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Epilepsy 101
Paul B. Atkinson, MD
MEG - Minnesota Epilepsy Group
Epilepsy Foundation
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Epilepsy Foundation Mission
Statement
“The Epilepsy Foundation leads the fight
to stop seizures, find a cure and
overcome the challenges created by
epilepsy.”
Topics Today
• Basics of how the brain works
• Definitions
– What is a seizure?
– What is epilepsy?
• Epidemiology of seizures and epilepsy
• Seizure types
• Evaluation and treatment of epilepsy
Topics Today
• Medically intractable epilepsy
– Definition
– Treatment options
• Safety issues in epilepsy
• Summary
• Time for questions
How the Brain Communicates
• Cells: Building blocks of all body systems
• Neurons: Brain cells that send information
within the brain or to/from the body
• 100 billion neurons in the human brain
• Electrical signals travel down long wires of
the neuron, called axons
• Proper function requires these electrical
signals to be well controlled
Neuron
Neuron
Neuronal Input
www.mult-sclerosis.org
Neurons
• If enough input is received, then an action
potential is generated
hyperphysics.phy-astr.gsu.edu
Synapse
Neuronal Connections
www.lavia.org
Normal Communication
• Rapid onset and offset
• Highly controlled and precise
Definition of Seizure
• Seizure: Uncontrolled, synchronous
firing of electrical signals from neurons
in the brain
– Provoked
– Unprovoked
Provoked Seizure
• Seizure with an identifiable, reversible cause
– Medical Conditions:
• Low blood sugar, low blood sodium levels
– Withdrawing from alcohol or benzodiazepines
– Medications
– Illicit Drugs:
• Cocaine, amphetamines, PCP
Unprovoked Seizure
• Seizure occurring due to known brain
lesion
– Stroke, tumor, trauma, infection, congenital
brain issues, Alzheimer’s disease
• Seizures with no provoking cause found
Definition of Epilepsy
• More than one unprovoked seizure
separated in time
– Minimally 24 hours apart
• 100 provoked seizures would not be
defined as epilepsy
• Definition being re-evaluated
Epidemiology of Seizures
• 10% of Americans will have a seizure
by the age of 75
• 300,000 with first seizure every year
– 120,000 under age 18
Epidemiology of Epilepsy
• 1% of Americans will be diagnosed with
epilepsy by age 20
• 1/26 people will develop epilepsy in their
lifetime
• 40 million people affected worldwide
• Incidence likely slightly higher in developing
countries
Data from the Epilepsy Foundation
Fourth Most Common US
Neurological Disorder
1.
2.
3.
4.
Migraine
Stroke
Alzheimer’s Disease
Epilepsy
– Prevalence higher than the combination of all autistic
spectrum disorder, Parkinson’s disease, MS, and cerebral
palsy combined.
Data from the Epilepsy Foundation
Epilepsy Incidence with Age
Hauser et al., Epilepsia 1993, 34: 453-468
Seizure and Epilepsy
Etiologies by Age
• Infancy and childhood
– Prenatal or birth injury
– Inborn error of metabolism
– Congenital malformation
• Childhood and adolescence
– Idiopathic (genetic) syndrome
– CNS infection
– Head trauma
Etiologies by Age Continued
• Adolescence and young adult
– Head trauma
– Drug intoxication and withdrawal*
• Older adult
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Stroke
Brain tumor
Acute metabolic disturbances*
Neurodegenerative diseases
Head Trauma
*Causes of acute symptomatic seizures, not epilepsy
Etiology of Epilepsy
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65 % Cryptogenic
10 % Vascular
8 % Congenital
6 % Trauma
4 % Neoplastic
4 % Degenerative
3 % Infection
Hauser et al., Epilepsia 1993, 34: 453-468
Epilepsy Risk for Special
Populations
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Static encephalopathy 25.8%
Cerebral palsy 13%
Static encephalopathy and CP 50%
Alzheimer’s disease 10%
Stroke patients 22%
Children of mothers with epilepsy 8.7%
Children of fathers with epilepsy 2.4%
Classification of Seizures
Focal versus Primary Generalized
Seizures
