EPILEPSY

EPILEPSY
General consideration & definitions
-Seizure:
clinical manifestation of an abnormal and excessive excitation of a
population of neurons in the brain (abnormal discharges of neurons)
- Epilepsy:
recurrent unprovoked or unexpected seizures

Etiology
- Genetic factor
- Brain damage (Inborn, Acquired)
- Drug induced
• Bupropion
• Systemic steroid
• Selective serotonin reuptake inhibitors:
(Flouxetine, Paroxetine, Serteraline, fluvoxamine)
• Monoamine oxidase inhibitors:
(Isocarboxazide, Phenlizine, Pargyline, Tranylcypramine )
• Central nervous system stimulants (amphetamine)
PATHOPHYSIOLOGY
 Neurons are interconnected with each others with synapses

 A small electrical current is discharged by neuron → release

neurotransmitters to synapses → permit communication with other
neuron → An excited neurons will activate the next neuron →
tramsmittion of information throughout the CNS

 A normal neuron dicharges reptitively at a low baseline frequency

 if the neurones are damaged, injured or suffer a metabolic or

chemical insult as in case of epilepsy→ a change in discharges
pattern → brusts of high frequency (abnormal discharges) follwed by
a period of inactivity

 This abnormal dicharges may remain localised or it may spread to

adjacent areas i.e generalized

 The area from which the abnormal discharge originates is known as

epileptic focus
 Neurotransmitter

Next neuron

Neurotransmitter
vesicle
synapse

Normal discharge Abnormal discharge

 Pathophysiology

Excitation Inhibition

glutamate,
aspartate Normal GABA
brain
 Pathophysiology

glutamate,
Aspartate

Excitation GABA

Inhibition
Epilepsy

6
Classification
A- Classified by etiology
o Idiopathic (essential) epilepsy where there is a clear genetic component
as over expression of synaptic vesicle protein SV2A
o Symptomatic (secondary) epilepsy due to causative factor (hypoxia, asphyxia
at birth, meningitis, head trauma, brain tumor, alcohol abuse, CVD, drugs)
B- Classified by epileptic seizures types
1- Generalized seizures
 Result in Loss of consciousness
 Abnormal discharges involve whole brain
o Tonic- Clonic (grand Mal)
o Absence attacks (petit mal)
o Myoclonic
o Atonic
2- Partial seizures:
 Consciousness is preserved or impaired but not lost
 Abnormal discharges involve localized area or certain lobe
 Simple partial seizures
 Complex partial seizure
 Secondary generalized seizures
3- Other types of epilepsy
 Intractable epilepsy
 Status epilepticus
 Febrile convulsions
 1- Generalized seizures
A-Tonic clonic convulsions
 Often called "grand mal" attacks
 Involve whole brain so it called generalized
 Convulsive in nature with loss of consciousness
 The most common of all epileptic seizures
 Without warning:
 The patient suddenly shows generalized stiffening of body
 Patient falls into ground
 Patient shows alternate periods of spasm and relaxation of muscle →
Jerky movements of face, arms, legs, trunk (convulsion)
 Patient has labored breathing or respiration may be cease → Cyanosis
or dusty blue color .
 The patient may show excessive salivation or be salivated
 he may Bite his tongue → bleeding from mouth
 After a few minutes, convulsion ceases and the consciousness
regained and afterward the patient shows drowsiness, confusion,
headache difficulty speaking and wish to sleep.
B- Absence attacks
● Often called "petit mal"
● These are a much rare form of generalized seizure.
● They happen almost exclusively in children
● Disappear as the child reaches adolescence
● 5- 50 seconds of loss consciousness .
● The child goes blinking rapidly and stares; fluttering of the eyelids,
● Smacking of lips
● The attacks last only a few seconds and often go unrecognized by
the child experiencing them (the child is unaware by what is
happing).
● Some children exhibit 100s episodes / day
● After seizure the child may be anxious because of miss period of time
● There is no need for any type of first aid
● It is not convulsive in nature
C- Myoclonic seizures
● "Myo" means muscle and "clonus" (KLOH-nus) means rapidly alternating
contraction and relaxation (jerking or twitching of a muscle)
● These are abrupt very brief involuntary shock-like jerks
● Involve the arms legs, and trunk and rarely whole body,
● They usually happen in the morning shortly after waking.
● They may sometimes cause the person to fall
● Recovery is immediate after approximately one minute.
D- Atonic seizures "drop attacks" or "drop seizures
• The attacks remains for less than 15 seconds.

