Epilepsy

Martin Veilleux, MD

Montreal Neurological Institute

McGill University

Definition SeizureSeizure: event characterized by a paroxysmal

cerebral neuronal discharge associated with clinical and behavioral manifestations

EpilepsyEpilepsy: condition characterized by recurring seizures

Non epileptic seizureNon epileptic seizure: clinical and behavioral manifestations that are not secondary to an epileptic discharge

Incidence Almost 5-9% of population will have a seizure at a

certain point in life 1-2% of population aged 20 years have epilepsy and

the incidence increases up to 3.4% by age 80 Provoked seizures are related to an acute injury to

the central nervous system Non provoked seizures can be subdivided in

idiopathic and secondary to a remote injury to the central nervous system

Annegers, JF. Neurology Clinics 12: 15-29, 1994

Epilepsy: Incidence according to age

Age (years)

0

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0 3 10 20 30 40 50 60 70 80

Epilepsies

Inci

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er 1

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Annegers JF. Dans: Treatment of Epilepsy: Principle and Practice, 2nd Ed. Baltimore, MD, Williams & Wilkins, 1997: 165-172

Terminology Idiopathic epilepsies:Idiopathic epilepsies: genetically determined, no

apparent structural cause, and seizures as the only manifestation of the condition

Symptomatic or cryptogenic:Symptomatic or cryptogenic: generally not genetic although there might be minor genetic predisposition, as a result of brain insult or lesion that can be documented (symptomatic) or not (cryptogenic). If brain damage is focal, it results in localization-related epilepsy and if diffuse, in generalized epilepsy.

International classification of epileptic seizures Partial seizures

Simple partial seizures (consciousness not impaired) With motor symptoms With somatosensory or special sensory symptoms With autonomic symptoms With psychic symptoms

Complex partial seizures (impairment of consciousness) Beginning as simple partial seizure and progressing to CPS With impairment of consciousness at onset

Partial seizures evolving to secondarily generalized seizures SPS evolving to generalized seizures CPS evolving to generalized seizures SPS evolving to CPS then to generalized seizures

Epilepsia 22 (4): 489-501, 1981

International classification of epileptic seizures Generalized seizures

Absence seizures Typical absence seizures Atypical absence seizures

Myoclonic seizures Clonic seizures Tonic seizures Tonic-clonic seizures Atonic seizures

Unclassified epileptic seizures (inadequate or incomplete data)

International classification of epilepsies

Localisation-related (focal, partial) Idiopathic

Benign childhood epilepsy with centrotemporal spikes Childhood epilepsy with occipital paroxysms Primary reading epilepsy

Cryptogenic (defined by seizure type, features) Symptomatic

Mesial TLE with hippocampal sclerosis Autosomal dominant TLE with auditory features Autosomal dominant NFLE Symptomatic focal epilepsies not otherwise specified

TLE, FLE, PLE, OLE

Chronic progressive epilepsia partialis continua of childhood

International classification of epilepsies

Generalized Idiopathic

Benign neonatal familial convulsions Benign neonatal convulsions Benign myoclonic epilepsy of infancy Childhood and juvenile absence epilepsy Juvenile myoclonic epilepsy Epilepsy with grand mal seizures on awakening Generalized epilepsy with febrile seizures plus Other generalized idiopathic epilepsies

Cryptogenic (now probably symptomatic) West syndrome (infantile spasms) Lennox-Gastaut syndrome Epilepsy with myoclonic-astatic seizures Epilepsy with myoclonic absences

International classification of epilepsies

Generalized Symptomatic

Nonspecific etiology Early myoclonic encephalopathy Early infantile encephalopathy with suppression bursts Other symptomatic generalized epilepsies (progressive myoclonic

epilepsies) Specific syndromes

Epileptic seizures may complicate many disease states

Undetermined epilepsies With both generalized and focal seizures

Neonatal seizures Severe myoclonic epilepsy of infancy Epilepsy with continuous spike-waves during SWS Acquired epileptic aphasia (Landau-Kleffner syndrome)

Special syndromes (febrile seizures, isolated seizures, etc.)

Epilepsy as a complex disease Few patients have affected relatives: family history in

a parent, sibling, or offspring: ~ 10% of patients In most families, pattern of inheritance is inconsistent

with a simple Mendelian model (dominant, recessive, X-linked). Most epilepsy syndromes are probably caused by sets of interacting genes, possibly also interacting with environmental factors (polygenic/oligogenic or multifactorial model)

Very good (0.8) concordance of IGE in identical twins in Australian and Lennox series, and in many case reports

Locus heterogeneity in epilepsy

KCNQ2 (20q13)

KCNQ3 (8q24)

CHRNA4 (20q13)

CHRNB2 (1q21)

SCN1A (2q24)

SCN2A (2q24)

SCN1B (19q13)

GABRG2 (5q31)

Benign familial neonatal seizures

ADN frontal lobe epilepsy

Generalized epilepsy with febrile

seizures plus

Offspring Risk of Epilepsy by Age 20:Factors increasing risk

Parent gender: maternal effectMother with epilepsy: 2.8-8.7%; father with epilepsy: 1-3.6%

Parent’s age at onset of epilepsyUnder 20 years: 2.3-6%: Over 20 years: 1-2.8%

Number of affected relativesRisk increases with more relatives affected

EEG abnormalitiesRisk increases with GSW in parent or relative (6x risk for sibs)

Parent’s seizure type

Localization-related epilepsy Represents about 70% of all epilepsies 40 to 50% of partial simple and complex seizures and

75% of partial secondarily generalized seizures are well controlled by AEDs.

