Transcript Levetiracetam in the Treatment of Epilepsy

A 29-year-old woman came for evaluation.
• The previous evening, her husband, who was in the next
room, heard unusual sounds and found her lying on the
bed looking dazed. She was confused for a few minutes but
quickly returned to normal.
• On questioning, she recalls an unwitnessed event about 1
month previously; at that time, she awoke feeling mildly
confused, had sore muscles, and discovered she had bitten
her tongue.
• How should she be evaluated and treated?
NEJM 2008;359:166
What is epilepsy?
What is epilepsy?
– Epilepsy is a disorder in which the person two or
more epileptic seizures.
Classification of Epileptic Seizures
Classification of seizures (International League
Against Epilepsy ILAE)
Partial seizures
57%
Generalized seizures
40%
3%
Unclassified seizures
Classification of epileptic seizures (ILAE)
I. Partial seizures
II. Generalised
A. simple partial
B. complex partial
C. partial seizures evolving
to generalised seizures
(sometimes called
secondarily generalised
seizures)
A. absence
B. myoclonic
C. clonic
D. tonic
E. tonic-clonic
F. atonic
III. Unclassified Epileptic Seizures
• Includes all those seizures that cannot be classified
because of incomplete data or because they defy
classification into the above categories
Simple partial seizures
Somatosensory.
Tingling of
contralateral
limb,
face, or side
of body
Central fissure
Postcentral
gyrus
Precentral
gyrus
Focal motor.
Tonic-clonic movements
of upper (or lower) limb.
LEG
TRUNK
ARM
ARM
FACE
Visual.
Sees flashes of light,
scotomas, unilateral
or bilateral blurring
Contraversive.
Head and eyes
turned to
opposite side
Auditory.
Hears ringing,
hissing or noises
Autonomic.
Sweating, flushing
or pallor, and/or
epigastric sensations
Complex partial seizures
Impairment of consciousness:
cognitive, affective symptoms
Formed auditory
hallucinations.
Hears music, etc
FRONTAL
LOBE
Dreamy state; blank, vacant
expression; déjà vu;
jamais vu; or fear
d
Ž
j
ˆ
PARIETAL
LOBE
POSTERIOR
TEMPORAL
GYRUS
OCCIPITAL
LOBE
Formed visual
hallucinations.
Sees house, trees
that are not there
Bad or unusual smell
Superior
temporal
gyrus
Dysphasia
Psychomotor phenomena.
Chewing movements, wetting lips,
automatisms (picking at clothes)
Absence seizure
Between seizures
patient normal
Seizure:
Vacant stare, eyes roll
upward, eyelids flutter
(3/sec), cessation
of activity, lack of
response
Tonic-clonic seizures
A. Tonic phase
Incontinence
B. Clonic phase
C. Post-ictal
confusional fatigue
Cyanosis
Epileptic cry
Cyanosis
Generalised stiffening
of body and limbs,
back arched
Eyes
blinking
Salivary
frothing
Clonic jerks of
limbs, body
and head
Limbs and body limp
Status epilepticus
• A condition characterized by an epileptic seizure that
is so frequently repeated or prolonged as to create a
fixed and lasting condition
• A medical emergency that requires prompt and
appropriate treatment
Some epilepsy triggers
In rare cases patients may have one specific trigger that brings
on a seizure, for example:
Flashing visual
stimuli
Looking at a particular
kind of pattern
Hearing a particular
piece of music
Reading
Epilepsy Syndromes: Examples
• Benign epilepsy of childhood with centrotemporal
spikes:
– Localization-related, idiopathic epilepsy
– Age of onset: 3-13 years
– Simple partial onset and generalizing to tonicclonic seizures
– No associated illnesses
– EEG findings are diagnostic.
– Aetiology is genetic.
– Prognosis is excellent.
