SEIZURE

DISORDERS
DR. WAIRIMU KARAIHIRA
BPHARM, MPHARM (CLINICAL PHARMACY)
OBJECTIVES
1. To classify and describe different types of
seizure disorders.
2. To outline the general principles of
management of epilepsy.
3. Outline the management of status epilepticus
4. Discuss the modalities involved in the
management of epilepsy in pregnancy.
CASE STUDY
A mother brings her 8 year old daughter, into the clinic to
see her paediatrician for her yearly check-up. When the
doctor asks the mother if there is anything she is
concerned about, she states that she notices that the girl
sometimes will stare off into space for extended period of
time, she sometimes will blink her eyes rapidly, and when
this occurs she seems to not be aware of her
surroundings. The mom is wondering whether this is just
Kali not paying attention or if there is something wrong
with her.
INTRODUCTION
 A seizure is the transient occurrence of signs and/or
symptoms due to abnormal excessive or synchronous
neuronal activity in the brain.
 These signs or symptoms ,may include alterations of
consciousness, motor, sensory, autonomic, or psychic events.
 Epilepsy describes a condition in which a person has a risk of
recurrent (two or more) seizures due to a chronic, underlying
process.
EPIDEMIOLOGY
 According to a study conducted in rural Kenya and other
African countries, half of the 2,170 people with active convulsive
epilepsy were children and 69% of the seizures began in
childhood.
 Other studies found that the prevalence of epilepsy is about 20
cases in every 1,000 people.
 About 77 new cases in every 100, 000 people are diagnosed
every year.
 These estimates are two to three times higher than in
developed countries.
EPIDEMIOLOGY
 The estimated prevalence of lifetime epilepsy in
children was 21–41 per 1,000, while the incidence of
active convulsive epilepsy was 39–187 cases per
100,000 children per year.
 The incidence of acute seizures was 312–879 per
100,000 children per year and neonatal seizures
3,950 per 100,000 live births per year.
PATHOPHYSIOLOGY
 Seizures are paroxysmal manifestations of the cerebral cortex.
 A seizure results when a sudden imbalance occurs between
the excitatory and inhibitory forces within the network of
cortical neurons.
 Certain neurotransmitters (e.g. glutamate, aspartate,
acetylcholine, norepinephrine, histamine, corticotrophin
releasing factor, purines, peptides, cytokines and steroid
hormones) enhance the excitability and propagation of
neuronal activity, whereas gamma-amino butyric acid (GABA)
and dopamine inhibit neuronal activity and propagation.
PATHOPHYSIOLOGY
 During a seizure, the demand for blood flow to the brain
increases to carry off CO2 and to bring substrate for metabolic
activity of the neurons.
 As the seizure prolongs, the brain suffers more from ischemia
that may result in neuronal destruction and brain damage.
 Mutation in several genes may be linked to some types of
epilepsy.
 Genes that code for protein subunits of voltage-sensitive and
ligand-activated ion channels have been associated with the
generalized epilepsy and infantile seizure syndromes.
PATHOPHYSIOLOGY
 One speculated mechanism for some forms of inherited
epilepsy are mutation of the genes which code for sodium
channel proteins
 These defective sodium channels remain open for long time
which triggers excessive calcium (Ca2+) release in the post
synaptic cells which may be neurotoxin to the affected cells
experimental and clinical findings support a crucial role of
inflammatory processes in epilepsy, in particular in the
mechanisms underlying the generation of seizures.
AETIOLOGY OF SEIZURES
 Genetic factors: increased incidence of epilepsy in relatives of those with
a disorder
 Head injury
 Stroke or cerebrovascular disorders
 Metabolic disturbances
 Electrolyte imbalance: sodium, calcium, magnesium
 Hypo or hyperglycaemia
 Uremic encephalopathy
 Hepatic encephalopathy
 Dialysis disequilibrium
 Hypoxia
AETIOLOGY OF SEIZURES
 High fever due to infections or heat stroke
 Infections such as meningitis, encephalitis, HIV, malaria
 Tumours or space occupying lesions
 Abrupt withdrawal of alcohol, barbiturates and narcotics
 Drugs: TCAs, lithium, aminophylline, high doses of
penicillin, phenytoin, clozapine
 Toxins such as lead
CLASSIFICATION
CLASSIFICATION
 Determining the type of seizure that has occurred is
essential for:
 Focusing the diagnostic approach on particular etiologies,
 Selecting the appropriate therapy,
 Providing potentially vital information regarding prognosis
 A fundamental principle is that seizures may be either
focal or generalized.
CLASSIFICATION: FOCAL
SEIZURES
 These are also called partial seizures and are further
subclassified into simple partial, complex partial and
secondarily generalised.
 General features of partial seizures
 Seizure activity is localized in one focal point within a hemisphere or
lobe.
 Presentation of the seizure depends on the part of the brain affected
by the seizure activity.
 The individual remains fully or partially conscious.
SIMPLE PARTIAL SEIZURES
 Also called aura/warning
 Location: one hemisphere or lobe from the onset,
involves a small area only
 Consciousness: fully conscious and aware of seizure
 Onset: Sudden
 Subjective account: The individual may describe feeling
fearful that the seizure will develop.
 Recovery/post-ictal state: quick
SIMPLE PARTIAL SEIZURES
Typical clinical manifestations
 Temporal lobe: epigastric rising sensation, déjà vu,
sudden sense of fear or elation or unusual taste or
smell
 Frontal lobe: stiffness or juddering of affecting part of
the body
 Parietal lobe: numbness or tingling sensation
 Occipital lobe: distorted vision, flashing lights, formed
hallucinations
SIMPLE PARTIAL SEIZURES
COMPLEX PARTIAL
SEIZURES
 Also known as aura or temporal lobe epilepsy
 Location: localised to one hemisphere or lobe from onset, involving
a larger area than SPS.
 Consciousness: partially conscious so often behaves in a confused
manner
 Onset: sudden
 Subjective account: Afterwards the individual may describe feeling
embarrassed, and can be more prone to depression.
 Recovery/post-ictal state: the individual may remain confused for
some time after the seizure
COMPLEX PARTIAL
SEIZURES
Typical features
 Temporal lobe CPS: semi-purposive
automatisms i.e. automatic repetitive behaviour
such as lip smacking, chewing, repeatedly
picking up objects or fiddling with clothes
 Frontal lobe CPS: crying, screaming, swearing,
unusual leg movements such as cycling motion,
stepping or kicking.
COMPLEX PARTIAL
SEIZURES
SECONDARILY
GENERALISED SEIZURES
 Location: seizure activity spreads from localised area to involve the
whole of the cortex
 Consciousness: Either fully or partially conscious at onset,
consciousness is lost when seizure becomes generalised.
 Onset: sudden
 Typical manifestations
 Seizure manifests as a simple partial or complex partial seizures, before activity
spreads and develops into a generalized seizure .
 If onset is slow, individual may be aware of SPS/CPS features.