Focal (Partial) Onset Seizures
• Seizure begins in one part of the brain
– Symptoms depend on which part of brain is
affected
Focal (Partial) Onset Seizures
• Simple - consciousness spared
– With motor signs
• Jacksonian march, versive head movements
– With somatosensory of special sensory symptoms
• Somatosensory, flashing lights, olfactory, gustatory,
vertiginous
– With autonomic symptoms or signs
• Epigastric sensation, pallor, sweating, pupillary dilation
– With psychic symptoms or signs
• Déjà vu, dreamy states, time distortion, fear, illusions
Focal (Partial) Onset Seizures
• Complex - consciousness impaired
– Clinical manifestations vary with site of origin and
degree of spread
– Purposeless automatisms
– Amnesia for the event
• Secondary generalized - from focal onset to
generalized seizure
– Generalized tonic-clonic, tonic, or clonic
– Typically 1-2 minutes
Primarily Generalized
Seizures
• Seizure that begins on both sides of the
brain at the same time
Generalized Onset Seizures
• Seizures with Tonic
and/or Clonic
Manifestations
– Tonic-clonic seizures
– Clonic seizures
– Tonic seizures
• Absences
– Typical absence
– Atypical absence
• Myoclonic seizure
types
• Atonic seizures
Seizures with Tonic and/or
Clonic Manifestations
• Tonic-Clonic seizures: “Grand Mal”
– Tonic contraction including respiratory muscles
• Tongue biting, urinary incontinence
• Cyanosis
• Lasts 30-40 seconds
– Clonic phase - convulsive movements
• Foaming at mouth, short grunting type of respirations may
occur, but remain cyanotic
• Usually 30-50 seconds
• Deep respirations as phase ends
Absence Seizures
• Typical Absence “Petit mal”
– 3 Hz spike and slow wave complexes, can
precipitate with HV
• Generally normal interictally
– Impairment of consciousness with no post-ictal
confusion
– One of few seizure types where you treat EEG
– Can have mild components of tonic, clonic, or
atonic features, or may have mild automatisms
Absence Seizures
• Atypical Absence
– Onset and resolution not as abrupt as typical
absence
– More pronounced loss in tone, automatisms
– Last longer - up to several minutes
– Slower spike-wave discharges at 1.5-2.5 Hz
– Interictal EEG abnormal
– Often seen in Lennox-Gastaut
Myoclonic Seizures
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Sudden, brief contractions
Usually bilateral, maximal in arms
One second in duration
Often multiple
May be photic or sensory triggered
Often maximal upon awakening
– Also increased at night when drowsy
• Must differentiate from non-epileptic
myoclonic jerks and action myoclonus
Atonic Seizures
• Abrupt onset
• Sudden loss in tone
• Head drop, slacking of jaw, or complete loss
of tone with falls
– Frequent injuries - helmet
• Last only a second or two in duration
• Poor response to AEDs
Typical Absence
Evaluation of New Onset
Seizures
Issues
• Was it a seizure?
– Provoked or unprovoked?
• Was it really the first seizure?
• What studies are needed?
• Treat or not to treat?
Acute Work-up in ER
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History
Physical exam
Labs
Imaging
Neurology Referral
Neurologist Visit
• History
– Was it really a seizure?
• Eye witness account of event, actions of patient,
duration, post-ictal phase, tongue biting, incontinence
– Is this really the first seizure?
• Past history of staring spells, confusional episodes,
waking on floor, blood on pillow, nocturnal incontinence,
childhood seizures
– Risk factors for epilepsy?
• Birth history, history of febrile seizures, past head
trauma, past brain infection, family history of seizures,
prior stroke or other brain injury
Neurologist Visit
• Complete neurological examination
• Review previous imaging and labs
• Decision to treat and/or further workup
– Electroencephalogram (EEG)
– Magnetic Resonance Imaging (MRI)
• Contrasted CT scan if MRI not obtainable
• Other workup needed?
– Cardiac monitoring, tilt table testing
EEG
MRI
MRI
Treat or Not to Treat?
