Transcript Facteurs de mauvais pronostic

Epilepsy
Martin Veilleux, MD
Montreal Neurological Institute
McGill University
Definition
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Seizure: event characterized by a paroxysmal
cerebral neuronal discharge associated with clinical
and behavioral manifestations
Epilepsy: condition characterized by recurring
seizures
Non epileptic seizure: clinical and behavioral
manifestations that are not secondary to an epileptic
discharge
Incidence
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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
Incidence per 100,000
180
160
140
120
100
Epilepsies
80
60
40
20
0
0
3
10
20
30
40
50
60
70
80
Age (years)
Annegers JF. Dans: Treatment of Epilepsy: Principle and Practice, 2nd Ed. Baltimore, MD, Williams &
Wilkins, 1997: 165-172
Terminology
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Idiopathic epilepsies: genetically determined, no
apparent structural cause, and seizures as the only
manifestation of the condition
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
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Partial seizures
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Simple partial seizures (consciousness not impaired)
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Complex partial seizures (impairment of consciousness)
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With motor symptoms
With somatosensory or special sensory symptoms
With autonomic symptoms
With psychic symptoms
Beginning as simple partial seizure and progressing to CPS
With impairment of consciousness at onset
Partial seizures evolving to secondarily generalized seizures
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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
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Generalized seizures
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Absence seizures
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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)
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Idiopathic
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Benign childhood epilepsy with centrotemporal spikes
Childhood epilepsy with occipital paroxysms
Primary reading epilepsy
Cryptogenic (defined by seizure type, features)
Symptomatic
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Mesial TLE with hippocampal sclerosis
Autosomal dominant TLE with auditory features
Autosomal dominant NFLE
Symptomatic focal epilepsies not otherwise specified
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TLE, FLE, PLE, OLE
Chronic progressive epilepsia partialis continua of childhood
International classification of epilepsies
Generalized
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Idiopathic
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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)
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West syndrome (infantile spasms)
Lennox-Gastaut syndrome
Epilepsy with myoclonic-astatic seizures
Epilepsy with myoclonic absences
International classification of epilepsies
Generalized
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Symptomatic
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Nonspecific etiology
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Early myoclonic encephalopathy
Early infantile encephalopathy with suppression bursts
Other symptomatic generalized epilepsies (progressive myoclonic
epilepsies)
Specific syndromes
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Epileptic seizures may complicate many disease states
Undetermined epilepsies
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With both generalized and focal seizures
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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
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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)
Benign familial
neonatal seizures
ADN frontal lobe
epilepsy
SCN1A (2q24)
SCN2A (2q24)
SCN1B (19q13)
GABRG2 (5q31)
Generalized
epilepsy with febrile
seizures plus
Offspring Risk of Epilepsy by Age 20:
Factors increasing risk
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Parent gender: maternal effect
Mother with epilepsy: 2.8-8.7%; father with epilepsy: 1-3.6%
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Parent’s age at onset of epilepsy
Under 20 years: 2.3-6%: Over 20 years: 1-2.8%
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Number of affected relatives
Risk increases with more relatives affected
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EEG abnormalities
Risk increases with GSW in parent or relative (6x risk for sibs)
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Parent’s seizure type
Localization-related epilepsy
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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
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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
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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
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Mesial temporal
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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
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Aura often auditory, complex perceptual, language
Late oroalimentary automatisms
Late manifestation indistinguishable from mesial temporal
Temporal lobe epilepsy
Frontal lobe epilepsy
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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
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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
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Somatosensory auras
Receptive language disturbance (dominant hemisphere)
Neglect (nondominant hemisphere)
Variable spread to:
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Occipital lobe (visual hallucinations)
Precentral regions (motor)
Mesial temporal regions
Occipital lobe seizures
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Elementary visual hallucinations
Loss of vision
Contralateral or ipsilateral deviation of the eyes
Forced blinking
Variable spread to:
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Parietal lobe (sensory symptoms)
Temporo-occipital regions (formed visual hallucinations)
Mesial temporal regions
Diagnosis
Loss of consciousness
Seizure
Syncopal event
Acute condition
Yes
Acute symptomatic
Febrile seizures
No
Unprovoked
Only one
Seizure
Many
Epilepsy
Assessment
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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
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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
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Cerebrovascular diseases
Idiopathic
Brain tumours
Head injury
Toxic-metabolic
Migrational neuronal defect
Others
Annegers, JF Neurology Clinics 12: 15-29, 1994
30-40%
30%
20%
5%
5-10%
5%
1%
Electroencephalography
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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
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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 sleepdeprived 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
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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
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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
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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
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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
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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
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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
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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.