• "Atonic" means "without tone," so in an Atonic seizure, muscles

suddenly lose strength where general sudden loss of muscle tone
takes place

• Atonic seizures are thought to originate in areas of the brain that

control muscle tone and posture

• The eyelids may droop

• The head may nod

• The person may drop things

• The patients fall to the ground when they're standing and often hits his
head and bruises his body

• Atonic seizures often begin in childhood and continues in

adolescence
 2- Partial seizures
A- Simple partial seizures
● The discharge remains localized so called partial

● Consciousness is fully preserved.

● Simple partial attacks are very rare and they usually progress to the
other forms of partial seizure.

● Stiffness or twitching of one part of the body

● Numbness or abnormal sensations

● If the seizure progresses with impairment of consciousness, it is called

a complex partial seizure.
 B- Complex partial seizures or frontal lobe seizure
● The consciousness is impaired but not completely lost
● It occurs in all age group
● it starts with aura where:
* The patient is anxious, irritable, repeats certain words or phrases
* He has Nausea & tendency to vomit
* He smells strange odor & and feel strange taste
* He hears strange sounds
* If asked a question, the patient gives inappropriate answer or fails
to answer
 At this point the seizure proceeds where ; The patient may present
with altered behavior such as :
* Plucking his clothes or tapping movements
* Acting in a confused manner
* Exhibits purposeless movements.
* Lip smacking or chewing movements, or a blank look on his face
* Performing aimless activities
* Wandering around in a drunken fashion
● This behavior may be mistaken with drug overdose or drunken
fashion
● After few minutes the patient recover his full consciousness but cant
recall the seizure events! !
C- Secondarily generalized seizures
● These are partial seizures either simple or complex in which the
discharge spreads to the entire brain.

● The spread of the discharge can occur so quickly that no feature of

the localized onset is apparent to the patient or an observer and only
an EEG with neuro-imaging can demonstrate the partial nature of the
seizure.

● The involvement of the entire brain leads to a convulsive attack with

the same characteristics as a generalized tonic clonic convulsion.
Diagnosis
Seizure Types
Single Recurrent

Epileptic

Partial

Non-epileptic Generalized
Simple Complex
• Syncope
• Migraine • Absence
• Toxic • Tonic-clonic Secondarily
• Cerebrovascular • Myoclonic Generalized
• Metabolic • Atonic
So Diagnosing of epilepsy depends on
1- Recurrent spontaneous seizures episodes.
2- Unpredictability and repetitive nature of the attack.
3- Clinical picture
Clinical history
Symptomatology description of Sz (spontaneously &
repetitively)
4- EEG
5- Laboratory tests
6- Neuro-imaging as NMR and MEG
Electroencephalogram
The most specific test for diagnosing epilepsy
It aims to record abnormal neuronal discharges
Discharges are electrically integrated by the neurons of the superficial layer of
the cortex can be recorded by EEG

Normal EEG

EEG tracing for epileptic seizure

EEG TRACING OF EPILEPTIC
SIEZURE
 Normal EEG

Absence attack tonic phase with high symmetric brusts

Sudden brief episodes Clonic phase with asymmetric spikes
fall to baseline Base line with spikes due to exhausted
No neuron exhaustion Neurons

Myoclonic
Generalised irregular spikes
 Normal EEG

Complex partial simple partial

MEG =Magnetoencephalogram

MEG
 A magneto-encephalogram (MEG) is a neuro-imaging device that measures
magnetic fields in the brain.

 These magnetic fields are generated by the electrical activity of neurons

(nerve cells) in the brain.

