SEIZURES AND EPILEPSY

David Spencer MD
School of Pharmacy 2008

Outline
Definitions and epidemiology
p
gy
Etiology/pathology
at op ys o ogy:
Pathophysiology:
Brief overview of molecular and
cellular basis of epileptogenesis

Evaluation of the patient with

seizures
Seizure types
Epilepsy syndromes
Treatment principles

Definitions
Seizure: paroxysmal episode of
neurological
g
dysfunction
y
caused byy
excessive electrical discharge of CNS
neurons
Epilepsy: syndrome of recurrent
unprovoked seizures

Incidence
10% will have a seizure in their lifetime
1% will have epilepsy
2,000,000
2 000 000 - 3,000,000
3 000 000 in USA

Incidence of Epilepsy by
Etiology: The Elderly

Ramsay et al Neurology. 2004 Mar 9;62(5 Suppl 2):S24-9

Acquired vs. Genetic Etiologies

Acquired

Head trauma
CNS infections
Stroke
Tumors
Vascular malformations
Neurodegenerative
diseases

Genetic
200 single gene defects
(1% of epilepsy)
Polygenic (Complex
genetic factors
contribute to ~40% of
epilepsy)

Pathophysiology:
Genetic Causes of Epilepsy
Gene defects affecting neuronal excitability
Ion channel defects

Genes encoding development

Neuronal migrational
g
disorders

Genes encoding cerebral energy metabolism

Mitochondrial disorders

Genetic Neurodegenerative disorders

Progressive
g
myoclonic
y
epilepsies
p p

Mechanisms of Epileptogenesis
Hyperexcitability
Intrinsic membrane properties of neurons
Changes in neural networks

Mechanisms of Epileptogenesis
Hyperexcitability
Intrinsic membrane properties
of neurons
Changes in ion channels
Number of channels
Gating
G ti properties
ti
Voltage dependency

Extrinsic Factors
Concentration of ions
Clearing of ions,
neurotransmitters from
extracellular space

Channelopathies
Na+ Channel
Generalized epilepsy with
febrile seizures +

K+ Channel
Benign
i Familial
ili l Neonatall
Convulsions

Ca++
C
Ch
Channell
Absence epilepsy

Mechanisms of Epileptogenesis
Hyperexcitability
R
Ratio
i off inhibitory
i hibi
to
excitatory synapses
Decrease in inhibitory
transmission (GABA)
Increase in excitatory
transmission
(Glutamate)
Complex interactions
Changes in
connectivity
(p
(plasticity)
y)

Excitatory and Inhibitory

Transmitter Receptors
Glutamate
Ionotropic
Metabotropic

GABA
GABAA
Fast
F synaptic
i inhibition
i hibi i
Opens Cl- channel
Hyperpolarizes cell

GABAB
G-protein coupled
Opens K+ or Closes
Ca2+ channels
Prolonged
hyperpolarization

GABA receptor
GABA site
Barbiturate site

Benzodiazepine
site

Steroid site
Picrotoxin site

Diagram
g
of the GABAA receptor
p
From Olsen and Sapp, 1995

Acute vs.
vs Chronic
Epileptogenesis
Acute process initiating a seizure
[Na+],
[Na+] [K+]
[K+], [Ca++]
[Ca++], GABA,
GABA Glutamate

Chronic process converting normal brain

i t epileptic
into
il ti brain
b i
Changes in gene expression
Changes in receptors, transporters, ion channels
Plasticity

Animal Models of Epilepsy

Increased Excitation
Kainic Acid (parenteral or intracerebral)

Stimulates Glutamate receptors

Causes prolonged seizures/status epilepticus
Leads to hippocampal damage
Model of human temporal lobe epilepsy

Animal Models of Epilepsy

Decreased Inhibition
Pentylenetetrazol (PTZ)
GABA antagonist
Model of absence epilepsy

Animal Models of Epilepsy

Electrical Stimulation
Kindling
Repeated subthreshold focal electrical (or chemical)
stimulation of hippocampus or amygdala
Initial applications produce afterdischarges
Increasing
I
i severity
it off clinical
li i l seizures
i
Spontaneous seizures