• How sure is diagnosis
• Provoked - treat underlying cause
• If was an unprovoked seizure, then the
decision is based on the likelihood of
recurrence in that patient, or the patient’s
desire
– High risk: Treatment seems appropriate
– Low risk: Treatment may not be necessary
• Evidence of prior seizures?
– Equals epilepsy, and would recommend treatment
Risk for Recurrence
• Normal exam, imaging, and EEG
– 25-30% risk of recurrence
• Normal exam, abnormal imaging or
EEG
– 50% risk of recurrence
• Abnormal EEG and MRI
– 70% risk recurrence
Medication Considerations
• Side effects - acute
• Long-term side effects
• Medication interactions
Goal in all patients is to have no seizures
and no side effects. Cannot always be
met, but should always be strived for.
Recurrence
• If patients opt not to be treated
– 80% of those that will recur do so in first 2
years
• Majority of which occur in first 6 months
Other Factors
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Driving
Employment
Social and cultural issues
Insurance issues
Treatment of Epilepsy
Epilepsy Treatment
• Anti-seizure medications
– Mainstay of treatment
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Surgery
VNS
RNS
Diet Therapies
Epilepsy Medications
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Carbamazepine
Clobazam
Clonazepam
Diazepam
Eslicarbazepine
Ethosuximide
Ezogabine
Felbamate
Gabapentin
Lacosamide
Lamotrigine
Levetiracetam
Lorazepam
Methsuximide
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Oxcarbazepine
Phenobarbital
Perampanel
Phenytoin
Pregabalin
Primidone
Rufinamide
Tiagabine
Topirimate
Tranxene
Valproic Acid
Vigabatrin
Zonisamide
Choosing a Medication
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Seizure type
Interactions with other medications
Concurrent medical conditions
Potential adverse effects
Titration schedule to effective dose
Cost
Once a medication is chosen,
what is the likelihood of
seizure control?
Efficacy of AEDs to Control Seizures
Monotherapy with
1st Drug
Monotherapy with
2nd Drug
36%
47%
Monotherapy with
3rd Drug
More than one AED
Medically Intractable
3%
1%
13%
Kwan and Brodie, NEJM 2000. 342:
314–319.
Medically Intractable Epilepsy
• Multiple medication trials, combined
medication therapy, and still having
seizures
• Newer medications release in past
decade
– No significant changes in efficacy
– Improved side effect profiles, reduced
medication interactions
Potential Options for Medically
Intractable Epilepsy
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Surgery
Vagal Nerve Stimulator (VNS)
Responsive Neurostimulation (RNS)
Dietary Treatments
Epilepsy Treatment - Surgery
• Patients should be considered after failing at
least 2 AEDs that have been raised to the
maximally tolerated dose
– Failed combined therapy
• Can be curative
• Underutilized
– Goal is to have evaluation within 2-3 years (some
advocate within first year)
– Early referral to an epilepsy center
Surgical Evaluation
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Continuous video EEG monitoring
Neuropsychological testing
MRI – 3T
MEG/MSI
Invasive video EEG monitoring
– Strip or grid electrodes
• Wada testing
• fMRI
• PET Scan
Epilepsy Surgery Outcomes
Temporal Extra
Lesional
Temporal
Seizure Free
Improved
Not improved
Total
68%
Callosotomy
45%
66%
8%
23%
35%
22%
61%
9%
20%
12%
31%
100%
100%
100%
100%
Reference: Engel, J. NEJM, Vol 334 1996, 647-653
• Not everyone who fails medications will
be a resective surgery candidate
– Primary generalized epilepsy
– Multiple ictal foci on EEG
– Eloquent cortex
• Not all patients who are good
candidates desire this type of therapy
Medical Devices
Vagal Nerve Stimulator (VNS)
• Good option for medically intractable epilepsy
in patients who are not candidates for surgery
or choose not to undergo resective surgery
• Potentially decrease seizure frequency
without contributing to polypharmacy or drug
interactions
VNS Components
• Generator
– Placed in the anterior left
chest, inferior to clavicle
• Leads
– Bipolar stimulating
electrodes
– Coiled around the vagus
nerve within the carotid
sheath
Programmable
• Wand connected to
PDA
• Interrogate device
• Reprogram
• Lead check
• Battery check
Image from vnstherapies.com
VNS
• Two forms of stimulus from VNS
– Programmed, intermittent, electrical
impulses to vagus nerve
• Programmed by neurologist
– Patient on-demand stimulation
• Magnet placed over device provides longer
stimulation
– Patients use when sense aura
– Families can use to attempt to abort seizures
• Magnet worn like a
watch by patients
• When placed over the
generator, triggers
stimulus programmed
by neurologist
• Can be taped over
generator to stop
stimulus - intolerable
side effects
Image from vnstherapies.com
Efficacy of VNS with Time
50
43
Percent Responder Rate
45
40
43
37
35
3 months
30
25
1 year
23
2 years
20
Year 3
15
10
5
0
Time
Adapted from Morris et al., Neurology 1999, 53: 1731-1735.
