• Dipiro’s Pharmacotherapy 10th
edition, Chapter 56
• National Institute for Health and Care Excellence, Epilepsies:
diagnosis and management
• Benamer, H. and Grosset, D. (2009). A systematic review of the
epidemiology of epilepsy in Arab countries. Epilepsia, 50(10),
• Clinical Pharmacokinetics of Levetiracetam: Clin Pharmacokinetics
• Epilepsy is a common neurologic condition in which a
person is prone to recurrent epileptic seizures.
• There are many types of epilepsies characterized by
different seizure types, ranging in severity and etiologies.
• The heart of all epilepsies is disturbed regulation of
electrical activity in the brain resulting in synchronized
and excessive neuronal discharge
5. • the International League Against Epilepsy (ILAE)
defines epilepsy not only as “a chronic condition of
the brain characterized by an enduring propensity to
generate epileptic seizures” but also by “the
neurobiological, cognitive, psychological, and
social consequences of this condition.”
• Epilepsy is the fourth most common neurologic disorder
• According to the World Health Organization (WHO), more
than 65 million people worldwide suffer from epilepsy
• Among children, epilepsy is most highly prevalent in children
under 5 years of age with the highest number of new cases
occurring under 2 years of age.
• The high frequency of epilepsy in the elderly is now also
being recognized with 1.5% of people older than 65 being
affected by epilepsy in the United States.
• The majority of patients with epilepsy have a good prognosis and will
be able to attain seizure freedom and enjoy normal life expectancy.
• However overall, the mortality rate of patients with epilepsy is 2 to
3 times that of the general population and life expectancy in some
of these patients is reduced.
• This increase in mortality has been attributed to a wide variety of
reasons including sudden unexplained death in epilepsy (SUDEP).
• Although all individuals with epilepsy experience seizures, not all
individuals who experience seizures will be diagnosed with
10. Seizures vs. Epilepsy
Some seizures are provoked and occur as a result of:
High fever, especially in infants (eg, febrile seizures).
systemic, toxic, or metabolic insults such as drug overdose;
alcohol, barbiturate or benzodiazepine withdrawal
acute neurologic illness (eg, brain hemorrhage)
systemic illnesses (eg, hypocalcemia, hypoglycemia, uremia, and
Brain tumor, infection, stroke
Complication of diabetes or pregnancy
These seizures do not constitute epilepsy, as they are a symptom of
the provoking insult.
12. Genetic Etiology
• Epilepsies with genetic etiology
usually present in infancy or
Examples of genetic epilepsies are:
• Juvenile Myoclonic Epilepsy (JME)
• Dravet Syndrome
• Childhood Absence Epilepsy (CAE)
13. Structural Etiology
• Structural etiologies can be of acquired or genetic origin
and refer to abnormalities visible on structural
• Common epilepsies caused by structural abnormalities
include mesial temporal lobe epilepsy and post-traumatic
14. Infectious Etiology
• The most common epilepsy etiology worldwide is
infectious and is generally acquired.
• An infectious etiology refers to a patient who
develops epilepsy as the sequelae of an infection, and
not to a patient who is experiencing seizures in the
setting of acute infection such as meningitis or
15. Metabolic and Immune Etiology
• Are less common etiologies
• Metabolic etiologies such as Lafora disease, which is
associated with abnormal glycogen metabolism and
subsequent development of insoluble glycogen
inclusion bodies resulting in epilepsy
• A range of immune epilepsies are also being
recognized, such as anti-N-methyl-D-aspartate (anti-
NMDA) receptor encephalitis which causes
autoimmune-mediated central nervous system
inflammation and resulting epilepsy.
16. Unknown Etiology
• Patients can also present with unprovoked seizures
that do not have an identifiable cause, and thus by
definition have epilepsy of unknown cause.
• These epilepsies may be due to an as yet unidentified
gene or may be the consequence of an as yet
unrecognized structural or metabolic disorder.
17. Risk Factors of epilepsy:
• Premature birth with small gestational weight
• Perinatal injury (eg, anoxia)
• History of alcohol withdrawal seizures
• History of febrile seizures
• Family history of seizures.
18. Triggers of epilepsy:
• Physical and emotional stress
• Sleep deprivation
• Sensory stimuli
• Hormonal changes occurring around the time of
• Drugs: theophylline, alcohol, high-dose
phenothiazines, antidepressants (especially
bupropion), and street drugs (lower seizure threshold)
Most seizures can be classified
by their mode of onset
(1)Generalized: Onset seizures
begin in both hemispheres of
(2) Focal: Onset seizures begin
in only one hemisphere of the
Focal seizures may be further characterized by whether
impairment or alteration of consciousness occurs.
(1) Simple partial seizures, when consciousness is not
impaired (focal seizures without dyscognitive features)
(2) Complex partial seizures, when the consciousness has
been impaired (with dyscognitive features)
•Focal seizures may spread beyond the one hemisphere of
the brain to the contralateral hemisphere to involve both
hemispheres (are now referred to as focal seizures evolving
to a bilateral convulsive seizure)
25. Clinical Presentation
(1)Focal seizures without dyscognitive features,
Such symptoms will vary depending on where the abnormal
•seizures may manifest as alterations in motor functions such
as clonic movements (eg, twitching or jerking) of the arm,
shoulder, face, or leg indicating seizure activity in motor
•Sensory or somatosensory symptoms may also occur, such as
feelings of numbness or tingling or a feeling of déjà vu,
indicating parietal or temporal lobe seizure activity.
•Visual disturbances or hallucinations may also indicate
seizure activity involving the occipital lobe
•while ringing or buzzing sounds in the ears may indicate
seizure activity in auditory areas of the brain.