Epilepsy Syndromes: Examples
• Juvenile myoclonic epilepsy
– Generalized, idiopathic with age-related onset
– Onset during teenage years
– Consists of myoclonic, absence and generalised
tonic-clonic seizures
– Specific gene locus in chromosome 6p21.2-p11
has been proposed
– Treatment is very specific: valproate
Epilepsy Syndromes: Examples
• Infantile spasms (West’s syndrome)
– Generalised, symptomatic and/or Idiopathic
– Ages of 4-12 months
– Characterized by a quick spasm that consists of
flexion at the neck, waist, arms and legs. May
occur a hundred times a day
– Impairment in psychomotor development
– 20% die before 5 years of age; of the survivors
75%-93% are mentally retarded; 25% of these will
develop Lennox-Gastaut syndrome
Epilepsy Syndromes: Examples
• Lennox-Gastaut Syndrome
– Generalized, idiopathic and/or symptomatic
– Devastating disorder in children (1-8 years) with
mixed types of seizures and progressive mental
retardation
– Seizures include tonic, tonic-clonic, atypical
absence, myoclonic and atonic seizures
– Cognitive deficit is present and may be associated
with behavioural problems
– Prognosis is poor and response to AED therapy
generally unsatisfactory
Incidence of seizure types
Generalised tonic-clonic 23.0%
Complex partial 36.0%
Other
generalised
8.0%
Absence 6.0%
Simple partial 14.0%
Myoclonic 3.0%
Unclassified 3.0%
Partial unknown 7.0%
Causes of epilepsy ?
Disruption of the balance between excitation and inhibition
Excess excitation
Lack of inhibition
epileptic seizures
epileptic seizures
Formation of epileptic seizures
Hughlings Jackson
An abnormal synchronous and sustained activity
(overexcitation) in a group of nerve cells
Epileptogenic focus
Interictal activity
Recruitment of surrounding, normal nerve cells
into a synchronous pattern of larger abnormal activity
Ictal activity
Epileptic seizure
Predisposing factors
 Disturbed levels of body water/electrolytes:
– ‘water intoxication’/hyponatraemia
– dehydration/hypernatraemia
– hypocalcaemia
– hypomagnesia
 Disturbed levels of blood glucose:
– hypoglycaemia
 Altered blood gases:
– reduction in oxygen supply to the brain, via e.g.
asphyxia, heart attack, head injury, stroke
 Raised body temperature:
– febrile convulsions
Predisposing factors
 Altered sleep patterns:
– sleep deprivation
 Hormonal disturbance:
– thyroid disturbance
– sex hormones
 Toxicity:
– accumulation of toxic waste due to renal failure
– congenital metabolic disorders e.g. phenylketonuria
– poisoning or drug overdose
Etiological categories of epilepsy
 Idiopathic – No identifiable cause, assumed to
have a probable genetic basis
 Cryptogenic – No cause is found, but there may
be an undiscovered physical cause which has yet
to be found
 Symptomatic – A cause for the condition can be
found (e.g. head injury, scarring due to infections
in the brain, stroke, brain tumor).
Aetiology of epilepsy
Degenerative brain
disorder 3.5%
Infection 2.5%
Neoplasm 4.1%
Idiopathic
and
cryptogenic
epilepsy
65.5%
Vascular
injury 10.9%
Trauma 5.5%
Congenital causes 8.0%
Symptomatic seizures in different age groups
100
90
80
70
60
50
40
30
20
10
0
Others
Degenerative
Cerebrovascular
Brain tumour
Trauma
Infection
Development
0–4
5–14
15–24
25–44
45–64
65+
Diagnosis of epilepsy
Diagnosis/evaluation of a seizure
• History taking
• Electroencephalography (EEG)
• Brain images (CT scan, MRI)
EEG morphologies
Normal
a)
K-complex
b)
Lambda complex
c)
Mu rhythm
d)
Spike
e)
f)
g)
Sharp waves
Repetitive spikeand-wave activity
Sleep spindle
h)
Vertex sharp wave
i)
Polyspike discharge
Specific EEG wave types
EEG activation techniques
•
•
•
•
•
•
Hyperventilation
Photic stimulation
EEG during sleep/awakening
EEG after sleep deprivation
Ambulatory EEG monitoring
Other sensory stimuli
Epidemiology
• Prevalence of epilepsy is approximately 6 to 8 per
1000 population in the United States.
• Affects about 45 million people worldwide.
