Epilepsy

Department of Pharmaceutical Sciences

North South University
 Epilepsy

Epilepsy is defined by the occurrence of at least two unprovoked seizures with or

without convulsions (ie, violent, involuntary contraction[s] of the voluntary muscles)
separated by at least 24 hours.

Epilepsy is often associated with with neurobiological, cognitive, psychological, and

social consequences.

A seizure results from an excessive discharge of cortical neurons and is characterized by

changes in electrical activity as measured by the electroencephalogram (EEG).
 Seizure and Epilepsy

●A seizure is the physical findings or changes in

behavior that occur after an episode of abnormal
electrical activity in the brain.

Epilepsy is a disorder of the brain.

●

●People are diagnosed with epilepsy when they

have had two or more seizures.
 Pathophysiology
Seizures result from excessive excitation or from disordered inhibition of neurons.

Initially, a small number of neurons fire abnormally.

Normal membrane conductances and inhibitory synaptic currents then break down,
and excitability spreads locally (focal seizure) or more widely (generalized seizure).

Epileptic seizures result only when there is also synchronization of excessive neuronal
firing.
Pathophysiology
Mechanisms that may contribute to synchronous hyperexcitability
include
• alterations of ion channels in neuronal membranes,
• biochemical modifications of receptors,
• modulation of second messaging systems and gene expression,
• changes in extracellular ion concentrations,
• alterations in vesicle trafficking and neurotransmitter release,
• alterations in neurotransmitter uptake and metabolism, and
• modification in the ratio and function of inhibitory circuits.
Classification of seizures
Classification of seizures
 Symptoms and signs
●Focal seizures (ie, partial seizures) begin in one hemisphere of
the brain, and unless they become secondarily generalized,
result in an asymmetric seizure.

Focal seizures manifest as

●

–alterations in motor functions (eg, twitching or shaking),

–sensory (eg, numbness or tingling) or somatosensory

symptoms,

–aberrations in behavior, or

–automatisms.
 Symptoms and signs

●Absence seizures generally occur in young

children or adolescents and exhibit a sudden
onset, interruption of ongoing activities, a
blank stare, and possibly a brief upward
rotation of the eyes.

●There is only a very brief (seconds) period of

altered consciousness.
 Symptoms and signs
•Generalized tonic-clonic (GTC) seizures are major convulsive
episodes and are always associated with a loss of consciousness.

• GTC seizures may be preceded by premonitory symptoms

(ie, an aura).
• Motor symptoms are bilateral.
• Tonic-clonic seizures begin with a short tonic contraction
(stiffening) of muscles followed by a period of rigidity and clonic
(jerking) movements.
 Diagnosis
Ask the patient and family to characterize the seizure for
• signs/symptoms,
• triggers,
• frequency,
• duration,
• precipitating factors,
• time of occurrence,
• presence of an aura,
• impairment of consciousness,
• ictal activity, and
• postictal state.
Physical and neurologic examination and laboratory examination may identify an etiology.
Diagnosis

• EEG is very useful in the diagnosis of

various seizure disorders.

• But epileptiform activity is found in only

about 50% of patients with epilepsy.

• Magnetic resonance imaging is very

useful (especially imaging of the temporal
lobes).
Goals of Treatment

1 2 3
The goals are to control or Complete suppression of Side effects and
reduce the frequency and seizures must be balanced comorbidities (eg, anxiety
severity of seizures, minimize against tolerability of side and depression) as well as
side effects, and ensure effects, and the patient social issues (eg, driving, job
compliance, allowing the should be involved in security, relationships, and
patient to live as normal a life defining the balance. social stigma) have significant
as possible. impact on quality of life.
Treatment
 Treatment

Focal onset seizures (newly

Generalized onset (tonic-clonic)
diagnosed)
• Carbamazepine • Lamotrigine
• Lacosamide • Levetiracetam
• Phenobarbital • Topiramate
• Phenytoin • Perampanel
• Topiramate
• Valproic acid
Generations of ASDs
Generations of ASDs
Generations of ASDs
 Carbamazepine