26. Clinical Presentation
(2)Focal dyscognitive seizures: the hallmark is
amnesia to the event.
•Similar clinical signs and symptoms as that described
except with impairment of consciousness.
•The patient may be able to respond to questions during the
seizure, although they may not respond appropriately.
•After the seizure (postictal period), the patient may display
altered consciousness, drowsiness, confusion, or even
paranoia for a variable period of time and frequently go
into a deep sleep.
27. Clinical Presentation
(3)Focal seizures evolving to a bilateral
convulsive seizure have clinical features that
differentiate it from generalized seizures. In some cases,
patients will describe somatosensory symptoms as a
“warning” prior to the convulsive seizure termed auras,
which are by definition restricted focal epileptic discharges.
There are two types of auras:
•Sensory auras: may include feelings of tingling,numbness,
flashing lights, odors, tastes, and epigastric distress
•Experiential auras: include feelings of fear, depression, joy,
anger, or memory phenomena such as feelings of familiarity
(déjà vu) or unfamiliarity (jamais vu).
29. 1- Generalized absence seizures
• Sudden onset interruption of ongoing
activities, a blank stare, and possibly a brief
upward rotation of the eyes. (lasts 2 to 30
seconds during which time the patient is
unaware of the environment and
• After cessation of the seizure, the patient
will often return to the previous activity as
if nothing had happened.
• These absence seizures generally occur in
young children through adolescence
30. 2- Myoclonic seizures
• Brief, shock-like muscle contractions
• These jerks can occur as a single jerk or
as a series of jerks with each jerk
typically lasting only milliseconds
• These jerks are synchronous and display
bilateral features usually involving the
whole body simultaneously, although
they can be asymmetric and confined to
• They are not associated with an
alteration in consciousness and are
typically worse in the late evening or
early morning either prior to going to
sleep or soon after awakening
31. 3- Generalized clonic seizures
Are seizures involving bilaterally rhythmic jerking
that are more sustained and rhythmic than that seen
in a myoclonic seizures.
4. Generalized tonic seizures
Involve bilaterally increased tone or “stiffening” of
the limbs typically lasting seconds to a minute
32. 5. Generalized onset tonic-clonic seizure
Consisting of an initial tonic phase followed by a
clonic phase. It is important to remember that GTC
seizures can also be secondarily generalized and that
these seizures must be differentiated from generalized
onset tonic-clonic seizures
33. 6-Atonic seizures
• Are not preceded by myoclonic or tonic features and can be
• They often occur in patients with intellectual impairment.
• They may present as a head drop, the dropping of a limb, or a
slumping to the ground (due to loss of postural tone).
• These patients often wear protective headware to prevent
A person is considered to have epilepsy if they meet any
of the following conditions:
1- At least two unprovoked (or reflex) seizures occurring
greater than 24 hours apart
2- One unprovoked (or reflex) seizure and a probability of
further seizures similar to the general recurrence risk (at
least 60%) after two unprovoked seizures, occurring over
the next 10 years
3- Diagnosis of an epilepsy syndrome
• Firstly, the presence of an aura should be determined. If
the presence of an aura can be confirmed, it becomes very
likely that the seizure is focal. The presence of ictal
motor, sensory, or autonomic features should all be noted
• The degree of mental status impairment during the event
should be determined.
• Tongue biting, cheek biting, and bladder or bowel
incontinence during the seizures should be asked about
and the seizure time course noted.
• Postictal phenomena (eg, fatigue, headaches, confusion,
and psychosis) should be assessed.
36. Diagnostic Tests
(1) Laboratory Tests
•There are currently no diagnostic lab tests for epilepsy
•In some cases, particularly following generalized convulsive
seizures, serum prolactin levels obtained within 10 to 20
minutes can be transiently elevated.
•Laboratory tests can be done to rule out treatable
causes of seizures
37. Diagnostic Tests
An abnormal epileptiform EEG
is found in only approximately
50% of the patients who have
epilepsy. Sometimes several
EEGs must be obtained before
convincing epileptiform activity
is detected. Video EEG is the
gold standard for diagnosing
epilepsy and involves admission
to the hospital and recording
video and EEG until the patient
has a typical event.
39. Diagnostic Tests
(4)A computed tomography (CT) scan
Typically is not helpful except in the initial evaluation
for a brain tumor, cerebral bleeding, or gross
40. Epilepsy-Related Health Screening
• Screening for comorbid medical, psychiatric, and
neurodevelopmental conditions commonly coexisting
with epilepsy is useful
• Common conditions that are typically screened for in
patients with epilepsy include depression (and
suicidal ideation), learning and development in
children, and bone health
42. Goals of Treatment:
• Antiseizure drug therapy is the mainstay of epilepsy
treatment. However, ASDs are symptomatic
treatment only. None have been proven to have any
disease modifying properties, and no ASDs are
curative. Therefore, the majority of patients will be
on life-long ASD therapy. Surgery is the only
possibly curative therapy.
43. Goals of Treatment:
1. To control or reduce the frequency and severity of
2. Minimize side effects
3. Ensure compliance (60% of patients with epilepsy are
4. Allowing the patient to live as normal a life as possible
• In most patients the goal is complete seizure freedom.
However, in 20% to 35% of patients this may not be
possible, and seizure control must be balanced with QOL
44. General approach
• Drug selection depends on the seizure type and epilepsy
classification, drug-specific adverse effects, patient
characteristics, and insurance coverage.
• Begin with monotherapy.
About 65% of patients can be maintained on one antiseizure
drug, although not necessarily seizure free.
• Some initiate ASDs after one unprovoked seizure, other do so
after one unprovoked seizure with an abnormal epileptiform
EEG. Others wait until a second unprovoked seizure has
occurred. Patients who have had two or more seizures should
generally be started on ASDs.
