Definition Epidemiology Etiology Pathophysiology Classification Diagnosis Treatment Anti Seizure Drugs Prices in Jordan Two Medical cases New drug approvals

1. Epilepsy and Seizure
Management
Prepared by:
Sara Abudahab and Ruba Ottom
Faculty of Pharmacy
University of Jordan

2. References:
• 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),
pp.2301-2304.
• centerwatch.com/drug-information/fda-approved-drugs/therapeutic-
area/10/neurology
• Clinical Pharmacokinetics of Levetiracetam: Clin Pharmacokinetics
2004;43;707-724
• Uptodate
• Lexicomp
• Drugs.com

3. Outline:
• Definition
• Epidemiology
• Etiology
• Pathophysiology
• Classification
• Diagnosis
• Treatment
• Anti Seizure Drugs Prices in Jordan
• Two Medical cases
• New drug approvals

4. Definition
• 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.”
Definition

6. Epidemiology
• Epilepsy is the fourth most common neurologic disorder
globally.
• 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.

7. Epidemiology
• 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
epilepsy.

8. Epidemiology in the Middle East

9. keep in mind that a seizure is a symptom of
epilepsy

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
eclampsia)
 Brain tumor, infection, stroke
 Complication of diabetes or pregnancy
These seizures do not constitute epilepsy, as they are a symptom of
the provoking insult.

11. Etiology
Epilepsy etiologies can be classified into six main
categories:
1- Genetic
2- Structural
3- Infectious
4- Metabolic
5- Immune
6- Unknown

12. Genetic Etiology
• Epilepsies with genetic etiology
usually present in infancy or
childhood.
Examples of genetic epilepsies are:
• Juvenile Myoclonic Epilepsy (JME)
including (EFHC1)
• 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
neuroimaging.
• Common epilepsies caused by structural abnormalities
include mesial temporal lobe epilepsy and post-traumatic
epilepsy.

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
encephalitis.

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
menses, puberty
• Pregnancy
• Drugs: theophylline, alcohol, high-dose
phenothiazines, antidepressants (especially
bupropion), and street drugs (lower seizure threshold)

19. Pathophysiology
• The underlying general pathophysiologic process at
the heart of all epilepsies is neuronal
hyperexcitability and hypersynchronization.

20. Pathophysiology

21. Classification

22. Classification
Most seizures can be classified
by their mode of onset
(1)Generalized: Onset seizures
begin in both hemispheres of
the brain
(2) Focal: Onset seizures begin
in only one hemisphere of the
brain.

23. Classification
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)

24. Clinical Presentation

25. Clinical Presentation
(1)Focal seizures without dyscognitive features,
Such symptoms will vary depending on where the abnormal
firing occurs.
•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
pathways.
•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
unresponsive)
• 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
(jerks).
• 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
body parts.
• 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
very brief.
• 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
trauma.

34. Diagnosis
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

35. Diagnosis
• 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
(2) EEG
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.

38. Diagnostic Tests
(3) Brain MRI
Is indicated in patients with epilepsy to identify
structural abnormalities

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
anatomical injury

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

41. Treatment

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
seizures
2. Minimize side effects
3. Ensure compliance (60% of patients with epilepsy are
noncompliant)
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
goals.

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.

45. General approach

46. When to withdraw ASDs
Factors favoring successful withdrawal of ASDs
include
•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
35 years
•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
functioning.
status epilepticus
is defined as any
recurrent or
continuous seizure
activity lasting
longer than 30
minutes in which
the patient does
not regain baseline
mental status.

49. Special considerations in the
female patients
- Contraception
- Catamenial epilepsy
- Pregnancy

50. Contraception
• Enzyme-inducing ASDs
(eg, Carbamazepine,Oxcarbazepine, Topiramate, Rufinamide,
Lamotrigine, Clobazam, Felbamate, Phenytoin and Phenobarbital)
may cause treatment failures in women taking oral
contraceptives
• A supplemental form of birth control is advised if breakthrough
bleeding occurs.

