vie

ilepsy: A practical approach

a,

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Epilepsies are among the most common of all the serious

zures and a favorable riskbenet balance for the great

syndrome and rare serious adverse events. The clinical goal

The term epilepsy encompasses a number of dierentsyndromes, the cardinal feature of which is a predispositionto recurrent unprovoked seizures [for discussion, see 4].

* Corresponding author. Fax: +49 30 8017679.E-mail address: dbschmidt@t-online.de (D. Schmidt).

Available online at www.sciencedirect.com

Epilepsy & Behavior 12 (2neurological disorders worldwide. Approximately 4 millionpersons in the European Union and the United States haveepilepsy, and 3% of the general population will have epi-lepsy at some point in their lives. The modern antiepilepticdrug (AED) eraspanning a period of more than 150years from the rst use of bromide in 1857 to 2008hasseen the introduction into clinical practice of a diversegroup of eective and safe drugs. These AEDs have pro-vided considerable benets for those aicted with epilepsyof all kinds. In as many as 6070% of newly treatedpatients, current AEDs lead to satisfactory control of sei-

must be the treatment and cure of epilepsy. In this shortreview, the practical management of epilepsy is briey sum-marized from the personal perspective of the authors, withonly few references. For an extensive discussion anddetailed references, see textbooks, guidelines for the clinicalmanagement of individuals with epilepsy, and monographs[13].

2. Denition, diagnosis, and prognosis of epilepsy

2.1. DenitionThe epilepsies are among the most common serious brain disorders, can occur at all ages, and are characterized by a variety of pre-sentations and causes. Diagnosis of epilepsy remains clinical, and neurophysiological investigations support the diagnosis of the syn-drome. Brain imaging is able to identify many of the structural causes of the epilepsies. Current antiepileptic drugs (AEDs) blockseizures without inuencing the underlying tendency to generate seizures, and are eective in 6070% of individuals. Several moderndrugs are as ecacious as the older medications, but have important advantages including the absence of adverse drug interactionsand hypersensitivity reactions. Epilepsy is associated with an increased prevalence of mental health disorders including anxiety, depres-sion, and suicidal thoughts. An understanding of the psychiatric correlates of epilepsy is important to the adequate management of peo-ple with epilepsy. Anticipation of common errors in the diagnosis and management of epilepsy is important. Frequent early diagnosticerrors include nonepileptic psychogenic seizures, syncope with myoclonus, restless legs syndrome, and REM behavioral disorders, thelast mostly in elderly men. Overtreatment with too rapid titration and too high doses or too many AEDs should be avoided. For peoplewith refractory focal epilepsy, vagus nerve stimulation oers palliative treatment with possible mood improvement and neurosurgicalresection oers the possibility of a life-changing cure. Potential advances in the management of epilepsy are briey discussed. This shortreview summarizes the authors how-to-do approach to the modern management of people with epilepsy. 2008 Elsevier Inc. All rights reserved.

Keywords: Epilepsy; Epilepsy management; Drug treatment; Antiepileptic drugs; Epilepsy surgery; Nonepileptic seizures

1. Introduction majority of patients, albeit with considerable dierencesin response depending on the type of seizure and epilepsyRe

Modern management of ep

Christian E. ElgeraClinic for Epileptology, Un

bEpilepsy Research

Received 8 January 200Available onli

Abstract1525-5050/$ - see front matter 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.yebeh.2008.01.003Dieter Schmidt b,*

sity Bonn, Bonn, Germany

up, Berlin, Germany

ccepted 9 January 2008March 2008w

www.elsevier.com/locate/yebeh

008) 501539

sy &Seizures, in turn, are sudden, brief attacks of altered con-sciousness; motor, sensory, cognitive, psychic, or auto-nomic disturbances; or inappropriate behavior caused byabnormal excessive or synchronous neuronal activity inthe brain [see 4]. The phenotype of each seizure is deter-mined by the point of origin of the hyperexcitability andits degree of spread in the brain. By convention, the diag-nosis of epilepsy requires that the patient has had at leasttwo unprovoked seizures. The estimated incidence is onecase per 2000 persons in the Western population per year,whereas the prevalence of active epilepsy with recent sei-zures is around 510 per 1000. For unknown reasons, theincidence of epilepsy is highest in the rst year of life andincreases again for those over 60 years of age. The cumula-tive incidence, that is, the chance of having epilepsy duringa lifetime of 80 years, is about 3% [5]. If given a sucientstimulus (e.g., hypoxia, convulsant agents, hypoglycemia),even the normal brain can discharge excessively, producinga seizure. However, a person with isolated nonrecurrent,externally provoked seizures that are also caused by exces-sive discharge of cerebral neurons is not thought to haveepilepsy as long as the seizures are not recurrent and eachseizure is preceded by a provocation (e.g., substance abuse,fever, exposure to alcohol combined with lack of sleep).The distinction is, however, tenuous and must be retrospec-tive, as epilepsy always begins with a rst seizure and,albeit uncommon, seizures may be precipitated in personswith epilepsy by exogenous factors, such as sound, light,and touch. Often, the epilepsy syndrome allows the diagno-sis of epilepsy even after a rst seizure.

2.2. Pathophysiology

Current theories try to explain the mechanism(s) for theabnormally increased propensity of the brain to developexcessive discharges of cerebral neurons. The early theoryaccording to which disruption of the normal balancebetween excitation and inhibition in the brain results in sei-zure generation may have been an oversimplication. Corti-cal networks that generate oscillations, on which inhibitoryneurons, neuronal communication (e.g., synaptic transmis-sion), and intrinsic neuronal properties (e.g., ability of a neu-ron tomaintain burst ring) are dependent, are thought to becrucial elements of seizure generation. The occurrence of epi-leptic activity may be an emergent property of such oscilla-tory networks [6]. Transition from normal behavior to aseizure behavior may be caused by a number of factorsincluding greater spread and neuronal recruitment second-ary to a combination of enhanced connectivity, enhancedexcitatory transmission, a failure of inhibitory mechanisms,and changes in intrinsic neuronal properties [7].

2.2.1. Generalized epilepsies

Generalized epilepsies result in seizures occurringthroughout the cortex because of a generalized lowering of

502 C.E. Elger, D. Schmidt / Epilepthe seizure threshold, and are usually genetically determined.Mutations in voltage-gated potassium, sodium, and chloridechannels, as well as in ligand-gated acetylcholine andGABAA (c-aminobutyric acid, subunit A) receptors, areknown to cause dierent forms of idiopathic epilepsy. Allbut one of the idiopathic epilepsies with a known molecularbasis are channelopathies. Where the ion channel defectshave been identied, however, they generally account for aminority of families and sporadic cases with the syndromein question. The data suggest that ion channel mutationsof large eect are a common cause of rare monogenic idio-pathic epilepsies, but are rare causes of common epilepsies.Additive eects of genetic variation, perhapswithin the sameion channel gene families, are likely to underlie the commonidiopathic generalized epilepsies with complex inheritance.A clinical syndrome often has multiple possible geneticcauses, and conversely, dierent mutations in one gene canlead to various epileptic syndromes. Most common epilep-sies, however, are probably complex traits with environmen-tal eects acting on inherited susceptibility, mediated bycommon variation in particular genes [7].

Absence seizures are a distinct form of generalized sei-zure generated by thalamocortical loops [8]. Absenceswere originally believed to be generated subcortically bythalamic neurons driving recruitment of neocortical neu-rons. However, paroxysmal oscillations within thalamo-cortical loops in absence seizures in rats seem tooriginate in the somatosensory cortex rather than thethalamus, with synchronization mediated by rapid intra-cortical propagation of seizure activity [8]. Together withneuroimaging ndings of subtle cortical structural abnor-malities in some patients with absence seizures and inpatients with juvenile myoclonic epilepsy, and the well-known potential of focal pathological change in the med-ial frontal lobe to generate absence-like seizures, the dis-tinction between focal and generalized epilepsies hasbecome more dicult.

2.2.2. Partial (focal, localization-related) epilepsies

In focal epilepsies, focal functional disruptionoftendue to focal pathological changes (e.g., tumor) or, rarely,to a genetic diathesis (e.g., autosomal dominant frontallobe epilepsy)results in seizures beginning in a localizedfashion; these seizures then spread by recruitment of otherbrain areas. The site of the focus and the speed and extentof spread determine the clinical manifestation of the sei-zure. Intensive studies of hippocampal sclerosis, the mostcommon pathological nding in adults with the most com-mon partial epilepsy, have demonstrated many localchanges, but their causative role, if any, in epileptogenesisis still unknown. Newer avenues of study (such as corticalmalformations) and newer conceptual mechanisms (such asthe role of glial cells, the neuronal microenvironment, andemergent complex network properties) are likely to yieldfurther insights into this complicated eld. For now, how-ever, although prevention remains elusive, our clinicalgoals must remain the treatment and cure of epilepsy [9].

Behavior 12 (2008) 501539To complicate things further, current AEDs suppressseizures without inuencing the underlying tendency to

generate seizures, suggesting that the process of seizuregeneration, which may be dierent for each seizure type,and the cellular and molecular mechanisms that determinethe underlying tendency to generate seizures may not beidentical. Despite important advances in recent years, ourunderstanding of the cellular and molecular mechanismsby which epilepsy develops, or epileptogenesis, is stillincomplete. For further discussion, see Refs. [2,3].

2.3. Clinical diagnosis

C.E. Elger, D. Schmidt / Epilepsy &The rst seizure that brings a patient to the attention ofa physician is usually a tonicclonic seizure. If there is nosuggestion of a provoked seizure or an acute cause, includ-ing substance abuse, lack of sleep, and medical disease,early-stage epilepsy is likely. Particularly in those who seemto have had several unprovoked tonicclonic seizures, acareful history will often bring to light additional seizuressuch as absence, myoclonic, and, more often, complex par-tial seizures, which not only conrm the diagnosis of epi-lepsy but often allow diagnosis of the epilepsy syndrome.The diagnosis of a seizure can be made clinically in mostcases by obtaining a detailed history and performing a gen-eral clinical examination with emphasis on neurologicaland psychiatric status. An eyewitness account of a typicalseizure(s), age and external circumstances at onset, fre-quency of each type of seizure, and longest and shortestintervals between them should be recorded. A seizure diaryhelps to ascertain treatment response. The history shouldcover the existence of prenatal and perinatal events, spon-taneous abortions, seizures in the newborn period, febrileseizures, any unprovoked seizures, and epilepsies in thefamily (Checklist 1.1). The existence of an aura should beascertained, and conditions that may have precipitatedthe seizure in the opinion of the patient should be docu-mented. A history of prior head trauma, infection, or toxicepisodes must be sought and evaluated. A family history ofseizures or neurological disorders is signicant.