Maximal Electroshock (MES)

Model of Generalized Tonic-Clonic seizures

Animal Models of Epilepsy

Application of other topical agents
Penicillin
Aluminum

Models of cortical dysplasia

Animal Models of Epilepsy

Limitations for Drug Development
Simple acute seizure models show response
of a healthy
y (not
(
chronically
y epileptic)
p p ) brain
to AEDs
Efficacy may be model or species specific
No good models for several seizure types
Reliance
R li
on few
f models
d l produces
d
me
too
drugs

Evaluation of the
Patient with Seizures

Does the Patient Have Epilepsy?

Syncope
TIA
Migraine
Sl
Sleep
disorder
di d
Psychogenic event

Description of the Typical Attack

Is there a warning (aura)?
What is the evolutionary pattern
What is the patient like after a typical
attack?

Assess Historical Risk Factors

Birth and developmental history
History of febrile seizures
Acquired brain insults (CNS infection, head
injury stroke)
injury,
Family history of seizures

The Influence of
Provocative Factors

Sleep deprivation
Menses
Physical/emotional stress
I
Intercurrent
illness
ill
Alcohol/drugs
Specific Triggers

The Physical and Psychological

Examinations

The Laboratory Examination

Serum and urine studies
Electroencephalogram
Ictal
Interictal

Neuroimaging

The Laboratory Examination

Serum and urine studies
Electroencephalogram
Ictal
Interictal

Neuroimaging

Serum and Urine Studies

Serum Chemistries
Na+
Ca2+
Glucose

Toxicology Screen
Antiepileptic
p p drug
g levels
CBC
Serum Prolactin

The Laboratory Examination

Serum and urine studies
Electroencephalogram
Ictal
Interictal

Neuroimaging

Focal Epileptiform Discharge

EEG: Simple Partial Seizure

Right temporal
seizure

EEG: Simple Partial Seizure

Continuation of
same seizure
Right temporal
seizures with
maximal phase
reversal in the
right sphenoidal
electrodes

Generalized Epileptiform
Discharge: Absence Seizure

The Laboratory Examination

Serum and urine studies
Electroencephalogram
Ictal
Interictal

Neuroimaging

Arteriovenous Malformation

C i l Dysplasia
Cortical
l i (perisylvian)
( i l i )

Heterotopic Gray Matter

CT vs. MRI
80
70
60

%
Abnormal

50
CT
MRI

40
30
20
10
0
McLach.

Latock

Schorner

Jabbri

Heinz

Specialized Neuroimaging
Studies
PET
SPECT
Magnetic Resonance Spectroscopy

Subtraction Ictal-Interictal SPECT

Classification of Seizures
Partial Seizures

Generalized Seizures

Types of Seizures: Partial

Simple Partial

Complex Partial

Generalized

Simple Partial Seizures (Aura)

Motor
Clonic, Versive, Dystonic

Sensory
Somatosensory, Visual, Auditory, Olfactory, Gustatory

Autonomic
Epigastric rising, Sweating, Flushing, Piloerection,
Pupillary Dilatation

Psychic
Fear, Dj vu, Jamais vu

Types of Seizures: Partial

Simple Partial

Complex Partial

Generalized

AUTOMATISMS
Stereotyped elemental behaviors
Usually occur during impaired
consciousness in complex partial
seizures

Automatisms in 79 patients
during complex partial seizures
Automatism
Chewing,
Ch
i
swallowing,
ll i
pursing
i lips
li
Looking around, smiling, grimmacing, crying
Attempting to sit up
Examining or fumbling with objects
Tonic adversive head turning
Bilateral arm movements
Bilateral leg movements
Fighting restraint
Verbalization
Standing up
Walking or running away
Source: Delgado-Escueta et al 1987

# of pts.
74
43
39
28
11
11
11
7
6
6
6

Types of Seizures: Partial

Simple Partial

Complex Partial

Generalized

Post-ictal Changes
Transient
Follows complex partial or
generalized tonic-clonic seizures.
Confusion,
Confusion Combativeness
Todds paralysis transient, posti l focal
ictal,
f l neurological
l i l deficit
d fi i