46. When to withdraw ASDs
Factors favoring successful withdrawal of ASDs
•A seizure-free period of 2 to 5 years
•Complete seizure control within 1 year of onset
•An onset of seizures after age 2 years and before age
•A normal EEG and neurologic examination.
Always withdraw ASDs gradually.
47. When NOT to withdraw ASDs
Factors favoring an unsuccessful withdrawal
of ASDs include
•A history of a high frequency of seizures
•Repeated episodes of status epilepticus
•Combination of seizure types
•Development of abnormal mental
is defined as any
longer than 30
minutes in which
the patient does
not regain baseline
• Enzyme-inducing ASDs
(eg, Carbamazepine,Oxcarbazepine, Topiramate, Rufinamide,
Lamotrigine, Clobazam, Felbamate, Phenytoin and Phenobarbital)
may cause treatment failures in women taking oral
• A supplemental form of birth control is advised if breakthrough
51. Catamenial epilepsy
• Estrogen has a seizure-activating effect
• while progesterone has a seizure-protective effect.
• For catamenial epilepsy (seizures just before or during
menses) or seizures that occur at the time of ovulation
((↑of estrogen compared to progesterone))
▫ Conventional ASDs should be tried first
▫ Intermittent supplementation with higher-dose ASDs
▫ Benzodiazepines should be considered
▫ Progestational agents may also be effective
• Seizures often improve in frequency at menopause.
• Women with epilepsy who are seizure free for 9 to 12 months
before becoming pregnant have an 84% to 92% chance of being
seizure free during pregnancy.
• Druring pregnancy clearance increases Lamotrigine (↓40%)Lamotrigine (↓40%) ,
phenytoin, carbamazepine, oxcarbazepin, and levetiracetam
and protein binding may be reduced so serum concentration
monitoring is important.
• Serum concentrations may also fluctuate during pregnancy
of phenobarbital, primidone, ethosuximide, and valproic acid.
• Valproic acid (category D) is associated
with a risk of MCMs 3.5 to 4 times that of
offspring of nonepileptic women. There is
also an increased risk of
neurodevelopmental effects including
effects on cognition.
• Topiramate (category C→ D) use during
pregnancy has been associated with cleft
palate and possibly low birth weight and
• Teratogenic effects may possibly be prevented by adequate
folate intake, although strong evidence is lacking.
• Folic acid (0.4–5 mg/day) are recommended Higher folate
doses should be used in women who have previously
delivered a child with a neural tube defect and women who are
taking valproic acid.
• Neonatal hemorrhagic disorder: Vitamin K, 10 mg/day
orally, given to the woman during the last month of pregnancy
may prevent neonatal hemorrhagic disorder. Alternatively,
parenteral vitamin K can be given to the newborn at delivery.
• Other adverse outcomes of maternal seizures are growth,
psychomotor, and mental retardation.
56. Conditions altering ASD protein binding
• For populations known to have altered plasma protein
binding, measure free rather than total serum
concentrations if the ASD is highly protein bound.
• Conditions altering ASD protein binding include:
▫ Chronic renal failure
▫ Liver disease
▫ Displacing drugs
▫ Age (neonates and the elderly)
57. Neonates and infants
• Neonates and infants display decreased efficiency in
renal elimination and may metabolize drugs more
• But by age 2 or 3 years children may metabolize
drugs more rapidly than adults.
• Thus, neonates and infants require lower doses of
• But children require higher doses of many ASDs
• Lower doses of ASDs are often required in the elderly
due to compromised renal or hepatic function.
• The elderly are more prone to experience neurocognitive
effects and drug–drug interactions
• Hypoalbuminemia is common in the elderly, and highly
bound ASDs (eg, valproic acid) can be problematic.
• 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.
60. 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.”
• The therapeutic range for ASDs may be different for different
seizure types (eg, higher for focal seizures with dyscognitive
features than for GTC seizures).
• 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.
• Usually dosing is initiated at one-fourth to one-
third of the anticipated maintenance dose and
gradually increased over 3 to 4 weeks to an
• Clinical response is more important than serum drug
• Evidence for comparable effectiveness is mostly
available for older agents and for a few newer ones.
• In general, the newer ASDs appear to have
comparable efficacy to the older drugs, and some
may be better tolerated.
• Carbamazepine, ethosuximide, gabapentin, levetir
acetam, oxcarbazepine, phenytoin valproic acid,
and zonisamide have strong enough evidence to be
labeled efficacious or effective or as probably
efficacious or effective as initial monotherapy in
certain seizure types.
• Some ASDs may possibly precipitate or aggravate
certain seizure types, and it is suggested that they be used
with caution in those patients.
Carbamazepine, gabapentin, oxcarbazepine, phenytoin
tiagabine, and vigabatrin in children with absence or
juvenile myoclonic epilepsy.
is defined as failure of adequate trials of two
tolerated and appropriately chosen and used ASD
schedules (whether as monotherapies or in
combination) to achieve sustained seizure
65. Adverse effects
• CNS side effects are frequent and include sedation,
dizziness, blurred vision, poor concentration and ataxia
(lack of muscle coordination).
• Barbiturates can cause more cognitive impairment than
other ASDs, but in children, they can cause paradoxical
• In general, the newer agents have less effect on cognition,
• The most widely recognized idiosyncratic reactions are
ASD-induced drug rashes, which can progress to Stevens-
Johnson Syndrome/toxic epidermal necrolysis.
• Others are hepatitis, blood disorders, and acute organ
failure(within the first 6 months).