 Recovery: Recovery depends on the type of generalised seizure that

develops. Most commonly develops into a tonic-clonic seizure
GENERALISED SEIZURES
 Subtypes
 Tonic-clonic (Grand mal)
 Tonic
 Atonic (Drop jerk)
 Myoclonic (Jerks)
 Absence (Petit mal)

 Features
 Seizure activity involves the whole of the cortex from the onset.
 The individual is unconscious during the seizure and so will have no
memory of the seizure itself.
TONIC-CLONIC SEIZURES
 They are the most common generalised seizures
 Location: Seizure activity involves whole of cortex from
onset.
 Typical presentation occurs in 5 phases
1. Prodromal phase
 A clear deterioration in function before the active phase of an
epilepsy
 There may be social withdrawal, a marked drop in functioning,
increasing difficulty with concentration, loss of motivation or energy
to participate in any activity, dramatic sleep and appetite changes
 This may run for a day or two, even a week.
TONIC-CLONIC SEIZURES
2. Aura phase
 Patients may have an aura (an unusual feeling that often warns the
patient that they are about to have a seizure). A yell or cry often
precedes the loss of consciousness
3. Tonic phase
 Onset of the seizure may be a sudden cry and they may drool and bite
their tongue.
 The individual goes stiff and falls to the ground if standing..
 Their breathing may be laboured and their colour may
change(becoming pale or blue).
 They may be incontinent.
TONIC-CLONIC SEIZURES
4. Clonic phase
 This is characterized by rhythmical jerking/convulsions of the body often lasting a
couple of minutes
 The patient may remain unconscious for a period of time.
 The seizure usually lasts 5 to 20 minutes