2.4. Appropriate studies

Once the seizures are classied (e.g., simple, complexpartial, partial-onset GTC or generalized absence, myo-clonic seizure or generalized-onset GTC) and, if possible,

Checklist 1.1History taking in a patient with new-onset epilepsy

Patient: Seizure onset, course, time of day. Earlier seizures? Postictalparesis, aphasia, speech problem, tongue bite, tiredness?

Observer: Onset, course, duration, eyes open or closed, facial color,facial and upper chest petechiae. Postictal speech, paresis, confusionand its duration, behavior?

Physician: Caution: Frequent early diagnostic errors include non-epileptic psychogenic seizures, convulsive syncope with myoclonus,and REM behavioral disorder, the latter mostly in elderly men (seenon-epileptic seizures). If in doubt that it is epilepsy, better wait forconrmation through EEG or by observing another seizure. A

delayed diagnosis usually causes no problem, while a premature anderroneous diagnosis of epilepsy may have grave implications.the epilepsy (idiopathic or symptomatic) or the epilepsysyndrome (e.g., temporal lobe epilepsy, generalized juvenilemyoclonic epilepsy) is classied, appropriate studies areordered including an electroencephalogram (EEG)(Fig. 1), magnetic resonance imaging (MRI) (Fig. 2 andTable 1), and serum glucose, sodium, magnesium, and cal-cium levels (Checklist 1.2). The EEG between seizures(interictal) in primarily generalized tonicclonic seizures ischaracterized by symmetric bursts of sharp and slow, 4-to 7-Hz activity. Focal epileptiform discharges occur in sec-ondarily generalized seizures. In absence seizures, spikesand slow waves appear at a rate of 3/second. Interictal tem-poral lobe foci (spikes or slow waves) occur with complexpartial seizures of temporal lobe origin. Because an EEGtaken during a seizure-free interval is normal in 30% ofpatients, one normal EEG does not exclude epilepsy. A sec-ond EEG performed during sleep in sleep-deprived patientsreveals epileptiform abnormalities in half of patients whoserst EEG was normal. Rarely, repeated EEGs are normal,and epilepsy may have to be diagnosed on clinical grounds.When the seizures are focal or an EEG is focally abnormal,when seizures begin in adulthood, or the physical examina-tion reveals focal pathological symptoms or signs, MRI isindicated to detect structural lesions caused by, for exam-ple, cortical malformation, traumatic brain injury, braintumor, and cerebrovascular disease, which are the mostcommon causes of symptomatic epilepsy. In our view,MRI is also useful in generalized epilepsy or generalizedseizures to search for dual pathology, for example, anunsuspected brain lesion [10]. A lumbar puncture shouldbe performed if fever and sti neck accompanying new-onset seizures suggest meningitis, subarachnoid hemor-rhage, or encephalitis.

Recommendation. Every patient with a newly diagnosedepilepsy should undergo MRI to identify structural causes

of epilepsy and an EEG to assist in the diagnosis of the syn-

drome. If the rst EEG is normal, order an EEG during

sleep; if the rst MRI scan is normal, repeat in the case ofdrug-resistant epilepsy as a rst step to explore surgical

options.

2.5. Classication of seizures

The academic classication of phenotypical epileptic sei-zures is constantly evolving. Seizures may be classied bytheir semiology as partial or generalized (Fig. 3) [11]. Inpartial seizures, the excess neuronal discharge is thoughtto originate within one region of the cerebral cortex. Ingeneralized seizures, the discharge bilaterally and diuselyinvolves the entire cortex. If the focal discharge spreadsrapidly, it may produce a generalized tonicclonic seizurebefore a focal manifestation is noted (Fig. 3).

2.5.1. Practical implications

For practical purposes, however, it is sucient to be

Behavior 12 (2008) 501539 503able to distinguish between generalized absence and partic-ularly myoclonic seizures and partial seizures before start-

Fig. 1. Electroencephalography. Panel 1: Interictal discharges are distinctive waves or complexes that can be recorded between seizures in the EEGs ofindividuals with epilepsy. Generally brief in duration, they may have a variety of morphologies described as sharp wave, spike wave, or spike-and-slowwave. Panel 2, top: A generalized discharge of bilateral spike-and-wave activity, predominantly in the frontal region. Panel 2, bottom: Single sharp-slow-wave, right mesial temporal region.

504 C.E. Elger, D. Schmidt / Epilepsy & Behavior 12 (2008) 501539

Fig. 2. Magnetic resonance imaging (MRI) in epilepsy. Panel 1: A1, Ammonshornsclerosis left, standard coronal angulation; A2, standard coronalangulation; B1, Ammonshornsclerosis (syn.: mesial temporal sclerosis) left, coronal temporal angulation; B2, coronal temporal angulation; C1, airsequence coronal and axial, temporal angulation. Panel 2: Cavernoma; A1, mesio-temporal right, air sequence; A2, T2 weighted; B1, frontal right, T2weighted; B2, T2* weighted (pronounced eect of old blood). Panel 3: Developmental tumors A, dysembryoplastic neuroepithelial tumor; temporo-lateralright, B1,2, ganglioglioma temporo-mesial right. Panel 4: Chronic inammation: A 1,2 = nc. amygdala right; B 1,2, Rasmussens Encephalitis, lefthemisphere. Panel 5: A1,2, Hypothalamic hamartoma. Panel 6: Cortical developmental abnormality left parietal (A+B) and occipital C (cortical dysplasiaType IIb (Palmini): A1, T2 weighted axial; B2, air sequence coronal; A2, air sequence coronal; B1, air sequence coronal; B2, inversion recoverysequence coronal. C1, T2 weighted; C2, air sequence (C: courtesy of Department of Radiology, University Bonn, Germany).

C.E. Elger, D. Schmidt / Epilepsy & Behavior 12 (2008) 501539 505

sy &506 C.E. Elger, D. Schmidt / Epileping AED treatment. The main reason is that some AEDsthat are useful in treating partial seizures and secondarily

Fig. 2 (conBehavior 12 (2008) 501539generalized GTCs, such as carbamazepine (CBZ), gaba-pentin (GBP), oxcarbazepine (OXC), phenytoin (PHT),

tinued)

sy &C.E. Elger, D. Schmidt / Epilepand pregabalin (PGN), may not work or may even exacer-bate absence or myoclonic seizures. On the other hand, eth-osuximide (ETS), which is useful but seldom used these

Fig. 2 (con

Table 1Suggested MRI protocols for epilepsy patients (standard investigations)

Temporal lobe epilepsy1. Hippocampal oriented T22. Hippocampal oriented u3. Isotropic T1-weighted thr4. (Gadolinium contrast-enh5. T2*-weighted sequence

Extratemporal lobe epilepsy1. ACPC oriented T2-weigh2. ACPC oriented FLAIR (3. Isotropic T1-weighted thr4. (Gadolinium contrast-enh5. T2*-weighted sequence

Special protocols: Rationale1. T2 relaxometry hippocam2. Magnetic resonance spectr3. Diusion tensor imaging (4. Functional MRI investiga5. Three-dimensional sequen6. Magnetic resonance angioBehavior 12 (2008) 501539 507days to treat absence seizures, is clearly not ecaciousagainst other seizure types. A number of AEDs are usefulfor both partial and generalized absence or myoclonic sei-

tinued)

-weighted (coronal + axial)id-attenuated inversion recovery (FLAIR) (coronal + axial)ee-dimensional sequence (MPRage)anced T1-weighted image if non-contrast-enhanced image is inconclusive)

ted (coronal + axial)coronal + axial)ee-dimensional sequence (MPRage)anced T1-weighted image if non-contrast-enhanced image is inconclusive)

pal signal abnormalitiesoscopy detection of metabolic abnormalitiesDTI) investigation of ber tractstion of eloquent cortical areasces automated voxel-based analysesgraphy investigation of brain vascularization

absence and myoclonic seizures is not fully explored as ofnow.

2.5.2. Partial (focal) seizures

Both simple and complex partial seizures result from alocalized brain disturbance; also referred to as focal sei-zures, these seizures may evolve into secondarily GTC sei-zures [see 4]. The site of dysfunction determines the clinicalmanifestation of partial seizures. Examples are: chewingmovements or smacking of lips (anterior temporal lobedysfunction), complex automatic behavior (temporal lobe,anteromedial temporal lobe), visual hallucinations withformed images (posterior temporal lobe), bilateral tonicposture (supplementory motor cortex, frontal lobe), local-ized twitching of muscles without impaired consciousnessin a Jacksonian seizure (motor cortex, frontal lobe), local-ized numbness or tingling (sensory cortex, parietal lobe),and visual hallucinations with ashes of light (occipital

Checklist 1.2Studies in patient with new-onset epilepsy

MAGNETIC RESONANCE IMAGING (MRI): Each patient withnew-onset epilepsy should have an MRI (temporal angulation,T1,T2, FLAIR, coronal and axial) to detect structural lesions causedby for example cortical malformation, traumatic brain injury, braintumor, and cerebrovascular disease, which are the most commoncauses of symptomatic epilepsy. Contrast media, inversion recovery,fast eld echo and 3D only in special cases. Even in idiopathicepilepsy, MRI is recommended to diagnose unsuspected dualpathology as discussed above.

ELECTROENCEPHALOGRAM (EEG): Each patient with new-onset epilepsy should have an EEG. EEG is most valuable within 24h of the seizure. Information gain is optimal up to the 4th EEG, if noparoxysmal interictal discharges are found, repeat EEG duringsleep. 24-hour EEG most meaningful in a patient with frequentseizures who can be expected to have seizures during the 24 hrecording. Interictal EEG discharges may support the diagnosis ofthe epilepsy syndrome.

COMPUTER TOMOGRAM (CCT): Computer tomograms areobsolete, except to detect fractures or hemorrhage in an emergencysituation.

508 C.E. Elger, D. Schmidt / Epilepsy & Behavior 12 (2008) 501539HEAD X-RAY: obsoleteCLINICAL CHEMISTRY: routine work-up, creatinkinase, Vitamin

B6 if seizures are unresponsive to AEDs, even in adults. CSF, onlywhen infectious disorders are suspected. Creatinkinase increasedwithin 12-24 h, prolactin increased within 30 min.

