1. Epilepsy
One of the oldest Known conditions
Dr. Krishna Mohan Rao, MD., D.M
Professor of Neurology
1
2. History
Epilepsy has been known since antiquity.
Mention has been made about epilepsy in
ancient Indian and Chinese texts.
The word epilepsy is derived from the Greek
verb epilambanein meaning to be seized,
to be taken hold of, or to be attacked.
19th century neurologist Hughlings Jackson
suggested “a sudden excessive disorderly
discharge of cerebral neurons” as the
cause of epileptic seizures
2
3. Famous people with e
pilepsy
Alexander
the Great
Alfred Nobel
Hercules Greek Hero
Julius Caesar
3
4. Definitions
Seizure
Paroxysmal neurological
dysfunction due to
abnormal, excessive
synchronous discharge
of a population of cerebral
neurons. (Cerebral dysrhythmia
)
Seizures usually brief (< 5 min)
and stop spontaneously
Convulsion, ictus, event, spell,
attack and fit are used to refer
to seizures.
Commonly generated in cortex
and hippocampus, may also b
e subcortical
Epilepsy
Group of neurologic
conditions, characterized
by recurrent unprovoked
seizures with the resultant
neurobiological, cognitive,
social and psychological
consequences.
A common operational
definition of epilepsy is
two or more unprovoked
seizures occurring more
than 24 hrs apart.
4
5. Types of Cerebral Dysrhythmia
Acute
Complication of acute CNS insult
Self limited
Require short term treatment
Chronic (recurrent) : Epilepsy
Continuous : Status Epilepticus
5
6. Definition of Epilepsy
Seizures are symptoms, while epilepsy is a
disease, so those terms should not be used
interchangeably
Epilepsy = “seizure disorder”
Epilepsy is a syndromic disease
Each epilepsy syndrome is determined
based on;
Type of seizures, age at seizure onset,
family history, physical exam, EEG findings,
and neuroimaging
6
7. Epidemiology of
Seizures and Epilepsy
Seizures
– Incidence: approximately 80/100,000 / yr
– Lifetime prevalence: 9%
(1/3 benign febrile convulsions)
– Almost 1% of the population will develop a
single, unprovoked Seizure
– 2% will develop Seizures due to acute CNS
insults
Epilepsy
– Incidence: approximately 45/100,000 /yr
– Lifetime risk of developing Epilepsy to
age 80: 3.4%
– Point prevalence: 0.5-1%
7
8. Epilepsy is a symptom of numerous disorders, but in the
majority of sufferers the cause remains unclear despite
careful history taking,examination and investigation!
Any process that alters the structure (macroscopic or
microscopic) or the function of the brain neurons
can cause epilepsy.
Etiology of Epilepsy
9. Age group by % all first seizures o
ccurring in each age group
Age
groups
First seizures
occurring - %
0-9 47
10-19 30
20-29 13
30-39 6
40+ 4
9
50% of all cases develop before 10 years of age.
11. Etiology of Seizures
Seizures are either provoked or unprovoked
Provoked Seizures or Symptomatic : Triggered b
y
certain provoking factors in otherwise healthy br
ain
– Metabolic abnormalities (hypoglycemia and hyperglycemia,
hyponatremia, hypocalcemia)
– Alcohol withdrawal
– Acute neurological insult (infection, stroke, trauma)
– Illicit drug intoxication and withdrawal
– Prescribed medications that lower seizure threshold
(theophylline, TCA)
– High fever in children
Unprovoked Seizures : Occur in the setting of
persistent brain pathology
11
12. Seizure Precipitants
• Metabolic and Electrolyte
imbalance (Low less often
high blood glucose, low
sodium, low calcium, low
magnesium)
•Stimulant or other
proconvulsant toxicity (i.e.,
cocaine)
•Sedative (i.e., valium or
alcohol) withdrawal
•Sleep deprivation
•AED medication
reduction or inadequate
AED treatment
• Hormonal variations
• Stress
• Fever or systemic
infection
• Concussion and/or
closed head injury
12
13. Partial Seizures Generalized Seizures
Simple Partial Seizures
(SPS)
Motor
oWith march
oWithout march
oVersive
oPostural
oPhonatory
Sensory
oSomatosensory
oOlfactory
oVisual
oAuditory
oGustatory
oVertiginous
Autonomic
Psychiatric
oDysphasic
oDéjà vu or jamais vu
oCognitive
oAffective
oIllusions
oStructured hallucinations
Complex Partial
Seizures (CPS)
–With automatism
–Without automatism
Secondary Generalized
Tonic-Clonic
Tonic-Clonic
(primary tonic-clonic)
Absence
Myoclonic
Clonic
Tonic
Atonic
Atypical Absence
Infantile Spasm
13
ILAE Classification of Seizures
14. ILAE Classification of Epilepsy
Localization-Related (named by
location)
Generalized (named by disease)
Idiopathic Benign Rolandic epilepsy (Benign childhood
epilepsy with centro-temporal spikes)
Benign occipital epilepsy of childhood
Autosomal dominant nocturnal frontal lobe
epilepsy
Primary Reading Epilepsy
Benign Neonatal Convulsions (+/- familial)
Benign myoclonic epilepsy in infancy
Childhood absence epilepsy
Juvenile absence epilepsy
Juvenile myoclonic epilepsy
Epilepsy with GTCs on awakening
Some reflex epilepsies
Symptomatic Temporal lobe
Frontal lobe
Parietal lobe
Occipital lobe
(Rasmussen’s encephalitis)
(Most Reflex epilepsies)
Early myoclonic encephalopathy
Early infantile epileptic encephalopathy
with suppression- burst (Ohtahara’s
syndrome)
Cortical abnormalities
-malformations
-dysplasias
Metabolic abnormalities
- amino acidurias
- organic acidurias
- mitochondrial diseases
- progressive encephalopathies of
childhood
West’s Syndrome
Lennox-Gastaut Syndrome
Cryptogenic (Any occurrence of partial seizures without
obvious pathology.)