Risk of recurrent seizures upon discontinuation of AEDs is 25% in partial simple seizures, 50-70% in secondarily generalized seizures and 50-80% in patients with partial seizures with psychic aura

Annegers, JF. Neurology Clinics 12: 15-29, 1994

Localization-related epilepsy Seizures arising from frontal and temporal lobes

comprise majority of localization-related or partial epilepsies

They constitute the majority of medically refractory seizures

50% of partial epilepsies originate from temporal lobe and 15-20% from the frontal lobe

Subjective clinical manifestations are diverse and reflect localization of the seizure origin

Temporal lobe seizures Auras occur in 80% of patients with TLE Auras include psychic/cognitive, sensory and

autonomic phenomena Ictal discharges may begin in clinically silent regions

with the aura experienced only after activity has spread to other regions

Auras may provide clue to the region of ictal onset Complex partial seizures in TLE usually last 1-2

minutes, longer than those from frontal origin

Temporal lobe seizures Mesial temporal

Aura often epigastric, psychic, affective, olfactory Impaired consciousness Fixed stare, widened palpebral fissure Early oroalimentary automatisms Limb automatisms (ipsilateral to seizure focus) Dystonic posturing or clonus (contralateral to seizure focus) Postictal confusion and amnesia Early non forced head deviation (ipsilateral)

Lateral temporal Aura often auditory, complex perceptual, language Late oroalimentary automatisms Late manifestation indistinguishable from mesial temporal

Temporal lobe epilepsy

Frontal lobe epilepsy Auras are less common, nonspecific and described

as vague cephalic sensations Auras can include epigastric, vague autonomic,

complex psychic (forced thinking) and olfactory sensation, affective experience and autonomic such as belching, defecation

Frontal lobe seizures frequently become secondarily generalized, up to 90% and are brief, bizarre, stereotyped, with hypermotor phenomena

More frequent nocturnal occurrence

Frontal lobe seizures Brief seizures, often in clusters Little or no postictal confusion Late forced head deviation (contralateral) Pedaling, bicycling, fencing posturing Rapid secondary generalization Prominent motor manifestations (clonic, tonic, tonic-clonic) Hyperkinetic complex or bizarre automatisms Frequent falls Nocturnal predominance Status epilepticus

Frontal lobe epilepsy

Parietal lobe seizures Somatosensory auras Receptive language disturbance (dominant hemisphere) Neglect (nondominant hemisphere) Variable spread to:

Occipital lobe (visual hallucinations) Precentral regions (motor) Mesial temporal regions

Occipital lobe seizures Elementary visual hallucinations Loss of vision Contralateral or ipsilateral deviation of the eyes Forced blinking Variable spread to:

Parietal lobe (sensory symptoms) Temporo-occipital regions (formed visual hallucinations) Mesial temporal regions

DiagnosisLoss of consciousness

Seizure Syncopal event

Acute condition

Yes No

Acute symptomatic

Febrile seizures

Unprovoked

Only one Many

Seizure Epilepsy

Assessment Detailed past medical history including complications

at birth, febrile seizures, head injury, CNS infection, psychomotor development, etc.

Detailed history of the seizure obtained from witness (aura, oral or manual automatism, head deviation, tonic or dystonic posturing of a limb, etc.)

Physical and neurological examination Awake and asleep EEG CT and/or MRI of the brain

Differential diagnosis Psychogenic nonepileptic seizures: 10-15% of these

patients also have epilepsy Syncope and cardiac arrhythmias Complicated migraine and migraine auras Transient global amnesia Acute hypoglycemia Movement disorder (acute dystonic reactions,

hemifacial spasm, nonepileptic myoclonus, parasomnias, cataplexy, hypnic jerks)

Etiology Cerebrovascular diseases 30-40% Idiopathic 30% Brain tumours 20% Head injury 5% Toxic-metabolic 5-10% Migrational neuronal defect 5% Others 1%

Annegers, JF Neurology Clinics 12: 15-29, 1994

Electroencephalography 40-50% of epileptic patients have interictal

epileptiform abnormalities (spikes or sharp waves) on their first EEG

After 4 or more EEGs, 90% of epileptic patients will have some interictal epileptic abnormalities on their EEG (Salinsky, 1987)

Interictal epileptiform discharges are more frequent during non-REM sleep

An epileptic seizure is recorded in 2.5 to 7% of routine EEGs (Mattson, 1980)

Electroencephalography Standard EEG performed in 157 adult patients within

first 48 hours of the first unprovoked seizure: abnormal in 70% and this was significantly associated with increased recurrence rate. 25% had epileptic abnormalities on the first EEG and sleep-deprived EEG revealed epileptic abnormalities in an additional 13% who had no epileptic activity on the standard EEG.