SINGLE-PHOTON- EMISSION -TOMOGRAM (SPECT) andPOSITON- EMISSION-TOMOGRAM (PET), MAGNETOENCEPHALOGRAPHY (MEG): only for presurgical work-up orscientic studies.zures and unclassiable seizures. These are valproate andsome of the newer AEDs such as lamotrigine (LTG), leveti-racetam (LEV), topiramate (TPM, only for primary GTCseizures), and zonisamide (ZNS). Phenobarbital (PHB)and primidone (PRM) may be useful in treating myoclonicseizures, but may worsen or exacerbate absence seizures.The role of levetiracetam and zonisamide in treating

absenceseizures

myoclonicseizures

cloniseizur

partial se

unclassifiabl

generalized

simple and complex partial seizures

Fig. 3. International classicalobe).

2.5.3. Generalized seizures

Generalized seizures may impair consciousness andcause bilateral motor manifestations from the onset. Suchattacks often have a genetic or metabolic cause. Theymay be primarily generalized (bilateral cerebral corticalinvolvement at onset) or secondarily generalized (local cor-tical onset with subsequent bilateral spread). Commontypes of generalized seizures include absence, tonicclonic,and myoclonic seizures [11].

2.5.4. Unclassiable seizures

Unclassiable seizures are seizures that are impossible toclassify as either focal or generalized based on their clinicalor EEG manifestations (e.g., atonic, tonic, and tonicclonicseizures without noticeable focal onset). This term is alsoused for those seizures in patients whose epilepsy has par-

ces

tonic-clonicseizures

atonicand tonicseizures

izures

e seizures

seizures

secondarily generalized tonic-clonic seizurestion of epileptic seizures.

tial and generalized elements because of focal and general-ized EEG ndings. Atonic seizures are brief, often but notalways generalized seizures in children. They are character-ized by complete loss of muscle tone and consciousness.The child falls or pitches to the ground, so that seizurespose the risk of serious trauma, particularly head injury.They may, however, be indistinguishable, even for an expe-rienced observer, from a tonic seizure with a very rapid

focal onset. In the absence of unequivocal evidence fromVideo/EEG-EMG recordings, the existence of atonic sei-zures is still a matter of debate, at least for some experts.

2.5.5. Nonepileptic seizures

Frequent early diagnostic errors include nonepilepticpsychogenic seizures, convulsive syncope with myoclonus,

Checklist 1.3Common non-epileptic seizures

PSYCHOGENIC NON-EPILEPTIC SEIZURES (PNES) are paroxysmal events that supercially resemble epileptic seizures, which are, however, notcaused by epileptic neuronal discharges but by psychopathological processes. Comparative and observational studies show that traumatic childhoodexperiences (especially sexual and physical abuse), trauma in adulthood, poor family relationships, psychiatric comorbidity, personality disorder,organic brain pathology, low social status as well as nancial and social gain can play a predisposing, precipitating or perpetuating role. Thissuggests that PNES are not a unitary pathological entity but an expression of a number of dierent psychosocial and psychiatric disorders. PNES arebest classied as manifestations of an underlying psychiatric disorder. Consequently, therapy has to be designed to suit individual patients or certainpatient groups. It often requires the collaboration of a multidisciplinary team. The prognosis of PNES is determined by the underlying psychosocialproblem or disorder. The preliminary observational evidence suggests that specic psychotherapies and pharmacotherapy with serotonin reuptakeinhibitors directed at comorbid conditions may be the most eective treatment for PNES. Successful long-term treatment is dicult.

SYNCOPE Diagnosing syncope is a great challenge in clinical medicine. Since patients usually do not have symptoms and signs during the interval, thediagnosis is primarily based on a meticulously taken history, if possible also from bystanders, which is particularly important when the patientsrecollection is incomplete. The rst step is to nd out whether or not the patient transiently lost consciousness (i.e. has an amnestic gap), fell to theground (if upright), and whether he showed convulsive manifestations. Additional features are: Predisposing factors (e.g. occurring only in uprightposition, drugs, sleep deprivation), prodromal sensations (stereotyped or not), eye open during onset, upward gaze, gentle or violent fall, oral andlimb automatisms, tonic and/or clonic manifestations (bilateral - rhythmical or irregular), phonations (unintelligible sounds or vocalizations), colorof the face (normal, pale, or cyanotic), loss of urine (but not discriminative), and the postictal behavior and recovery of orientation. A lateral tonguebite must be searched for and is very suggestive of an epileptic seizure, while a median tongue bite is seen with non-epileptic psychogenic seizures. Todistinguish between epileptic seizure and circulatory syncope is often dicult, since the latter frequently shows, contrary to common belief, a stibackward fall and short tonic and clonic and manifestations. Conversely, epileptic falls are not always convulsive. Psychogenic pseudo-seizures areidentied by the typical eye closure from the beginning and the long duration of the seizure of over 5 minutes, which are both very rare in epilepticseizures or syncope.

REM BEHAVIORAL DISORDER REM sleep behavior disorders (RBD) are episodes of motor agitation arising during REM sleep due to theabsence of muscular atonia and are characterized by more or less purposeful gestures enacting attack or defense reactions, sometimes associated withemotional expressions of joy, laughter or sorrow. They occur often in elderly men. RBD often herald other signs and symptoms ofneurodegenerative disorders like Parkinsonian syndromes. If correctly diagnosed, they can be treated successfully.

RESTLESS LEGS Restless legs syndrome (RLS) is characterized by deep ill-dened paraesthesias in the legs arising during postural rest, especiallywhen the patient is trying to fall asleep. Motor agitation of the legs is associated with periodic involuntary movements, named nocturnal myoclonus(NM) or periodic limb movements in sleep (PLMS). NM may appear independently of RLS and can induce sleep fragmentation, but not necessarilyan insomniac complaint.

C.E. Elger, D. Schmidt / Epilepsy & Behavior 12 (2008) 501539 509Fig. 4. Eye closure and gaze in various epileptic and nonepileptic seizuresextratemporal lobe seizure; C, closed eyes during a psychogenic; non-epileptic. A, Staring during a temporal lobe seizure; B lateral gaze during anattack, D, upward gaze during a syncope.

res

seiz

on

onmmmmmmon

sy &restless legs syndrome, and REM behavioral disorder,mostly in elderly men [12] (see Checklist 1.3).

For dierential diagnosis, one strategic question iswhether the eyes are open or closed at the onset of theattack (Fig. 4). Closed eyes are typical of nonepileptic psy-chogenic seizures (Table 2). In contrast, a staring gaze ischaracteristic of temporal lobe seizures. A lateral gaze isoften seen with extratemporal lobe seizures, for example,frontal lobe seizures. An upward gaze is often observedin patients having a syncopal episode.

Recommendation. Classication of paroxysmal eventsinto partial seizures, generalized seizures, unclassiable sei-

zures, and nonepileptic seizures can be dicult in some casesand, for patients with frequent seizures, video/EEG monitor-

ing is advisable. A movie of the seizure taken with a mobile

phone is often helpful. Eyes are closed in nonepileptic psycho-

genic seizures, whereas syncope is frequently characterized

by an upward gaze. Unless and until an epileptic seizure is

rmly diagnosed and classied, the diagnosis of epilepsy

and treatment should be deferred, if possible.

2.6. Classication of epilepsies

Pragmatically, epilepsies can be classied in severalways, as either generalized or partial (or localization-related) and idiopathic or symptomatic (Fig. 5) [13]. In gen-eralized epilepsies, the predominant type of seizure beginssimultaneously in both cerebral hemispheres. Many formsof generalized epilepsy have a strong genetic component;in most, neurological function is normal. In partial epilep-sies, by contrast, seizures originate in one or more localizedfoci, although they can spread to involve the entire brain.Most partial epilepsies are believed to be the result of

Table 2Clinical features of epileptic seizures versus psychogenic nonepileptic seizu

Clinical feature Epileptic

Eyes closed UncommStereotyped seizure semiology CommonSeizure duration >2 minutes UncommSeizure onset at sleep Not uncoEnuresis Not uncoInjury, burns Not uncoMedial tongue bite Uncomm

510 C.E. Elger, D. Schmidt / Epilepone or more central nervous system insults, but in manycases the nature of the insult is never identied. The otherdivision separates epilepsies with demonstrable etiologies(symptomatic epilepsies) from those with a presumablegenetic basis where no symptomatic etiology can be found(idiopathic epilepsies). For pragmatic classication, idio-pathic epilepsy must be distinguished from symptomaticepilepsy, and partial epilepsy must be distinguished fromgeneralized epilepsy. In clinical practice, epilepsy syn-dromes are conveniently divided in those that begin inchildhood, adolescence, middle age, and old age. Pragmat-ically, one should be able to distinguish between epilepsysyndromes that in general are easy to treat and those withmixed outcome and nally catastrophic epilepsy syn-dromes. Also, the rate of seizure recurrence after AED dis-continuation in seizure-free patients diers considerablyamong various epilepsy syndromes; for example, the riskis moderate in pediatric idiopathic partial and childhoodabsence syndromes, but prohibitively high in idiopathicjuvenile myoclonic epilepsy and symptomatic epilepsy, par-ticularly with adult onset. Epilepsy syndromes also dierconsiderably in their prognosis for cognition, memory,and mortality. For further discussion, see [2,3].

Recommendation. Pragmatically, a syndrome diagnosis ofepilepsy is advisable, because the seizure prognosis varies for

dierent syndromes. In any case, the diagnosis of an idio-pathic generalized epilepsy should be excluded before start-

ing treatment with an AED useful only for partial seizures.

If in doubt, an AED that works against partial and absence

or myoclonic seizures should be considered.