67. Adverse effects
• A side effect of long-term use of ASDs is osteomalacia or
• It is hypothesized that phenytoin, phenobarbital,
carbamazepine, oxcarbazepine, felbamate,
and valproic acid may interfere with vitamin D metabolism.
• Patients taking these drugs should receive vitamin D
supplementation and calcium and bone mineral density testing
if other risk factors for osteoporosis are present.
68. Drug–drug Interactions
• Pharmacokinetic interactions are common complicating
factor in ASD selection.
• Phenobarbital, phenytoin, and carbamazepine are
potent inducers of cytochrome P450 (CYP450), epoxide
hydrolase, and uridine diphosphate
glucuronosyltransferase enzyme systems.
• Valproic acid inhibits many hepatic enzyme systems and
displaces some drugs from plasma albumin.
• Felbamate and Topiramate can act as inducers with
some isoforms and inhibitors with others.
• It is FDA approved for use in patients with focal onset
seizures, GTC seizures, and mixed seizure types. It may
worsen absence seizures and tonic-clonic seizures in patients
with other generalized seizure types
• Food, especially fat, may enhance the bioavailability of
• Leukopenia is the most common hematologic side effect (up
to 10%) but is usually transient. Carbamazepine may be
continued unless the white blood cell count drops to less than
(2.5 × 109
73. • Hyponatremia (ADH↑) occurs less frequently than
with oxcarbazepine, Na concentrations are
recommended, especially in the elderly.
• Rashes may occur in 10% of patients.
• Other side effects include nausea, hepatitis,
osteomalacia, cardiac conduction defects, and lupus-
• Compared to other first generation ASDs, it causes
minimal cognitive impairment.
74. • Carbamazepine may interact with other drugs by inducing
their metabolism. Valproic acid increases concentrations of
the 10,11-epoxide active metabolite10,11-epoxide active metabolite without affecting the
concentration of carbamazepine.
• Autoinduction of its own
metabolism starts 3–5 days after
initiating and is complete in 21 to 28
• Reversal of autoinduction is rapid
• It is indicated for use as monotherapy or adjunctive therapy
for partial seizures.
• Is a produrg of monohydroxy active metabolite.
• It generally has fewer side effects than phenytoin, valproic acid,
• Hyponatremia is reported in up to 25% of patients.
• About 25% to 30% of patients who have had a rash with
carbamazepine will have a similar reaction with oxcarbazepine.
• In patients converted from carbamazepine, the typical
maintenance doses are 1.5 times the carbamazepine.
• One of the latest ASDs to be clinically used in 2009
• Eslicarbazepine acetate is a prodrug that undergoes
hydrolysis to S-licarbazepine, the major active metabolite of
• It is FDA approved for monotherapy or adjunctive therapy of
focal onset seizures.
• It causes less hyponatremia than oxcarbazepine and can be
dosed once daily.
• 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.
• Phenytoin is prone to many drug interactions.
• Absorption may be saturable at higher doses (above 400 mg).
• Do not change brands without careful monitoring.
79. • Therapeutic Drug Monitoring (TDM):
• Checklist algorithim
• At concentrations greater than 50 mcg/mL (200 μmol/L),
phenytoin can exacerbate seizures.
• If protein-binding interactions are suspected, free rather than
total phenytoin serum concentrations are a better therapeutic
• Phenytoin decreases folic acid absorption, but folic acid
replacement enhances phenytoin clearance and can result in
loss of efficacy.
• Less prescribed.
• Phenobarbital, a potent enzyme inducer, interacts
with many drugs.
• Phenobarbital impairs cognitive performance.
• In children, paradoxical hyperactivity can occur.
• Long-term use is associated with osteomalacia,
megaloblastic anemia, and folate deficiency.
• Tiagabine is adjunctive therapy for patients 12 years
and older with focal onset seizures who have failed
• Side effects are usually transient and can be
diminished by taking it with food.
• It has a potential to cause seizures and status
epilepticus in some patients.
• Tiagabine is displaced from protein by naproxen,
salicylates, and valproate.
• Gabapentin is a second-line
agent for patients with focal onset seizures.
• Binding is saturable, causing dose dependent bioavailability.
• It is eliminated exclusively renally, and dosage adjustment is
necessary in patients with impaired renal function.
• Dosing titration
• Pregabalin, a schedule V controlled substance.
• It is FDA approved as adjunctive therapy for adults with
focal onset seizures.
• It is considered a second-line agent for those who have
failed initial treatment.
• It is eliminated unchanged primarily by renal excretion;
dosage adjustment is required in patients with significant
• Drug interactions are unlikely.
• Was approved in 2008
• Lacosamide is a schedule V controlled substance
approved as adjunctive therapy in patients 17 years old
or greater with focal onset seizures.
• Moderate hepatic and renal impairment both increase
systemic drug exposure by up to 40%.
• Lacosamide can cause a small increase in the median PR
• The starting dose is 100 mg/day in two divided doses,
with dose increase by 100 mg/day every week until a
daily dose of 200 to 400 mg has been reached.
• Approved in 2011
• Ezogabine is approved for adjunctive treatment of
focal onset seizures, and is recommended only after
several alternative drugs have been tried.
may increase systemic exposure to ezogabine with an
increase in side effects.
• It can ↑ lamotrigine clearance and ↓ digoxin clearance.
• It may cause falsely elevated results on urine and
serum bilirubin laboratory tests.
• It must be taken three times daily.
86. Ethosuximide (Absence seizures)
• Is a very narrow spectrum ASD
line for Absence seizures
• Titration over 1 to 2 weeks to maintenance doses of
20 mg/kg/day usually produces therapeutic serum
• There is some evidence for nonlinear metabolism at
higher serum concentrations.
• Valproic acid may inhibit metabolism of
ethosuximide, but only if the metabolism of
ethosuximide is near saturation.
