Clinical Epilepsy: Syndromes,

Causes, and Effects

Russell M. Bauer, Ph.D.
Department of Clinical & Health
Psychology

Seizures vs Epilepsy
Seizures
Definition: the clinical
manifestation of an abnormal
and excessive excitation of a
population of cortical neurons
Incidence: approximately
80/100,000 per year
Lifetime prevalence: 9%
(1/3 benign febrile
convulsions)

Epilepsy
Definition: a tendency toward recurrent
seizures unprovoked by systemic or
neurologic insults
Incidence: approximately 45/100,000 per
year Approximately 181,000 people will
experience seizures or develop epilepsy
each year
Point prevalence: 0.5-1% (2.5 million)
14 years or younger
13%
15 to 64 years
63%
65 years and older
24%
Cumulative risk of epilepsy through 74
years old: 1.3% - 3.1%

Partial (focal) Seizures

Simple Partial Seizure

no loss of awareness

Complex Partial Seizure

Impaired consciousness/ level of awareness (staring)
Clinical manifestations vary with origin & degree of spread
Presence and nature of aura
Temporal lobe: smell, epigastric sensation, deja vu
Automatisms (manual, oral)
Other motor activity

Frontal: bicycling and fencing posture

Duration (typically 30 seconds to 3 minutes)
Amnesia for event

Partial Seizure with Secondary

Generalization

Localization of Partial Seizure Focus

20%

70%

10%

Temporal Lobe Complex Partial Seizure

Rhythmic 5-7 Hz theta from the mesial temporal lobe

Primarily Generalized Seizures

Absence
Typical (3 Hz spike and wave)
Atypical (2.5 to 4.5 Hz spike and wave, polyspike)
Brief staring (<30sec); automatisms rare; not post-ictal confusion

Myoclonic
Brief, shock-like muscle contractions
- Head
- Upper extremities
Usually bilaterally symmetrical
Consciousness preserved
Precipitated by awakening or falling asleep
May progress into clonic or tonic-clonic seizure
May be associated with a progressive neurolgic deterioration
Juvenile Myoclonic Epilepsy (JME)
Polyspike wave
Onset late adolescence
Chromosome 6p
Progressive Myoclonic Epilepsies

Atonic/ Tonic/ Tonic-Clonic

Absence Seizure
3 Hz spike and wave

Seizure vs Epilepsy
Seizures
Nonepileptic

Epilepsy
(recurrent seizures)

Cardiovascular
Drug related
Syncope
Idiopathic
Metabolic (glucose, Na, Ca, Mg)
(primary)
Toxic (drugs, poisons)
Poison
Infectious
Febrile convulsions
Nonepileptic seizures
Alcohol/drug withdrawal
Substance abuse
Psychiatric disorders
Sleep disorders (parasomnias, cataplexy)

Symptomatic
(secondary)

Incidence per 100,000

Epidemiology of Seizures and Epilepsy

Epilepsy: Incidence Rates by Seizure Type

90
80
70
60
50
40
30
20
10
0

Con
4%

CHI
5%

V
1%

Hemorrhage
Head Trauma
2%
7%
Unknown
24%
Other*

N
4%
D
1%
Inf
0%

19%

Cerebral
Infarct
33%

Id
85%

Atherosclerosi
s
15%

Partial
Generalized tonic-clonic
Primary Generalized

10

20

30

40

50

60

70

80

Age
Data from Rochester, Minn (1935-1979). Adapted with permission from Annegers JF. In: The Treatment of Epilepsy: Principles and Practice. 2nd ed.
Baltimore, Md: Williams & Wilkins; 1997:165-172.
Hauser et al, 1992
Ramsay RE, et al. Neurology. 2004;62(5 suppl 2):S24-S29

Includes known etiologies such as arteriovenous malformation

.
and venous angioma.

Seizure Precipitants
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
Severe sleep deprivation

EEG Abnormalities
Background abnormalities
-Significant asymmetries and/or degree of slowing
inappropriate for clinical state
Transient abnormalities associated with seizures
-Spikes (< 70 m sec)
-Sharp waves (~70 200 msec)
-Spike-wave complexes
May be focal, lateralized or generalized

EEG Abnormalities

Treatment of New Onset Epilepsy

Re fractory/
Pharmacore sistant
36%
Sz -free w/ 1st AED
47%

Sz -fre e w/ 3rd
AED/Polythe rapy
4%

S z-free w/ 1st AED

Sz -fre e w/ 2nd AED
13%

S z-free w/ 2nd AED

S z-free w/ 3rd AED/Polytherapy
Refractory/Pharmacoresistant

Kwan P, Brodie MJ. N Engl J Med

2000; 342: 314-9.