5. Recovery/Post-ictal phase
 Colour and breathing return to normal.
 Typically the individual is very tired, and confused.
 They may experience muscle aches and may wish to sleep.
 The patients may experience prolonged weakness after the event; this is termed
Todd’s palsy
TONIC-CLONIC SEIZURES
TONIC SEIZURES
 Location: involves the whole cortex from onset.
 Onset: sudden
 Consciousness: Lost
 Typical manifestations: Brief increase in body muscle
tone, usually causing the person to fall backwards if
standing.
 Recover/post-ictal phase: Recovery is usually quick.
Injuries are common to the back of the head
ATONIC SEIZURES
 Location: involves the whole of the cortex from the onset
 Onset: sudden
 Consciousness: lost
 Typical clinical manifestation: Brief loss of muscle tone,
usually causing the person to fall forwards if standing
 Recovery/post-ictal: Recovery is usually quick. Injuries
are common to the face.
MYOCLONIC SEIZURES
 Location: seizure activity involves the whole of the cortex from onset
 Onset: sudden
 Consciousness: lost
 Typical clinical manifestation:
 Brief jerking or shock-like movements, usually of the arms and legs, but also of the
head or trunk
 This seizure commonly occur in the morning and on waking, often in clusters.
 Usually occur with other seizure types, most often tonic-clonic.

 Recovery/post-ictal: Recovery is usually quick. Between repeated

clusters of seizures, the person may be confused.
ABSENCE SEIZURES
 Location: Seizure activity involves whole of
cortex from onset.
 Onset: sudden
 Consciousness: lost
 Recovery/post-ictal: Recovery is usually quick.
 This type usually occurs in children and young
adults, often remits.
ABSENCE SEIZURES
TYPICAL ABSENCE SEIZURES ATYPICAL ABSENCE SEIZURES
 The person briefly goes blank/stares and is  usually associated with loss of muscle tone or
unresponsive movement, e.g. brief head nod.
 They may flutter their eyelids or their eyes may  Usually lasts 10 -30 seconds.
turn.  Brief staring spells with variably reduced
 Usually last 3-20 seconds. responsiveness
 Brief staring spells (“petit mal”) with impairment  Gradual (seconds) onset and resolution
of awareness  Generally not provoked by hyperventilation
 Sudden onset and sudden resolution
 Onset typically after 6 years of age
 Often provoked by hyperventilation
 Often in children with global cognitive impairment
 Onset typically between 4 and 14 years of age
 Patients often also have Atonic and Tonic
 Often resolve by 18 years of age seizures
EPILEPSY SYNDROMES
 Epilepsy syndromes can be defined by a group of features usually occurring together
 Patients usually share similar seizure type as well as cause (if known), precipitating
factors, age of onset, characteristic EEG patterns, severity, chronicity, family history
and prognosis.
 They include:

1. Nocturnal frontal lobe epilepsy: Childhood onset, nocturnal, seizures- complex

motor movements/vocalization
2. Benign rolandic epilepsy: Late childhood, nocturnal, simple partial seizures
involving face
3. Benign occipital epilepsy of childhood: Childhood onset, seizures with visual
symptoms- scotoma/blindness
4. Childhood absence epilepsy: Childhood, absence seizures, EEG- 3 Hz spike-wave
discharges
EPILEPSY SYNDROMES
5. Juvenile myoclonic epilepsy: Teenagers, early morning
myoclonic jerks, EEG- 4-6 Hz generalized spike-wave
discharges
6. Lennox-Gastaut syndrome: Teenagers, MR + GTC
seizures + EEG- 2 Hz slow spike-wave pattern
7. Temporal lobe epilepsy: Teenage onset, complex partial
seizures, poor response to AED
8. West syndrome: Mental retardation + infantile spasms +
EEG- hypsarrythmia
DIAGNOSIS
 History taking
 Details of birth and childhood: hypoxia, cerebral palsy, trauma
 Family history
 Medication regimen
 Past medical history
 History of drug and alcohol abuse