87. “The brain is a monstrous,
beautiful mess”-William F.
• Psychiatric vs. Neurological disorders
• Temporal lobe
• Secondary causes (Autoimmune disease)
• “I had anti-NMDA-receptor autoimmune
encephalitis, it would make me the 217th
person worldwide to be diagnosed with it”
• Different spectrum of drugs
on different stages
Dr. Souhel Najjar
89. Valproic Acid
• Very broad-spectrum: It is first-line therapy for primary
generalized seizures, such as absence, myoclonic, and atonic
seizures, and is approved for adjunctive and monotherapy
treatment of focal onset seizures. It can also be useful in mixed
• The enteric-coated tablet is metabolized in the gut to valproic
• When switching from Depakote to Depakote-ER, the dose should
be increased by 14% to 20%. (due to reports of breakthrough
seizures on once-daily dosing.)
90. Side effects:
•GI complaints may be minimized
with the enteric-coated formulation
or by giving with food.
•Thrombocytopenia is common.
•Pancreatitis is rare.
•Valproic acid is an enzyme inhibitor that increases serum
concentrations of phenobarbital, carbamazepine 10,11-
epoxide and lamotrigine.
•Carbapenems and combination oral contraceptives may
lower serum levels of valproic acid.
• Topiramate is a first-line for partial seizures as an adjunct or
for monotherapy. It is also approved for tonic-clonic seizures in
primary generalized epilepsy and for generalized seizures in
• Approximately 50% of the dose is excreted renally as unchanged
drug. the dose should be adjusted in renally impaired patients.
• Kidney stones occurs in 1.5% of patients.
• It has also been associated with
and metabolic acidosis and weight loss.
newer ASDs it has
more effects on
• Lamotrigine is useful as both adjunctive therapy and
monotherapy for partial seizures and can be considered first-
or second-line therapy.
• It is also approved for primary Generalized Tonic Clonic
seizures, and for primary generalized seizure of Lennox-
• Rashes are usually generalized, erythematous, and
morbilliform, but Stevens–Johnson reaction has also occurred.
• The incidence of the more serious rashes appears to be
increased in patients who are also receiving valproic acid and
who have rapid dosage titration. Valproic acid substantially
inhibits the metabolism of lamotrigine and alters dosing.
• It is effective in the adjunctive treatment of focal
onset seizures in patients one month of age and
older, myoclonic seizures in patients 12 years and
older, and primary GTC seizures in patients 6 years
• Adverse effects include sedation, fatigue,
coordination difficulties, agitation, irritability, and
lethargy. It is generally well tolerated.
• It can be loaded orally or intravenously.
• The recommended initial adult dose is 500 mg orally twice
• Renal elimination of unchanged drug accounts for 66% of
levetiracetam clearance, and the dose should be adjusted for
impaired renal function. It is metabolized in blood by
nonhepatic enzymatic hydrolysis
• Felbamate is approved as adjunctive treatment for seizures of
Lennox–Gastaut syndrome and is effective as monotherapy or
adjunctive therapy for focal onset seizures as well.
• Because of reports of aplastic anemia (1 in 3000 patients) and
hepatitis (1 in 10,000 patients), felbamate is recommended
only for patients refractory to other ASDs.
• Risk factors for aplastic anemia may include:
A history of cytopenia
ASD allergy or toxicity
Viral infection and/or immunologic problems
• Vigabatrin is monotherapy for infantile spasms in infants 1
month to 2 years of age, and a third-line adjunctive agent
for refractory complex partial seizures in patients 10 years
• It is excreted unchanged in the urine. Dosage adjustment is
necessary in pediatric and renally impaired patients.
• It can cause permanent bilateral concentric visual field
constriction and reduce visual acuity. Vision should be
checked at baseline and every 3 months for up to 6 months
• Zonisamide, a broad-spectrum sulfonamide ASD, is approved
as adjunctive therapy for partial seizures
• Sedation and Word-finding difficulties are common.
• Symptomatic kidney stones may occur in 2.6% of patients.
• Modest weight loss
• Use it cautiously (if at all) in patients with a history of
• It is suitable for once- or twice-daily dosing, but once-daily
dosing may cause more side effects (due to more serum
• It is FDA approved for adjunctive treatment of seizures
associated with Lennox–Gastaut syndrome . However, it may
also have a role in focal onset epilepsies and other generalized
onset epilepsies after failure of other agents.
• Abrupt discontinuation can cause a withdrawal syndrome (eg,
behavioral disorder, tremor, anxiety, dysphoria, insomnia,
convulsions, and psychosis).
• As an inducer of CYP3A4, clobazam may lower serum levels
of some oral contraceptives.
• Many patients develop some tolerance.
• Approved in October 2012
• it is approved for focal onset seizure with or without
secondary generalization, primary GTC seizures
• It is a new drug and should be reserved for use after failure of
• Perampanel has a half-life of approximately 100 hours, and its
clearance in increased two- to threefold by enzyme inducing
• It has a boxed warning pertaining to monitoring for
psychiatric, behavioral, mood, and personality change which
may be life threatening.
108. “I had a seizure a few weeks ago and
banged up my head.”
• History of Present Illness:
Carter McNeely is a 68-year-old man
whose seizures are well controlled with
carbamazepine monotherapy. The
seizure from 2.5 weeks ago was the first
seizure in 20 months. During the
seizure, he fell to the floor and sustained
a laceration to his occipital region that
required staples for closure.
109. History of Present Illness cont.:
• Two seizures were witnessed by other residents who
described him as “falling to the ground and starting to
shake.” One seizure occurred in the day room when a
facility nurse was in the room, and he documented that
Mr McNeely fell to the ground, developed rhythmic
extensions to both his legs, became incontinent of urine,
and was sleepy and disoriented for 2 hours after the
episode. He has only been treated with carbamazepine.