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.

52. Pregnancy
• 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.

53. Pregnancy
• 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
hypospadias.

54. Pregnancy
• 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.

55. Pharmacokinetics and special
populations
- Protein binding
- Neonates and infants
- Elderly

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
▫ Hypoalbuminemia
▫ Burns
▫ Pregnancy
▫ 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
slowly
• But by age 2 or 3 years children may metabolize
drugs more rapidly than adults.
• Thus, neonates and infants require lower doses of
ASD
• But children require higher doses of many ASDs
than adults.

58. Elderly
• 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.

59. Serum concentration
monitoring

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.

61. Dosing
• 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
effective dose.
• Clinical response is more important than serum drug
concentrations.

62. Efficacy and Side effects

63. Efficacy
• 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.

64. Efficacy
• Some ASDs may possibly precipitate or aggravate
certain seizure types, and it is suggested that they be used
with caution in those patients.
• Examples
Carbamazepine, gabapentin, oxcarbazepine, phenytoin
tiagabine, and vigabatrin in children with absence or
juvenile myoclonic epilepsy.
Drug resistance:
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
freedom.

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
excitement.
• In general, the newer agents have less effect on cognition,
except Topiramate.
• 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).

66. Stevens-Johnson Syndrome/toxic
epidermal necrolysis

67. Adverse effects
• A side effect of long-term use of ASDs is osteomalacia or
osteoporosis.
• 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.

69. Anti-Seizure Drugs (ASDs)

71. Narrow spectrum ASDs

72. Carbamazepine
• 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
carbamazepine.
• 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
2500/mm3
(2.5 × 109
/L)

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-
like reactions.
• Compared to other first generation ASDs, it causes
minimal cognitive impairment.
Carbamazepine

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
days.
• Reversal of autoinduction is rapid
after discontinuation.
Carbamazepine

75. Oxcarbazepine
• 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,
or carbamazepine.
• 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.

76. Eslicarbazepine
• 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
oxcarbazepine.
• 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.

77. Phenytoin
• Phenytoin is a first-line ASD for many seizure types, and is
FDA approved for focal onset seizures and GTC seizures. It
may exacerbate seizures in generalized epilepsies.
• It has many acute and long-term side effects.
• Phenytoin is prone to many drug interactions.
• Absorption may be saturable at higher doses (above 400 mg).
• Do not change brands without careful monitoring.

78. Phenytoin
• PHENYTOIN side effects:
P: P-450 interactions
H: Hirsutism
E: Enlarged gums
N: Nystagmus
Y: Yellow-browning of skin
T: Teratogenicity
O: Osteomalacia
I: Interference with folic acid
absorption (hence anemia)
N: Neuropathies: vertigo, ataxia,
headache

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
guide.
• Phenytoin decreases folic acid absorption, but folic acid
replacement enhances phenytoin clearance and can result in
loss of efficacy.
Phenytoin

80. Phenobarbital
• 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.

81. Tiagabine
• Tiagabine is adjunctive therapy for patients 12 years
and older with focal onset seizures who have failed
initial therapy.
• 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.

82. Gabapentin
• 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

83. Pregabalin
• 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
renal dysfunction.
• Drug interactions are unlikely.

84. Lacosamide
• 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
interval.
• 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.