2.6.1. Symptomatic epilepsies

The causes of sporadic or recurrent seizures are numer-ous, and they include acquired structural brain damage,altered metabolic states and inborn brain malformations.Among the partial epilepsies alone, the diversity of demon-strated causes is bewildering, raising the concern that theunderlying mechanisms are equally diverse and that no sin-gle drug could prevent all forms of partial epilepsy. How-ever, one feature common to the diverse partial epilepsiesof humans is a latent period from the time of injury tothe rst seizure, which may be several months (e.g., aftertraumatic brain injury) to several years and even one ortwo decades (e.g., in cases with cortical malformations).By targeting plasticity mechanisms that underlie theenhanced seizure susceptibility that often follows brain

ures Psychogenic nonepileptic seizures

Very commonLess commonNot uncommon

on Uncommonon Uncommonon Uncommon

Not uncommon

Behavior 12 (2008) 501539insults such as head trauma, status epilepticus, or neonatalhypoxia, antiepileptogenic drugs of the future would pre-vent, or reverse, progressive worsening of the epileptic pro-cess. Currently, however, only surgical resection ofepileptogenic brain oers the chance to reverse epilepsythat has not fully responded to AED treatment (see below).

2.6.2. Temporal lobe epilepsy

Temporal lobe epilepsy (TLE) represents the majority ofthe partial symptomatic/cryptogenic epilepsies. Excellentresults after epilepsy surgery in well-selected patients haveencouraged the search for localizing and lateralizing signsthat could assist in the identication of the best surgical

rali

sy &Symptomatic, cryptogenic, e.g., West Syndrome,

Lennox-Gastaut Syndrome

Gene

C.E. Elger, D. Schmidt / Epilepcandidates. Seizure types in TLE include simple partial,complex partial, and secondarily generalized seizures. InTLE, seizures most often arise in the amygdalohippocam-pal region of the mesial temporal lobe; hence the mostcommon partial epilepsy is called mesial temporal lobeepilepsy.

2.6.3. Mesial temporal lobe epilepsy

More than 90% of patients with mesial TLE report anaura, most commonly an epigastric sensation that oftenhas a rising character. Other autonomic symptoms, psychicsymptoms, and certain sensory phenomena such as olfac-tory sensations also occur. The complex partial seizures

Partiaepileps

Epileps

Symptomatic, cryptogenic, e.g., temporal lobe epilepsies,

frontal lobe epilepsies, parietal lobe epilepsies,occipital lobe epilepsies

epileps

Repeated seizures, whichcannot be classified as

partial or generalized,e.g., Sleep Grand mal

Epilepsy

Other, rare andunclassifiable epilepsies

Generalized and partial seizures,

e.g., newborn seizures

Fig. 5. International classication of eIdiopathic, age-related onset, e.g., childhood absence epilepsy,

juvenile myoclonic epilepsy, juvenile absence epilepsy,

Grand mal- on-awakening-epilepsies,

Reflex-epilepsies

zed

Behavior 12 (2008) 501539 511of mesial TLE often involve motor arrest, oroalimentaryautomatisms, or nonspecic extremity automatisms atonset. Ictal manifestations that have lateralizing valueinclude dystonic posturing (contralateral), early head turn-ing (usually ipsilateral), and adversive head turning in tran-sition to generalization (contralateral). Well-formed ictallanguage favors right temporal localization. Ictal vomiting,spitting, and drinking tend to be right-sided. In TLE, com-plex partial seizures generally last 12 minutes and postic-tal confusion usually occurs. When postictal aphasia isnoted, a left-sided lateralization is favored. Men withmesial TLE with hippocampal sclerosis more often havesecondarily GTC seizures, whereas women have isolated

Occasion-related and acute symptomatic seizures

Status epilepticus

Single seizures

lies

ies

Idiopathic age-related onset, e.g., Rolandic epilepsy, adolescent epilepsies,

nocturnal frontal lobe epilepsies,familial temporal lobe epilepsies

ies

Febrile seizures

pilepsies and epileptic syndromes.

sy &auras and a lateralized EEG seizure pattern more often,suggesting that seizure spread is more extended or occursmore frequently in men than in women. Our currentknowledge of mesial TLE is extensive, yet still insucientto draw nal conclusions on the optimal approach to itstherapy. Mesial TLE has been well characterized and canusually be identied with noninvasive studies includingscalp electroencephalography and video monitoring withictal recording, MRI, SPECT, positron emission tomogra-phy, neuropsychological assessment, and historical andclinical data. Sometimes, invasive EEG is needed to con-rm mesial temporal lobe seizure onset, which, combinedwith the underlying pathological abnormality (the sub-strate) of mesial temporal sclerosis (hippocampal neuronalloss and gliosis), denes mesial TLE. This disorder is themost common refractory partial epilepsy, and also theone most often treated surgically, because medical treat-ment fails in 75% of cases, and surgical treatment with con-tinued drug treatment succeeds in a similar percentage.

2.6.4. Lateral temporal lobe epilepsy

A lateral temporal onset is less common (lateral TLE),and is most often suggested by an auditory aura. Somato-sensory and visual auras are highly unlikely with TLE, andsuggest neocortical extratemporal localization. A cephalicaura is nonspecic, but is more common in frontal lobeepilepsy.

2.6.5. Frontal lobe epilepsy

Seizures are usually brief (30 seconds to 2 minutes), ster-eotypic, often nocturnal, and frequent, for example, 322per night, occurring during slow wave sleep. Clinical fea-tures include explosive onset, screaming, agitation, stien-ing, kicking or bicycling of the legs, and incontinence.Nocturnal frontal lobe epilepsy (NFLE) represents a spec-trum of clinical manifestations, ranging from brief, stereo-typed, sudden arousals, often recurring several times pernight, sometimes with a quasi-periodic pattern, to morecomplex dystonicdyskinetic seizures and to prolongedsomnambulic behavior. Episodes of increasing intensityhave been labeled as paroxysmal arousal, nocturnal parox-ysmal dystonia, and episodic nocturnal wandering. NFLEaects both sexes with a higher prevalence for men, is fre-quently cryptogenetic, and displays a strong familial traitfor parasomnias and epilepsy. Seizures occur more fre-quently between 14 and 20 years of age, but can aect per-sons at any age and tend to increase in frequency duringlife. Interictal and ictal EEGs are usually normal; the useof sphenoidal leads may be helpful. Long-term video/EEG monitoring may demonstrate frontal or bifrontal epi-leptic discharges. MRI is normal in many patients. Thecondition is often misdiagnosed as a sleep disorder or psy-chiatric problem. Carbamazepine taken at night is ofteneective at low doses, but a third of patients are resistantto AED treatment. Seizures are dicult, with only half

512 C.E. Elger, D. Schmidt / Epilepthe patients being controlled on carbamazepine or valproicacid. Epilepsy surgery is an option. Autosomal dominantNFLE is a genetic variant of NFLE, in itself both clinicallyand biologically heterogeneous. NFLE should be suspectedin the presence of frequent stereotyped paroxysmal noctur-nal motor events arising or persisting into adulthood.Video/polysomnography is mandatory to conrm thediagnosis.

2.6.6. Idiopathic epilepsies

About 1% of all people develop recurrent unprovokedseizures for no obvious reason and without any other neu-rological abnormalities. These are named generalized orfocal idiopathic epilepsies, generalized or partial, and theyare assumed to be mainly genetic in origin [4,11]. So far, lit-tle is known about the genes that underlie epileptogenesisin idiopathic generalized epilepsies (IGEs). In addition tothe large group of idiopathic epilepsies, more than 200 sin-gle-gene disorders are known in which epilepsy is a more orless important part of the phenotype. These include syn-dromes as diverse as neurodegenerative disorders fromthe group of progressive myoclonus epilepsies, mentalretardation syndromes like fragile X syndrome and Angel-mans syndrome, neuronal migration disorders, and mito-chondrial encephalomyopathies.

2.6.7. Unclassiable epilepsies

These encompass a number of heterogeneous seizuresyndromes that cannot be diagnosed as either partial orgeneralized, partly because of incomplete data (e.g., tonicand atonic or astatic seizures) or failure to clinicallyobserve the onset of seizures (e.g., tonicclonic seizuresduring sleep). In addition, a number of syndromes maybe unclassiable because both partial and generalized sei-zures may occur (e.g., generalized epilepsy with febrile sei-zures plus, epileptic encephalopathies, progressivemyoclonus epilepsies) [13]. In addition, epilepsies can beclassied according to their time of onset in life. Often,all classications are used to classify an individual epilepsy.

2.6.8. Epilepsies starting in childhoodThe childhood-onset epilepsies can be divided into

benign, intermediate, and catastrophic based on theirimpact on childhood development. The clearest benign epi-lepsy is benign Rolandic epilepsy, which often does notrequire medication treatment. Although seizures andEEG features usually resolve completely at puberty, neuro-psychological decits and behavior problems are seen insome children. The denition of benign occipital epilepsyincluding Panayiotopoulos syndrome is still often vague.In the intermediate category, childhood absence epilepsyoften has associated learning disorders and a poor socialoutcome. About 50% of children with cryptogenic partialseizures have a very benign course, even though their epi-lepsy syndrome is not well dened. Generalized epilepsywith febrile seizures plus (GEFS+) has a dominant inheri-tance with a dened defect in cerebral sodium channels, but

Behavior 12 (2008) 501539varies considerably in severity within aected members ofthe same kindred. The catastrophic epilepsies in childhood

sy &all have an inconsistent response to AED treatment andinclude continuous spike waves in slow sleep (with variableseverity), LandauKlener syndrome (with a confusingoverlap with autistic regression), LennoxGastaut syn-drome (with broad dening features), and myoclonicasta-tic epilepsy (with important overlaps with LennoxGastaut). Although many of the epilepsies that begin inchildhood are benign, some interfere seriously with cogni-tive and social development. Intractable childhood epilepsymay have a negative eect on the mothers mood in manyfamilies. Child behavior problems are a strong predictor ofmaternal depressive symptoms.

2.6.9. Epilepsies starting during adolescence

Epilepsy is the commonest serious neurological condi-tion aecting adolescents. Specic epilepsy syndromesbegin during adolescence and create a signicant neurolog-ical burden. Idiopathic generalized epilepsies are the mostfrequent group with adolescent onset, and juvenile myo-clonic epilepsy (JME) is the most common form. This con-trasts with a variety of progressive myoclonic epilepsiesthat also are rst seen in adolescence and have a geneticorigin and specic treatments. Finally, although mesialtemporal lobe epilepsy associated with hippocampal sclero-sis may have its origin in childhood, often the child doesnot come to surgical evaluation until adolescence or youngadulthood. The characteristic clinical history, seizure semi-ology, and MRI ndings allow the diagnosis. Applyingthese same criteria to children and adolescents reveals thathippocampal sclerosis is the most common lesion responsi-ble for their intractable temporal lobe epilepsy. Adoles-cence is a time of dramatic change in growth, hormonal,psychological, and social situations. Seizure frequency,teenage pregnancy, driving, and alcohol and drug use oftenbecome major issues during the adolescent years. Further-more, adolescents often have diculty accepting the chro-nicity of epilepsy and complying with medications, whichcan result in physical injury and perceived or real obstaclesto employment.