 Physical and Neurologic examination

 Diagnostic techniques
 CT scan, MRI, EEG, ECHO, ECG, FHG, Drug-toxin screening,
urinalysis, RBS, UECs, HIV, Toxoplasmosis
MANAGEMENT
MANAGEMENT
 Antiepileptic drug therapy is the mainstay of treatment for
most patients with epilepsy.
 Treatment plans must be individualized
 The overall goal is to completely prevent seizures without
causing any untoward side effects, preferably with a single
medication and a dosing schedule that is easy for the
patient to follow.
 Seizure classification is an important element in designing the
treatment plan, because some antiepileptic drugs have different
activities against various seizure types.
 ANTIEPILEPTIC DRUGS
MOLECULAR TARGETS AEDS
Voltage gated sodium channels Phenytoin, fosphenytoin, Carbamazepine, Lamotrigine,
Lacosamide,
Voltage gated calcium channels (T-type) Ethosuximude
Voltage gated potassium channels (Kv7) Retigabine
GABAa receptors Phenobarbital, benzodiazepines,
GAT-1 GABA transporter Tiagabine
GABA transaminase Vigabatrin
Synaptic vesicle 2 A Levetiracetam
a2d Gabapentin, pregabalin
AMPA receptor Perampanel
Mixed/unknown Valproate, Felbamate, Topiramate, Zonisamide,
Rufinamide, adrenocorticotropin
GENERAL PRINCIPLES OF
THERAPY
1. Drug choice should depend on seizure type or epileptic syndrome, efficacy,
cost, pharmacokinetic profile, ADRs and comorbidities.
2. Aim to treat only one drug with the lowest possible dose that causes minimal
side effects.
3. Treatment should be introduced slowly, starting with a small dose to minimise
side effects.
4. Drugs should be introduced slowly then gradually increased to an initial
maintenance dose. Assess seizure control and change dose of drug if necessary
5. Phenytoin requires strict therapeutic drug monitoring as small changes in dose
cause considerable plasma level changes.
6. A patient should remain on the same brand of medication because
pharmacokinetics and bioavailability are different for different formulations.
GENERAL PRINCIPLES OF
THERAPY
7. Altering drug regimens- if there is no seizure control with maximal dose
of one drug, or if intolerable side effects occur, the first drug can be
replaced with another first line drug. The second drug is added
gradually to the first. Once a good dose of the second drug is
established the first one is slowly withdrawn.
8. Drug withdrawal- abrupt withdrawal of drugs especially barbiturates
and benzodiazepines causes rebound seizures. Withdrawal should be
done in a slow stepwise fashion. If a drug needs to be withdrawn rapidly
due to life threatening side effects, diazepam or another benzodiazepine
should be used to cover the withdrawal phase.
9. Follow up and monitoring of treatment should be done so as to know
when to make dose changes and to assess compliance of the patients to
therapy and any side effects.
GENERAL PRINCIPLES OF
THERAPY
10. Newer antiepileptic drugs are not superior to the older
antiepileptics, they are only better tolerated.
11. Stopping treatment- most patients need life long therapy.
However patients who have been seizure free for more than
two years can be considered for withdrawal of therapy.
Drug withdrawal should be carried out slowly in staged
decrements and only one drug at a time should be withdrawn.
12. Monitoring of therapy is done by therapeutic drug
monitoring. Plasma levels are checked ,correlated with clinical
features and doses adjusted.
Medical Treatment of First
Seizure
Whether to treat first seizure is controversial
 16-62% of unprovoked seizures will recur within 5 years
 Relapse rate may be reduced by antiepileptic drugs
 Relapse rate increased if:
 abnormal imaging
 abnormal neurological exam
 abnormal EEG
 family history

 Quality of life issues are important (ie driving)

Starting AEDs
 Discuss likely adverse effects

 Discuss unlikely but important adverse effects

 Discuss likelihood of success

 Discuss recording/reporting seizures, adverse effects, potential precipitants

NON-PHARMACOLOGICAL
MANAGEMENT
 Adequate sleep
 Avoidance of alcohol, stimulants, etc.
 Avoidance of known precipitants
 Stress reduction — specific techniques

 Diets: ketogenic diet, modified Atkins diet, low

glycaemic diet.
SURGERY
 Surgery is used for epilepsy syndromes not responsive to medical management
 Unacceptable seizure control despite maximum tolerated doses of 2-3 appropriate
drugs as monotherapy
 Epilepsy syndrome amenable to surgical treatment
 Potentially curative
 Resection of epileptogenic region (“focus”) avoiding significant new neurologic deficit