Epidemiology: prognosis effect of treatment
110
Untreated
Treated
% seizure free
100
90
80
70
60
50
40
0
3
6
12
months after first seizure
18
24
Epidemiology: prognosis
Predictors of remission:
• young age at onset
• young age at diagnosis
• generalized seizures
• normal neurological examination
• idiopathic etiology
Epilepsy and quality of life
•
•
•
•
•
Burden of epileptic seizures
Chronic drug treatment
Pregnancy
Employment
Driving
Treatment
•
•
•
•
•
•
•
•
Treatment of underlying causes
Not to treat
Trigger avoidance
Drug therapy
Surgery
Vagus nerve stimulation
Ketogenic diet
Complementary therapies
Common surgical procedures
Procedure
Indication
Hemispherectomy
Children with severe unilateral
epilepsy syndromes such as
Rasmussen’s syndrome; such
epilepsies usually have some preexisting loss of motor function on
the contralateral side.
Subpial transection
Partial-onset seizures arising from
a region of cortex that is nonresectable.
Focal resection
1. Sub-dural grid used to localise the
site of seizure onset
2. Frontal lobectomy of non-dominant
hemisphere (red area indicates the
extent of resection)
Vagus nerve stimulation
VNS lead transmits
signals from the generator
to the vagus nerve
Generator is implanted
under the skin in the
upper left chest
Ketogenic diet
• A high fat/low carbohydrate diet
• Tried occasionally in children with severe
epilepsy syndromes such as Lennox-Gastaut
syndrome and generalised myoclonic
seizures. The aim is to achieve a state of
body chemistry called ‘ketosis and acidosis’.
Complementary therapies
• Relaxation
– Many complementary therapies involve relaxation.
Yoga, meditation or other relaxation therapy might
help some people to avoid seizures being brought
on by stress.
• Aromatherapy
– Aromatherapy massage can be very relaxing and
is liked by many people. Finding a qualified
therapist is important as some of the essential oils
used can be dangerous.
Complementary therapies
• Acupuncture
– Probably not effective in the control of seizures, but it can be
effective in reducing stress and anxiety. Again, a qualified
therapist would be recommended.
• Biofeedback
– Some people can learn a technique which may delay a
seizure or prevent them from happening
– People with partial seizures are able to learn and use it to
prevent the initial seizure from spreading to become
generalised. It is most appropriate for people with the kind if
partial seizures that start with ‘aura’-type symptoms
– E.g. Someone whose simple partial seizures take the form of
tingling in the arm may find that rubbing the arm can
sometimes stop the seizure developing into a tonic-clonic
type
Drug therapy
AED - History
1857 Bromides
1912 Phenobarbital
Ethosuximide
1937 Phenytoin
50ies Carbamazepine
1960 Benzodiazepine
70’s Valproate
1989 Zonisamide
Vigabatrin
1990 Lamotrigine
Oxcarbazepine
1991 Felbamate
1993 Gabapentin
1995 Topiramate
1996 Tiagabine
1999 Levetiracetam
Generations of AEDs
Standard
Phenytoin (PHT), Pfizer
(Dilantin)
Carbamazepine (CBZ), Novartis
(Tegretol)
Sodium valproate (VPA), Sanofi
Synthelabo (Depakine)
Ethosuximide (ESM), Pfizer
Barbiturates
Phenobarbital (PB)
Primidone (PRM)
New
Felbamate (FBM), Carter-Wallace
Vigabatrin (VGB), Aventis(Sabril)
Lamotrigine (LTG), GSK(Lamictal)
Gabapentin (GBP), Pfizer(Neurontin)
Topiramate (TPM), Janssen-Cilag(Topamax)
Tiagabine (TGB), Sanofi Synthelabo(Gabatril)
Oxcarbazepine (OCBZ), Novartis(Trileptal)
Benzodiazepines
Clonazepam (CZP)
Clobazam (CLB)
Zonisamide (ZNS), Athena
Standard AEDs: efficacy against common
seizure types and syndromes
Seizure type
Agent
Partial
2o generalised
Tonicclonic
Absence
Myoclonic
LennoxGastaut
Infantile
spasms
CBZ
+
+
+
–
–
0
0
VPA
+
+
+
+
+
+
+
PHT
+
+
+
–
–
0
0
ESM
0
0
0
+
0
0
0
PB
+
+
+
0
?+
?
?
PRM
+
+
+
0
?
?
?
CZP
+
+
+
?
+
?+
?+
CLB
+
+
+
?