85. Ezogabine
• Approved in 2011
• Ezogabine is approved for adjunctive treatment of
focal onset seizures, and is recommended only after
several alternative drugs have been tried.
• Alcohol:
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
• 1st
line for Absence seizures
• Titration over 1 to 2 weeks to maintenance doses of
20 mg/kg/day usually produces therapeutic serum
concentrations.
• 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.
Allman
• 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

88. Broad spectrum ASDs

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
seizure disorders.
• The enteric-coated tablet is metabolized in the gut to valproic
acid.
• 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.
Drug Interactions:
•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.
Valproic Acid

91. Topiramate
• 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
Lennox–Gestaut syndrome.
• Approximately 50% of the dose is excreted renally as unchanged
drug. the dose should be adjusted in renally impaired patients.
Side effects:
• Kidney stones occurs in 1.5% of patients.
• It has also been associated with
word-finding difficulties
and metabolic acidosis and weight loss.
Compared with
newer ASDs it has
more effects on
cognition

92. Lamotrigine
• 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-
Gastaut Syndrome.

93. Lamotrigine
• 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.

94. Levetiracetam
• 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
and older.
• Adverse effects include sedation, fatigue,
coordination difficulties, agitation, irritability, and
lethargy. It is generally well tolerated.
• It can be loaded orally or intravenously.

95. Levetiracetam
• The recommended initial adult dose is 500 mg orally twice
daily.
• 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
0

96. Felbamate
• 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

97. Vigabatrin
• 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
and older.
• 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
after discontinuation.

98. Zonisamide
• Zonisamide, a broad-spectrum sulfonamide ASD, is approved
as adjunctive therapy for partial seizures
Side effects:
• 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
sulfonamide allergy.
• It is suitable for once- or twice-daily dosing, but once-daily
dosing may cause more side effects (due to more serum
fluctuations).

99. Clobazam
• 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.

100. Perampanel
• 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
other ASDs
• Perampanel has a half-life of approximately 100 hours, and its
clearance in increased two- to threefold by enzyme inducing
ASDs.
• It has a boxed warning pertaining to monitoring for
psychiatric, behavioral, mood, and personality change which
may be life threatening.

101. US Guidelines
Seizure Type Effective Drug FDA approved:
Focal onset seizures
(newly diagnosed)
Adults and
adolescents:
Carbamazepine
Gabapentin
Oxcarbazepine
Phenobarbital
Phenytoin
Topiramate
Valproic acid
Carbamazepine
Lacosamide
Phenobarbital
Phenytoin
Topiramate
Valproic acid
Focal onset seizures
(refractory
monotherapy)
Oxcarbazepine
Lamotrigine
Topiramate
Carbamazepine
Lamotrigine
Oxcarbazepine
Phenobarbital
Phenytoin
Topiramate
Valproic acid
Generalized seizures
absence (newly
diagnosed)
Lamotrigine Ethosuximide
Valproic acid
Generalized onset
(tonic-clonic)
Topiramate Lamotrigine
Levetiracetam
Topiramate

103. ASDs Prices

104. Generic Name Brand Name Dose Price (JD)
Carbamazepine Tegretol 200mg 4.23
400mg 5.63
250mg syrup (2%( 5.44
Neurotop 300mg 8.36
600mg 9.09
Oxcarbazepine Trileaptal Syrup 60mg/ml 12.77
600mg tab 24.69
150mg tab 11.97
300mg tab 12.82
Gapapentin Gabatrex 100mg 3.31
300mg 12.58
400mg 15.2
Neurotin 300mg 11.85
400mg 13.79

105. Generic Name Brand Name Dose Price (JD)
Gabapentin Gabanet 400mg 28.06
300mg 23
Neuroplex 300mg 19.57
400mg 23
Neurona 400mg 15.84
Lacosamide Vmpat 150mg 146.39
100mg 97.59
Lamotrigine Loxol 25mg 8.47
50mg 18.17
100mg 27.74
Levetiracetam Keppra 500mg 100 tabs 49.57
100mg oral sol 54.16
Permapanel Fycompa 2mg 29.91
4mg 111.27
6mg 111.27
8mg 111.27

106. Generic Name Brand Name Dose Price (JD)
Phenytoin Epanutin 100mg cap 6.88
Pregabalin Lyrica 150mg 63.37
75mg 11.23
Zega 75mg 8.99
150mg 61.05
Regab 50mg 6.94
75mg 8.99
150mg 15.82
Vigabatrin Sabril 500mg 43.78
Valproic acid Depakine 200mg 3.17
500mg 6.62
Depakine-crono 500mg 8.04
Sodium valproate Valpro 576mg syrup 3.33
200mg sol 2.76
Valpro-crono CR 500mg 6.87

107. Cases
1- The casebook case
2- Real medical case from JUH

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
adjusted.

