishing chances of becomingseizure-free after trying three antiepileptic drugs, 143 individuals continuing to have focal seizures should havesurgical treatment considered early on. The most commonoperations are temporal lobe resections, which are cost-effective procedures 144 carrying a 6070% chance of making the individual seizure free 145,146 with improvedquality of life.147 The chance of a good outcome is greatestif the underlying cause is removed, driving researchefforts to improve imaging detection of the cause beforeoperation. If surgical treatment is proposed, localisation

of the site of seizure onset or critical point in a network, isnecessary. This localisation is usually accomplished withlonglasting scalp video EEG recordings. If the site of seizure onset is not clear, or if there is discrepancybetween data, invasive EEG recordings might be necessary,with depth electrodes placed stereotactically within thebrain tissue or subdural strips and grids of electrodesplaced on the surface of the brain. This technique hasrestricted spatial sampling, and the approach needs to beindividualised for each patient to test specic hypothesesthat can be generated with functional imaging. 148

Complete seizure control might not be a realisticobjective, but useful palliation can still be gained with acerebral resection or techniques such as corpuscallosotomy and multiple subpial transection. Vagalnerve stimulation, by a subcutaneous pulse generator,can also provide palliation when resective surgery is not aviable option. 149 On average, a 50% reduction of seizurescan be expected in up to 3040% of patients, but seizurefreedom is seldom seen. 150 Deep brain stimulation isbeing assessed for refractory epilepsy, and at presentthere is no consensus about its usefulness. With theheterogeneity of structural and functional networks thatmight sustain epilepsy, the likelihood of achieving morethan palliation through an effect on a nal commonpathway does not seem probable.

New treatment prospectsThere remain diffi culties in epilepsy treatment. Treatmentshould be individualised but remains empirical, andantiepileptic drugs fail for some patients. Despite thesuccess of surgery in the treatment of such refractory focalepilepsy, it is suitable for less than 10% of these patients. 151 Thus, new treatment strategies remain necessary.

Early prediction of seizures could have an enormouseffect on the treatment of epilepsy, since it would allowaction to be taken to prevent the seizure occurringsuch an approach is already used in catamenial epilepsy,and by people who have lengthy aura. Use of EEG inpredicting seizures is a fast-growing technique. Non-linear analyses of signals can anticipate seizures byseveral minutes. In practical terms, at present there are

limitations of sensitivity and specicity, and theusefulness of this method in clinical practice is yet to beestablished. 152154

With advances in stem-cell science and viral geneexpression systems, interest has grown in focalapproaches to the treatment of epilepsy. 155 At present,such approaches remain experimental. Focal treatmentsuse two approaches: (1) focal application of drugs, cells,or a virus to the epileptogenic zone; (2) focal applicationto areas that regulate seizure threshold, propagation, orboth. The rst approach is dependent on identifyingwhere the seizures originate. The advantage over surgeryis that tissue destruction can be avoided, and thus thisapproach could be used in eloquent cortex. If the focuscannot be identied, similar methods could be used to

express or release antiepileptic compounds into areasthat regulate cortical excitability and seizure threshold. 156

ConclusionsThe epilepsies are common, and heterogeneous by virtueof different seizure types, syndromes, causes,comorbidities, and other individual patient factors.Although up to 70% of patients will have their conditioncontrolled with drugs, the remainder continue to haveseizures and their negative effects on quality of life,morbidity, and risk of mortality. Surgical treatment is life-changing for a small proportion of patients. As genomicsand proteomics unfold, the causation of epilepsies willbecome better understood, and will prompt selection of optimum treatment and development of new treatments.For selected individuals, methods to anticipate seizuresand local drug delivery hold promise. Individuals withepilepsy will still need sympathetic, well informedprofessional advisers to integrate the science with apersons life and thus generate holistic care plans.Conict of interest statementJ S Duncan has been consulted by and received fees for lectures fromEisai, GE Healthcare, Pzer, GlaxoSmithKline, SanoAventis, and UCB;he has had departmental and grant support from MedTronic,Cyberonics, and VSM MedTech. J W Sander has been consulted by andreceived research grants and fees for lectures from Eisai, Pzer,Sano-Aventis, UCB, and Schwartz Pharma; he has received fees forlectures from Novartis. S M Sisodiya has received fees for lectures orresearch grant support from Pzer, GlaxoSmithKline, and UCB.M C Walker has been consulted by, received fees for lectures andresearch grants from UCB; he has received fees for lectures from Pzer,has been consulted by Eisai, and has received research grant fundingfrom Johnson & Johnson.

AcknowledgmentsWe thank Jane de Tisi for formatting, referencing, and preparing thismanuscript, and the National Society for Epilepsy for its support.

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