Long-term Side Effects in Clinical Trials EO1-EO5
70.0%
P
e
r
c
e
n
t
A
f
f
e
c
t
e
d
60.0%
50.0%
3 Months
40.0%
12 Months
24 Months
30.0%
36 Months
20.0%
10.0%
0.0%
Hoarseness
Cough
Paresthesia
Dyspnea
Adapted from Morris et al., Neurology 1999, 53: 1731-1735.
Retrospective Trial of 436
Consecutive Patients
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3 removed due to infection
33 patients lost to follow-up
Ages 1-76
Follow up to 11 years
– 22.5% with greater than 90% seizure
reduction
– 40.5% with greater than 75% seizure
reduction
– 63.75% Responder rate
Elliott et al. Epi & Behav. 20: 57-63, 2011
Retrospective Trial of 65
Consecutive Patients
• VNS in for at least 10 years – mean
seizure reduction at specific time points
– 6 months: 35.7%
– 1 Year: 52.1%
– 2 Years: 58.3%
– 4 Years: 60.4%
– 6 Years: 65.7%
– 8 Years: 75.5%
– 10 Years: 75.5%
Elliott et al. Epi & Behav. 20: 478-483, 2011
Responsive Neurostimulation:
RNS
Responsive Neurostimulation:
RNS
• Implantable device for intractable partial
onset seizures
• Approved November of 2013
• Patients can have up to 2 foci of seizure
onset
RNS
• Records EEG
• Can have 2 leads
that stimulate
– Strip electrodes on
cortical surface
– Depth electrodes
• Stimulates in
attempt to abort
seizure
Image from Neuropace.com
RNS
Images from Neuropace.com
RNS
• EEG patterns are learned by recording
seizures
• Once patterns identified, then
programmed to stimulate
• EEG pattern and stimulation paradigm
can be modified with time
RNS
• Pivotal trial – 31 centers
– 240 enrolled
– 191 implanted
– Mean Reduction in seizures
• 37.9%
– Responder rate (50% reduction in
seizures) at 1 year was 43%
• 2 years 46%
Morrell et al. Neurology 77: 1295-1304, 2011
Pivotal trial final 2 year data
Median reduction in seizures – 53%
Heck et al. Epilepsia 55: 432-441, 2014
Heck et al. Epilepsia 55: 432-441, 2014
RNS Complications
• Intracranial Hemorrhage
– 9/191 Patients (4.7%)
• 6 Related to postoperative complications
• 3 occurred later due to seizure related trauma
– No permanent sequelae
• Infection
– 10/191 (5.2%)
• 4 devices explanted
• 5 postoperative
• 2 secondary to infected scalp laceration from
seizure
Morrell et al. Neurology 77: 1295-1304, 2011
Dietary Options
Dietary Options for Medically
Intractable Epilepsy
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Ketogenic Diet
Modified Atkins Diet
MCT Diet
Low Glycemic Index Treatment
Ketogenic Diet
• First reports of effectiveness in medical
literature in 1921
• Primarily been used in children
• Resurgence of use in the past two
decades
• 4:1 ratio of fat : protein/carbohydrate
– 90% of calories are derived from fat
– Calorie and fluid restriction
– 3:1 ratio effective for some, better tolerated
Ketogenic Diet
• Initiated in the hospital setting
– 24-48 hour fast
– Initiation of the diet increasing the
ketogenic ratio to goal over 4-5 days
• Mechanism of action for seizure
reduction
– Multiple and not fully delineated
Henderson et al., J Child Neurol 2006, 21: 193-198
Ketogenic Diet Effectiveness
• 2006 meta-analysis of 19 studies
– 860 total patients with efficacy data
– Mean age 5.78 +/- 3.43 years
– 422 patients adhering to the diet
• 83.6% achieved a 50% reduction in seizures
• 52% achieved greater than 90% reduction
• 24% achieved complete seizure control
Henderson et al., J Child Neurol 2006, 21: 193-198
