stephan eisenschenk, md department of neurology 1 clinical epilepsy
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1Stephan Eisenschenk, MDDepartment of Neurology
Clinical Epilepsy
www.neurology.ufl.edu/Epilepsy
2Stephan Eisenschenk, MDDepartment of Neurology
Seizures vs Epilepsy
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)
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%
Seizures Epilepsy
3Stephan Eisenschenk, MDDepartment of Neurology
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
4Stephan Eisenschenk, MDDepartment of Neurology
Localization of Partial Seizure Focus
70%70% 10%10%
20%20%
5Stephan Eisenschenk, MDDepartment of Neurology
Temporal Lobe Complex Partial Seizure
Rhythmic 5-7 Hz theta from the mesial temporal lobeRhythmic 5-7 Hz theta from the mesial temporal lobe
6Stephan Eisenschenk, MDDepartment of Neurology
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
7Stephan Eisenschenk, MDDepartment of Neurology
Absence Seizure
3 Hz spike and wave
8Stephan Eisenschenk, MDDepartment of Neurology
Seizure vs Epilepsy
Seizures
CardiovascularDrug relatedSyncopeMetabolic (glucose, Na, Ca, Mg)Toxic (drugs, poisons)PoisonInfectiousFebrile convulsionsPseudoseizureAlcohol/drug withdrawalSubstance abusePsychiatric disordersSleep disorders (parasomnias, cataplexy)
Nonepileptic Epilepsy(recurrent seizures)
Idiopathic(primary)
Symptomatic(secondary)
9Stephan Eisenschenk, MDDepartment of Neurology
Psychogenic Nonepileptic Seizures
• Represent genuine psychiatric disease
• 10-45% of refractory epilepsy at tertiary referral centers
• Females > males
• Psychiatric mechanism: dissociation, conversion, unconscious (unlike malingering)
• Association with physical, sexual abuse
• Epileptic and nonepileptic seizures may co-exist
• Video-EEG monitoring often helps clarify the diagnosis
• Once recognized, approximately 50% respond well to specific psychiatric treatment
10Stephan Eisenschenk, MDDepartment of Neurology
Epidemiology of Seizures and Epilepsy
010
2030
4050
6070
8090
0 10 20 30 40 50 60 70 80Age
Inci
den
ce p
er 1
00,0
00
Partial
Generalized tonic-clonic
Primary Generalized
Epilepsy: Incidence Rates by Seizure TypeEpilepsy: Incidence Rates by Seizure Type
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
Hemorrhage2% Head Trauma
7%
Other*19%
Atherosclerosis15%
Cerebral Infarct
33%
Unknown24%
Head Trauma5%Congenital
4%
Idiopathic85%
Degenerative1%
Neoplastic4%
Vascular1%
Infectious0%
.* Includes known etiologies such as arteriovenous malformation and venous angioma.
11Stephan Eisenschenk, MDDepartment of Neurology
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
12Stephan Eisenschenk, MDDepartment of Neurology
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
13Stephan Eisenschenk, MDDepartment of Neurology
EEG Abnormalities
14Stephan Eisenschenk, MDDepartment of Neurology
Medical Treatment of First Seizure(s)•Whether to treat first seizure is controversial
•16-62% will recur within 5 years
•Relapse rate for second seizure is reduced by AEDs,
BUT long term prognosis of whether the patient will have refractory epilepsy is not
•Increased risk of relapse
Abnormal imaging
Abnormal EEG
Family history of epilepsy
•Currently, most patients are not treated for the first seizure unless there is an increased risk for relapse
15Stephan Eisenschenk, MDDepartment of Neurology
First Tonic-clonic Seizure
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 1 2 3 4
Treated
Untreated
YEARS
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 1 2 3 4
Treated
Untreated
YEARS
Cumulative time-dependent probability of initiating a period of seizure remission according to whether an AED was given after the first tonic-clonic seizure
1 year seizure-free 2 years seizure-free
Treatment Does NOT Improve Prognosis of Epilepsy
16Stephan Eisenschenk, MDDepartment of Neurology
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)
17Stephan Eisenschenk, MDDepartment of Neurology
First-Generation Branded AgentsDilantin phenytoin 1938 Parke-DavisTegretol carbamazepine 1974 NovartisDepakote divalproex sodium 1978 Abbott
Second-Generation AgentsSecond-Generation Agents
FelbatolFelbatol felbamatefelbamate 19931993 Wallace LaboratoriesWallace Laboratories
NeurontinNeurontin gabapentingabapentin 19931993 Parke-DavisParke-Davis
LamictalLamictal lamotriginelamotrigine 19941994 Glaxo Smith KlineGlaxo Smith Kline
TopamaxTopamax topiramatetopiramate 19971997 Ortho-McNeilOrtho-McNeil
GabitrilGabitril tiagabinetiagabine 19971997 Abbott LaboratoriesAbbott Laboratories
TrileptalTrileptal oxcarbazepineoxcarbazepine 20002000 NovartisNovartis
ZonegranZonegran zonisamidezonisamide 20002000 ElanElan
KeppraKeppra levetiracetamlevetiracetam 20002000 UCB PharmaUCB Pharma
LyricaLyrica pregabalinpregabalin 20052005 PfizerPfizer
Rational Use of AEDs: Flooding the Market
18Stephan Eisenschenk, MDDepartment of Neurology
FDA Indications for AEDs:Monotherapy and/or Add-On Therapy
MonotherapyCarbamazepine
Divalproex ER
Ethosuximide
Oxcarbazepine
Phenobarbital
Phenytoin
Primidone
Lamotrigine1
Felbamate1
Topiramate
1Approved for conversion to monotherapy.