This was started by his family practice physician after his
second seizure. An EEG was obtained at that time and
was unremarkable. Because the seizures are so
infrequent, the dose of carbamazepine has never been
110. Past Medical History and Current
Tonic–clonic seizures Carbamazepine XR 200 mg*2 PO
HTN Lisinopril 20mg*1 PO
Dyslipidemia Atorvastatin 40mg*1 PO and low-cholesterol diet
BPH Dutasteride 0.5mg*1 PO
Primary prophylaxis Aspirin 81 mg*1 PO
Multivitamin with minerals one tablet PO once daily
111. Family and Social Histories:
• Mother died at age 74 of “natural causes”; had HTN for
many years. Father died at age 70 of “natural causes”; did
not have any known medical illnesses. All of his children
and grandchildren are alive and well. One son and one
daughter have HTN.
• Retired factory worker; resides in an assisted living
facility. He is widowed and has six children and nine
grandchildren, whom he sees frequently. He denies past
or present tobacco and illicit drug use. He reports a
history of regular alcohol use but now only drinks one
beer that his grandson brings to him every Saturday
End points and
possibly from long-
reduced in elderly
and moderate drug
to live as
Unstable 1.Add Levetiracetam
start with 500mg*1 then
titrate to 500mg*2 in a
week or two and check
Given orally regardless
2.And tapper off
100mg every two weeks
And no side
Sodium: 135 -
Chloride: 96 - 106
Unstable Test for VitD, PTH,
Calcium and phosphate
Dietary intake of 800-
1000IU VitD and
End points and
or reduce the
the patient to
normal a life
and living in facility,
the patient needs
depression and anxiety
and counseling by a
Unstable Patient is advised to
keep a seizure diary
A.A is a 7 years old male already diagnosed with
generalized tonic clonic seizures .
Patient On topamax 25*2 admitted to the hospital due
to increased seizure frequency of 4 days duration , No
altered conciousness .
Intervention Follow up
Efficacy issue :
The patient is
taking low dose
quality of life
( seizures )
dose according to
his weight is 200
mg daily in 2
divided doses .
W must increase
the dose by 25-50
mg in a weekly
intervals over 5-7
weeks up to the
PH of the blood
; the patient
forget to give
the patient the
uncontrolled Aware the parent
of the importance
of giving him the
drug twice daily
Intervention Follow up
state that the
quality of life
( seizures )
uncontrolled Aware the
patient of the
pain in the
back, belly or
3- blood in
4- Nausea and
129. Carnexiv (carbamazepine)
• Approval Status: Approved October 2016
• Carnevix is supplied as an injection for intravenous
• The recommended total daily dose is 70% of the total daily
dose of oral carbamazepine from which patients are being
• Divide the total daily dose of Carnexiv equally in four
infusions separated by 6 hours; dilute each dose
of Carnexiv in 100 mL of diluent and infuse intravenously
over 30 minutes.
• Use of Carnexiv is not recommended for periods longer than
New drug approval
130. Briviact (brivaracetam) Oral Solution
Approved February 2016
10mg/ml oral soln, 300ml=£115.83.
Adjunct in partial-onset seizures with or without
Initially 50—100mg daily in two divided doses.
Maintenance 50—200mg daily in two divided
Under 16 years, not recommended. Over 16 years,
New drug approval
133. Napoleon I of France 1769–1821
• In 2003, John Hughes
concluded that Napoleon
had both psychogenic
attacks due to stress and
epileptic seizures due to
chronic uremia from a
severe urethral stricture
caused by gonorrhea.
134. Julius Caesar 100–44 BC
• Roman military and
political leader. There is
documentation of symptoms
experienced by Caesar
beginning on his 50th
birthday that some scholars
believe were complex
Notes de l'éditeur
For example, seizures provoked by transient high-temperature fevers will not recur when the patient is afebrile. Therefore, it is possible to have a seizure and to not have epilepsy.
Juvenile Myoclonic Epilepsy (JME) including mutations in EF-hand containing protein-1 (EFHC1)
Dravet Syndrome associated with mutations in sodium channel, voltage gated, type I alpha subunit (SCN1A)
Childhood Absence Epilepsy (CAE) associated with many dierent mutations in Ttype Ca 2+ channels and GABA receptor subunits.
-Mesial temporal lobe epilepsy:
a common type of adult-onset epilepsy and is responsible for many of the drug resistant epilepsies seen in tertiary care epilepsy clinics.
In mesial temporal lobe epilepsy, sclerosis occurs in the hippocampus, the main structure of the mesial temporal lobe and is characterized by glial scarring, reduced hippocampal volume seen on magnetic resonance imaging (MRI), and decreased cellular density seen on biopsy.
Traumatic brain injury from blunt force injury or stroke may cause structural lesions in the brain that may also cause epilepsy.
Initially during a seizure, a small number of hyperexcitable neurons fire abnormally in synchrony. Normal membrane conductances and inhibitory synaptic currents break down, and excess excitability spreads, either locally to produce a localized focal seizure or more widely to produce a generalized seizure.
The clinical manifestations depend on the site of the focus, the degree of irritability of the surrounding area of the brain, and the intensity of the impulse.
Hyperexcitability may result from a number of mechanisms. like alterations in the number, type, and biophysical properties of voltage- or ligandgated K+ , Na+ , Ca2+ , and Cl– ion channels in neuronal membranes may play a significant role.
There are many other possible mechanisms including:
Alterations in vesicle trafficking and neurotransmitter release, uptake and metabolism.