 An MEG is used to identify abnormal electrical discharges that produce

magnetic signals in the brain and, by mapping the sources i.e it identifies
where these discharges come from

 It also enables mapping of normally functioning areas of the brain so that

surgery can remove only what is absolutely necessary.

 Unlike an MRI, which delivers a magnetic pulse to produce brain images, the
MEG records magnetic fields that are created by the electrical activity of
neurons.

 To allow these tiny magnetic fields to be detected, the MEG equipment is

housed in a special magnetically shielded room that keeps out all the outside
magnetic fields that are present in day-to-day life.

 the patient put his head inside an part of the device looks like old fashion hair
dryer where the sensor of the device that detect the magnetic field is found
 Magnetic Resonance Imaging (MRI)
valuable when structure abnormalities are suspected (stroke,
tumor, hydrocephalus)
should be carried to anyone with seizures or when a structural
lesion is responsible for epilepsy
Differential diagnosis
A- Febrile Seizures
- Ages 3 months to 10 years
- Fever
- Non- CNS infection
- Generalized seizures mainly tonic clonic i.e convulsive
- Lacts for 5-15 minutes or even 25 min
- EEG resembles tonic clonic one
B- Migraine
- Positive family history
- Headache that worse with movement
- Visual disorder or light flashes or haloes
C-Breath-holding spells
- Age 6 months to 3 years,
- Cry, loss of consciousness
- Apnea and cyanosis
- Family history positive
- Normal EEG.
D- Sleeping disturbance
- Sleep walking ,
- Nightmare
- Night terrors
Treatment of epilepsy
ANTI-CONVULSANTS
▪ Phenytoin (Epanutin,™), Phenobarbitone (Sominal™), Carbamzepine
(Tegretol™), Oxacarbazine (Trileptal™) & Primidone (Mysoline™)
All used for grand mal epilepsy

▪ Valoproate (Depakin, Convulex™)

used for grand and petit mal epilepsy

▪ Sulthiam (Ospolot ™), Ethosuximide and Trimethadione

All used for petit mal epilepsy

▪ Topiramate (Topamax, Topiramate™)

used for myoclonic seizures

▪ Gabapentin (Neurontin™) , pregabalin (lyrica™) tiagabine levetricetam

are used as adjuvant therapy to minmize doses and SE of first line
drugs they are not first line drugs or they are 2nd line drugs
NB;
Levetricetam used as adjuvant therapy for refractory partial seizure
 Types of epilepsy Drugs used
Tonic-clonic seizures VPA, CBZ, PB, PRM,PHT

Absence seizures VPA, ES, CNP

Myoclonic seizures VPA, CNP, PRM, Topiramate

Partial seizures CBZ, VPA, PRM but not ES & BZ

A. Mode of action of drug therapy:

1. Drugs that Block sodium channels (Phenytoin, carbamazepine,
Oxcarbazepine, Lamotrigine, felbamate, Topiramate)

2. Drugs Potentiate the action of GABA (Valoproic acid,

Benzodiazepines, Phenobarbitone, Primidone, Topiramate)

3. Drugs that Block calcium channels (Ethosuximide, Trimethadione)

4. Drugs inhibit glutamate activity (Felbamate)

5. Drug that bind to synaptic vesicle protein SV2A (Levetricetam)

Phenytoin Block sodium channels for grand mal
 Carbamazepine
Block sodium channels
For grand mal and mainly partial seizures
 Oxacarbazepine
Block sodium channel
For grand mal seizures
Valoproate enhances GABA action For grand mal, petit mal and
myoclonic
 Phenobarbitone
Enhance GABA action
For grand mal myoclonic and
partial seizures
 Clonazepam

Clonazepam

Diazepam

Clonazepam

Clonazepam

Diazepam

Benzodiazepines enhance GABA action; used for petit mal and

myoclonic seizures
 Topiramate
Enhance GABA action
Block sodium channel
For myoclonic seizures
 Lamotrigine
Block sodium channel
2nd line
 Gabapentin
Potentiate GABA action
2nd line
 Pegabalin
Potentiate GABA action as they are GABA analouge
2nd line
B-The Pk parameters of anti-epileptic drugs
All these drugs mentioned above can be taken orally as they exhibit
good absorption pattern from GIT

They have an affinity to bind plasma proteins (Valoproate > Phenytoin

> Phenobarbitone > Carbamezipine > Primidone).
On the other hand Gabapentin, Ethosuximide, Levtricetam, and
Trimethadione have no affinity to bind plasma proteins

They are metabolised by liver. Some of them are enzymes inducers

(Phenytoin, Phenobarbitone, Carbamezipine, Primidone, Topiramate).