2.6.10. Epilepsies starting in the elderly

Longer life expectancy in the general population is thereason for the second peak in the incidence of epilepsy inpersons 60 and older; the incidence exceeds 1 per 1000 atage 70 and above. Partial seizures in the elderly may beassociated more frequently with Todds paresis, and postic-tal confusion may last longer than 24 hours and be compli-cated by prolonged aphasia. De novo absence status mayoccur, particularly in the elderly with substance abuse. Sta-tus epilepticus is associated with a higher mortality in theelderly. The seizure-related risk of injury including frac-tures is higher in the elderly [14].

2.7. Status epilepticus

C.E. Elger, D. Schmidt / EpilepIn status epilepticus, seizures follow one another with-out recovery of consciousness or intervening periods ofnormal neurological function. Generalized convulsive sta-tus epilepticus may be fatal. It may result from too rapidwithdrawal of anticonvulsants. Confusion may be the onlymanifestation of complex partial or absence status epilepti-cus, and an EEG may be needed to diagnose seizure activ-ity. Epilepsia partialis continua is a rare form of focal(usually hand or face) motor seizures that recur at intervalsof a few seconds or minutes for days to years at a time. Inadults, it is usually due to a structural lesion, such as astroke. In children, it is usually due to a focal cerebral cor-tical inammatory process (Rasmussens encephalitis), pos-sibly caused by a chronic viral infection or autoimmuneprocesses.

Recommendation. The diagnosis of status epilepticusshould be made only after unequivocal evidence of epilepsy

is obtained; psychogenic status should be suspected in refrac-

tory cases, particularly in persons with the following prole:

no clear neurological decit, a psychiatric history, and, sur-

prisingly, a health professional background.

2.8. Comorbidity

Comorbid conditions, including anxiety, suicidalthoughts, depression, cognitive decline, migraine, psycho-genic nonepileptic disorders, injuries, and increased mortal-ity are common in patients with epilepsy. In thecommunity, epilepsy is associated with a twofold preva-lence of mental health disorders, including anxiety disor-ders, suicidal thoughts, and major depression, comparedwith the general population, although the prevalence ofpanic disorders including agoraphobia is not increased(Table 3) [15].

Depression is estimated to occur in as many as 50% ofpatients with refractory partial epilepsy, especially of tem-poral lobe origin. In patients with refractory left temporallobe epilepsy, memory functions decline 10 years earlierthan in age-related controls, and left temporal lobe resec-tion leads to a further decline in verbal memory. Right tem-poral lobe epilepsy sometimes causes visuospatial memoryabnormalities. Although depression is common, and can betreated well with serotonin reuptake inhibitors, it oftengoes undiagnosed and remains untreated. Other less com-mon psychiatric comorbid conditions include autism, psy-chosis, and psychogenic nonepileptic seizures. Migrainealso seems to be more common in patients with epilepsy,particularly in those with a history of head trauma, partialseizures, and a family history of migraine. Furthermore,endocrine reproductive disorders and sexual dysfunctionare more prevalent in persons with epilepsy of either gen-der. Comorbidity with other conditions may be caused bythe epilepsy itself, by adverse events on endocrine functionof drug or surgical treatment, overuse of AEDs, and psy-chosocial factors. Finally, patients with epilepsy also showan increased risk for injury and have a shorter life expec-tancy, particularly those with refractory epilepsy.

Behavior 12 (2008) 501539 513Recommendation. Depression, suicidal thoughts, and anx-

iety disorders are common comorbid conditions in patients

with epilepsy, particularly in refractory cases. Eective and

safe treatment is available.

2.9. Prognosisentered one or more periods of 5-year remission but did

Table 3Psychiatric comorbidity in people with epilepsy and the general population

Psychiatric disorder (lifetime) Ep

Major depressive disorder 17.Mood disorder 24.Anxiety disorder 14.Mood disorder/anxiety disorder/dysthymia 34.Panic disorder/agoraphobia 6.6Suicidal ideation 25.Any mental health disorder 35.

Source. Modied from Ref. [15].a The 95% condence interval is given in parentheses.

GROUP 1GROUP 1

514 C.E. Elger, D. Schmidt / Epilepsy &Remission with Remission with 2.9.1. Seizures

Within a year of treatment, drug therapy completelyeliminates seizures in one of two patients with new-onsetepilepsy and greatly reduces the frequency of seizures inanother one of six; in one of three, however, seizures can-not be controlled by AEDs (Fig. 6). It is not well knownhow often drug resistance, a major clinical problem, occursearly or late in the course of epilepsy and how often epi-lepsy follows a continuous, remitting, or relapsingremit-ting pattern. To provide evidence if, in fact, dierentpatterns of evolution of drug resistance and remission exist,a prospective, long-term population-based study of 144patients followed for 40 years (median) since their rst sei-zure before the age of 16 was performed. At the end of thefollow-up, 67% patients were in terminal 5-year remission,on or o antiepileptic drugs, the remainder will never enterremission (19%), and 14% will have only transient periodsof 5-year remission. In 16% of those with terminal remis-sion, rst remission continued uninterrupted, whereas halfNewly diagnosed epilepsyNewly diagnosed epilepsy

first AED first AED 50%50%

RemissionRemissionwith further with further

AEDsAEDs20%20%

ContinuingContinuingseizuresseizures

2020 30%30%

GROUP 2GROUP 2 GROUP 3GROUP 3

Fig. 6. Outcome of treatment of epilepsy.not maintain remission at the end of follow-up [16]. Thisoutcome suggests that patients seem to fall broadly intothree groups: (1) In 50% of patients, the seizure prognosisis good to excellent. This group includes those with self-limiting epilepsies with few seizures, for whom AEDsmay not even be necessary for seizure control, and the rstsingle AED controls the epilepsy; once seizure control isachieved, AEDs may be successfully tapered in manypatients. Whether the AEDs suppress or aect the courseof epilepsy in this group is unclear. (2) In another 1020%, seizure prognosis is still good, but there may be astruggle to nd the right AED. Seizure control may takeyears to achieve, and the relapse rate is high whether AEDsare withdrawn or not. Many need drug treatment for life.Surgery may improve the seizure outcome in this group.(3) Up to 30% carry a bad seizure prognosis with a contin-uous tendency to have seizures. AEDs seem to be palliativerather than suppressant, but new AEDs may improve out-come in some patients. Predictors of good outcome includeless than weekly seizures prior to treatment and nonsymp-tomatic etiology [for review, see 5].

2.9.2. Injuries and mortality

Accidents and injuries occur slightly more frequentlyamong people with epilepsy than in the general population,of those with terminal remission became seizure free onlyafter a delay of 9 years, suggesting improvement over time.However, outcome may worsen over time in 14%, who

ilepsy (N = 253) No epilepsy (N = 36717)

4% (10.024.9)a 10.7% (10.211.2)4% (16.032.8) 13.2% (12.713.7)1% (7.221.1) 11.2% (10.811.7)2% (25.043.3) 19.6% (19.020.2)% (2.910.3) 3.6% (3.33.9)0% (17.432.5) 13.3% (12.813.8)5% (25.944.0) 20.7% (19.520.7)

Behavior 12 (2008) 501539particularly in those with symptomatic epilepsy, frequentseizures, and associated handicaps. The majority of acci-dents are minor and occur at home. The most frequentinjuries among patients with epilepsy are contusions,wounds, fractures, abrasions, and brain concussions. Themortality in population-based studies is two to three timeshigher for people with epilepsy than in the general popula-tion. This is largely related to the etiology of the epilepsyand is probably not inuenced by its treatment. On theother hand, most fatalities in patients with chronic, ther-apy-resistant epilepsy seem to be seizure related and areoften sudden unexpected deaths (SUDEP). The frequencyof such seizure-related deaths is most likely to be reducedby intensied treatment aimed at early seizure control,although appropriate studies for denitive evidence are still

lacking [for review, see 5]. Apparently, there is an increasedrate of trac accidents in drivers with epilepsy, even if pop-ulation-based prospective data are lacking. Many of theseaccidents are seizure related.

Recommendation. Epilepsy is a benign disorder for at

least 50% of all patients. If the rst AEDs do not lead to sei-zure freedom within a year, the future outlook is guarded and

seizure control, if it occurs, as it does in 2030% with a

change of regimen, may take time, often several years.

Uncontrolled epilepsy occurs in 36% and is associated with

an increased risk of comorbidity, injury, and death.

3. Drug treatment

ing the current or likely future need for concomitant med-ication for comorbidity, and nally cost (Fig. 7).

The following AEDs have been approved by regulatoryagencies in the United States and Europe: acetazolamide,carbamazepine, clonazepam, clorazepate, ethosuximide,ethotoin, felbamate, gabapentin, lamotrigine, levetirace-tam, mephenytoin, methsuximide, oxcarbazepine, pheno-barbital, phenytoin, pregabalin, primidone, tiagabine,topiramate, trimethadione, valproate, vigabatrin, and zon-isamide. The following additional agents are used mainlyfor the acute therapy of status epilepticus: diazepam, fos-phenytoin, lorazepam, midazolam, and propofol.

Recommendation. AEDs provide satisfactory control ofseizures for most patients with epilepsy. About 65% ofpatients with new-onset epilepsy respond, seizure recurrence

seizure recurrence. High-risk features are symptomatic epi-lepsy with GTC seizures, complex or simple partial sei-

Checklist 2.1GENERAL TREATMENT PRINCIPLES

a m

o blengld brugtienl harid

uirerrupstopwith

C.E. Elger, D. Schmidt / Epilepsy & Behavior 12 (2008) 501539 5151. Treatment aims primarily to control seizures, and a return to health withpreventing or reversing associated psychiatric complications.