●Food, especially fat, may enhance the bioavailability of

carbamazepine.
●Controlled- and sustained-release preparations dosed every 12 hours
are bioequivalent to immediate-release preparations dosed every 6
hours.
● The sustained-release capsule can be opened and sprinkled on food.
Carbamazepine may interact with other drugs by inducing their
●

metabolism.
●Extended-release preparations can be dosed twice daily, but
immediate-release preparations must be given four times daily.
●Compared to other first generation ASDs, it causes minimal
cognitive impairment.
Phenytoin
• Phenytoin is a first-line ASD for many seizure types, and is FDA approved
for focal onset seizures and GTC seizures.
• It may exacerbate seizures in generalized epilepsies.
• It has many acute and long-term side effects.
• Do not change brands without careful monitoring.
• The intramuscular route is best avoided, as absorption is erratic.
Fosphenytoin can safely be administered IV and intramuscularly.
• Phenytoin is prone to many drug interactions. If protein-binding
interactions are suspected, free rather than total phenytoin serum
concentrations are a better therapeutic guide.
Generations of ASDs
Generations of ASDs
Generations of ASDs
Generations of ASDs
 Treatment

1 2 3
Begin with monotherapy Up to 60% of patients Provide the patient with a
• About 65% of patients can be with epilepsy are seizure and side effect
maintained on one antiseizure noncompliant; this is the diary.
drug (ASD), although not most common reason for
necessarily seizure free.
treatment failure.
 Treatment
Initiate ASD with a low dose and titrate gradually to a moderate
dose. If seizures continue, titrate to a maximum dose.

If the first ASD is ineffective or causes intolerable side effects, add a

second ASD (preferably with a different mechanism of action), and
then taper and discontinue the ineffective or intolerable drug.
If the second ASD is ineffective, then polytherapy may be indicated.
 Treatment

Start at a lower dose and titrate more slowly in elderly patients.

●

Factors favoring successful withdrawal of ASDs include

●

● a seizure-free period of 2 to 4 years,

● complete seizure control within 1 year of onset,
● an onset of seizures after age 2 years and before age 35 years, and
● a normal EEG and neurologic examination.
Epilepsies in children, young people and adults
NICE guideline [NG217]Published: 27 April 2022

https://www.nice.org.uk/guidance/ng217
Generalised tonic-clonic seizures

Monotherapy

5.1.1 Offer sodium valproate as first-line monotherapy for generalised tonic-clonic

seizures in:
• boys and men
• girls aged under 10 years and who are unlikely to need treatment when they are
old enough to have children women who are unable to have children.

5.1.2 Offer lamotrigine or levetiracetam as first-line monotherapy for generalised

tonic-clonic seizures in women and girls able to have children (including young girls who

are likely to need treatment when they are old enough to have children). If the first

choice is unsuccessful, offer the other of these options.

Generalised tonic-clonic seizures

Monotherapy

5.1.3 If first-line monotherapy with sodium valproate is

unsuccessful for generalised tonic-clonic seizures, offer
lamotrigine or levetiracetam as second-line monotherapy
treatment.

If the first choice is unsuccessful, try the other of these options.

5.1.4 Do not offer sodium valproate monotherapy for

generalised tonic-clonic seizures in women and girls able to have
children unless other treatment options are unsuccessful.
Generalised tonic-clonic seizures

Add-on treatment
5.1.5 If monotherapy is unsuccessful in people with generalised tonic-clonic
seizures, consider 1 of the following first-line add-on treatment options:
• clobazam
• lamotrigine
• levetiracetam
• perampanel
• sodium valproate, except in women and girls able to have children
• topiramate.

If the first choice is unsuccessful, consider the other first-line add-on options.
Treating childhood-onset epilepsies

Dravet syndrome
• Dravet syndrome is a distinctive epilepsy syndrome that presents in the first year of life with a
reported incidence of 1:15,700.
• Early clinical presentation of Dravet syndrome is unique
• Recurrent, convulsive seizures, which are often prolonged and triggered by fever, in a
developmentally normal infant
• Normal MRI and nonspecific EEG findings
• SCN1A mutations are found in over 85% of patients clinically diagnosed with Dravet syndrome.
Mutations that cause Dravet syndrome generally occur de novo, but less commonly can be
inherited.

https://dravetfoundation.org/hcp-resources/diagnosis-and-treatment/
Dravet syndrome

“Other” includes vagus nerve stimulation (VNS), levetiracetam, zonisamide, bromides, clonazepam, and ethosuximide
(for absences).
**Phenytoin may be of benefit for treatment of status epilepticus. Maintenance therapy with sodium channel
blockers is contraindicated.
 Pharmacokinetics and
special populations

For populations known to Conditions altering ASD Unbound concentration

have altered plasma protein binding include: monitoring is especially
protein binding, useful for phenytoin.

