Anti-seizure medications

By Dawit S.(R3)

Aug,2023
Outlines
Introduction
Definition of epilepsy
Aim of therapy
Initiation and mechanism of action
Monitoring
Choice of AED in some epileptic syndromes
Side effects
Status Epilepticus
Reference
Introduction
 The traditional aim of therapy in epilepsies is
total freedom from seizures with no clinically
significant adverse effects.
 This has now been broadened to include
optimal outcomes of health-related quality of
life with regard to physical, mental,
educational, social and psychological
functioning of the patient.
The mainstay of treatment is usually with
antiepileptic drugs (AEDs) in continuous
prophylactic schemes. However, AEDs are
ineffective for about 20% of patients
These patients are candidates for neurosurgical
interventions, other pharmacological or non-
pharmacological treatments.
Main question- Does the patient suffer from
epilepsy?
Epilepsy
AED
AED treatment is the mainstay of the
management of epilepsies. The laudable aim
is freedom from seizures with minimal, if any,
adverse drug reactions (ADRs).
This is achieved in about 50–70% of patients
with a single, appropriately selected AED at
target therapeutic doses.
This seizure-free rate varies significantly with
seizure type and epileptic syndrome.
Polytherapy should be avoided if possible, but
it is inevitable in about 30–50% of patients
who fail to respond to single-drug therapy.

Freedom of seizures should not be pursued at

any cost and, in particular, at the expense of
ADRs
Initiation of AED
First seizure with
• Normal neurodevelopmental status, EEG and MRI- no
treatment should be started
Treatment is started If
• Abnormal EEG, MRI, developmental and neurologic
exam
• Positive family history of epilepsy, recurrence risk is
higher
Other considerations in older children
• Motor driving status,
• Swimming
• Sports
Mechanism of action of AED
1. Blockade of voltage-dependent ion channels (K+,
Na+ and Ca2+ channels)
2. Increasing the activity of the inhibitory GABAergic
system
3. Decreasing the activity of the excitatory
glutamatergic system.

• Most medications have multiple mechanism of action

and the exact mechanism responsible for their activity
in human epilepsy is usually not fully understood
Choice of AED
Additional considerations
 The presence of comorbid conditions
 Potential for paradoxical seizure aggravation
 Ease of use
 Teratogenicity
 Titration
Management of common epileptic syndromes
West Syndrome
Hormonal therapy (ACTH or prednisolone)
and vigabatrin have been proposed as first-line
therapy for infantile spasms
Lennox-Gastaut syndrome
Difficult-to-treat epilepsy syndrome.
Treatment varies according to the seizure
type.
Drop attacks (tonic, atonic, or myoclonic
astatic seizures)
– Clobazam, valproate, lamotrigine,
topiramate, felbamate, and rufinamide are
effective.
Lennox-Gastaut syndrome
Atypical absence seizures
– Valproate, lamotrigine, or ethosuximide are
often suitable drugs to try because they are
relatively less toxic than many of the alternative
drugs.

 Ketogenic diet and Vagus nerve stimulator

(VNS) can also be effective in these children
with treatment resistant seizures.
Dravet syndrome
 Is Extremely pharmacoresistant
 Goals of Rx are:
– Avoid prolonged status epilepticus
– Reduce frequency of brief seizures
– Avoid problematic adverse effects of multiple agents used at
high doses
 Sodium channel agents should be avoided as they
exacerbate seizures
 First-line therapy typically involves valproic acid,
clobazam, or topiramate
 Has 15% Mortality rate
Dravet syndrome
Stiripentol, which is available in some
countries, is useful, particularly if used in
combination with valproate and clobazam.

Cannabidiol has recently been approved by

the FDA for the treatment of seizures
associated with Lennox-Gastaut syndrome or
Dravet syndrome in patients ≥ 2 yr.
Benign myoclonic epilepsies
Best treated with valproate, particularly when
patients have associated generalized tonic-
clonic and absence seizures.
 Zonisamide, clonazepam, lamotrigine, and
topiramate are alternatives.
 Severe myoclonic epilepsies are treated with
medications effective for Lennox-Gastaut
syndrome, such as topiramate, clobazam,
valproate, and zonisamide.
 Epilepsy with myoclonic–Atonic
seizures
Doose syndrome
 Valproate, which is effective in myoclonic
jerks, atonic seizures and absences, is the most
efficacious of the AEDs.
 Add-on small doses of lamotrigine have a
beneficial pharmacodynamic interaction with
valproate.
Side effect
Stevens- Johnson -like syndrome
Rickets from phenytoin, phenobarbital,
primidone, and carbamazepine
Irreversible hepatic injury and death
Virtually all AEDs can produce sleepiness, ataxia,
Nystagmus, and slurred speech with toxic levels.
The U.S. (FDA) has determined that the use of AEDs
may be associated with an increased risk of suicidal
ideation and action and has recommended counseling
about this side effect before starting these medications.
Patients with drug-resistant
Wrong dx or drug
Inadequate drug level
Lifestyle factors (alcohol ,sleep deprivation
and stress)
Underlying progressive brain disease or
metabolic disease
Intractable syndrome
Monotherapy
Better efficacy,
Minimization of ADRs and drug
interactions,
Improved compliance
Polytherapy
Establish optimal dose of baseline agent
Add drug with another mode of action
Titrate new agent slowly and carefully
Be prepared to reduce dose of original drug
Replace less effective drug if response is still
poor
Try range of different duo therapies
Add third drug if still sub optimal control
Monitoring
For the older AEDs, before starting treatment,
baseline laboratory studies. including complete
blood count, liver enzymes, and possibly kidney
function tests and urinalysis, are often obtained
and repeated periodically.
Laboratory monitoring is more relevant early
on, because idiosyncratic adverse effects such as
allergic hepatitis and agranulocytosis are more
likely to occur in the first 3-6 mo. of therapy.
 When adding a new AED, the doses used are often affected by
the background medications. For example, if the patient is
receiving enzyme inducers, the doses needed of valproate,
lamotrigine, topiramate, zonisamide, and perampanel are often
higher, sometimes 1.5-2 times, than the usual maintenance
doses.
 On the other hand, if the patient is taking valproate (an
enzyme-inhibiting AED), the doses of phenobarbital or
lamotrigine are approximately half of what is usually needed.
 Thus, changes in the dosing of the background medication are
often done as the interacting medication is being started or
stopped.
 Discontinuation of Therapy
Indicated when children are free of seizures
for at least 2 yr.
In more severe syndromes, such as temporal
lobe epilepsy secondary to mesial temporal
sclerosis, Lennox-Gastaut syndrome, or severe
myoclonic epilepsy, a prolonged period of
seizure freedom with treatment is often
warranted before AEDs are withdrawn, if
withdrawal is attempted at all.
 con't
Discontinuation of AEDs should be extremely
slow, in small doses and in long steps of weeks
or months.
The rate of relapse increases with a faster rate of
AED discontinuation.
Furthermore, with fast discontinuation of AEDs
there is a risk of seizures that are directly related
to the withdrawal effects of certain AEDs
(phenobarbital and benzodiazepines)
Surgery for epilepsies
 If a patient has failed three drugs, the chance of achieving
seizure freedom using AEDs is generally < 10%.