Highest seizure recurrence rate in patients with focal epileptic activity.

CT or MRI of the brain: abnormal in 50% of patients

Schreiner A. et al., Clinical EEG 34(3): 140-4, 2003

Electroencephalography Long-term EEG monitoring can be useful in selected

cases to confirm the patient has epileptic seizures, to determine seizure type (focal versus idiopathic generalized), seizure frequency, evaluation of seizure precipitants, change in AED, and surgical localization.

In-patient EEG recordings (EEG telemetry) can provide additional information in selected patients considering the antiepileptic medications can be reduced as an in-patient. It provides more information in regard to seizure localization for surgery.

Cascino GD. Neurologic Clinics 19(2): 271-287, 2001

Right temporal spikes

Bitemporal spikes

Right temporal ictal discharge

Generalized 3Hz spikes and waves

Electroencephalography During seizures of temporal lobe origin, EEG shows

more frequently rhythmic theta over temporal regions, and less commonly focal attenuation or focal ß activity.

During seizures of frontal lobe origin, EEG may reveal focal or generalized attenuation, fast activity, slowing, sharp waves or rhythmic spikes or rhythmic spike and waves, secondary bilateral synchrony, or normal EEG

Neuroimaging MRI of the brain is the test of choice in the evaluation

of patient with epilepsy. It is not indicated in patients with idiopathic

generalized epilepsies and in benign focal epilepsies of childhood.

MR imaging has replaced CT when anatomic brain imaging is required to see low-grade tumours and vascular malformations.

Neuroimaging MR imaging is clearly superior to detect structural

abnormalities such as malformation of cortical development (cortical dysplasia, heterotopia, double cortex, etc), hamartomas and volumetric asymmetries (hippocampal atrophy, mesial temporal sclerosis)

MR spectroscopy, PET and ictal SPECT are not clinically useful except that they may help to localize seizure focus in patients referred for epilepsy surgery.

Hippocampal sclerosis 32 yo man who had right

otitis at age 5 months complicated by seizure and brief left-sided hemiplegia. A few seizures from age 4 to 10 years. In his 20’s, he had 1 partial seizure per month. Since age 29, he has at least 1 partial seizure per week, at times, 2-3 per day, on CBZ and LTG.

Periventricular nodular heterotopias

25-year-old man first seen in ER in July 2009 for episode of LOC while riding in subway. No prior history of aura or seizures. No family history of seizures. He has a university degree. Normal neurological exam. EEG shows spikes arising from left temporal lobe. He was started on Tegretol CR 300 mg bid.

Cavernous hemangiomas 38 yo man. At age 10, he

had a GTC seizure and on CT of the brain, he had a left frontocentral hematoma that was evacuated. At age 13, another GTC seizure and another bleed. Since then, daily twitchings of the right cheek, lips, anterior neck, fingers despite trials with Tegretol, Dilantin, Sabril, Topamax, Frisium.

Double cortex 29 yo woman with PMH of

GTC seizures since age 19 years, tried on Dilantin and Tegretol. She reports 2-3 GTC seizures/week and staring and shaking of the limbs for 1-2 min. followed by drowsiness lasting hours, occurring once per month. MRI of brain reported as normal. EEG telemetry: right frontal, right and left anterior temporal foci, and NES. Callosotomy in 12/2004.

TreatmentMonotherapy

Adequate control 70%

Insufficient control30%

Polytherapy with 2 or more AEDs

Satisfactory control15%

Insufficient control15%

Experimentalanticonvulsants

Refractory to all10%

Epilepsy surgery in 5%

Treatment objectives Seizure freedom Monotherapy No adverse events with AEDs Social and professional adjustment

Should one treat first seizure?

No antiepileptic medication after a first unprovoked seizure if: the patient is otherwise healthy, EEG is normal or shows mild non specific and non

localized abnormalities, the patient has no past history of CNS injury.

Should one treat first seizure? Treatment of the underlying condition in presence of an

acute symptomatic seizure (systemic infection, toxic-metabolic condition)

Antiepileptic medication recommended if recurrent unprovoked seizure or isolated seizure associated with an acute cerebral injury (encephalitis, cerebral infarct, etc.)

Should one treat first seizure? After a single tonic-clonic seizure, recurrence rates in

children and adults vary from 27 to 52% depending on several risk factors. Majority of recurrences occur early, with 50% occurring within 6 months of the initial event and over 80% within 2 years.

Factors associated with increased recurrence risk: etiology of seizure (remote symptomatic), abnormal EEG, and first seizure occurring during sleep.

After 2 tonic-clonic seizures, the risk of a third seizure is over 70%.

