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

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)

Epidemiology of Seizures and Epilepsy

90 80 70 60 50 40 30 20 10 0 0
Epilepsy: Incidence Rates by Seizure Type
Con 4% CHI 5% V 1% N 4% D 1% Inf 0%
Hemorrhage Head Trauma 2% 7% Unknown 24% Other* 19%

Incidence per 100,000

Id 85%

Cerebral Infarct 33%

Atherosclerosi s 15%

Partial Generalized tonic-clonic Primary Generalized

10

20

30

40
Age

50

60

70

80

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

9
*

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% Sz-free w/ 2nd AED 13%

S z-free w/ 1st AED 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 350000000 300000000 250000000 200000000 150000000 100000000 50000000 0

15% 5% 9%

27%

Epilepsy Psychiatric d/o's Pain disorders Headache/migrain e Other

44%

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

Second Gen. AEDs First Gen. AEDs

Ja n-

AED Prescription Volume (%)

50

40

Carbamazepine Depakote ER Keppra Neurontin Topomax

Depakote DR Depakote sprinkles Lamictal Phenytoin Trileptal

KEPPRA 4.7% LAMICTAL 8.1% TRILEPTAL 8.0%

GABITRIL 1.8%

ZONEGRAN 2.1%

30

NEURONTIN 60.6%

20
TOPAMAX 14.8%

10

0-17

18-34

35-44

45-54

55-64

>65

Age Group (years)

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 Gabapentin Lamotrigine Serious Adverse Events None 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 None Hyponatremia (more common in elderly), rash Stupor or spike wave stupor Nephrolithiasis, open angle glaucoma, hypohidrosis (predominantly children) Rash, renal calculi, hypohidrosis (predominantly children) Nonserious Adverse Events Weight gain, peripheral edema, behavioral changes Tics and insomnia

Levetiracetam Oxcarbazepine Tiagabine Topiramate Zonisamide

Irritability/behavior change None Weakness Metabolic acidosis, weight loss, language dysfunction 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. 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. 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. 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. Blood levels below therapeutic levels are to be considered on an individual basis. Applicants and licensed drivers with only chronic nocturnal seizures will be considered on an individual basis. Applicants and licensed drivers with syncopal episodes who have no clear diagnosis established will be considered on an individual basis

2. 3.

4.

5. 6. 7.

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 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

2nd

Monotherapy AED Trial

47%

13%

3rd Monotherapy/Polytherapy AED Trial

4%

Strongly consider videoEEG Monitoring

Non-epileptic Epilepsy

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

Psychogenic, migraine, syncope, sleep disorders, movement disorders, etc.

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

Ganglioglioma

Dysembryoplastic Neuroepithelial Tumor

Cortical Dysplasia

AVM

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

Etiology

Seizure Burden (Duration, Frequency, Status)

Epileptiform Activity

Seizure-Related Variables That May Affect Cognition and Behavior

Seizure Syndrome

Age at Onset

Etiology

Seizure Burden (Duration, Frequency, Status)

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 JME Generalized with absence or GTCS
Centrotemporal spikes benign Occipital epilepsy

Outcome Presumed favorable Unknown

Mostly favorable (interictal abn) Unknown
Elger et al. (2004)

Mild executive deficits Mild attentional deficits

Mild Heterogeneous Mild Heterogeneous

Adverse Syndromes
Deficit CSWDS Landau Kleffner Variable (diffuse or executive) Auditory agnosia, Expressive Language Outcome Variable - duration dependent Variable early onset worse

West Syndrome Lennox-Gastaut

Retardation, regression Retardation, decline

Poor, retardation
Poor, retardation worse early onset
Elger et al. (2004)

Localization Related Syndromes

Deficit Outcome

Frontal

Executive function, attention, speed Material-specific memory (executive 2 gen), naming, achievement Unknown (variable)

Unknown

Temporal

Very slow deterioration

Unknown (heterogeneous)

Parietal Occipital

Elger et al. (2004)

Seizure-Related Variables That May Affect Cognition and Behavior

Epileptic Syndrome

Age at Onset

Etiology

Seizure Burden (Duration, Frequency, Localization)

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

Early (7.8 yr) N 37 FSIQ 90* Naming 47 Verbal Mem 44 NV Mem 46 WCST PE 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

Age at Onset

Etiology

Seizure Burden (Duration, Frequency, Localization)

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

Age at Onset

Etiology

Seizure Burden (Duration, Frequency, Localization)

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 58

N = 166

Seizure-free Auras Seizures Hypertension/ Diabetes Heart Disease

T-SCORE

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

100

QOLIE-89 Summary Score

80

60

40

20

0 0 5 10 15 20 25 30

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

Average Monthly Seizure Rate

Gilliam F, et al. 2000

Relationship of Adverse Events to QOL Scores

100

QOLIE-89 Summary Score

80

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

60

40

20

0 20 30 40 50 60 70

AEP Summary Score

Gilliam F, et al. 2000

Psychiatric Comorbidities
Epilepsy (range)
Depression Anxiety Psychosis 11%60% 19%45% 2%8%
100

General Pop. (range)

2%4% 2.5%6.5% 0.5%0.7%
r = -0.66 p<0.0001

QOLIE -89 S um m ary Score

80

60

40

20

0 0 10 20 30 40 50

Profile of Mood States Depression Scale Score

POMS

(non-modifiable)

(modifiable)

Elger et al. (2004)