 Others are enzymes inhibitors as Valproate.

 Ethosuximide, gabapentin, lamotragine , Leveticetam and

Trimethadione have no effect on liver microsomal enzymes.

 Lamotragine induces its own metabolism only

 Primidone (active drug) is metabolised into Phenobarbiton (active

metabolite).

 These anti-epileptic drugs can be excreted by kidney.

C. Adverse effects of anticonvulsants
 Phenytoin :
 Megaloblastic anaemia, nystagmus, diplopia, development of fibrous
overgrowth of gingiva
 Valoproate:
 Transient nausea,vomiting and GIT pain
 Hepatotoxicity due to its metabolite 2-propyl-4- pentanoic acid
 Carbamzepine:
 CNS (Dizziness, ataxia, uncommon nystagmus, diplopia and slurred
speech)
 Dermatological (urticaria, exfolative dermatitis)
 Blood (leukopenia, thrombocytopenia)
 Hypersensitivity to TCA povokes cross hypersensitivity to
carbamezipine & oxacabazine
 Phenobarbitone : Excessive sedation and CNS depression
 Topiramate : Nervousnss, parasethesia, nephrolithiasis (kidney stones)
so increased fluied intake is recommended
 Lamotragine: Macropapular rash (dose dependant)
 Gabapentin: Dizziness, edema, headache,
Caution should be taken for elderly and patient with renal impairment
 Levetricetam ; Diziness, headache, sleep disturbance, weakness
General principles of treatment
1. Initiation of therapy in newly diagnosed patients
 Evaluate the type of seizures (EEG)
 A single first-line antiepileptic drug is the most suitable for the
patient's seizure type
 It should be introduced slowly starting with a small dose as rapid
introduction may induce side effects that will lose the patient's
confidence.
 However more care is needed with Phenytoin as the plasma level-
dose relationship is not linear, and small dose changes may result in
considerable plasma level changes

2. Altering drug regimens

 If the maximal tolerated dose of a drug does not control seizures or if
side effects develop, the first drug can be replaced with another first
line antiepileptic drug.
 The second drug should be added gradually to the first.
 Once a good dose of the new drug is established, the first drug
should then slowly be withdrawn.
 3. Duration of treatment
 Full drug therapy should continue for 2-3 years after the last fit.
 After this period the drugs can be withdrawn gradually.
 If another fit occurs, then a further 2-3 years period is necessary before
another trial of drug withdrawal

4. Withdrawal of drugs
 Antiepileptic medication should not be withdrawn abruptly, in
particular for Barbiturates and Clonazepam, to avoid rebound seizures
and status epileptics.
The withdrawal of individual antiepileptic drugs should be carried out in
a slow stepwise fashion to avoid the precipitation of withdrawal
seizures (over 2-3 or even 6 months).
 If drug needs to be withdrawn rapidly, benzodiazepine can be used to
cover the rapid withdrawal phase.
5. Poly therapy
A combination of two or more anti-epileptics (poly-therapy) can be used
for an epileptic patient.
Poly-therapy is a very common technique in the management of epilepsy
in order to :
1. obtain a pharmacodynamic additive effect (minimize seizure frequency)
2. to guard against adverse drug reactions by reduction of doses.
The outcome of this poly-therapy regimen is usually unexpected due to:
The variation of PK parameters among anticonvulsant drugs.
So, it is very important to determine the outcome of poly-therapy, this can
be achieved by monitoring both drugs plasma levels and provoked side
effects if any.