O’Dell, C. and S. Shinnar. Neurology Clinics, 19(2): 289-311, 2001

Choice of antiepileptic drug Type of epilepsy Age of the patient Clinical efficacy Tolerability Drug interaction profile Clinician’s familiarity with AED

Choice of antiepileptic drug Monotherapy is the best pharmacotherapeutic option.

If monotherapy is poorly tolerated or ineffective, the strategy is to switch to another drug. If the first AED has partial efficacy and is well tolerated, it is worth trying another AED in combination.

Several patients are managed with 2 drugs or more and a rational approach is to combine AEDs with different mechanisms of action.

Significant adverse events associated with AED are responsible for initial treatment failure in 20-40% of patients.

Choice of antiepileptic drug

In partial epilepsy, with or without secondarily generalized seizures, carbamazepine and phenytoin are still considered to be first-line AED although one can also use valproic acid and phenobarbital as first-line AED.

Newer AEDs clobazam, lamotrigine, topiramate, gabapentin, vigabatrin, levetiracetam, oxcarbazepine are mostly used as add-on medication but may be considered as first-line agents in some patients.

Antiepileptic medications In partial seizures, all new AED have demonstrated

their efficacy as add-on treatment in patients with resistant epilepsy using a 50% seizure reduction as gold standard. Lamotrigine and gabapentin are less effective but better tolerated than vigabatrin, topiramate or tiagabine.

Monotherapy studies comparing efficacy and tolerability of new AEDs with carbamazepine as standard reference drug for treatment of partial seizures demonstrate oxcarbazepine, lamotrigine, vigabatrin and probably gabapentin have similar efficacy and are better tolerated than carbamazepine.

Antiepileptic medications New AEDs are devoid of significant liver enzyme

inducing or inhibiting properties (vigabatrin, lamotrigine, gabapentin and tiagabine).

All new AEDs have been shown to be effective as adjunctive agents in placebo-controlled trials in patients with refractory partial epilepsy with or without secondary generalization.

In monotherapy studies, comparison between new and established drugs have demonstrated equivalence for lamotrigine, gabapentin, topiramate, oxcarbazepine and levetiracetam with carbamazepine and valproate.

Hiritis N, Brodie MJ. Curr Opin Neurol 19:175-180, 2006

AEDs in treating different seizure types

Partial seizures (including secondarily generalized)

Carbamazepine, phenytoin, phenobarbital, primidone, valproic acid, oxcarbazepine, gabapentin, lamotrigine, topiramate, clobazam, levetiracetam, tiagabine, zonisamide

Broad spectrum (all seizure types, including partial, absence, myoclonic, tonic, clonic, secondarily generalized)

Valproic acid, lamotrigine, topiramate, levetiracetam, clonazepam, zonisamide

Absence only Ethosuximide

Infantile spasms Valproic acid, vigabatrin, zonisamide

Cochrane review of add-on AEDDrug Odds ratio for responder rate Odds ratio for discontinuation

Vigabatrin 3.67 (2.44-5.51) 2.58 (1.26-5.27)

Gabapentin 1.93 (1.37-2.71) 1.05 (0.68-1.61)

Oxcarbazepine 2.96 (2.20-4.00) 2.17 (1.59-2.97)

Lamotrigine 2.71 (1.87-3.91) 1.12 (0.78-1.61)

Levetiracetam 3.81 (2.78-5.22) 1.25 (0.87-1.80)

Topiramate 3.32 (2.52-4.39) 2.06 (1.38-3.08)

Tiagabine 3.16 (1.97-5.07) 1.81 (1.25-2.62)

Zonisamide 2.44 (1.81-3.30) 1.64 (1.20-2.26)

Hiritis N, Brodie MJ. Curr Opin Neurol 19:175-180, 2006

Choice of antiepileptic drug In primary generalized epilepsy, valproic acid is the

most effective AED. Other useful medications include lamotrigine, topiramate, clobazam, and levetiracetam.

In idiopathic generalized seizures, lamotrigine and topiramate are effective.

Lamotrigine may aggravate severe myoclonic epilepsy

Topiramate exhibits efficacy in the treatment of drop attacks and generalized seizures in Lennox-Gastaut syndrome

Topiramate is not effective against absence seizures.

Special issues in epilepsy In the elderly, AED with simple pharmacokinetic

properties and without drug-drug interaction may be preferred (gabapentin). Also AED administered once a day and with short dose escalation might be preferable. A recent study by Brodie et al. showed lamotrigine is as effective and better tolerated than carbamazepine in the elderly.

Rate of failure of oral contraceptive is high in women taking enzyme-inducing AEDs. Vigabatrin, lamotrigine, gabapentin and tiagabine do not reduce the effect of OC while topiramate and oxcarbazepine alter metabolism of sex hormones.