 Palliative
 Partial resection of epileptogenic region
 Disconnection procedure to prevent seizure spread
 Callosotomy
 Multiple subpial transections
Vagus Nerve Stimulator
 Intermittent programmed electrical stimulation of left vagus nerve

 Option of magnet activated stimulation

 Adverse effects local, related to stimulus: hoarseness, throat discomfort,

dyspnea)
 Mechanism unknown

 Clinical trials show that 35% of patients have a 50% reduction in seizure
frequency and 20% experience a 75% reduction after 18 months of therapy.
 May improve mood and allow AED reduction

 FDA approved for refractory partial onset seizures and refractory

depression
STATUS
EPILEPTICUS
Status epilepticus
 Status epilepticus exists when seizures recur within a short
period of time , such that baseline consciousness is not
regained between the seizures.
 They last for at least 30 minutes.
 Can lead to systemic hypoxia, acidemia, hyperpyrexia,
cardiovascular collapse, and renal shutdown.
 The most common, generalized tonic-clonic status epilepticus is
life-threatening and must be treated immediately with
concomitant cardiovascular, respiratory and metabolic
management
STATUS EPILEPTICUS IN CHILDREN
EPILEPSY AND
PREGNANCY
EPILEPSY AND PREGNANCY
 96% of pregnancies in mothers with epilepsy produce normal children
 There is an increased rate of fetal malformations associated with antiepileptic
drug exposure
 Seizures during pregnancy may be harmful
 Tonic-clonic seizures are associated with intracranial hemorrhage, fetal
bradycardia and lower IQ in children
 Status associated with increased fetal and maternal mortality in some studies
 Major congenital malformations (malformation that affects physiologic
function or requires surgery) due to AEDs include neural tube defects,
cardiac defects, genitourinary defects and oral clefts
EPILEPSY AND PREGNANCY
Valproate has been consistently associated with poorer
outcomes
 MCM rate with valproate monotherapy 6.2-16.3% across 5 registries
 Most studies show dose- related increase in risk with doses >
750mg/day
 Polytherapy regimens including valproate also substantially
increased risk of MCM
 Valproate is associated with lower IQs in exposed children compared
with other AEDs (10pts on average)
 Valproate is associated with an increased risk of autism and autism
spectrum disorder in exposed children
EPILEPSY AND PREGNANCY
 Probably safest AEDs (range of published MCM rates)
 Lamotrigine (2-5.2%)
 Levetiracetam (3%)
 Carbamazepine (2.2-6.3%)
 Phenytoin (2.9-6.7%)
 Probably have risk lower than valproate (more data needed)
 Oxcarbazepine
 Zonisamide
 Gabapentin

 Have significant risk greater than some other AEDs

 Topiramate
 Phenobarbital
 Valproate
EPILEPSY AND PREGNANCY
Education
 Most women with epilepsy have normal children

 Risk of fetal malformations is increased with AED exposure

 AED teratogenicity is related to exposure in the first trimester of pregnancy

 Effects on cognitive development likely occur throughout pregnancy but particularly

in 3rd trimester
 Planning should begin well before pregnancy

 Seizures may be deleterious to the fetus

 Compliance with AED treatment is important

 Prenatal diagnosis of fetal malformations is possible

EPILEPSY AND PREGNANCY
Before pregnancy
 Confirm epilepsy diagnosis (exclude non-epileptic seizures)
 Attempt AED monotherapy with lowest effective dose
 Consider switching AEDs prior to pregnancy, particularly if
on valproate
 Establish baseline therapeutic levels
 High dose folate supplementation: 5 mg/day
EPILEPSY AND PREGNANCY
During pregnancy
 Continue folate supplementation

 Recommend level II ultrasound

 Monitor AED levels at least monthly and adjust dose accordingly

 Lamotrigine clearance increases dramatically over the course of pregnancy

 Metabolism also increased for levetiracetam, oxcarbazepine, phenobarbital and phenytoin

 Carbamazepine levels may be relatively stable, but depends on the individual patient

 Patients need a post-partum dosing plan to avoid toxicity post-partum

QUESTIONS
1. Do you think there is something wrong with
Kali? If so, what would your diagnosis be?
2. Support your answer in (1) above.
3. What tests would you perform to figure out
what may be going on?
4. What pharmacological agents are indicated
for this patient?