Kwan and Brodie. NEJM 2000; 342: 314-319.

Mohanraj and Brodie. Epil Behav 2005; 6: 382-387

Kwan and Brodie. NEJM 2000; 342: 314-319.

Mohanraj and Brodie. Epil Behav 2005; 6: 382-387

Rational Use of AEDs: All Prescriptions

Market Dynamics for All Indications and Epilepsy
450000000
400000000

15%

350000000

27%

5%

300000000

Psychiatric d/ o's

9%

250000000

Epilepsy

Pain disorders

200000000

Headache/ migrain
e
Other

150000000
100000000

44%

50000000
0

AED Prescription Volume (%)

Second Gen. AEDs

50

40

Carbamazepine
Depakote ER
Keppra
Neurontin
Topomax

First Gen. AEDs

KEPPRA
4.7%

Depakote DR
Depakote sprinkles
Lamictal
Phenytoin
Trileptal

GABITRIL
1.8%

ZONEGRAN
2.1%

LAMICTAL
8.1%
TRILEPTAL
8.0%

30

20

NEURONTIN
60.6%

TOPAMAX
14.8%

10

0-17

18-34

35-44

45-54

55-64

Age Group (years)

>65

PharMetrics. April 2002 to June 2003.

Source: IMS NPA, Dec. 2003
MAT 03/2004

All substances are

poisons; there is none
which is not a poison.
The right dose
differentiates a poison
from a remedy.
Paracelsus (1493-1541)

Summary of Serious and Non-serious

Adverse Events of the Newer AEDs
AED

Serious Adverse Events

Nonserious Adverse Events

Gabapentin

None

Weight gain, peripheral edema,

behavioral changes

Lamotrigine

Rash, including Stevens Johnson and toxic

epidermal necrolysis (increased risk for
children, also more common with concomitant
valproate use and reduced with slow titration);
hypersensitivity reactions, including risk of
hepatic and renal failure, DIC, and arthritis

Tics and insomnia

Levetiracetam

None

Irritability/behavior change

Oxcarbazepine

Hyponatremia (more common in elderly), rash

None

Tiagabine

Stupor or spike wave stupor

Weakness

Topiramate

Nephrolithiasis, open angle glaucoma,

hypohidrosis (predominantly children)

Metabolic acidosis, weight loss,

language dysfunction

Zonisamide

Rash, renal calculi, hypohidrosis (predominantly

children)

Irritability, photosensitivity,
weight loss

Rational Use of AEDs

So Why Should Prescribing Practices Change?
Patients often required long term (or lifetime) treatment due to driving status
State of Florida *15A-5.004 Neurological Guidelines for Applicants with Seizures
(*the following changes to the seizure guidelines became effective in August 1992 and have been
used as policy since that date)
1.

Applicants and licensed drivers should be seizure free for a period of 2 years before being approved for
licensing; but if under regular medical supervision, may apply at the end of 6 months for review by the
Medical Advisory Board. Petit mal or absence seizures and partial seizures with complex symptomology will
also follow these guidelines. The isolated seizure with a normal EEG may be reviewed after 3 months.

2.

Applicants and licensed drivers who have been approved after 6 months seizure free may be required to submit
follow-up reports at the end of 1 year from the date of approval.

3.

Applicants and licensed drivers who have a chronic recurring seizure disorder (or who have been treated for
such for 1 year) and medications have been discontinued will not be licensed to drive during the period of
drug withdrawal and for a period of 3 months following complete cessation of treatment. If the patient has
seizures during this period, licensing may be considered after a 3 month seizure free interval upon return to
adequate therapy.

4.

If there is a question about the seizure type or the medications the applicant of licensed driver is on, it is the
prerogative of the Medical Advisory Board to question the treating physician further in an effort to clarify the
nature of the seizures.

5.

Blood levels below therapeutic levels are to be considered on an individual basis.

6.

Applicants and licensed drivers with only chronic nocturnal seizures will be considered on an individual basis.

7.