Add-On TherapyCarbamazepine Levetiracetam
Divalproex ER Gabapentin
Ethosuximide Phenytoin
Oxcarbazepine Tiagabine
Phenobarbital Zonisamide
Primidone
Physician’s Desk Reference, 2004.
19Stephan Eisenschenk, MDDepartment of Neurology
Treatment of New Onset Epilepsy
Kwan P, Brodie MJ. N Engl J Med 2000; 342: 314-9.
Sz-free w/ 1st AED47%
Sz-free w/ 3rd AED/Polytherapy
4%
Sz-free w/ 2nd AED13%
Refractory/Pharmacoresistant
36%
Sz-free w/ 1st AED
Sz-free w/ 2nd AED
Sz-free w/ 3rd AED/Polytherapy
Refractory/Pharmacoresistant
20Stephan Eisenschenk, MDDepartment of Neurology
Kwan and Brodie. NEJM 2000; 342: 314-319.Mohanraj and Brodie. Epil Behav 2005; 6: 382-387
21Stephan Eisenschenk, MDDepartment of Neurology
Kwan and Brodie. NEJM 2000; 342: 314-319.Mohanraj and Brodie. Epil Behav 2005; 6: 382-387
22Stephan Eisenschenk, MDDepartment of Neurology
Kwan and Brodie. NEJM 2000; 342: 314-319.Mohanraj and Brodie. Epil Behav 2005; 6: 382-387
23Stephan Eisenschenk, MDDepartment of Neurology
0
10
20
30
40
50 Carbamazepine Depakote DRDepakote ER Depakote sprinklesKeppra LamictalNeurontin PhenytoinTopomax Trileptal
AE
D P
resc
ript
ion
Vol
um
e (%
)
0-17 18-34 35-44 45-54 55-64 >65 Age Group (yearsAge Group (years))
Why Should Current Prescribing Practices Change?
PharMetrics. April 2002 to June 2003IMS NPA, Dec 2003.Kwan P, Brodie MJ. N Engl J Med 2000; 342: 314-9.
4%13%
47%
36%
Sz-free with 1st AED
Sz-free with 2nd AED
Sz-free with 3rdAED/PolytherapyPharmacoresistant
24Stephan Eisenschenk, MDDepartment of Neurology
Rational Use of AEDs: All PrescriptionsMarket Dynamics for All Indications and Epilepsy
TOPAMAX14.8%
TRILEPTAL8.0%
LAMICTAL8.1%
GABITRIL1.8%
ZONEGRAN2.1%
KEPPRA4.7%
NEURONTIN60.6%
0
50000000
100000000
150000000
200000000
250000000
300000000
350000000
400000000
450000000
Second Gen. AEDs First Gen. AEDs
27%
44%
9%
5%
15%
Epilepsy
Psychiatric d/ o's
Pain disorders
Headache/ migraine
Other
0
10
20
30
40
50 Carbamazepine Depakote DRDepakote ER Depakote sprinklesKeppra LamictalNeurontin PhenytoinTopomax Trileptal
AE
D P
resc
rip
tio
n V
olu
me
(%)
AE
D P
resc
rip
tio
n V
olu
me
(%)
Age Group (years)Age Group (years) PharMetrics. April 2002 to June 2003. Source: IMS NPA, Dec. 2003MAT 03/2004
0-17 18-34 35-44 45-54 55-64 0-17 18-34 35-44 45-54 55-64 >>65 65
25Stephan Eisenschenk, MDDepartment of Neurology
“All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.”