Epilepsy with myoclonic-astatic seizures
Epilepsy with myoclonic absence
15. Epilepsy - Classification
Focal seizures – account
for 80% of adult epilepsies
- Simple partial seizures
- Complex partial seizures
- Partial seizures secondarilly
- generalised
Generalised seizures
Unclassified seizures
15
Asynchronous burst
firing in some
hippocampal
and
cortical neurons
Asynchronous
burst firing
in
abnormal
thalamocortical
interaction
19. Complex Partial
Aura is common
– Represents the ictal onset
– Stereotypical, but may be difficult to
describe
Absence or alteration of consciousness
Automatisms
Amnesia
Postictal confusion
May secondarily generalize
19
21. Absence seizures
(Petit-mal seizures)
Brief stare with unresponsiveness
May have associated eye flutter or simple
automatisms
Sudden onset with arrest of activity
No aura or postictal confusion
Generalized 3 per second spike and wave
80% will experience resolution with age
20% will have convulsive seizures.
21
28. Myoclonic seizures
Brief contraction of a muscle, muscle group, or
several muscle groups caused by cortical discharge
Can be single or repetitive
Severity range from imperceptible twitch to severe
jerking (may result in propulsion of hand-held objec
ts/ fall)
Recovery is immediate and conciousness is not lost
Myoclonus can be induced by action, noise, startle,
photic stimulation or percussion
If occuring as part of idiopathic generalised seizure
s, myoclonus occurs on waking or on drop
ping off to sleep
May occur at any age
EEG: generalised spike/ spike and wave/ polyspike
and wave, often assymmetrical and irregular,
frequently predominant in frontal area. Interictal EE
G varies depending on underlying epil
epsy aetiology.
31. Acute Vs Chronic epileptogenesis
Acute process initiating a seizure
- [Na+], [K+], [Ca++], GABA, Glutamate
Chronic process converting normal brain in
to epileptic brain
- Changes in gene expression
- Changes in receptors, transporters, ion
channels
- Plasticity
31
32. Basic Mechanisms of Epilepsy
In epileptic tissue there is an
imbalance between excitation
and inhibition that enhances
and allows for a prolonged
discharge.
There is also augmentation of
mechanisms that synchronize
neuronal discharges.
32
33. Evaluation of a First Seizur
e
History & physical exam.
Blood tests: CBC, electrolytes, glucose,
Calcium, Magnesium, phosphate,
hepatic and renal function
Lumbar puncture only if meningitis
or encephalitis suspected and potential
for brain herniation is ruled out
Blood or urine screen for drugs
Electroencephalogram
CT or MR brain scan
33
35. EEG
Ictal vs interictal
Distinguish from epileptiform convulsions
from non-ictal behavioural manifestations
50 % epilepsy patients show interictal
epileptiform discharges in the first EEG
10% will not show any significant
abnormality
0.5% healthy individuals can have
abnormal recordings
Frequent seizures more likely to have a
positive yield
EEG within 24 hours can have a yield
of 50%
35
37. EEG Abnormalities
Background abnormalities: significant
asymmetries and/or degree of slowing
inappropriate for clinical state or age
Interictal abnormalities associated with
seizures and epilepsy
– Spikes (< 70 m sec)
– Sharp waves (~70 – 200 msec)
– Spike-wave complexes
May be focal, lateralized, generalized
37
38. Neuroimaging
Detects abnormalities in
21-37% pts with epilepsy
MRI is modality of choice when
there is a suggestion of an underlying
focal process
If not available or contraindicated,
CT is adequate to assess for gross
pathology
38
40. Single Photon Emission CT (SPECT)
Positron Emission Tomography (PET)
MRI spectroscopy
Functional MRI
Functional cerebral changes
Useful adjuncts in candidate epileptic
surgery
41. Other tests
Prolactin (PRL)
Elevated PRL measured within
20 min of a suspected event,
should be considered a useful
adjunct to differentiate GTC /
CPS from psychogenic non-epile
ptic seizure among adults
A normal PRL should not be used
to distinguish seizure from syncop
e.