Seizure Types: Generalized

Absence
Generalized Tonic-Clonic
Myoclonic
Tonic
Atonic

Seizure Types
yp

Epilepsy Syndromes

Seizure Type
yp vs. Epileptic
p p Syndrome
y
A group of signs and symptoms that occur together
and characterize a particular abnormality
A seizure type is determined by the patients
patient s
behavior and EEG pattern during the ictal event.
An epileptic syndrome is defined by:
Seizure type(s)
History
EEG (ictal and interictal)
Imaging
Etiology-Genetics

Epilepsy Syndrome
Focal
(Localization-Related)
(Localization
Related)

Idiopathic
Idi
thi
(Genetic)

Symptomatic
or Cryptogenic
(L i l)
(Lesional)

Generalized

Epilepsy Syndrome: Example

Symptomatic Localization-related Epilepsy

Onset in early teens

Focal onset seizures
Focal right temporal EEG sharp waves
MRI shows right hippocampal sclerosis

Prognosis
Usually refractory to medications
Epilepsy surgery is curative in up to 80-90%

Epilepsy Syndrome
Focal
(L li ti
(Localization-related)
l t d)

Idiopathic
Idi
thi
(Genetic)

Symptomatic
(Cryptogenic)

Mesial Temporal
p
Sclerosis

Generalized

Epilepsy Syndrome: Example

Idiopathic Generalized Epilepsy

Onset at puberty
Mix of generalized seizures
Generalized spike/wave on EEG
Normal intellect and neurological exam
Normal MRI

Treatment
T t
t andd Prognosis
P
i
Responds well to monotherapy (VPA or LTG)
Unlikely to spontaneously remit

Epilepsy Syndrome
Focal
(Localization-related)
(Localization
related)

Idiopathic
Idi
thi
(Genetic)

Symptomatic
(Cryptogenic)

Generalized

Juvenile
Myoclonic
Epilepsy

Juvenile Myoclonic Epilepsy

Onset in teenage years

Myoclonic seizures (A.M.)
(A M )
Generalized tonic-clonic seizures
Ab
Absence
iin 10-30%
10 30%
Normal intellect
Family history in ~ 50%
Excellent response to valproate (Depakote)
An idiopathic generalized epilepsy syndrome

Epilepsy Syndrome: Example

Symptomatic Generalized Epilepsy

Onset on childhood
Mix of generalized seizures
X
Impaired intellect
Abnormal MRI (multifocal or diffuse abnormality)
Generalized slow spike-wave on EEG

Prognosis
P
i
Poor: usually refractory to many medications
Non-medical
Non medical options may be considered

Epilepsy Syndrome
Focal
(L li ti
(Localization-related)
l t d)

Generalized

Idiopathic
Idi
thi
(Genetic)

Symptomatic
(Cryptogenic)

Lennox-Gastaut
S d
Syndrome

Treatment
Avoid seizure triggers
Sleep deprivation
Alcohol
Medication withdrawal

Medications
Surgery
S

Unmasking Photosensitivity

Treatment for First Seizure?

Individualize Decision!
Estimate risk of recurrence
Overall, 16-62% will recur within 5 years
30% recurrence rate with normal evaluation
Abnormal imaging, abnormal neurological exam,
abnormal EEG or family history increases relapse risk

Individual determination
Driving?
Working?
Consequences of 2nd seizure?
Reference: First Seizure Trial Group. Randomized Clinical Trial on the efficacy of
antiepileptic drugs in reducing the risk of relapse after a first unprovoked tonicclonic
l i seizure.
i
N
Neurology
l
1993
1993; 43 (3
(3, part1):
t1) 478-483.
478 483 R
Reference:
f
C fi ld P,
Camfield
P
Camfield C, Dooley J, Smith E, Garner B. A randomized study of carbamazepine
versus no medication after a first unprovoked seizure in childhood. Neurology
1989; 39: 851-852.

37%

TREATMENT GOAL
Complete seizure control
No side effects

Antiepileptic Drug Choice

Adverse effects

Individual circumstances

Effectiveness for epilepsy syndrome

Pharmacokinetics

Cost

Drug Interactions

What If Seizures Don

Dontt Respond
to Medications?