2. The underlying causative disorder, if amenable, and comorbidity need t3. A normal life with social activities should be encouraged including chal

avoided, in particular excessive alcohol intake and sleep deprivation shouIn case of fever continue drug treatment. Patients should self control d

5. Family members must be taught a commonsense attitude toward the palessens feelings of inferiority and self-consciousness and other emotiona

6. Exercise is recommended; even such sports as swimming and horseback7. Continued treatment with antiepileptic drugs is usually necessary.8. No single drug controls all types of seizures, and dierent drugs are req9. Once seizures are controlled, the drug should be continued without inte10. Most licensing agencies permit automobile driving after seizures have11. At that time, discontinuing the drug should be considered in patientsThe rst 5 years of treating epilepsy in patients withnew-onset epilepsy is crucial. The general treatment princi-ples can be summarized in 11 points (Checklist 2.1). AEDsprovide satisfactory control of seizures for most patientswith epilepsy. About 65% of patients with new-onset epi-lepsy respond, seizure recurrence occurs in 5%, and 35%have uncontrolled epilepsy. The rst AED controls seizuresin 5 of 10 patients; in the other 5 patients, drug treatmentfails because of poor ecacy in 2 patients, intolerableadverse events and idiosyncratic reactions in 2 patients,and other reasons for withdrawal (1 patient).

Modern AEDs are a diverse group of eective and safedrugs that have provided immeasurable benets for thoseaicted with seizure disorders of all kinds. Although themechanism of action of antiepileptic drugs is of great scien-tic interest, our current failure to better understand thegeneral mechanisms of seizure generation and of epilepto-genesis, let alone those mechanisms operant in an individ-ual patient, requires us to choose the best AED for anindividual on clinical grounds. Pragmatically, the choiceof the AED among rst-line agents needs to be individual-ized based mainly on the patient prole, including the e-cacy of the drug for the seizure or epilepsy syndrome,tolerability, safety, ease of use, pharmacokinetics, includ-12. If seizures cannot be controlled with drug treatment, however, surgical opconsidered early. Complacency should be avoided.zures, and idiopathic generalized epilepsies. Earlytreatment after a rst GTC seizure has, however, not beenshown to improve the long-term prognosis or lower themortality or risk of injury (Fig. 8) [17]. A number ofpatients with good prognosis (e.g., uncomplicated febrileseizures, often benign idiopathic partial epilepsies) maynot even need drug treatment (see Section 2.9). Also,

inimum of adverse events. Additional goals are social re-integration and

e treated as well.es that healthy persons face. A seizure provoking life style should bee minimized. Cocaine and several other illicit drugs can trigger seizures.compliance with a tablet dispenser.t. Overprotection should be replaced with sympathetic support thatndicaps.ing can be permitted when seizures are controlled.

d for dierent patients. Patients rarely require several drugs.tion until at least 1-2 yr seizure-free.ped for 1 yr.a low relapse risk.occurs in 5%, and 35% have uncontrolled epilepsy. Seizure

precipitation can be avoided by lifestyle changes, particularly

in adolescents. If two or three drug regimens have not

brought complete seizure control, the diagnosis of epilepsy

and of the epilepsy syndrome should be reevaluated, and if

refractory epilepsy is conrmed, surgical options should be

considered.

3.1. Starting treatment

The decision to start drug treatment in a patient withunquestionable epilepsy requires a careful individual riskbenet assessment (Fig. 8). AEDs are able to prevent fur-ther seizures and reduce the severity of seizures, and treat-ment is recommended in all persons with a high risk oftions including resection and vagus nerve stimulation should be

3-5 years0

First seizure

Early epilepsyChronicepilepsy

inatED

60%

35%

0%

516 C.E. Elger, D. Schmidt / Epilepsy & Behavior 12 (2008) 501539Treatment,patient`s Combof A

Single drugtreatment

65%Seizure freedom 2adverse events of AEDs, including central nervous systemtoxicity and hypersensitivity reactions, have to be balancedagainst the potential benet. Psychosocial consequences incase of another seizure (e.g., losing ones drivers license oran otherwise seizure-sensitive social setting) may weigh fordrug treatment in some patients. Drug treatment is usually

preference

Fig. 7. Overview on management principles and estimates of seizure freedom a50% of patients become seizure free for 12 months with the rst AED, if not, aAfter failure of several AEDs, surgical options should be considered in suitab

unprovoked

Histo

Treatm

others

EEG

MRI

epilepsysyndrome

Patient'spreference

Fig. 8. Algorithm for starting drug treatment in a patient presenting with a rspossible, if not, it may be prudent to observe another seizure before making a decision to start an AED is usually based on the patients preference after infooften possible after review of the seizure and with the support of the EEG an

Checklist 2.2STARTING TREATMENT

Does the patient wish to be treated?Do you know your AED? (Test: Do you know the contraindications of the dHave you given out a written scheme for dosing and drug titration?Does the patient have your emergency phone number?Dont promise too much, respect the known response to rst AEDDrug resistant 20%

ions

ModernAEDs

Epilepsysurgery

80%

5% 60%not indicated if the diagnosis of epilepsy is uncertain, ifprovoked seizures occur that can be prevented withoutdrugs, and, last not least, if the informed patient or care-giver does not want drug treatment (Checklist 2.2).

Recommendation. Drug treatment of epilepsy is generallyadvisable if seizures are disabling or can be reasonably

fter treatment in the rst 35 years of new-onset epilepsy. Approximatelychange of medical regimen is achieving seizure freedom in another 2030%.le cases.

provoked nonepileptic

ry

ent

generalized

partial

t seizure. After a careful history, the clinical diagnosis of epilepsy is usuallynal diagnosis. In a patient with a rst generalized tonic-clonic seizure, thermed consent. If the diagnosis of an epilepsy syndrome can be made, as isd the MRI, AED treatment is usually started, after informed consent.

rug you wish to prescribe?)

expected to recur suciently frequently to adversely aect

the individual person more than the adverse eects of AEDs.

The decision to start treatment after a single tonicclonic sei-

zure needs to be individualized because current AEDs prevent

seizures in most patients but do not seem to aect the course

of epilepsy.

3.2. Mechanism of drug action

AEDs prevent seizures by acting on diverse moleculartargets to selectively modify the excitability of neurons sothat seizure-related ring is blocked without disturbingnonepileptic activity. However, the drugs have the remark-able ability to protect against seizures while permitting nor-mal functioning of the nervous system. AEDs protectagainst seizures by a variety of dierent mechanisms (Table4) [18].

In the end, AEDs are only a step on the way to the ulti-mate goal of epilepsy medicine, which is to provide treat-ments that prevent epilepsy or reverse it (Table 4).Although AEDs prevent seizures, they are not antiepilepto-genic, able to prevent epilepsy or to aect the underlyingtendency to generate seizures. Antiepileptogenic strategiesare being developed using various animal models of

chronic epilepsy. By targeting plasticity mechanisms thatunderlie the enhanced seizure susceptibility that often fol-lows brain insults such as head trauma, status epilepticus,and neonatal hypoxia, antiepileptogenic drugs of the futurewould prevent, or reverse, progressive worsening of the epi-leptic process.

Recommendation. Unfortunately, the mechanism underly-

ing the therapeutic action of AEDs, although of great scien-

tic interest and merit, is of little practical help in making a

rational choice of AED, unless and until we better understand

the mechanism of epilepsy and seizure generation for individ-

ual syndromes and patients.

3.3. Pharmacokinetics

From a clinical perspective, the ideal AED does notrequire monitoring of plasma concentrations, is metaboli-cally inert, is not involved in drug interactions, and canbe conveniently taken once or twice a day [19]. Unfortu-nately, a number of currently used classic AEDs induceor, less commonly, inhibit the cytochrome P450 system(carbamazepine, CBZ; phenobarbital, PHB; phenytoin,PHT) or inhibit enzymes involved in glucuronidation (val-proate, VPA) (Table 5) [20]. Fortunately, modern AEDs

Table 4Antiepileptic drugs and their molecular targetsa

Drug Sodiumchannels

Calciumchannels

GABAsystem

Glutamatereceptors

Partial-onsetizur

PrimaryGTC

Absenceseizure

Myoclonicseizure

Infantilespasms

LennoxGastaut

a It is convenient to categorize the actions of AEDs into those that involve (chaotetionmiscitatbnowhecco

C.E. Elger, D. Schmidt / Epilepsy & Behavior 12 (2008) 501539 517inhibition, and (3) inhibition of synaptic excitation. Voltage-gated ionsubthreshold electrical behavior of the neuron, allow it to re action pparoxysmal depolarization shift, and ultimately are integral to the generaelements in neurotransmitter release, which is required for synaptic transbursting, synchronization, and seizure spread. Synaptic inhibition and expermit synchronization of neural ensembles and allow propagation of the ainhibitory neurotransmission, therefore, can also suppress bursting and,spread. For convenience, three groups of compounds can be categorized ase

Group APhenytoin + +Carbamazepine + +Lamotrigine + HVA +Zonisamide + T-type +

Group BPhenobarbital HVA GABAA R AMPA +Benzodiazepines GABAA R +Vigabatrin GABA-T +Tiagabine GABA

transporter+

Ethosuximide +? T-typeGroup CGabapentin HVA a2d GABA

turnover+

Pregabalin HVA a2d GABAturnover

+

Levetiracetam HVA +

Source. Modied from Ref. [18].calcium) channel activity; Group B: GABA-mediated mechanisms; Group Crandomized controlled trials, several open studies, and generally accepted util(+) (+) +

1) modulation of voltage-gated ion channels, (2) enhancement of synapticnnels (including sodium, calcium, and potassium channels) shape thentials, regulate its responsiveness to synaptic signals, contribute to theof seizure discharges. In addition, voltage-gated ion channels are crucialsion. Consequently, they are key targets for AEDs that inhibit epilepticion are mediated by neurotransmitter-regulated channels; these channelsrmal discharge to local and distant sites. AEDs that modify excitatory andn they inhibit synaptic excitation, can have prominent eects on seizurerding to their primary mechanisms. Group A: predominant sodium (ande seizure syndrome

+ (+) ++ (+) (+) (+)

+ ++ + + (+) (+)

+ (+)

+ (+): mixed, complex, or poorly understood actions. +, ecacy results fromity; (+), less extensive base of evidence.

inh

trancre

sy &are available that are less enzyme inducing (oxcarbazepine,OXC) or are not at all metabolized by the oxidative cyto-chrome P450 (gabapentin, GBP; lamotrigine, LTG; leveti-racetam, LEV; pregabalin, PGN; or topiramate, TPM)and, therefore, are less likely to be involved in drug inter-actions (Table 5).