Biochemical modifications of receptors
Modulation of second messaging systems and gene expression
Changes in extracellular ion concentrations
---For instance, synaptic vesicle protein 2-A, a protein responsible for fusion of vesicles to the membrane, has been found to be upregulated in certain models of epilepsy, and is the target of the ASD levetiracetam.----However, hyperexcitability that results simply in increased firing of random individual neurons by itself does not result in epileptic seizures. Epileptic seizures result only when there is also synchronization of excessive neuronal firing
The intrinsic organization of local circuits of certain cerebral structures including the hippocampus, the neocortex and the thalamus contribute to synchronization and promote generation of epileptiform activit
-----Modifications in the ratio and function of inhibitory circuits in these structures play an important role in promoting epileptogenesis, as a large number of these neurons are interconnected and can become simultaneously inhibited, and then synchronously excited.
Although under normal circumstances, these neurons are asynchronous, it is believed that under abnormal circumstances, they become synchronous and act as pacemakers promoting epileptiform activity.
Furthermore, sprouting and reorganization of neuronal projections in abnormal tissue may also lead to a chronic susceptibility to seizures. Therefore, both excitation and inhibitory connections lie at the heart of the pathophysiologic mechanisms behind epileptogenicity
it is important to understand that the classification of seizures is separate from the classification of epilepsies and epilepsy syndromes.
In some cases the classification of seizures will be very similar to the epilepsy classification.
In other cases there will be many seizure types occurring within an epilepsy syndrome
Impairment of consciousness is usually defined by loss of awareness of external stimuli or by the inability to respond to external stimuli in a appropriate manner.
Recognizing the difference between generalized onset seizures and secondarily generalized seizures may be difficult, but certain distinguishing features such as presence of aura and characteristic findings on electroencephalogram (EEG) aid in distinguishing between the two.
Focal seizures are sometimes followed by convulsive seizures. During convulsive or generalized tonic-clonic (GTC) seizures, the patient experiences loss of consciousness, followed by a sudden sharp tonic contraction of muscles with a subsequent period of rigidity and clonic movements oftentimes described as jerking of the arms and legs.
Auras are focal nondyscognitive seizures which may progress to focal dyscognitive seizures and then to seizures with bilateral convulsions.
Other features that aid in distinguishing generalized-onset seizures from secondarily generalized seizures are age of onset, family history of seizures, the presence of genetic mutations, and findings on EEG, computed tomography (CT), and MRI
The patient has neither a warning that the seizure is going to occur, nor does the patient have postictal confusion or lethargy after the seizures.
Atonic seizures are the hallmark of Lennox-Gastaut Syndrome
Focal (eg, partial) seizures may present with just motor symptoms (twitching or shaking, usually one-sided) or just sensory symptoms (numbness, tingling, usually one-sided)
Focal dyscognitive (eg, complex partial) seizures are associated with altered consciousness or impairment in awareness
Absence seizures can be almost nondetectable with only very brief (seconds) periods of altered consciousness
Convulsive (eg, GTC) seizures are major convulsive episodes and are always associated with a loss of consciousness
2 However, this is not the standard for most patients and is generally reserved for cases unresponsive to medication or difficult to characterize.
3 (eg, sclerosis in the mesial temporal lobes and traumatic brain injury)
Up to 60% of patients with epilepsy are noncompliant; this is the most common reason for treatment failure.
Start at a lower dose and titrate more slowly in elderly patients.
According to the American Academy of Neurology Guidelines, discontinuation of ASDs may be considered in patients seizure free for 2 to 5 years, if there is a single type of focal seizure or primary generalized seizures, if the neurologic examination and IQ are normal, and if the EEG normalized with treatment.
The mechanism of action of most ASDs includes effects on ion channel (sodium and Ca) kinetics, augmentation of inhibitory neurotransmission (increasing CNS GABA), and modulation of excitatory neurotransmission (decreasing or antagonizing glutamate and aspartate).
ASDs effective against GTC and focal seizures probably work by delaying recovery of sodium channels from activation. Drugs that reduce corticothalamic T-type Ca currents are effective against generalized absence seizures.
It is suggested that women taking these ASDs should take twice the usual dose of emergency contraception.
Acetazolamide has been used with limited success.
Fluctuations in ASD serum concentrations during pregnancy may be due to reduced gastric motility, nausea and vomiting, increased drug distribution, increased renal elimination, altered hepatic enzyme activity, or changes in protein binding.
Valproic acid should not be used in pregnancy, but when it is used, doses should not exceed 500 to 600 mg/day.
Hypospadias is a male birth defect in which the opening of the tube that carries urine from the body (urethra) develops abnormally, usually on the underside of the penis. The opening can occur anywhere from just below the end of the penis to the scrotum.
ASDs with low protein binding will accumulate in breast milk.
Unbound concentration monitoring is especially useful for phenytoin.
Some elderly patients have increased receptor sensitivity to CNS drugs, making the accepted therapeutic range invalid.
Clinicians should determine the optimal serum concentration for each patient.
Many newer ASDs have been tested only as adjunctive therapy, but many providers will use them off-label as monotherapy.
After 12 months of treatment, the percentage who are seizure free is highest for those with only GTC seizures (48%–55%), lowest for those who have only focal seizures (23%–26%), and intermediate for those with mixed seizure types (25%–32%).
Concentration-dependent side effects can often be alleviated by decreasing the dose or avoided by increasing the dose very slowly.
When acute organ failure occurs, it usually happens within the first 6 months of ASD therapy.