Antiepileptic MedicationCarbamazepineCarbamazepine aplastic anemia, hepatotoxicity,

sedation, skin rash

PhenytoinPhenytoin gum hypertrophy, sedation, skin rash,

hypertrichosis

Valproic acidValproic acid hepatoxicity, weight gain, intentional tremor, endocrine

dysfunction

PhenobarbitalPhenobarbital sedation, cognitive and behavioural impairment, skin rash

MysolineMysoline similar to phenobarbital

Antiepileptic MedicationEthosuximideEthosuximide gastric irritation

ClobazamClobazam sedation, tachyphylaxis

LamotrigineLamotrigine skin rash, Stevens-Johnson syndrome, sedation

TopiramateTopiramate sedation, cognitive impairment, weight loss, open-angle glaucoma,

nephrolithiasis

GabapentinGabapentin mild cognitive impairment, weight gain

VigabatrinVigabatrin occasional psychiatric symptoms, visual field constriction, cognitive

impairment

Antiepileptic MedicationLevetiracetamLevetiracetam sedation, agitation and

anxiety in children

OxcarbazepineOxcarbazepine sedation, dizziness, SIADH in older patients

ZonisamideZonisamide sedation, dizziness, psychosis, depression, kidney stones

(sulfa)

Common drug-drug interactionsAED OCA Other drugs Enzyme induction

Carbamazepine (+) in estradiol

Antivirals, erthromycin CBZ level

CBZ concentration of verapamil, cyclosporine, MTX, steroids, warfarin

(+) p450 isoenzymes

Phenytoin (+) in estradiol

Amiodarone, diltiazem, INH, omeprazole,

fluconazole increase [PHT]. Antiviral [PHT]

(+) p450 isoenzymes

Phenobarbital (+) in estradiol

PB lowers [ ] of cyclosporin, steroids,

anti-fungals, verapamil, warfarin

(+) p450 isoenzymes

Valproic acid

(+/-) in estradiol

VPA levels by cimetidine, and level by

MTX, rifampin

VPA inhibits UGT, inhibits clearance of LTG,

VPA is protein bound, displaces PHT,CBZ

Ethosuximide (-)

INH increases ETX level,

Rifampin increases clearance of ETX

(-)

Common drug-drug interactions

AED OCA Other drugs Enzyme induction

Gabapentin (-) (-) (-)

Lamotrigine OCA [LTG] (-)(+/-) with modest

induction of glucuronidation

Levetiracetam (-) (-) (-)

Topiramate(+) dose-dependent in

estradiol(-) on warfarin. Modest

in lithium and digoxin (+/-) may reduce [PHT]

Oxcarbazepine (+) in estradiol OXC by verapamil(+/-) may reduce LTG and increase PHT and

Pb

Zonisamide (-) (-) (-)

Pharmacokinetics: new AEDs

AEDProtein binding

Elimination T 1/2 (h)

Site of elimination

Gabapentin 0% 4-6 100% renal

Lamotrigine 55% 15-30 90% hepatic

Topiramate 9-17% 15-23 40-70% renal

Levetiracetam 0 6-8 66% renal

Oxcarbazepine 40% 4-9 70% hepatic

Zonisamide 40-60% 24-60 70% hepatic

Treatment Outcome During first year of treatment, 43 to 48% patients

reported no recurrent seizure depending of the AED used (no statistical difference between carbamazepine, phenytoin, valproic acid, phenobarbital). Treatment success was higher with carbamazepine and phenytoin.

In a more recent study, Mattson et al. found valproic acid to be slightly less effective than carbamazepine.

Mattson RH et al. NEJM 313 : 145-151, 1985

Mattson RH et al. NEJM 327 : 765-771, 1992

Treatment Outcome

Mattson et al. showed that monotherapy with carbamazepine, phenytoin, valproic acid or phenobarbital can control partial seizures up to 70% of adult epileptics and in another 15 to 20% of patients, seizures can be controlled by a combination of AEDs.

Seizure control remains problematic in 15% of patients.

Mattson RH et al. NEJM 313 : 145-151, 1985

Focal epilepsy and response to AED Series of 550 adults and adolescents followed

prospectively since 1994, of whom 70% were newly diagnosed. All had MRI of the brain. Structural abnormality identified in 66% (symptomatic epilepsy).

57% were seizure-free for more than 1 year. 35% continued to have seizures despite appropriate AED therapy,

Patients with hippocampal sclerosis less likely to be controlled (42%) and more likely to receive more than 1 AED. Of the seizure-free patients, 66% received only 1 AED

Stephen LJ et al. Epilepsia 42 (3):357, 2001

Epilepsy and pregnancy

Major malformations: occur in 2-3% of general population and in 4-7% of offspring of epileptic women

Major malformations (MM) include congenital heart defects, cleft lip/palate, urogenital defects and neural tube defects (NTD). NTDs are more commonly associated with VPA. The risk of major malformations is higher in women on AED polytherapy (15-25%) as compared to AED monotherapy (5-8%).

Cardiac malformations are more frequent with PB, VPA and CBZ, hypospadias with VPA, oral cleft with PB, PHT

Epilepsy and pregnancy

Rate of major malformations in children exposed to CBZ monotherapy is 6.7%, LTG is 2.8-3.1%, and VPA is 8.9%. Risks with newer AEDs are unknown but probably low with LEV, GBP, OXC

Exposure to VPA monotherapy compared to CBZ has an OR of 2.5 major malformations.