The absence of drug interactions is a very importantadvantage for an AED. Most patients with epilepsy aretreated for several years, and a majority need AEDs fortheir lifetime. As a consequence, the long-term conse-quences need to be taken into account. For example,women might wish to take oral contraceptives at some peri-ods in life; people become overweight or develop comorbid

Table 5Simplied synopsis of drug interaction properties of common AEDs

AED Enzyme inducer (CYP)a Enzyme

Carbamazepine (CBZ) Yes NoClobazam (CLB) No NoEthosuximide (ETS) No NoFelbamate (FBM) No NoGabapentin (GBP) No NoLamotrigine (LTG) Yes YesLevetiracetam (LEV) No NoOxcarbazepine (OXC) Yes NoPhenobarbital (PHB) Yes NoPhenytoin (PHT) Yes NoPregabalin (PGN) No NoPrimidone (PRM) Yes NoTopiramate (TPM) Yes (>200 mg/day) NoValproate (VPA) No YesVigabatrin (VGB) No NoZonisamide (ZNS) No No

Source. Modied from Ref. [20].a CYP, cytochrome P450 system; UGT, uridine diphosphate glucuronyl

plasma concentration; ., decrease in plasma concentration; .., major de

518 C.E. Elger, D. Schmidt / Epilepconditions such as depression, anxiety disorders, migraine,cardiovascular disease, diabetes, and cancer and mayrequire additional medication. The increasing incidenceof epilepsy in the elderly who commonly suer from multi-morbidity also require AEDs that do not interact. Finally,one in three patients with new-onset epilepsy will require acombination or a succession of AEDs over the life span foroptimal seizure control. In addition, AEDs that interactwith other drugs, for example, through enzyme inductionor enzyme inhibition, will also disadvantageously aectthe endogenous sexual and other hormone metabolism,and may contribute to adverse events. Taking enzyme-inducing CBZ, OXC, PHB, PHT, and primidone (PRM)mayin contrast to GBP, LEV and TPM at doses below200 mg/daylead to reduced ecacy of comedicationincluding oral contraceptives and other AEDs. Adding anoral contraceptive may lower the plasma concentrationsand ecacy of LTG, and vice versa. VPA does not interactwith oral contraceptives, but may, however, inhibit glucu-ronidation of, for example, LTG. Fewer clinically relevantinteractions with drugs or endogenous substances occurwith OXC, TPM, and VPA instead of the classic enzyme-inducing AEDs, which are the least advantageous agentsin that respect. Finally, many classic AEDs share the disad-vantage of both causing clinically relevant interactions andbeing aected by other drugs. For all these good reasons,the absence of enzyme induction or enzyme inhibitionactivity is a plus for any AED (Table 5).

Up to one in three patients with new-onset epilepsyrequire a combination of dierent AEDs for seizure con-trol. In uncommon cases, even more than two AEDs maybe needed. During combination therapy, a number of druginteractions may occur when classic AEDs are used. Druginteractions may interfere with drug ecacy. A prototypicexample is the combination of CBZ and VPA. When VPAis added to CBZ, adequate VPA plasma concentrations

ibitor (CYP, UGT) Eect of drug on disposition of other AEDs

LTG, TGB, VPA (..)No relevant changePHT, VPA (N), CBZ (.)No relevant changeNo relevant changeNo relevant changeAt OXC doses >900 mg (.)CBZ, LTG, PHT, TGB, VPA (..)CBZ, LTG, OXC, PHT, TGB, VPA (..)No relevant changeCBZ, LTG, PHT, TGB, VPA (..)No relevant changeNo relevant changePHT (.), other AEDs (JI)CBZ-E, LTG, PHB, free PHT (N)No relevant change

sferase system; TGB, tiagabine; JI, no relevant change; ., increase inase in plasma concentration.

Behavior 12 (2008) 501539cannot be achieved in most cases because CBZ lowers theplasma concentration of VPA. However, drug interactionsmay also increase the plasma concentrations to toxicplasma levels, for example, the increase in plasma concen-tration of LTG in the presence of VPA. Although this com-bination is benecial for many patients, tremor maydevelop and the combination has been shown to be moreteratogenic than LTG alone or in combination withanother AED, except VPA. However, modern AEDs suchas GBP, levetiracetam (LEV), PGN, and tiagabine (TGB)as are much better suited for combination therapy theyare much less or not at all involved in drug interactionsamong AEDs (Table 5). By initiation of epilepsy treatmentwith modern noninteracting AEDs, such complications canbe prevented.

A large number of patients with epilepsy rely on addi-tional medication other than AEDs for birth control ormanagement of disorders. Depression, anxiety disorders,and migraine are common in patients with epilepsy.Patients with epilepsy are not immune to development ofsuch common diseases as stroke, myocardial infarction,and cancer, all of which require medication that may beinterfered with by classic enzyme-inducing AEDs. Persons

o re

iltia

o re

sy &Table 6Clinically relevant eect of AEDs on the disposition of other drugs

AED .a NBenzodiazepines No relevant change N

Carbamazepine Anticoagulants, quinidine, contraceptives,corticosteroids, cyclosporine A, folate, digitalisglycosides, donezepil, doxycycline, felodipine,mebendazole, methadone, muscle relaxants,nifedipine, nimodipine, praxiquantel,theophylline, verapamil

D

Felbamate No relevant change N

C.E. Elger, D. Schmidt / Epilepwith epilepsy may require antibiotics, which increaseplasma concentrations of AEDs and may thus cause toxic-ity (Table 6). Starting treatment with modern noninteract-ing AEDs prevents such complications.

Recommendation. Adverse drug interactions can be mini-

mized by avoiding enzyme-inducing or -inhibiting classic

AEDs and using benecial combinations of AEDs, if needed

for seizure control.

3.4. Adverse eects

Possible adverse eects of AEDs are listed in Tables 7and 8 [21,22]. The main advantages of some of the modern

Gabapentin No relevant change No reLamotrigine Lower ecacy of oral contraceptives Disco

contrplasmpatien

Levetiracetam No relevant change No reOxcarbazepine Felodipine, contraceptives, nifedipine, nimodipine No re

Phenobarbital Anticoagulants, quinidine, contraceptives,corticosteroids, cyclosporine A, diltiazem, digitalisglycosides, donezepil, doxycycline, felodipine,folate, griseofulvin, haloperidol, mebendazole,methadone, metoprolol, nifedipine, nimodipine,metronidazole, muscle relaxants, praxiquantel,propanolol, tacrolimus, tamoxifen, theophylline,verapamil

No re

Phenytoin Anticoagulants, quinidine, contraceptives,corticosteroids, cyclosporine A, digitalisglycosides, donezepil, doxycycline, folate,mebendazole, methadone, muscle relaxants,nifedipine, nimodipine, praxiquantel,theophylline, verapamil

Diltia

Pregabalin No relevant change No re

Primidone See PHB See PTiagabine No relevant change No reTopiramate Contraceptives (TPM >200 mg/day), No reVigabatrin No relevant change No reValproate Itroconazole Antic

Zonisamide No relevant change No re

Source. Modied from Refs. [19,20].Abbreviations: See Table 5.a ., Ecacy of specied drug may be lower with comedication of specied

specied AED; JI, no relevant change in disposition.Comments

levant change Higher sedation when taken with othersedating drugs (e.g., alcohol, PHB)

zem Lithium neurotoxicity may be functionallyincreased with comedication of AED. MAOinhibitors contraindicated

levant change

Behavior 12 (2008) 501539 519AEDs include absence of hypersensitivity reactions, weightproblems, and drug interactions that cause central nervoussystem toxicity. There is no need for routine laboratorymonitoring and safety is improved without life-threateningorgan damage. Patients receiving carbamazepine shouldhave a complete blood count once a month for the rstyear of therapy. If the WBC or RBC count decreases signif-icantly, the drug should be discontinued immediately.Patients receiving valproate should have liver function testsevery 3 months for 1 year; if serum transaminase or ammo-nia levels increase signicantly (to more than twice theupper limit of normal), the drug should be discontinued.An increase in ammonia up to 1.5 times the upper limit

levant changentinuation of oralaceptives may increasea concentration in somets

Compromised ecacy of oral contraceptiveshas been reported in some patients

levant change Partly metabolized by non-hepatic hydrolysislevant change Lithium neurotoxicity cannot be ruled out

with comedication of OXC; MAO inhibitorscontraindicated

levant change Methotrexate toxicity may be functionallyincreased with comedication of AED

zem, disulram Lithium neurotoxicity may be functionallyincreased with comedication of AED; MAOinhibitors contraindicated

levant change Pregabalin may cause peripheral edema.Exercise caution when co-administeringpregabalin and thiazolidinedione antidiabeticagents

HBlevant changelevant changelevant changeoagulants VPA may functionally increase

anticoagulationlevant change

AED; N, toxicity of specied drug may be higher with comedication of

Table 7Overview on adverse eects of AEDsa

CBZ CLB ETS FBM GBP LEV L

Early-onset adverse eventsSomnolence ++ + + +Dizziness ++ + + + +Seizure aggravation + + +Gastrointestinal + ++ + (+) (+)Liver failure +Hypersensitivity (SJS/TEN) + + + +Rash + +

Late-onset adverse eventsSedation ++ +EncephalopathyDepression +Behavioral problems +Psychotic episodes (+) ++ (+) + (+)Leukopoenia ++ + +Aplastic anemia + + ++Thrombopenia +Megaloblastic anemia (+)

520 C.E. Elger, D. Schmidt / Epilepsy &Pancreatitis (+)Nephrolithiasisof normal can be tolerated safely. When an overdose reac-tion occurs, the amount of drug is reduced until the reac-

Osteoporosis (+)Hyponatremia (+)Weight gain + +Weight lossCognition impaired + +TeratogenicitySummary 9 8 10 7 5 3 4

Source. With data from Refs. [21,22].a In general, although exposure to some modern AEDs is still limited, treatme

with treatment with some of the classic AEDs (see summary of risks). It shouldhere can be lowered by slow titration and avoiding above-average dosage andin Table 8. (+), minimally increased risk in clinical use; +, risk higher than for AAEDs, see Table 5.