Incorrect diagnosis
Noncompliance
Incorrect medication choice
Inadequate medication levels
M di ll refractory
Medically
f
seizures
i

Case
17 year old boy with history of headaches
g
with ppseudotumor cerebri
diagnosed
Headaches resolved
No seizure risk factors
Developed frequent seizures with unusual
d
description
i i

Non-Epileptic Seizures
(NES)
Seizures

Epileptic

Non epileptic
Non-epileptic

Physiologic

Psychogenic

- 90%

10% Syncope
Movement Disorders
Hypoglycemia
Parasomnias...

Conversion
Somatization
Dissociative
Factitious...

Pseudoepilepsy
Pseudoseizures
Non epileptic events
Non-epileptic
Hysterical seizures
Psychogenic seizures

Physiologic Non
Non-Epileptic
Epileptic
Events

Psychogenic Non
Non-Epileptic
Epileptic
Events

Non-epileptic seizures
Video-telemetry monitoring is the gold
standard for diagnosis
g
Proves the diagnosis
Patients may not accept the diagnosis without
clear-cut laboratory documentation

Frontal Lobe Seizures vs.

vs
Non-epileptic Seizures
Feature
Arises from sleep
Brief duration
Hypermotor activity
Postictal confusion
Clustering pattern
A
Associated
i t d Injuries
I j i
Stereotyped
Affective Change
EEG Change

Frontal Lobe
++
++
++
+/+
+
++
+/-

Non-Epileptic
++
+/+
+
++
-

Types of Epilepsy Surgery

Epilepsy Surgery
Focal Resection

Corpus Callosotomy

Vagus Nerve Stimulation

Medically Refractory Seizures

PET
SPECT

Epilepsy
p p y Surgery?
g y

Wada Test

Video EEG

MRI

Surgically Remediable
Epilepsy Syndromes
Mesial Temporal Sclerosis
80
80-90%
90% seizure-free
seizure free

Other Symptomatic Partial Epilepsies

With discrete lesion (70%?)
Without discrete lesion

Hemispheric
H i h i Disorders
Di d in
i Children
Child

Refractory Epilepsy
26-year-old with complex partial seizures
and secondarily
y GTC seizures for 8 years
y
History of prolonged febrile convulsion
Poor response to 3 monotherapy and 2
combination trials of antiepileptic meds
MRI:
MRI right
i h mesial
i l temporall sclerosis
l
i

Refractory Epilepsy

Incorrect diagnosis No
Noncompliance No
Inadequate medication levels No
Incorrect medication choice No
Medically refractory seizures Yes
Syndrome: Mesial Temporal Sclerosis
S
Seizure
i
free
f with
i h further
f h medd trials
i l = 5%
Seizure free with epilepsy surgery = 80-90%

Appropriate for Surgical Evaluation

Mesial Temporal Sclerosis

Mesial Temporal Sclerosis

Anterior Temporal Lobectomy

Selective
Amygdalohippocampectomy

Selective
A
Amygdalohippocampectomy
d l hi

Anterior Temporal Lobectomy

Ketogenic Diet
Main experience with children, especially
with multiple seizure types
Anti-seizure effect of ketosis (beta
hydroxybutyrate)
Low carbohydrate, low protein, high fat
after fasting to initiate ketosis
Long-term adverse effects unknown

Vagal Nerve Stimulation

Approved for the treatment of refractory
ppartial seizures in ppatients over 12 yyears old
Palliative
Patients may reduce,
reduce but not discontinue AEDs

> 40,000 patients to date

Vagal Nerve Stimulator

Vagal Nerve Stimulation

Partial Seizures
37% have > 50% reduction at one year

Atonic Seizures
50% have > 50% reduction at one year

Idiopathic Generalized Epilepsies

59% have
h
> 50% reduction
d i at one year

The Future?

Summary

Definitions and epidemiology

Etiology/pathology
Pathophysiology:
E l i off the
Evaluation
h patient
i with
i h seizures
i
Seizure types
Epilepsy syndromes
Treatment principles