Women with AEDs during pregnancy should undergo prenatal screening to detect any fetal MM. NTDs should be screened for by maternal serum α-fetoprotein and ultrasound at 16 to 20 weeks.

Epilepsy and pregnancy Cognitive outcome in children born to epileptic

mothers have an increased risk of mental deficiency affecting 1.4 to 6% of children as compared to 1% of control subjects. IQ level correlated negatively with in utero exposure to PRM, PB, PHT, CBZ, VPA and polytherapy.

Microcephaly reported with exposure to PB, PRM and polytherapy.

Rates of fetal death (later than 20 weeks’ gestational age) is about 1.3-14% in epileptic mothers as compared to 1.2-7.8% in women without epilepsy.

Epilepsy and pregnancy In order to reduce risks of MMs, women who have

epilepsy and have childbearing potential should take at least 4 mg of folate per day (usual dose: 5 mg/d)

Epilepsy and pregnancy Effect of pregnancy on seizure frequency is variable but 50-83%

of pregnant women with epilepsy report no change in seizure frequency, 20-30% have an increase in seizure frequency, and 7-25% a decrease.

Factors playing a role in seizure frequency during pregnancy: sleep deprivation, noncompliance, marital and financial stress.

Clearance of almost all AEDs increases during pregnancy resulting in reduced drug levels. LTG clearance is markedly increased and quickly returns to baseline after parturition. Optimal approach to monitoring AED levels during pregnancy is to measure free AED level.

Epilepsy and pregnancy Because of risk of bleeding at the time of giving birth, it is

recommended to give vitamin K 10 mg/ orally during last month of pregnancy and 1 mg IV or IM at birth.

In women with epilepsy, only 1-2% will have GTC seizures during labour and an additional 1-2% during the first 24 hours after delivery, particularly in women with IGE

Most infants of women with epilepsy can breastfeed without complications. Concentrations of the different AEDs in breast milk are considerably less than in maternal serum.

If one is to stop AED before pregnancy, it should be done at least 6 months before planned conception. If a woman is on VPA, one could consider a change of AED in the months prior to planned conception.

Identification of refractory seizure Series of 525 consecutive non selected patients

(children and adults) seen between 1984-1997, of whom 89% had never been treated. All of the had MRI of the brain.

Seizure freedom lower in group previously treated with AED (56%) as compared to never treated (64%).

In the series, 27% had idiopathic seizures, 29% symptomatic, 45% cryptogenic.

81% treated with single AED, 2/3 receiving an established AED and 1/3 a newer AED. No difference in terms of seizure freedom between the 2 groups.

Kwan P, Brodie, NEJM 342: 314-9, 2000

Identification of refractory epilepsy

30% of patients with epilepsy have inadequate seizure control with drug therapy

Prevalence of persistent seizures higher in symptomatic or cryptogenic epilepsy and in patients with more than 20 seizures before starting treatment

Seizure-free rate is about 67% in those treated with a single established drug as compared to a new drug (69%). Among those previously untreated, 47% became seizure-free with first AED and 14% with second AED.

Kwan P, Brodie, NEJM 342: 314-9, 2000

Refractory seizures Prevalence of persistent seizures is higher (40%) in

patients with symptomatic or cryptogenic epilepsy as compared to idiopathic epilepsy (26%).

In localization-related epilepsy, seizure freedom at 1 year was lower in MTS (42%) as compared to cortical dysplasia (54%), cerebral atrophy (55%), cortical gliosis (57%), primary tumour (63%), cerebral infarction (67%), AVM (78%).

Stephen L. Epilepsia 42: 357-362, 2001

Refractory epilepsy Definition: failure of 2 to 3 AEDs to control seizures

or lack of seizure control within a defined time period after diagnosis, e.g., 1-2 years

Limitations: 2 AEDs may fail because of inappropriate drug selection (misclassified seizures or epilepsy types), insufficient amount of AED or administered inappropriately, drug interactions, noncompliance, genetic factors (MDR1 gene), etc. At times, a patient with refractory epilepsy may respond to a new specific AED.

Kwan P. et al. NEJM 342: 314-9, 2000

Markers of refractory epilepsy

Early onset of seizures (< 2 years) Type of epilepsy (partial epilepsies, catastrophic

epilepsies of childhood) Difficulty to rapidly control seizures Failure of the first antiepileptic medication Brain abnormality on MRI (hippocampal sclerosis,

malformation of cortical development) Poor compliance to antiepileptic medication

Arroyo S. et al. Epilepsia 43(4): 437-444, 2002

Temporal lobe surgery After temporal lobe resection for seizures, approx.

2/3 of patients became seizure-free except for patients with simple partial seizures.

10-15% of patients not improved by surgery. 50% of patients who underwent localized neocortical

resection for TLE became free of disabling seizures and 15% remained unimproved.