• measure free rather than • chronic renal failure, liver

total serum
concentrations if the ASD
is highly protein bound.
disease,
hypoalbuminemia,
burns, pregnancy,
malnutrition, displacing
drugs, and age (neonates
and the elderly).
 Pharmacokinetics and special populations

Neonates and infants display decreased efficiency in renal elimination

and may metabolize drugs more slowly.

By age 2 or 3 years children may metabolize drugs more rapidly than

adults.

Thus, neonates and infants require lower doses of ASD

But children require higher doses of many ASDs than adults.

 Pharmacokinetics and special populations

Lower doses of ASDs are often required in the elderly due to compromised renal or hepatic function.

The elderly often take many medications, and thus are more prone to experience neurocognitive effects and
drug–drug interactions involving ASDs that affect the CPY450 system (eg, carbamazepine, phenytoin,
valproic acid, and phenobarbital).
They also experience body mass changes which can affect elimination half-life and volume of distribution.

Lamotrigine is often considered a drug of choice for elderly patients with focal onset seizures because of
effectiveness and tolerability.
 Anti-seizure medication and recommendation for use in
girls and women with epilepsy in childbearing age.

Article Copyright © 2022 Authors, Source DOI: 10.1177/17562864221101687.

 The role of serum concentration monitoring

Seizure control may occur before the “minimum” of the therapeutic serum range is reached, and
some patients may need serum concentrations beyond the “maximum.”

Clinicians should determine the optimal serum concentration for each patient.

Serum concentration determinations can be useful to document lack of or loss of efficacy, establish
noncompliance, and guide therapy in patients with renal and/or hepatic disease and patients taking
multiple drugs, as well as in women who are pregnant or taking oral contraceptives.
 Evaluation of therapeutic outcomes

Monitor long term for seizure control, side effects, social adjustment
including quality of life, drug interactions, compliance, and side effects.
Clinical response is more important than serum drug concentrations.

Screen periodically for psychiatric disorders (eg, anxiety and

depression).
Ask patients and caregivers to record severity and frequency of seizures.
 Compare efficacy, tolerability, and indications of
first and second-generation ASDs.

❑ Antiseizure drugs (ASDs), also known as antiepileptic drugs (AEDs), are used to treat epilepsy and other seizure disorders.
There are two generations of ASDs, with the second generation being developed to improve upon the efficacy and tolerability
of the first generation.
❑ First-generation ASDs were introduced in the 1950s and include drugs such as phenobarbital, phenytoin, carbamazepine,
and valproic acid. These drugs are effective at controlling seizures, but they also have a high risk of adverse effects, including
sedation, cognitive impairment, and the potential for liver toxicity.
❑ Second-generation ASDs were developed in the 1990s and include drugs such as gabapentin, lamotrigine, levetiracetam,
topiramate, and zonisamide. These drugs have a better safety profile than first-generation ASDs, with a lower risk of adverse
effects and drug interactions. They are also more selective in their mechanism of action, which allows for better targeting of
specific seizure types.
❑ According to the American Academy of Neurology (AAN) and the American Epilepsy Society (AES), second-generation
ASDs are preferred over first-generation ASDs for the treatment of epilepsy and other seizure disorders. The AAN and AES
guidelines state that second-generation ASDs are better tolerated and have fewer drug interactions, making them safer and
more effective in the long-term management of seizures (Krumholz et al., 2021).
❑ However, the choice of ASD depends on the individual patient and their specific seizure type. For example, valproic acid is
still considered the drug of choice for generalized seizures and myoclonic seizures, while carbamazepine is preferred for focal
seizures (Krumholz et al., 2021).
❑ In conclusion, second-generation ASDs are preferred over first-generation ASDs due to their improved safety profile,
tolerability, and efficacy. However, the choice of ASD should be individualized based on the patient's specific seizure type
and medical history.