Transcript Clinical Epilepsy: Syndromes, Causes, and Effects

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%
2
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
3
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
6
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
0
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.
9
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
Refractory/
Pharmacoresistant
36%
Sz-free w/ 1st AED
47%
Sz-free w/ 3rd
AED/Polytherapy
4%
S z-free w/ 1st AED
Sz-free 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%
27%
350000000
5%
300000000
Psychiatric d/o's
9%
250000000
Epilepsy
Pain disorders
200000000
Headache/migrain
e
Other
150000000
100000000
44%
50000000
Ja
n-
01
M
ar
-0
1
M
ay
-0
1
Ju
l-0
1
Se
p01
N
ov
-0
1
Ja
n02
M
ar
-0
2
M
ay
-0
2
Ju
l-0
2
Se
p02
N
ov
-0
2
Ja
n03
M
ar
-0
3
M
ay
-0
3
Ju
l-0
3
Se
p03
N
ov
-0
3
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
NEURONTIN
60.6%
20
TOPAMAX
14.8%
10
0
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
S z- f re e wit h 1s t A E D
S z- f re e wit h 2 nd A E D
2nd
S z- f re e wit h 3 rd
A E D / P o lyt he ra py
P ha rm a c o re s is t a nt
Monotherapy AED Trial
13%
47%
3rd Monotherapy/Polytherapy AED Trial
4%
Strongly consider videoEEG Monitoring
Non-epileptic
Epilepsy
Psychogenic, migraine, syncope,
sleep disorders, movement disorder’s, 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
Non–SeizureRelated
Variables
Factors Affecting Cognitive Function in
Epilepsy
SeizureRelated
Variables
TreatmentRelated
Variables
Non–SeizureRelated
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 syndromes—e.g., BECTS
(Rolandic), absence
– Adverse syndromes—e.g., Lennox-Gastaut
– Variable syndromes—Localization 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 2º
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, Sillanpää (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
Äikiä, Epilepsy & Behavior (2001)
Äikiä , 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
5
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
AEP Summary Score
60
70
Gilliam F, et al. 2000
Psychiatric Comorbidities
Epilepsy
(range)
General Pop.
(range)
Depression
11%–60%
2%–4%
Anxiety
Psychosis
19%–45%
2%–8%
2.5%–6.5%
0.5%–0.7%
QOLIE- 89 Sum m ary Sc ore
100
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)