QOL scores improve after temporal lobectomy as early as 1 year after surgery

Engel, J et al. Neurology 60: 538-547, 2003

Temporal lobe surgery Surgical complications seen in about 11% of patients,

of whom 3% are left with permanent neurological deficit.

Postoperative cognitive and behavioral disturbances reported in 6% of patients, permanent in 3%.

Mortality in randomized clinical trials of AEDs as high as 0.78% per year, as compared to 0.4% for surgical and immediate postoperative (less than 1 month) risk.

Engel, J et al. Neurology 60: 538-547, 2003

AED withdrawal Discontinuing AEDs in patients who are seizure free

for 2 or more years is feasible: 60 to 75% of children and adults with epilepsy will remain seizure-free. Risk of relapse of 25% at 1 year and 29% at 2 years.

Seizure recurrence risk is greater in: remote symptomatic epilepsy, age at onset of seizures (higher if onset under 2 years and during teens), abnormal EEG, epilepsy syndromes such as JME, Lennox-Gastaut, longer duration of epilepsy, number of seizures, etiology (higher with symptomatic), longer duration of epilepsy and number of seizures.

Discontinuing AEDs 60 to 75% of children and adults with epilepsy, who

have been seizure free for more that 2 or 4 years on AED, remain seizure free when AED are withdrawn.

Factors of good prognosis: etiology (better with cryptogenic and idiopathic), age of onset between 2 and 10 years of age, normal EEG (better predictor of outcome in children), epilepsy syndrome (LGS, JME), duration of epilepsy and number of seizures

O’Dell C, Shinnar S. Neurology Clinics 19(2): 289-311, 2001

Status Epilepticus: Definition

Operational definition: 5 minutes of continuous convulsive motor activity, or repetitive seizure activity without full recovery of consciousness between seizures.

Rationale for the definition: (1) uncertainty regarding relationship between the duration of seizures and neuronal damage, (2) most GCSE do not last more than 5 minutes and (3) patients with seizures lasting more than 5 minutes should be treated acutely with AEDs.

Treiman DM et al. NEJM 339: 792-8, 1998Lowenstein, DH Epilepsia 41(Suppl 1): S3-8, 1999

Status Epilepticus: Features Reported incidence of 10 to 15% in adult epileptic

patients and up to 10-12% in epileptic children. First manifestation of a seizure disorder in 12 to 30%

of adult patients with seizures (Hauser, 1990). More common in children, mentally handicapped and

in the elderly with structural cerebral pathology. 22-26% of patients with SE have a preexisting

epilepsy

Hauser WA. Neurology 40(Suppl.2): 9-12, 1990

SE: Classification Convulsive SE: generalized tonic, clonic, myoclonic,

tonic-clonic, partial motor Non-convulsive SE (NCSE) in ambulatory patients:

partial complex and absence SE represents about 4-20% of SE.

Patients with NCSE have (1) prolonged (>30 minutes) change in conscious or behavioural function or recurrent complex partial seizures or continuous “epileptic twilight state”, (2) ictal EEG with generalized or recurrent focal epileptic activity, and (3) a prompt effect of IV diazepam on EEG and clinical manifestations.

Drislane FW J Clin Neurophys 16(4): 323-331, 1999

Causes of SE

Cerebrovascular disease 20% Known epilepsy and withdrawal of AEDs20% CNS infections 19% Toxic-metabolic 19% Hypoxic-ischemic encephalopathy 12% Traumatic brain injury 5% Tumour 4%

SE: Clinical Presentation At first, SE may be characterized by generalized tonic

clonic movements. Convulsive motor activity is at first continuous, then

clonic movements become less pronounced and severe and may eventually stop.

At the time of subtle SE or NCSE, patients are deeply comatose, EEG reveals ictal activity and prognosis is usually poor.

EEG Monitoring EEG monitoring (continuous or intermittent)

underused in diagnosis and management of SE Useful in patients with prolonged and severe post-

ictal unresponsiveness after treatment of SE, with atypical features suggesting the possibility of pseudoseizures, and in refractory SE. In the VA study, 20% of the initially randomized patients had nonepileptic seizures.

Of 236 comatose patients who had EEG and no overt signs of seizure activity, prevalence of NCSE was about 8%.

Treiman DM and al. NEJM 339: 792-8, 1999Towne et al. Neurology 54: 340-5, 2000

Medications: Early SE

Benzodiazepines as a first-line AED to stop SE: Diazepam 10 mg bolus, given IV (rate: 2-5 mg/min) or

rectally (Diastat), repeated once 15 min later if SE continues. Onset of action within 1-3 min and duration of action of 20 min.

Lorazepam IV 0.1 mg/kg (4 mg bolus), repeated once 10 min later if SE persists. Onset of action within 2-3 min and duration of action of 4-14 h.

Midazolam IV bolus of 0.1-0.2 mg/kg (10 mg). Onset of action within 1-5 min and duration of action of 1-5 h.