Applicants and licensed drivers with syncopal episodes who have no clear diagnosis established will be
considered on an individual basis

Treatment/Evaluation Sequence for

Pharmacoresistent Epilepsy
1st Monotherapy AED Trial

Sz-free with 1st A ED

Sz-free with 2nd A ED
Sz-free with 3rd
A ED/P olytherapy
P harmacoresistant

2 Monotherapy AED Trial

nd

13%

47%

3rd Monotherapy/Polytherapy AED Trial

4%

Strongly consider videoEEG Monitoring

Non-epileptic

Epilepsy

Psychogenic, migraine, syncope,

sleep disorders, movement disorders, etc.

36%
Kwan P, Brodie MJ.
NEJM;342:314-319.

Epilepsy Surgery/VNS Therapy/

Neuropace Evaluation

Polytherapy AED Trials

Resective Surgery

Stimulator Therapy

Other Treatments of Epilepsy

Medical
Experimental AED trials
Ketogenic diet
Surgical
Resective
Multiple Subpial Transection
Vagal Nerve Stimulator
Experimental
Thalamic Stimulators
Stereotactic Radiosurgery
Responsive Neurostimulators

Evaluation for Surgery- Neuroimaging

MRI
-hippocampal volumetrics
greater than ~0.5cc difference increases chances for seizure
remission
-1.5 mm coronal cuts with sequences sensitive to gray-white
differentiation and to gliosis
-inversion recovery/high resonance for cortical dysplasia

PET
Ictal/interictal SPECT
MR Spectroscopy
Decreased NAA (due to neuronal loss)
Normal to high Cho and Creatine (represents astrocytosis)

Epilepsy Surgery- Neuroimaging

Hippocampal atrophy in
temporal lobe epilepsy

Cortical Dysplasia

Ganglioglioma

AVM

Dysembryoplastic
Neuroepithelial Tumor

Cavernous Angioma

Evaluation for Surgery- Subdural Grid Electrodes

Left Anterior Temporal Loectomy

Factors Affecting
Adaptation in Epilepsy
SeizureRelated
Variables

TreatmentRelated
Variables

NonSeizureRelated
Variables

Factors Affecting Cognitive Function in

Epilepsy
SeizureRelated
Variables

TreatmentRelated
Variables

NonSeizureRelated
Variables

What Seizure Related Factors May

Affect Cognition in Epilepsy?
Seizure
Syndrome

Onset Age

Seizure
Burden
(Duration,
Frequency,
Status)

Etiology

Epileptiform
Activity

Seizure-Related Variables That May

Affect Cognition and Behavior
Seizure
Syndrome

Seizure
Burden
(Duration,
Frequency,
Status)

Age
at
Onset

Etiology

Epileptiform
Activity

Epileptic Syndrome
Some epilepsy syndromes are known to be
associated with more adverse cognitive
consequences than others.
Idiopathic Benign syndromese.g., BECTS
(Rolandic), absence
Adverse syndromese.g., Lennox-Gastaut
Variable syndromesLocalization related
epilepsies

Idiopathic Syndromes
Deficit

Outcome

JME

Mild executive
deficits

Presumed favorable

Generalized with
absence or GTCS

Mild attentional
deficits

Unknown

Centrotemporal
spikes benign

Mild Heterogeneous

Mostly favorable
(interictal abn)

Occipital epilepsy

Mild Heterogeneous

Unknown
Elger et al. (2004)

Adverse Syndromes
Deficit

Outcome

CSWDS

Variable (diffuse or
executive)

Variable - duration
dependent

Landau Kleffner

Auditory agnosia,
Expressive Language

Variable early onset

worse

West Syndrome

Retardation, regression

Poor, retardation

Retardation, decline

Poor, retardation
worse early onset

Lennox-Gastaut

Elger et al. (2004)

Localization Related Syndromes

Deficit

Outcome

Frontal

Executive function,
attention, speed

Unknown

Temporal

Material-specific
memory (executive 2
gen), naming,
achievement

Very slow
deterioration

Unknown (variable)

Unknown
(heterogeneous)

Parietal Occipital

Elger et al. (2004)

Seizure-Related Variables That May

Affect Cognition and Behavior
Epileptic
Syndrome

Seizure
Burden
(Duration,
Frequency,
Localization)

Age
at
Onset

Etiology

Interictal
Epileptiform
Activity

Adults with Childhood Seizure

Onset

Less Education
Decreased rates of employment
Lower rates of marriage
Poorer physical health
Increased incidence of psychiatric disorders

Jalava et al., 1997a,b,c, Sillanp (1998)

Total and Segmented Volumes

(7.8 years vs. 23.3 years)

Hermann et al, Epilepsia 2002;43:1062-71

Total Lobar White Matter

Hermann et al, Epilepsia 2002;43:1062-71

Cause or Effect?
Does white matter volume abnormality
reflect neurodevelopmental abnormality
associated with early insult to developing
brain?
Does early lesion affect subsequent normal
development of white matter connectivity?