Paracelsus (1493-1541)
26Stephan Eisenschenk, MDDepartment of Neurology
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
27Stephan Eisenschenk, MDDepartment of Neurology
Pregnancy and AED Therapy:Risks of Congenital Abnormalities
• Congenital malformations
– Most common: orofacial clefts, heart defects
– Less common: microcephaly, neural tube defects
• Major malformations
– General population: 2% to 4%
– Newborns prenatally exposed to AEDs: 4% to 8%
– Multiple AEDs and higher doses may substantially increase malformation rate
• Minor malformations
– Increased 2 to 3 fold (10% to 30%)
So EL. Med Clin North Am. 1993;77:203-214. Foldvary N. Neurol Clin. 2001;19:409-425.Schachter SC. Epilepsia. 1999;40(suppl 9):S20-S25.Holmes LB, et al. N Engl J Med. 2001;344:1132-1138.
28Stephan Eisenschenk, MDDepartment of Neurology
AEDs and Bone Health• Increased incidence of osteopenia, osteomalacia,
and fracture with some AEDs– No prospective trials have been performed to
define the frequency of fractures in epilepsy • Factors associated with reduced BMD
– Polypharmacy– Generalized seizures
• All tested AEDs have been shown to reduce BMD– Primarily associated with enzyme-inducing
AEDs and phenytoin• Strong association for decreasing bone mineral
density– Carbamazepine– Phenobarbital– Phenytoin– Primidone
• Conflicting findings on bone mineral density– Divalproex– Lamotrigine
• Limited information on newer AEDs
0
10
20
30
40
50 Carbamazepine Depakote DRDepakote ER Depakote sprinklesKeppra LamictalNeurontin PhenytoinTopomax Trileptal
AE
D P
resc
rip
tio
n V
olu
me
(%)
AE
D P
resc
rip
tio
n V
olu
me
(%)
Age Group (years)Age Group (years)
PharMetrics. April 2002 to June 2003. Source: IMS NPA, Dec. 2003Pack AM, et al. Epilepsy Behav. 2003;4:169-174.Ensrud KE, et al. Neurology. 2004;62:2051-2057
0-17 18-34 35-44 45-54 55-64 0-17 18-34 35-44 45-54 55-64 >>65 65
29Stephan Eisenschenk, MDDepartment of Neurology
AEDs and Bone Health
30Stephan Eisenschenk, MDDepartment of Neurology
Rational Use of AEDsSo 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
31Stephan Eisenschenk, MDDepartment of Neurology
Treatment/Evaluation Sequence for Pharmacoresistent Epilepsy
1st Monotherapy AED Trial
2nd Monotherapy AED Trial
Epilepsy Surgery/VNS Therapy/Neuropace Evaluation
Resective Surgery Stimulator Therapy
3rd Monotherapy/Polytherapy AED Trial
Polytherapy AED Trials
4%
13%47%
36%
Sz-free with 1st AED
Sz-free with 2nd AED
Sz-free with 3rd AED/Polytherapy
Pharmacoresistant
Kwan P, Brodie MJ. NEJM;342:314-319.
Strongly consider videoEEG Monitoring
Epilepsy
Psychogenic, migraine, syncope, sleep disorders, movement disorder’s, etc.
Non-epileptic
32Stephan Eisenschenk, MDDepartment of Neurology
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
33Stephan Eisenschenk, MDDepartment of Neurology
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 SpectroscopyDecreased NAA (due to neuronal loss)
Normal to high Cho and Creatine (represents astrocytosis)
34Stephan Eisenschenk, MDDepartment of Neurology
Epilepsy Surgery- Neuroimaging
Ganglioglioma DNT
AVM Cavernous AngiomaCortical Dysplasia
Hippocampal atrophy in temporal lobe epilepsy
35Stephan Eisenschenk, MDDepartment of Neurology
Evaluation for Surgery- Subdural Grid Electrodes
36Stephan Eisenschenk, MDDepartment of Neurology
Left Anterior Temporal Loectomy
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