Studies have found that there is a strong association between the presence of an inherited variant of the HLA-B gene, HLA-B*1502, in Asians and south Asians, and the risk of developing Stevens–Johnson syndrome as well as toxic epidermal necrolysis with carbamazepine (and possibly phenytoin, lamotrigine, and oxcarbazepine). This variant is found in up to 15% of individuals of Asian, southeast Asian, and south Asian origin. Patients with this variant should generally avoid these drugs. Also, the HLA genotype HLA-A*3101 is associated with carbamazepine-induced skin reactions in Chinese, Japanese, and European people
Laboratory tests may reveal elevated bone-specific alkaline phosphatase and decreased serum Ca and 25-OH vitamin D, as well as intact parathyroid hormone.
Any patient taking ASDs who complains of lethargy, vomiting, fever, or rash should have a laboratory assessment, including white blood cell counts and liver function tests.
Use caution when ASDs are added to or discontinued from a drug regimen.
Primidone also inducer
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 be continued unless the white blood cell count drops to less than 2500/mm 3 (2.5 × 10 9 /L) and the absolute neutrophil count drops to less than 1000/mm 3 (1 × 10 9 /L).
Extended-release preparations can be dosed twice daily, but immediate-release preparations must be given four times daily.
The interaction of Erythromycin and Clarithromycin (CYP3A4 inhibition) with carbamazepine is particularly significant.
The relationship between dose and serum concentration is linear. It does not autoinduce its own metabolism.
Concurrent use of oxcarbazepine with contraceptives may render these agents less effective.
Oxcarbazepine may increase serum concentrations of phenytoin and decrease serum concentrations of lamotrigine
See manufacturer’s recommendations for dosing by weight.
It is mostly renally excreted, and dosage adjustment is needed when creatinine clearance is less than 50 mL/min (0.8 mL/s).
It may increase the PR interval on the ECG.
It inhibits CYP2C19, and its metabolism is induced by carbamazepine, phenytoin, phenobarbital, and primidone.
The intramuscular route is best avoided, as absorption is erratic. Fosphenytoin can safely be administered IV and intramuscularly.
Equations are available to normalize the phenytoin concentration in patients with hypoalbuminemia or renal failure.
Zero-order kinetics occurs within the usual therapeutic range, so any change in dose may produce disproportional changes in serum concentrations.
It can be loaded orally, but in nonacute situations, phenytoin may be initiated in adults at oral doses of 100 mg three times daily. Subsequent dosage adjustments should be done cautiously because of nonlinearity in elimination. Most adult patients can be maintained on a single-daily dose, but children often require more frequent administration. Only extended-release preparations should be used for single-daily dosing.
Phenytoin tablets and suspension contain phenytoin acid, whereas the capsules and parenteral solution are phenytoin sodium.
Ninety-two mg of phenytoin acid is approximately equal to 100 mg of phenytoin sodium. Caution:
Phenobarbital, a potent enzyme inducer, interacts with many drugs. Valproic acid, felbamate, oxcarbazepine, and phenytoin may inhibit its metabolism.
Minimal effective adult dosing level is 30 mg/day, but those taking enzyme inducing drugs may require up to 50 to 60 mg/day.
is initiated at 300 mg at bedtime and increased to 300 mg twice daily on the second day and 300 mg three times daily on the third day. Further titrations are then made. When the total daily dose is 3600 mg/day or greater, divide the daily dose into at least four doses.
There is a linear relationship between daily doses and serum concentrations up to 800 mg/day.
Ezogabine or Retigabine
Lower doses are recommended in the elderly.
It can cause urinary retention and QT prolongation.
It is usually given in two equal doses daily.
Once-daily dosing is possible with the extended-release divalproex, but more frequent dosing is the norm due to reports of breakthrough seizures on once-daily dosing.
Although carnitine supplementation may partially ameliorate hyperammonemia, it is expensive and is not generally supported.
The free fraction may increase as the total serum concentration increases, and monitoring free concentrations may be more useful than total concentrations, especially at higher serum concentrations and in patients with hypoalbuminemia.
At least 10 metabolites have been identified, and some may be active. One may account for hepatotoxicity (4- ene –valproic acid), and it is increased by enzyme-inducing drugs. Most hepatotoxicity deaths were in children with intellectual disability who were younger than 2 years and receiving multiple drug therapy.
Lennox-Gastaut syndrome is a form of severe epilepsy that begins in childhood. It is characterized by multiple types of seizures and intellectual disability. People with Lennox-Gastaut syndrome begin having frequent seizures in early childhood, usually between ages 3 and 5
It increases the clearance of ethinyl estradiol.
Dose increments may occur every 1 or 2 weeks. For patients on other ASDs, doses greater than 400 mg/day do not appear to lead to improved efficacy and may increase side effects.
and tubular reabsorption may be prominently involved.
In some intractable seizure patients, the oral dose has been titrated rapidly over 3 days up to 3000 mg/day (1500 mg twice daily).
Cytopenia is a reduction in the number of mature blood cells. It takes a number of forms: Low red blood cell count: resulting in anemia. Low white blood cell count: leukopenia or neutropenia. Because neutrophils make up at least half of all white cells, they are almost always low in leukopenia.
It may aggravate myoclonic and absence seizures.
Vigabatrin induces CYP2C9 and decreases phenytoin plasma levels by ~20%.
It is dosed twice daily because of slow absorption and a short half-life.
Drug interactions are common.
Children may have a higher clearance of rufinamide than adults.
Start dosing in adults at 100 mg/day and increase by 100 mg/day every 2 weeks.
In the elderly and poor metabolizers of CYP2C19, initiate dosing as in patients weighing less than 30 kg.
Because Mr McNeely lives alone in an assisted living facility, only half of the documented seizures have been witnessed by another individual who could provide a description.
e description of his seizures is vague because there have been only six seizures documented since he developed epilepsy 3 years ago.
atorvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by an average of 24% and 54%