Age of Onset and

Neuropsychological Outcome
N
FSIQ
Naming
Verbal Mem
NV Mem
WCST PE

Early
(7.8 yr)
37
90*
47
44
46
13

Late
(23.3 yr)
16
100
52
51
55
8

Healthy
Controls
62
107
55
52
62
8

Hermann et al, Epilepsia 2002;43:1062-71

Childhood TLE Onset

Generalized cognitive compromise
Reduction in cerebral volume, particularly white
matter (~6-12%)
Cerebral volume reduction not limited to temporal
lobe
Less focal impairment (e.g., memory)
Less surgical risk
Greater likelihood of functional reorganization (e.g.,
bilateral language, pathologic left handedness)

Seizure-Related Variables That May

Affect Cognition and Behavior
Seizure
Syndrome

Seizure
Burden
(Duration,
Frequency,
Localization)

Age
at
Onset

Etiology

Epileptiform
Activity

Etiology
Individuals with known causes for their
epilepsy (e.g., head injuries, brain infections)
typically have more detectable cognitive
difficulties than those with no known etiology

Seizure-Related Variables That May

Affect Cognition and Behavior
Seizure
Syndrome

Seizure
Burden
(Duration,
Frequency,
Localization)

Age
at
Onset

Etiology

Epileptiform
Activity

Seizure Burden
Individuals with poorly controlled and
severe seizures often have more detectable
cognitive consequences than individuals
with well-controlled and/or minor seizures

Cumulative Seizure Effects?

(is epilepsy progressive?)
Structural Imaging vs Behavior
Cognitive and behavioral impairments
present prior to treatment
Newly diagnosed L TLE patients have
verbal memory impairment
iki, Epilepsy & Behavior (2001)
iki , Epilepsy Research 1995;22:157-164

Progressive Hippocampal
Sclerosis
Progressive
hippocampal atrophy
occurred only in patients
with TLE and
continuing seizures
n=12 unilateral TLE
Repeat MRI=2.5-5.2 yr
Fuerst et al, Ann Neurol 2003;53:413-6

Neuropsychological Effects of
Poorly Controlled Seizures

20 longitudinal studies in children-adults

12/20 reported relationship/decline
5/20 mixed results
3/20 no relationship

Dodrill, Epilepsy & Behavior (2004)

Neuropsychological Effects of
Seizures
Decreased scores with higher number of
seizures
IQ lower with increased seizure frequency
Greater performance improvement in
controls than patients
Losses seen beyond memory
Dodrill, Epilepsy & Behavior (2004)

Cross-sectional TLE
Neuropsychological Outcome

Jokeit et al, JNNP 1999;67:44-50

Educational Attainment and Seizure

Duration

Jokeit et al, JNNP 1999;67:44-50

Epilepsy and Quality of Life

Seizures, Hypertension, Diabetes, and

Heart Disease QoL
61

Seizure-free
Auras
Seizures
Hypertension/ Diabetes
Heart Disease

N = 166

T-SCORE

58
55
52
49
46
Overall Emotional Social
Role
Energy/
Quality Well-Being Function Emotional Fatigue
of Life

Pain

Role Physical Health

Physical Function Perception

Vickrey BG. Epilepsia. 1994;35:597-607

Comparison of Average Monthly

Seizure Rate to HRQOL
QOLIE-89 Summary Score

100
80
60
40
20

N = 194
(r = -0.024,
P = NS)

0
0

10

15

20

25

30

Average Monthly Seizure Rate

Gilliam F, et al. 2000

Relationship of Adverse Events to QOL Scores

QOLIE-89 Summary Score

100

N = 194
(r = -0.71,
P<.0001)

80

60

40

20

0
20

30

40

50

60

70

AEP Summary Score Gilliam F, et al. 2000

Psychiatric Comorbidities

11%60%
19%45%
2%8%

2%4%
2.5%6.5%
0.5%0.7%

100

QOLIE-89

Depression
Anxiety
Psychosis

General Pop.
(range)

QOLIE-89 Summary Score

Epilepsy
(range)

r = -0.66
p<0.0001

80

60

40

20

0
0

10

20

30

POMS

40

Profile of Mood States Depression Scale Score

50

(non-modifiable)

(modifiable)

Elger et al. (2004)