Ketogenic Diet Effectiveness
• 2006 meta-analysis of 19 studies
– 438 dropped out
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Ineffectiveness – around 47%
Too restrictive of diet – around 11%
Illness/side effects – around 16%
Poor compliance – around 8%
Other/lost to follow up – around 17%
Henderson et al., J Child Neurol 2006, 21: 193-198
Ketogenic Diet Effectiveness
in Adults
• Meta-analysis of 9 studies with data
from adult patients
• 122 patients identified
– 75 from a 1930 study where diet was the
only therapy
– 49% achieve greater than 50% reduction in
seizures
– 10% seizure freedom
Payne et al., Epilepsia 2011, 52: 1941-1948
Modified Atkins Diet
• Does not require hospitalization to
initiate
• No fast
• No fluid, calorie, or protein restrictions
• No weighing of food
• 65% of calories from fat
• Carbohydrates – start at 15 g/day
– Increase to 20-30 g/day after 1st month
Other Diets
• MCT Diet
– Modified ketogenic diet
– 60% of calories from MCT oil
– Allows for more proteins and carbs
– Modified MCT Diet
• 30% of calories from MCT oil
• Better tolerated from GI stanpoint
Other Diets
• Low Glycemic Index Treatment
– Not restrict fluids or protein
– Loosely monitor fats and calories
– Restricts carbs to 40-60 g/day
• Low glycemic carbs only
Safety and Counseling
What To Do When Someone
is Having a Seizure
What To Do When Someone
is Having a Seizure
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Stay calm
Time the seizure with a watch
Don’t try to hold the person down
Move any objects away from them that
may cause harm
• Try to put something soft under their
head
What To Do When Someone
is Having a Seizure Cont.
• Loosen tight clothing around the neck if
causing difficulty with breathing
– Neckties
• Try to roll them on their side to let
secretions fall out of the mouth
– Don’t place anything in the mouth
• Talk calmly and gently as they come out
of the seizure
• Stay with them until the seizure is over
Counseling
• Water safety
– Drowning risk increased 17-22 fold in those with
seizures
• No swimming or bathing alone, showers safer
• Other risky situations
– Climbing ladders, working at height, heavy
machinery
Counseling
• Driving
– Minnesota and Wisconsin laws are 90 days
– No mandatory provider reporting, self reporting
– Laws vary by state
Conclusions
• Seizures and epilepsy are common
• The first steps in evaluating new onset
seizures are physical examination, labs,
imaging, and EEG
• Seizure types
– Partial onset
– Generalized onset
Conclusions
• Treatments
– Medications are the mainstay
– Two thirds well controlled on medication
• Medically intractable epilepsy
– Definition
– Treatment options
• Surgery
• Stimulating devices
• Diets
• Safety issues in epilepsy
Treatment Goals
• No seizures, no side effects
• If seizures continue – discuss other
options to help with seizure control
• Work as a team with my patients
– Discuss options and come to decisions
together
• Live life
Famous People with Epilepsy
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Harriet Tubman
Julius Caesar
Lil Wayne
Prince
Florence Griffith
Joyner
• Samari Rolle
• Alexander the Great
Famous People with Epilepsy
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Danny Glover
Neil Young
Napoleon Bonaparte
Vincent van Gogh
George Gershwin
Socrates
Coach Kill
Thank You
Questions?