41
43. First Aid
Tonic-Clonic Seizure
Turn person on side with face turned
toward ground to keep airway clear,
protect from nearby hazards
Transfer to hospital needed for:
– Multiple seizures or status epilepticus
– Person is pregnant, injured, diabetic
– New onset seizures
DO NOT put any object in mouth or
restrain
43
44. Medical Treatment of
First Seizure
Whether to treat first seizure is
controversial
16-62% will recur within 5 years
Relapse rate might be reduced by antiepileptic
drug treatment
Abnormal imaging, abnormal neurological exam,
abnormal EEG or family history increase relapse
risk
Quality of life issues are important
44
45. When to initiate AED treatment?
General Principles
Usually after two or more unprovoked seizur
es
Risks – benefit considerations
Likelihood of recurrence
- CNS structural abnormality
- Specific epilepsy syndromes e.g. JME
Social consequence of recurrence
Infrequent seizures
Precipitating lifestyle factors
Anticipated poor compliance
TREAT
after 1 seizure WAIT-and-SEE
after 1 or 2 seizures
46. Strategies for managing newly diagnosed epilepsy
Newly diagnosed epilepsy
First drug
Second drug
Refractory
Rational duotherapy Surgical assessment
Seizure-free
Seizure-free
47%
13%
40%
47. Ten commandments in the pharmacological
treatment of epilepsy
Choose the correct drug for the seizure
type or epilepsy syndrome
Start at low dosage and increase
incrementally
Titrate slowly to allow tolerance to central
nervous system side-effects
Keep the regimen simple with once- or
twice-daily dosing, if possible
Measure drug concentration when seizures
are controlled or if control is not readily
obtained (if possible)
48. Counsel the patient early regarding the
implications of the diagnosis and the
prophylactic nature of drug therapy
Try two reasonable mono-therapy options b
efore adding a second drug
When seizures persist, combine the best
tolerated first-line drug with one of the
newer agents depending on seizure type
and mechanism of action
Simplify dose schedules and drug regimens
as much as possible in patients receiving
poly-pharmacy
Aim for the best seizure control consistent
with the optimal quality of life in patients
with refractory epilepsy
50. Therapy of epilepsy
Current antiepileptic drugs are effective in controlling
seizures in about 75% of patients
In 50% of patients we obtain nearly complete eliminations of seizure
occurrence
In additional 25% of patients we can significantly reduce the frequency
and severity of seizures
The choice of drugs is based on type of seizures, tolerabilit
y of a drug and response to therapy (empiric part)
The therapy is often started with the lower dose and the do
se is “titrated” gradually thereafter
The use of antiepileptics is often limited by their adverse
effects
50
51. Choosing Antiepileptic Drugs
Seizure type / Epilepsy syndrome
Comorbid conditions
Adverse side effects or events
Interactions / other medical conditions
Pharmacokinetic profile
Cost
Efficacy
ALL FEMALES (and also consider in males):
• Folate 1 - 4 mg/day
• MVI
• Calcium (1200-1330 mg per day)
51
52. Antiepileptic Drug Interactions
Drugs that induce metabolism of other
drugs: carbamazepine, phenytoin,
phenobarbital
Drugs that inhibit metabolism of other
drugs: valproate, felbamate
Drugs that are highly protein bound:
valproate,phenytoin, tiagabine,
carbamazepine
Other drugs may alter metabolism or
protein binding of antiepileptic drugs
52
54. Classification of Anticonvulsants
Action on Ion
Channels
Enhance GABA
Transmission
Inhibit EAA
Transmission
Na+: Inhibition
Phenytoin,
Carbamazepine
Lamotrigine
Topiramate
Valproic acid
Ca++: Inhibition
Ethosuximide
Valproic acid
Benzodiazepines
(diazepam, clonazepam)
Barbiturates (phenobarbital)
Valproic acid
Gabapentin
Vigabatrin
Topiramate
Felbamate
Felbamate
Topiramate
Na+:
For general tonic-clonic
and partial seizures
Ca++:
For Absence seizures
Most effective in myoclonic
but also in tonic-clonic and
partial seizures
Clonazepam: for Absence
54
55. FDA Indications for AEDs:
Monotherapy and/or Add-On Therapy
Monotherapy
Carbamazepine
Divalproex ER
Ethosuximide
Oxcarbazepine
Phenobarbital
Phenytoin
Primidone
Lamotrigine1
Felbamate1
Topiramate
1Approved for conversion to monotherapy.