+
+
?+
Key: + proven efficacy, ?+ probable efficacy, 0 ineffective, – worsens control
? effect unknown
New AEDs: efficacy against common seizure types
and syndromes
Seizure type
Agent
Partial
2o generalised
Tonicclonic
Absence
Myoclonic
LennoxGastaut
Infantile
spasms
LTG
+
+
+
+
+
+
?+
GBP
+
+
?+
0
?–
?
?
VGB
+
+
?+
–
–
?
+
OCBZ
+
+
+
–
–
0
0
TPM
+
+
+
?
+
+
?
TGB
+
+
?
?
?
?
?
FBM
+
+
?+
?+
?
+
?
Key: + proven efficacy, ?+ probable efficacy, 0 ineffective, – worsens control,
? effect unknown
Tolerability
–
–
–
–
–
Dose-related side effects
Idiosyncratic side effects
Chronic side effects
Drug interactions
Teratogenicity
Modes of action
– Decreased excitation – via blockade of sodium
channels, interaction with voltage-sensitive
calcium channels or blockade of glutamate
receptors.
– Increased inhibition – via an increase in the
concentration of GABA in the synaptic cleft.
Blocking presynaptic glutamate release
Treated
epileptic neurone
Untreated
epileptic neurone
Synaptic vesicle
(glutamate
neurotransmitter)
AED blocks
Na+ and
Ca2+ channels
Na+
+
Na
Na+
+
Na
2+
Ca
+
Na
Ca2+
Ca2+
2+
Ca
2+
Ca
2+
Ca
Presynaptic
neurone
+
Na
Presynaptic
neurone
Glutamate released in
response to Na+ and Ca2+
influx into the presynaptic
neurone
Stabilised
presynaptic
neurone
Modes of action
AEDs that inhibit sodium channels
AEDs that inhibit voltagedependent calcium channels
Standard
New
Standard
New
Phenytoin
Carbamazepine
Valproate
Phenobarbital
Lamotrigine
Oxcarbazepine
Topiramate
Zonisamide
Ethosuximide
Zonisamide
Blocking postsynaptic glutamate receptors
AED blocks
non-NMDA
receptor,
reducing
ion flow
Ca2+
Na+
Ca2+
Na+
Mg2+
K+
AED blocks NMDA receptor,
reducing ion flow
NMDA receptor
+
Na+ K
Non-NMDA receptor
Key
Postsynaptic neurone
Glutamate
Glycine
Modes of action
AEDs acting at NMDA receptors
AEDs acting at non-NMDA
(AMPA/kainate) receptors
Standard
New
Standard
New
–
Felbamate
Phenobarbital
Topiramate
GABA transmission and
its interaction with AEDs
Presynaptic neurone
Postsynaptic neurone
Chloride ion channel
GABAA receptors
1. In the resting presynaptic
neurone, GABA is
stored in vesicles.
2. The membrane of the postsynaptic
neurone has chloride ion channels,
which are normally closed.
There are GABAA receptors located
on the chloride channels.
GABA transmission and
its interaction with AEDs (continued)
Benzodiazepines and barbiturates
bind at GABAA receptors and so
potentiate GABA-mediated inhibition.
Topiramate enhances GABAA
receptor function.
Hyperpolarisation
3. Arrival of an electrical impulse
causes the vesicles to fuse with
the presynaptic membrane and
so release GABA into the
synaptic cleft.
4. Binding of GABA and GABAA
receptors causes the chloride
channels to open; this enables
an influx of Cl- into the postsynaptic
neurone. This influx of negatively
charged ions hyperpolarises the
postsynaptic membrane, in this
way making ‘firing’ of the
postsynaptic neurone even more
difficult than usual.
GABA transmission and
its interaction with AEDs (continued)
Subsequently, GABA is
removed form the synaptic
cleft by reuptake via
special sites in the presynaptic
neurone and glial cells.
Following reuptake, it is
broken down by the enzyme
GABA-transaminase (GABA-T)
and converted to succinate.
Tiagabine inhibits the reuptake of GABA
Vigabatrin increases brain levels of GABA by
irreversibly inhibiting GABA-transaminase
Modes of action
AEDs that influence GABA transmission
Standard
New
Valproate
Barbiturates
Benzodiazepines
Topiramate
Tiagabine
Vigabatrin