110. Past Medical History and Current
medications
Disease Medication
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
evening.

112. Lab tests:
Actual Normal Comment
Na 127 mEq/L 135 - 145 mEq/L Hyponatremia
K 4.7 mEq/L 3.5-5.0 mEq/L --
Cl 90 mEq/L 96 - 106 mEq/L Hypochloremia
CO2 25 mEq/L 23 - 29 mEq/L --
BUN 10 mg/dL 7 - 20 mg/dL --
SCr 0.6 mg/dL 0.6 - 1.2 mg/dL --
Glu 100 mg/dL 79–160 mg/dL --
Hgb 13.5 g/dL 13.5 - 17.5 g/dL --
Hct 41% 38.8 – 50% --
RBC 3.9 × 10 6 /mm3 4–6.2 × 106
/μL --

113. Lab tests cont.:
Actual Normal Comment
T. Chol 155 mg/dL < 200 --
TG 123 mg/dL <160 --
HDL-C 39 mg/dL >=35 --
LDL-C 91 mg/dL <130 --
WBC 5.1 × 10 3 /mm3 5 – 10 × 10 3 /mm3 --
MCV 97 μm3 80-96 μm3 --
Carbamazepine 6 mcg/mL 4-12 mcg/mL --

114. EEG:
Sleep-deprived EEG unremarkable.
Photic stimulation failed to produce any other changes
Assessment:
Sixty-eight-year-old man with fairly well-controlled
seizures on carbamazepine monotherapy

115. Medical
condition
TRPs Goals
Current
status
Intervention
Follow up
Monitoring
parameter
End points and
frequency
Tonic-
Clonic
epilepsy
1-Adverse Drug
Reaction of
Carbamazepine
(Hyponatremia and
hypochloremia
possibly from long-
term use)
2-Safer
medication is
available
(Carbamazepine:
Elimination is
reduced in elderly
and moderate drug
interaction with
Atorvastatin)
1.To
control or
reduce the
frequency
and severity
of seizures
2.Minimize
side effects
3.Ensure
compliance
4.Allowing
the patient
to live as
normal a
life as
possible
Unstable 1.Add Levetiracetam
start with 500mg*1 then
titrate to 500mg*2 in a
week or two and check
for efficacy
Given orally regardless
of food
2.And tapper off
Carpamazepine by
100mg every two weeks
3.Monitor
Hyponatremia and
hypochloremia
baseline and
annual renal
function tests
(SCr, BUN,
and
electrolytes)
Symptoms of
somnolence,
dizziness,
incoordination,
agitation, and
psychosis
Normal tests
And no side
effects of
Levetiracetam
Annually
Daily until
normalized
Sodium: 135 -
145 mEq/L
Chloride: 96 - 106
mEq/L
Tonic-
Clonic
epilepsy
Need additional
monitoring of
bone health
Unstable Test for VitD, PTH,
Alkaline phosphatase,
Calcium and phosphate
levels
Dietary intake of 800-
1000IU VitD and
1200mg elemental
Calcium daily
VitD, PTH,
Alkaline
phosphatase,
Calcium and
phosphate
levels
Normal tests
Calcium: 8.5-10.5
VitD: 10–50
ng/mL
Alkaline
phosphatase: 38–
126 IU/L
Every 3-6months