Lowenstein DH. NEJM 338: 970-976, 1998Roth HL. Neurologic Clinics 16(2): 257-284, 1998

Medications: Early SE

Benzodiazepines as a first-line AED to stop SE: 4 mg of IV lorazepam and 10 mg of IV diazepam stop SE in

89% and 76% of cases respectively in double-blind randomized study of 81 patients (Leppik, 1983). Times for onset of action did not differ significantly. Adverse effects in about 13% of patients. No significant difference between the 2 drugs in terms of efficacy but lorazepam has a longer duration of action.

Midazolam may work in SE refractory to IV diazepam, lorazepam or phenytoin (Kumar et al.)

Leppik IE. JAMA 249(11) 1452-4, 1983Kumar A. Crit Care Med 20: 483-8, 1992

Medications: Early SEBenzodiazepines as a first-line AED to stop SE:

According to San Francisco out-of-hospital study, response rates (cessation of seizures upon arrival to ER) were 21% for placebo, 43% for diazepam (5 mg) and 59% for lorazepam (2 mg).

According to VA study, no difference with respect to seizure termination (within 20 minutes) and recurrence between lorazepam alone (0.1 mg/kg), diazepam (0.15 mg/kg) plus phenytoin (18 mg/kg), phenobarbital (15 mg/kg), or phenytoin alone.

Alldredge BK et al. NEJM 345: 631-7, 2001Treiman DM et al. NEJM 339: 792-8, 1998

Status Epilepticus: Outcome Mortality rate in tonic clonic SE is stable at around 15-20%,

most patients dying from the underlying condition rather than SE itself.

Morbidity is greatly increased the longer the duration of SE, and patients whose seizures last longer than 1 hour have a higher mortality (55%).

Mortality rate of 60-70% in anoxic encephalopathy Adults have a significantly higher mortality rate (25% as

compared to 2.3% in children), particularly the elderly population.

Fountain NB. J Clin Neurophys 41(Suppl 1): S23-30, 2000

Status Epilepticus: Outcome Patients with a previous history of seizures have a mortality rate

of 16%, while patients without history of seizures have a mortality of 54%, reflecting the higher proportion of lethal acute cerebral insults causing SE.

Permanent neurological and mental deterioration may result from SE, particularly in children.

SE lasting more than 30-45 minutes can cause cerebral injury, especially in the limbic structures.

Patients with SE are at greater risk for future episodes and chronic epilepsy.

Yaffe K et al. Neurology 43: 895-900, 1993

Status Epilepticus: Sequelae Reasons for morbidity in convulsive SE are adverse systemic

metabolic effects of SE, brain injury caused by acute brain insult that induced SE, and direct neuronal damage from abnormal electrical activity of SE

Sequelae in convulsive SE include: death in 10-35%, cognitive deficit in 10-35%, chronic epilepsy in 30% and recurrent SE in 10-25% of children

Predictors of disability: acute symptomatic seizures and length of hospitalization, EEG findings of NCSE, ictal discharges and periodic discharges

Kaplan PW J Clin Neurophys 16(4): 341-352, 1999

Status Epilepticus: Sequelae Sequelae in NCSE such as absence SE: none Sequelae in complex partial SE: variable with memory deficits.

Usually related to vascular or other neurological insults. Morbidity attributable to underlying illnesses rather than NCSE,

for instance in anoxic-hypoxic encephalopathy

Drislane, FW J Clin Neurophys 16(4): 323-331, 1999

Refractory Status Epilepticus Definition: SE lasting more than 60 minutes despite adequate

doses or documented therapeutic levels of ≥ 2 antiepileptic medications

RSE occurs in 9 to 31% of SE Associated with increased hospital length of stay and functional

impairment at discharge High mortality rate of 40 to 77% (average: 50%) associated with

older age, etiology (anoxic), long seizure duration, high Apache scale score

Claassen J et al. Neurology 58(1):139-142, 2002

Refractory SE: treatmentLorazepam 4 mg IV

Phenytoin (fosphenytoin) 20 mg/kg IV

Midazolam or PropofolBolus 10 mg Bolus 2 mg/kg

Infusion 0.05-0.4 mg/kg/hr Infusion 1-5 mg/kg/hr

PentobarbitalBolus 5 mg/kg

Infusion 0.5-5 mg/kg/hr

LidocaineBolus 1-2 mg/kg

Infusion 3-4 mg/kg/hr

KetamineBolus 2 mg/kg

Infusion 10-50 mg/kg/min

Isoflurane 1-2%

Lawn ND, Wijdicks EFM, CJNS 29: 206-215, 2002

Refractory SE: Treatment

General anesthesia with either propofol, bolus of 1-2 mg/kg followed by drip of 1-5 mg/kg/hour sufficient to cause burst suppression on the cEEG, or IV midazolam bolus followed by drip, or

Bolus of pentobarbital of 12 mg/kg, followed by intravenous drip of 1-2 mg/kg/hour.

Anesthetics continued for 12-24 hours after the last clinical or electrographic seizure, then dosage slowly tapered particularly with propofol.

Lowenstein DH. NEJM 338: 970-976, 1998