Add-On Therapy
Carbamazepine Levetiracetam
Divalproex ER Gabapentin
Ethosuximide Phenytoin
Oxcarbazepine Tiagabine
Phenobarbital Zonisamide
Primidone
Physician’s Desk Reference, 2004.
55
57. Choices of antiepileptic drugs by type of ad
ult seizure disorder
Seizure Type Initial Drug Therapy Alternative or Adjunctive
Partial
(Simple, Complex,
secondarily
generalized )
Carbamazepine,
Phenytoin
Valproate
Felbamate, Gabapentine
Lamotrigine, Zonisamide,
Oxacarbazepine
Topiramate, Leveteracetam
Primary
generalized
Tonic-clonic
Carbamazepine,
Phenytoin
Valproate
Gabapentin, Lamotrigine,
Topiramate, Leveteracetam
Myoclonic Valproate Clonazepam, Lamotrigine,
Leveteracetam
Atonic Valproate Clonazepam, Lamotrigine
Felbamate
Absence Ethosuximide,Valproate Clonazepam, Lamotrigine
57
58. Combination antiepileptic regimens
for refractory seizures
COMBINATION INDICATION
Valproate and lamotrigine or
levetiracetam
Partial or generalized seizures
Valproate and ethosuximide Generalized absence
Carbamazepine and valproate Complex partial seizures
Vigabatrin and lamotrigine or
tiagabine
Partial seizures
Topiramate and lamotrigine or
levetiracetam
Numerous types
58
61. GENERIC
NAME
USUAL DOSE
CHILDREN, ADULTS
mg/Kg mg/day
INDICATIONS SERUM
HALF
LIFE,
Hrs
EFFECTIVE
BLOOD
LEVEL,
µg/mL
Tiagabine 0.3-1.0 30-45mg/k
g
GTC, partial,
Adjunctive therapy
5-9 5-70
Clobazam 5-10 10-20mg Adjunctive to GTC,
partial
10-77
Clonazepam 1-3 0.5 to 4 Adjunctive to GTCS
partial , infantile
Spasms, LGS, SE
20-80 0.01-0.07
ACTH 40-60
Units/da
y
Infantile spasms
Vigabatrin 40-100 1000-3000 Generalized,
refractory partial,
infantile spasms,
Lennox-gastaut
4-7 7-40
felbamate 45-80 1200-3600 Adjunctive to GTCS,
Refractory partial
and Lennox Gastaut
20 40-100
61
62. Therapeutic drug monitoring
Indications for use:
Uncontrolled seizures despite administration of
greater-than-average doses.
Seizure recurrence in a previously controlled patie
nt.
Documentation of intoxication.
Assessment of patient compliance.
Documentation of desired results from a dose
change or other therapeutic maneuver.
Assessment of therapy in patients with infrequent
seizures.
When precise dosage changes are required.
62
63. Duration of therapy &
Discontinuing AEDs
Seizure freedom for 3 years
implies overall >60% chance of successful withdrawal
in some epilepsy syndromes.
withdrawal of each AED over at least 6 weeks would
seem to be a safe approach.
Favorable factors
Control achieved easily on one drug at low dose
– No previous unsuccessful attempts at withdrawal
– Normal neurologic exam and EEG
– Primary generalized seizures except JME
– “Benign” syndrome
Consider relative risks/benefits (e.g., driving, pregnan
cy)
63
66. Mechanisms governing excitability
Basic mechanism of neuronal excitability is the
action potential
Hyperexcitable state can result from:
– Increased excitatory synaptic transmission
– Decreased inhibitory neurotransmission
– Alteration in voltage-gated ion channels
– Alteration in intra or extracellular ion concentrations
(favoring depolarization)
– Summation of synchronous subthreshold excitatory
stimuli
66
70. Juvenile Myoclonic Epilepsy of janz
(JMEJ)
Myoclonic seizures with onset in
late childhood or adolescence
May develop generalized convulsive
or absence seizures
Interictal EEG shows normal back-
ground with polyspike-wave bursts
Autosomal dominant inheritance
– Chromosome 6
70