116. Medical
condition
TRPs Goals
Current
status
Intervention
Follow up
Monitoring
parameter
End points and
frequency
Tonic-
Clonic
epilepsy
Need additional
monitoring of
mental health
1.To control
or reduce the
frequency
and severity
of seizures
2.Minimize
side effects
3.Ensure
compliance
4.Allowing
the patient to
live as
normal a life
as possible
Unstable Elderly
Widow
can't drive
and living in facility,
the patient needs
assessment of
depression and anxiety
and counseling by a
social worker
Depression and
anxiety
Stable mental
health
Tonic-
Clonic
epilepsy
Non pharma-
cological
therapy
Unstable Patient is advised to
keep a seizure diary
Seizures
frequency
Seizure Free

117. Real Medical Case from JUH

118. HPI
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 .

119. PMH
• Viral meningitis 3 years ago

120. FH
• He has one healthy brother . His mother is a teacher ,
she is medically free .
• The father is an accountant and he is medically free.
• His parents are not relatives.

121. ROS
• Cardiovascular : normal s1 and s2 sounds
• Respiratory : Good air entry bilateral, no added sound
• Skin : no hypo or hyperpigmented skin lesions

122. Medications
• Topamax 25*2

123. Vital signs
• Temperature : 37c
• Pulse : 110
• Respiratory rate :28
• BP : 110/60
• Weight : 20 Kg
• Height : 120cm

124. Labs
RBS : 77 Urea : 36 Creatinine : 0.29
Na : 134 K : 4.1 Hb & Ht :13.4/39.1
WBC :13.00 MCV: 78.3 MCH :26.9
RBC : 5.00 MCHC :34.3 RDW : 14.3
Neut-sig% : 70 Eosinophil % : 0.2 Basophil % : 0.3
Lymphocyte % : 15.1 Monocyte % : 4 Platelets count : 400

125. • EEG is normal

126. Medical
condition
Treatment
related
problem
Goal Current
status
Intervention Follow up
Generalized
tonic-clonic
seizure
Efficacy issue :
The patient is
taking low dose
of topiramate
1- Improve
quality of life
2- Eliminate
symptoms
( seizures )
with minimal
side effects
Uncontrolled on
current dose
The recommended
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
recommended
maintenance dose
Frequency of
seizures
Signs of
decreased
sweating and
fever
PH of the blood
(7.35-7.45)
Adherance issue
; the patient
parents state
they are
sometimes
forget to give
the patient the
Obtain seizures
freedom
uncontrolled Aware the parent
of the importance
of giving him the
drug twice daily
Seizures
freedom

127. Medical
condition
Treatment
related
problem
Goal Current
status
Intervention Follow up
Generalized
tonic-clonic
seizure
Knowledge
issue,,
The parents
state that the
patient
doesn’t drink
adequate fluid
1- Improve
quality of life
2- Eliminate
symptoms
( seizures )
with minimal
side effects
uncontrolled Aware the
patient of the
importance of
maintain fluid
intake to
prevent the
drug from
causing
kidney stones
Watch the
signs of
kidney
stones :
1-Pescence of
pain in the
back, belly or
side
2- burning
during
urination
3- blood in
the urine
4- Nausea and
vomiting
5- Fever

128. New drug approvals

129. Carnexiv (carbamazepine)
• Approval Status: Approved October 2016
• Carnevix is supplied as an injection for intravenous
administration
• The recommended total daily dose is 70% of the total daily
dose of oral carbamazepine from which patients are being
switched;
• 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
7 days
New drug approval

130. Briviact (brivaracetam) Oral Solution
Approved February 2016
•Price:
10mg/ml oral soln, 300ml=£115.83.
•Indications:
Adjunct in partial-onset seizures with or without
secondary generalization.
•Adults:
Initially 50—100mg daily in two divided doses.
Maintenance 50—200mg daily in two divided
doses.
•Children:
Under 16 years, not recommended. Over 16 years,
as adult.
New drug approval

131. Famous people with epilepsy

132. Vincent Van Gogh (1853 - 1890)
• Temporal lobe epilepsy

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
partial seizures.