COMIDAL- L® tablets is a combination of phenytoin and phenobarbitone

 6. Monitoring antiepileptic therapy or TDM:
 Therapeutic drug monitoring (TDM) involves
1. Measurement of plasma drug levels and their pharmacokinetic
interpretation
2. Evaluation of seizures control
3. Evaluation of SE

 It is important for patients receiving Phenytoin, valoproate and

carbamazepine, but is less useful in patients receiving other drugs

 Stabilized patients may require TDM only once or twice a year.

7. Antiepileptic drugs and Pregnancy
 We must evaluate benefit risk ratio

 Most antiepileptic drugs can cause fetal abnormalities such as

 Trimethadione causes nephrosis

 Phenytoin cause folate deficiency

 Valoproic acid cause hepatotoxicity

 Many antiepileptic drugs specially enzyme inducers increase clotting

factors turnover , so administration of vitamin K during the last days of
pregnancy is essential.

 Only one drug at low dosage as possible is used to minimize

teratogenic risks.

 Lamotrigine is not teratogenic but it is adjuvant therapy to decrease

the dose of first line drug with subsequent reduction of side effects
 OTHER TYPES OF EPILEPSY
A. Febrile convulsions
 Convulsions associated with fever so termed febrile convulsions
 May occur in the young 3−10 year
 Prolonged lasts for 10-15 minutes or longer
 Absence of CNS infection
 Treatment
 Tepid sponging (Tempo cool®) and use of paracetamol
 The drug of choice is phenobarbitone or diazepam (I.V or rectal)
 Phenytoin and carbamazepine are ineffective
 Valoproic acid can cause hepatotoxicity

P-cetamol
 B. Intractable or refractory epilepsy
 It is a type of epilepsy characterized by unsatisfactory response of the
epileptic patients to a normal dose of a single anti-epileptic first line agent
for one year

 It is common in children

Treatment of intractable epilepsy

o High ketogenic diet (high fats, low carbohydrate and adequate proteins)

o Vitamin B6 at high doses to maintain nerve cells integrity

o Poly-therapy

o Vagal nerve stimulation

o Surgery
 Ketogenic diet

High fat Enough protein Low carbohydrate

 The ketogenic diet
• It is a high-fat, adequate-protein, low carbohydrate diet that in
medicine is used primarily to treat difficult-to-control (refractory)
epilepsy in children.

• The diet mimics aspects of stravation by forcing the body to burn fats
rather than carbohydrate

• Normally, the carbohydrates contained in food are converted into

glucose, which is then transported around the body and is particularly
important in fuelling brain function.

• However, if there is very little carbohydrate in the diet, the liver

converts fat into fatty acids and ketone bodies.

• The ketone bodies pass into the brain and replace glucose as an
energy source.

• An elevated level of ketone bodies in the blood, a state known as

ketosis, leads to a reduction of both neurons activity and reduction in
the frequency of epileptic seizures
Vitamin B6 to maintain neurons integrity
 Vagal nerve stimulation or VNS
 Vagus nerve stimulation (VNS) is an adjunctive treatment for certain
types of intractable epilepsy.
 VNS uses an implanted stimulator that sends electric impulses to
vagus nerve in the neck via a lead wire implanted under the skin.
 Proposed mechanisms include elevation of levels of inhibitory GABA
related to vagal stimulation and inhibition of aberrant neuronal
activity
Surgery
• Validity: It is valid for partial seizures

• Technique: Epilepsy surgery is a procedure that removes an area of your brain

where your seizures originate.

• When: surgery is considered when the patient have tried at least two first line
anti-seizure drugs without success for at least 1 or 2 years.

• Operation: Removing a portion of the brain (Resective surgery)

o It is The most common type of epilepsy surgery is the removal of the portion
of the brain usually about the size of a golf ball that's causing the seizures.

o This type of surgery is highly successful.