Table 8Major malformation rates after exposure to monotherapy of individualAEDs

n Major malformations

No AED, n = 173 2.4% (0.96.0)a

Carbamazepine, n = 700 2.3% (1.43.7)Valproate, n = 572 5.9% (4.88.2)b

Lamotrigine, n = 5390 2.1% (1.04.0)

Source. UK Registry: May 2003: 2637 completely documented pregnan-cies, total frequency of severe malformations = 4.1%.a The 95% condence interval is given in parentheses.b Signicantly versus carbamazepine and lamotrigine [23]. No data are

available on other AEDs from prospective studies. Fetal antiepileptic drugsyndrome (abnormal facies, digital hypoplasia, microcephaly, and possi-bly developmental delay) occurs dose dependently in up to 4% of thechildren of epileptic women who take AEDs during pregnancy. Amongcommonly used drugs, carbamazepine and lamotrigine appear to be theleast teratogenic; valproate may be the most teratogenic. There issuggestive evidence that malformations may be less frequent below atotal daily dose of 1000 mg of valproate and 200 mg of lamotrigine [24].Yet, because uncontrolled tonicclonic seizures during pregnancy lead tofetal injury and death, continued AED treatment is generally advisable.For abbreviations, see Table 5.TG OXC PGN PHB PHT TGB TPM VPA VGB ZNS

+ ++ ++ ++ + ++++ ++ ++ ++ + +

+ + + +++ + +

++ + + + ++ + +

++ (+)+ + ++

+ + + +++ + + ++ ++ +(+) (+) (+) (+) (+) ++

(+) + ++ +

+++ +

+(+) +

Behavior 12 (2008) 501539tion subsides. When more serious acute poisoning occurs,the patient is given ipecac syrup or, if obtunded, is lavaged.After emesis or lavage, activated charcoal is administered,followed by a saline cathartic (e.g., magnesium citrate).Hemodialysis may be considered. The suspect drug shouldbe discontinued, and a new AED started simultaneously.For more detailed discussion of adverse events, see [1].

Recommendation. Adverse eects of AED treatment can

be minimized by slow dose escalation up to average daily

maintenance doses (unless increments are needed for seizure

control), by avoidance of enzyme-inducing agents and poly-

therapy, if possible, and by use of appropriate well-tolerated

modern AEDs for both new-onset and refractory epilepsy.

3.5. Integrative choice of drug

Pragmatically, the choice of the AED among rst-lineagents needs to be individualized based mainly on thepatient prole, including the ecacy for the seizure or epi-lepsy syndrome, tolerability, safety, ease of use, pharmaco-kinetics, including the current or likely future need forconcomitant medication for comorbidity, and nally cost(Checklist 2.3).

+ + (+)+

++ + + ++

++ + + +++

6 4 14 13 7 9 9 12 9

nt with a number of modern AEDs appears to be advantageous compared, however, be noted that the incidence of many early adverse events showncombination therapy, if possible. Teratogenicity is discussed in more detailEDs without + sign; ++, highest risk among AEDs. For abbreviations of

f pa

iental se me

atioe prrmo

sy &3.5.1. Partial seizures

A number of AEDs are recommended based on theirbenetrisk balance (Tables 9 and 10) [25,26]. The modernAEDs for therapy of previously untreated adolescents andadults with partial epilepsy, such as gabapentin, lamotri-gine, levetiracetam, oxcarbazepine, and topiramate, havea number of advantages compared with classic AEDs suchas carbamazepine, phenobarbital, phenytoin, primidone,and valproate. The new AEDs are generally similar in e-cacy, with the possible exception of gabapentin, whichseems to be inferior in ecacy compared with CBZ, andare at least similar or better with respect to tolerability atadequate dosages than classic AEDs for patients with par-tial epilepsy. However, none of the modern AEDs evalu-ated in the SANAD trials was more ecacious thancarbamazepine or valproate in their respective comparisongroups [27,28]. Carbamazepine leads to complete seizurecontrol in about 50% of patients; subsequent regimens withcombination or substitution achieve control in up to 1015%. One in three patients remains with uncontrolled par-tial seizures. In addition to the AEDs mentioned, eca-cious second-line AEDs such as pregabalin andzonisamide are available for combination if the rst drugfails to control seizures.

If several of these drugs individually or in combinationhave failed, surgery should be considered. Third-line agentsare available: clobazam, phenobarbital, phenytoin, primi-done, tiagabine. Less often used agents with either tolera-bility or safety problems or no Class I evidence ofecacy (acetazolamide, bromide, felbamate, sulthiame,vigabatrin) should be used as a last resort. Given the sim-

Checklist 2.3Considerations on the choice of AED

All AEDs for a given class of seizures are similarly ecacious in percent oindividual response.

Chose the AED with the optimal risk-benet prole for the individual patIdeally, the drug should be as ecacious as CBZ or VPA for the individu

teratogenicity compared to CBZ, no idiosyncratic reaction), should not bCBZ or show no or less enzyme inhibition compared to VPA.

* The choice between numerous AEDs will be made after careful considersuitable new AEDs which are less or not at all enzyme inducing, should bchildbearing age, patients with cognitive decits or depression, with hooverweight, concomitant disorders or medication and the elderly.

C.E. Elger, D. Schmidt / Epilepilar ecacy in control of partial seizures, the choice amongrst-line AEDs needs to be individualized based mainly onthe patient prole, including the epilepsy syndrome, toler-ability, gender issues, pharmacokinetics, current or likelyfuture need for concomitant medication for comorbid con-ditions, and cost.

3.5.2. Generalized seizures

A number of AEDs are recommended based on theirbenetrisk balance (Tables 9 and 10). Despite requiringdierent treatment strategies, typical absence seizures, juve-nile myoclonic epilepsy, and related idiopathic generalizedepilepsies are often erroneously grouped with partial andother epilepsies under the broad term epilepsy. Further-more, antiepileptic drugs are tested and licensed mainlyfor partial epilepsies, and there may be inappropriate gen-eralizations for their use in epilepsy. This is exempliedby gabapentin, carbamazepine, oxcarbazepine, and phenyt-oin, which induce myoclonic seizures, and vigabatrin andtiagabine, which induce absence seizures; they are contrain-dicated in the idiopathic generalized epilepsies, which con-stitute a large minority of epilepsy syndromes. Valproate isstill the drug of rst choice for patients with idiopathic andsymptomatic generalized epilepsy despite its disadvantages,particularly weight gain and teratogenicity, because theecacy of valproate is unsurpassed by any modern suitableAED such as lamotrigine or topiramate (Fig. 9) [28].Although lamotrigine and topiramate are used for previ-ously untreated adolescents and adults with generalizedor unclassied epilepsies, the ecacy of lamotrigine is infe-rior to that of valproate, whereas topiramate is not inferiorto valproate.

Absence seizures are fundamentally dierent from anyother type of seizure and, therefore, unique in terms ofpharmacological treatment. Typical absence seizures areoften easy to diagnose and treat. Valproate, ethosuximide,and lamotrigine, alone or in combination, are rst-linetherapy. Valproate controls absences in 75% of patientsand also GTC seizures (70%) and myoclonic jerks (75%);however, it may be undesirable for some women. Similarly,lamotrigine may control absence and GTC seizures in pos-sibly 50 to 60% of patients, but may worsen myoclonicjerks; skin rashes are common. Ethosuximide controls70% of absences, but it is unsuitable as monotherapy ifother generalized seizures coexist. Combinations of any

tients responding, however (unexplained) individual dierence exist for

eizure or epilepsy, but better tolerated and safer (e.g., no increasedtabolized and have no or less enzyme induction properties compared to

n of all other individual relevant factors (see checklist). In particular,eferred over classic AEDs in adolescents and adults including women ofnal or metabolic disturbances, increased risk for osteoporosis,

Behavior 12 (2008) 501539 521of these three drugs may be needed for resistant cases.Low dosages of lamotrigine added to valproic acid mayhave a dramatic benecial eect. Clobazam, particularlyin absence seizures with myoclonic components, and acet-azolamide may be useful adjunctive drugs.

Generalized myoclonic seizures are dierent pharmaco-logically from absence seizures. Primidone and phenobar-bital, which may be a last resort for treatment ofrefractory juvenile myoclonic epilepsy, are ineective andmay even worsen absence seizures. The epilepsy syndromemay also play a role. For example, lamotrigine, which iseective in children with typical absence seizures, may wor-sen myoclonic seizures in infants with severe myoclonic epi-lepsy. Children are in general more vulnerable. Controlled

Table 9Choice of antiepileptic drugsa

Antiepilepticdrug

Absence, myoclonicseizures, PGTC

Partial,sec. GTC

Partial,children

Neither partial norgeneralized seizures

LennoxGastautsyndrome

Most important benet(s) Most important disadvantage(s)

Clobazam Good transient adjunctive ag Loss of ecacy (tolerance)Carbamazepine Unsurpassed ecacy: PS Enzyme inducer, cognitive adverse events

in the elderlyEthosuximide Absence only Ecacy: absence Rare: psychotic episodes, anorexiaFelbamate Ecacy: drop attacks Rare: aplastic anemia, liver failure;

irritabilityGabapentin Ecacy: PS, no drug interact High doses may be requiredLamotrigine Ecacy: PS, PGTC, absence,

myoclonic, mood stabilizerSlow titration, rash

Levetiracetam Ecacy: PS, no titration, few uginteractions

Psychiatric abnormalities

Oxcarbazepine Ecacy: PS, fewer adverse ev tsthan CBZ

Rare symptomatic hyponatremia(caution: patients on diuretics)

Phenobarbital Myoclonic andPGTC only

, IV , IV Ecacy: PS, PGTC, myoclon IV Enzyme inducer, mental slowing

Phenytoin ,IV

, IV Ecacy: PS, IV Enzyme inducer, no dose-linearpharmacokinetics

Pregabalin Ecacy: PS, no drug interact s Weight gainPrimidone Myoclonic and

PGTC onlyEcacy: PS, PGTC, myoclon Enzyme inducer, mental slowing

Tiagabine Ecacy: PS, PGTC, no druginteractions

Rare: may provoke absence status

Topiramate Myoclonic andPGTC only

Ecacy: PS, PGTC, absence,myoclonic, weight reduction

Cognition including aphasic problems,rare: anorexia

Vigabatrin IS only Ecacy: PS, IS, no enzyme in cer Irreversible visual eld defectsValproate , IV , IV , IV , IV , IV Ecacy: PS, PGTC, absence,

myoclonicWeight gain, teratogenicity

Zonisamide Ecacy: PS, PGTC, absence,myoclonic

Rare; nephrolithiasis

Source. Modied with data from Refs. [25,26].a , First choice, class I or II evidence; , second choice or adjunctive therapy, class IIII evidence; , third choice or adjunctive the py, no cla