 Therefore, proper evaluation for surgery is necessary as

soon as patients fail two or three AEDs, usually within 2 yr
of the onset of epilepsy and often sooner than 2 yr.

 Early surgical intervention, when successful, might also

prevent or reverse the disabling psychosocial consequences
of uncontrolled seizures during critical periods of
development.
Candidacy for epilepsy surgery requires proof
of resistance to AEDs used at maximum,
tolerably nontoxic doses; absence of expected
unacceptable adverse consequences of surgery;
and a properly defined epileptogenic zone
(area that needs to be resected to achieve
seizure freedom).
 Epilepsy surgery is often used to treat drug-resistant
epilepsy of a number of etiologies, including
 cortical dysplasia,
 tuberous sclerosis,
 polymicrogyria,
 hypothalamic hamartoma,
 Landau-Kleffner syndrome, and hemispheric
syndromes, such as Sturge-Weber syndrome,
hemimegalencephaly, and
 Rasmussen encephalitis.
Surgery for epilepsies
 Focal resection of the epileptogenic zone is the most common
procedure.
 Hemispherectomy is used for diffuse hemispheric lesions in
cases such as Rasmussen encephalitis;
 multiple subpial transection, a surgical technique in which
the horizontal connections of the epileptic focus are partially
cut without resecting it, is sometimes used for unresectable
foci located in eloquent cortex, as in Landau-Kleffner
syndrome.
 In Lennox-Gastaut syndrome, corpus callosotomy is used as a
palliative procedure for drop attacks.
Types of surgical interventions
1. Curative (definite)
2. Palliative (functional)
Vagus nerve stimulation
 Is often used for drug-resistant epilepsies
of various types and for seizures of diffuse
focal or multifocal anatomic origin that do
not yield themselves to resective surgery.
This technique is considered palliative
rather than curative because it most often
leads to seizure frequency reduction rather
than seizure cessation.
Ketogenic diet
The ketogenic diet is a high-fat, low-
carbohydrate, low-protein regimen.
The ketogenic ratio (fat :carbohydrate plus
protein) ranges from 2:1 to a maximum of 5:1.
The ketogenic diet is generally well tolerated
and over 94% of patients have maintained
appropriate growth parameters.
Adverse event- Nephrolitiasis, reduced bone
mass, gastritis, hyperlipidemia
Ketogenic diet
 Is undergoing a mini-renaissance in drug-resistant childhood
epilepsies and particularly epileptic encephalopathies.
 Particularly effective for epileptic spasms and epilepsies with
myoclonic seizures.
 Overall, estimates indicate that complete cessation of all
seizures occurs in 16% of patients, a greater than 90%
reduction in seizures occurs in32%,
 Greater than 50% reduction in seizure occurs in 56%.
 Half the children will continue on the diet for at least 1 year;
 40–50% of those starting the diet will have a greater than
50% reduction in seizures after 12 months
 Management of Status Epilepticus
 The ILAE has refined the definition of SE to reflect the time at
which treatment should be initiated (t1 ) and time at which
continuous seizure activity leads to long-term sequelae (t2 )
including neuronal death, neuronal injury, and alteration of
neuronal networks, depending on the type and duration of
seizures.
 Refractory SE -

 seizure not been controlled with appropriate doses of benzodiazepines

and 1 or 2 doses of nonbenzodiazepine antiseizure drugs.

 After the second or third medication is given, the patient needs to be

intubated and continuous infusions of antiseizure drugs or anesthetic

therapies are often recommended.
 Super Refractory SE

 Patients with super refractory status epilepticus (SRSE) have persistent

seizure activity or seizure recurrence despite 24 hr of medications such

as midazolam, pentobarbital, and/or propofol.
Reference
Nelson Textbook of Pediatrics, 21th edition
Panayiotopoulos : A Clinical Guide to
Epileptic syndrome and their Treatment
Swaiman’s Pediatric Neurology; 6th edition
Thank you