Treatment
Monotherapy
Adequate control
70%
Insufficient control
30%
Polytherapy with
2 or more AEDs
Satisfactory control
15%
Experimental
anticonvulsants
Insufficient control
15%
Refractory to all
10%
Epilepsy
surgery in 5%
Treatment objectives
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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:
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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?
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Treatment of the underlying condition in presence of an
acute symptomatic seizure (systemic infection, toxicmetabolic 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?
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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
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Type of epilepsy
Age of the patient
Clinical efficacy
Tolerability
Drug interaction profile
Clinician’s familiarity with AED
Choice of antiepileptic drug
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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
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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 firstline 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
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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
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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 AED
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)
Drug
Hiritis N, Brodie MJ. Curr Opin Neurol 19:175-180, 2006
Choice of antiepileptic drug
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In primary generalized epilepsy, valproic acid is the
most effective AED. Other useful medications include
lamotrigine, topiramate, clobazam, and levetiracetam.
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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.
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Special issues in epilepsy
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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 Medication
Carbamazepine
Phenytoin
Valproic acid
Phenobarbital
Mysoline
aplastic anemia, hepatotoxicity,
sedation, skin rash
gum hypertrophy, sedation, skin rash,
hypertrichosis
hepatoxicity, weight gain,
intentional tremor, endocrine
dysfunction
sedation, cognitive and behavioural
impairment, skin rash
similar to phenobarbital
Antiepileptic Medication
Ethosuximide
gastric irritation
Clobazam
sedation, tachyphylaxis
Lamotrigine
skin rash, Stevens-Johnson syndrome,
sedation
Topiramate
sedation, cognitive impairment, weight
loss, open-angle glaucoma, nephrolithiasis
Gabapentin
mild cognitive impairment, weight gain
Vigabatrin
occasional psychiatric symptoms,
visual field constriction, cognitive
impairment
Antiepileptic Medication
Levetiracetam
Oxcarbazepine
Zonisamide
sedation, agitation and
anxiety in children
sedation, dizziness,
SIADH in older patients
sedation, dizziness, psychosis,
depression, kidney stones (sulfa)
Common drug-drug interactions
AED
Carbamazepine
Phenytoin
Phenobarbital
Valproic acid
Ethosuximide
OCA
Other drugs
Enzyme
induction
(+)  in estradiol
Antivirals, erthromycin 
CBZ level
CBZ  concentration of
verapamil, cyclosporine,
MTX, steroids, warfarin
(+) p450 isoenzymes
Amiodarone, diltiazem,
INH, omeprazole,
fluconazole increase
[PHT]. Antiviral  [PHT]
(+) p450 isoenzymes
(+)  in estradiol
PB lowers [ ] of
cyclosporin, steroids,
anti-fungals, verapamil,
warfarin
(+) p450 isoenzymes
(+/-)  in estradiol
VPA levels  by
cimetidine, and level  by
MTX, rifampin
(-)
INH increases ETX level,
Rifampin increases
clearance of ETX
(+)  in estradiol
VPA inhibits UGT, inhibits
clearance of LTG, VPA is
protein bound, displaces
PHT,CBZ
(-)
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
AED
Protein
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
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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
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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
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
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 αfetoprotein 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, 1998
Lowenstein, 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 420% 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
Known epilepsy and withdrawal of AEDs
CNS infections
Toxic-metabolic
Hypoxic-ischemic encephalopathy
Traumatic brain injury
Tumour
20%
20%
19%
19%
12%
5%
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 postictal 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, 1999
Towne 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, 1998
Roth 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, 1983
Kumar A. Crit Care Med 20: 483-8, 1992
Medications: Early SE
Benzodiazepines 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, 2001
Treiman 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 1025% 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: treatment
Lorazepam 4 mg IV
Phenytoin (fosphenytoin) 20 mg/kg IV
Midazolam
or
Bolus 10 mg
Infusion 0.05-0.4 mg/kg/hr
Propofol
Bolus 2 mg/kg
Infusion 1-5 mg/kg/hr
Pentobarbital
Bolus 5 mg/kg
Infusion 0.5-5 mg/kg/hr
Lidocaine
Ketamine
Bolus 1-2 mg/kg
Infusion 3-4 mg/kg/hr
Bolus 2 mg/kg
Infusion 10-50 mg/kg/min
Lawn ND, Wijdicks EFM, CJNS 29: 206-215, 2002
Isoflurane
1-2%
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