• Risks include
o Memory problems
o Behavioral changes (depression and mood changes)
o Temporary double vision
o Reduced visual field.
 C. Status epilepticus
Status epilepticus is characterized by frequent seizures with loss of
consciousness in-between
 Treatment
- Positioning the patient to avoid injury
- Supporting respiration
- Maintaining blood pressure
- Correcting hypoglycemia if any
- Drugs of choice: Diazepam (IV), clonazepam (IV).
- Alternative: Phenytoin (IV), general anesthesia.
 Treatment strategy
1. Seizures’ abortion:
Drugs used include intravenous diazepam 10 mg I.V repeated every
10 minutes (Maximum dose is 120 mg)
2. Prevent relapse:
Phenytoin: LD 500-1000 mg I.V. (slowly); MD 200-400 mg daily
 Other clinical applications of anticonvulsants
A. Arrhythmia: Phenytoin
 Membrane stabilizer where it blocks sodium influx , suppress repetitive action
potential with subsequent membrane stabilization leading to stopping of
activity
B. Trigeminal neuralgia : Carbamzepine as Tegretol® or Neurotop®
 They blocks sodium influx , suppress repetitive action potential with
subsequent stopping of activity
C. Hypnotic for sleep disorder :Phenobarbitone, primidone, diazepam
 As they have CNS depressant effect
D. Neuropathic pain: Gabapentin, Pregabalin & Lamotrigine
 Due to enhancement of GABA action
E. Treatment of physiologic jaundace : Phenobarbiitone (somineletta ®)
 Mainly enzyme inducers antepileptics specially, where they induce
bilirubin metabolis
 Phenobarbiitone (somineletta ® syrup) is commonly used
F. Wound healing : Phenytoin spray (Helsol® spray)
1- Due to stimulatory effect of phenytoin on connective tissue formation
2- Due to enhancement of fibroblast proliferation,
3- Due to Facilitation of collagen deposition and stabilization of fibrin
4- Due to Glucocorticoid antagonism that inhibts fibroblasts
 OTHER
CLINICAL
USES
OF
PHYSIOLOGIC ANTEPILEPTICS
JAUINDACE

Phenytoin spray
Wound healing
promoter

HYPNOTIC
ANXIOLYTIC

NEUROPATHIC
PAIN

TRIGEMINAL
NEURALGIA
 Epilepsy and First Aid for Seizures
What Should I Do for a Person Who Has a Seizure?
• Loosen clothing around the person's neck.
• Do not try to hold the person down or restrain him or her, this can
result in injury.
• Do not insert any objects in the person's mouth; this can also cause
injury.
• Remove sharp objects (glasses, furniture, and other objects) from
around the person to prevent injury.
• After the seizure, it is helpful to lay the person on his or her side to
maintain an open airway and prevent the person from inhaling any
secretions.
• After many seizures, there may be confusion for a period of time and
the person should not be left alone.
• In many cases, especially if the person is known to have epilepsy, it is
not necessary to call an ambulance.
• If the seizure lasts longer than five minutes, or if another seizure begins
soon after the first, or if the person cannot be awakened after the
movements have stopped, an ambulance should be called.
• If you are concerned that something else may be wrong, or the
person has another medical condition such as heart disease or
diabetes, you should contact a doctor immediately.
• New drugs for epilepsy
 Perampanel

• Trade name

• Manufactured and marketed by Eisai co.

• Available as 2, 4, 6, 8, 10, 12 mg tablets

• U.S FDA approved Fycompa on October 22, 2012 to be used as

adjunctive treatment in refractory partial-onset epilepsy with or
without secondary generalization in patients aged 12 years or
older.
 Mechanism of action

• Perampanel is a highly selective, non competitive

AMPA receptor antagonist on postsynaptic neurons.

• Perampanel is the first and only licensed AMPA

receptor antagonist.
 Mechanism of action (cont.)
Glutamate receptors
• AMPA receptor (α-amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid).

• NMDA receptor (N-methyl D-aspartate)

• Kainate receptor.
 Mechanism of action (cont.)

Glutamate binding to these receptors leading to

excitatory postsynaptic potential (EPSP)

AMPA EPSP

NMDA
Mechanism of action (cont.)
Mechanism of action (cont.)