Julia B. Toub, MD

Providence Brain & Spine Institute

November 12-13, 2015

I HAVE NO FINANCIAL RELATIONSHIPS

TO DISCLOSE.

1. Seizure: the clinical manifestation of an abnormal and

excessive synchronization of a population of cortical

neurons.

2. Practical definition of epilepsy (2014)

– ≥ 2 unprovoked seizures separated by at least 24 hours.

– 1 unprovoked (or reflex) seizure and a probability of further

seizures similar to the general recurrence risk (at least 60%)

after two unprovoked seizures, occurring over the next 10

years

– Epilepsy Syndrome

3. Epileptogenesis: The process by which normal brain

undergoes changes that generate seizure.

• Worldwide prevalence ~ 50,000,000 underestimated due to:

– Limited access to healthcare

– Social/cultural stigma

• ~3,000,000 Americans

• As common as breast cancer with a similar mortality.

• 10% of the population will have a seizure at some point in

their lives; 1-3% will be diagnosed with epilepsy.

• Seizures arising from the whole brain all at one time

• Seizure subtypes a. Absence

b. Tonic-Clonic

c. Tonic

d. Clonic

e. Myoclonic

f. Atonic/Astatic

• Generalized Epilepsy Syndromesa. Childhood absence epilepsy (CAE)

b. Juvenile absence epilepsy (JAE)

c. Juvenile myoclonic epilepsy (JME)

d. Generalized epilepsy with febrile seizures plus (GEFS+)

e. Benign myoclonic epilepsy in infancy

f. Epilepsy with myoclonic absences

• Onset age 4-8 years

• Clinical:

– Brief staring spells

– “Daydreaming,”

– Eye-flutter

– +/- GTC

• Classic EEG 3-HZ spike-wave

• Juvenile absence epilepsy is similar but with onset age 9-13

years and longer/less frequent absences.

• Common. ~25% of genetically-based generalized epilepsy and ~10% of all epilepsies

• +/- seizures in childhood

• Onset usually during teenage years; infrequently in 20s and 30s.

• Hereditary component; genetically heterogeneous and often no family history

• Clinical – GTC, myoclonic, absences, especially in AM

– “Klutzy”, frequently dropping things

– Triggers: sleep-deprivation, EtOH, psychological stressors

– Photosensitivity

• Requires lifelong therapy

• Typical EEG: Generalized spike/poly-spike wave

• Generalized epilepsy with febrile seizures plus (GEFS+)

• Familial epilepsy syndrome

• GTCs during illness (usually febrile illness)

• Autosomal dominant; heterogeneous inheritance pattern with

incomplete penetrance

• SCN1A mutation (sodium channel neuronal type 1 alpha

subunit) most common but some other genes may also be

implicated.

• Some patients stop having seizures in mid-childhood but

others persist to have GTCs later in life along with other

seizure subtypes.

• Seizures arise from part of the brain.

• Focal seizure subtypesa. Without dyscognitive features: No alteration in level of

consciousness.

*** Previously “simple partial”

b. With dyscognitive features: Accompanied by altered consciousness.

*** Previously “complex partial”

c. Secondarily generalized

• Focal epilepsy syndromesa. Most focal epilepsies are not associated with any classified epilepsy

syndrome

b. Benign Rolandic epilepsy

c. Childhood Epilepsy with Occipital Paroxysms

d. Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

• May originate from any single focus or multiple foci.

• Temporal lobe epilepsy

– The most common focal epilepsy

– Mesial temporal > lateral temporal.

• Structural-metabolic:

– Associated with the neurocutaneous syndromes: TS, NF1,

NF2, Sturge Weber (overlap with genetic subclass)

– Secondary to prior neurological insults (stroke, tumor)

– Malformations of cortical development/cortical dysplasias

– Vascular malformations

• Benign childhood occiptal epilepsies: Benign rolandic

epilepsy, Panayiotopoulos syndrome.

• Frontal:

– Primary motor area: Jacksonian march, often escalating to GTC.

– Supplementary motor area (SMA): “Hypermotor”, asymmetric tonic, brief, may lack postictal period.

• Lateral Temporal:

– Auditory/visual hallucinations, vestibular symptoms, language impairment (dominant)

• Mesial Temporal:

– Epigastric/olfactory/gustatory aura, prodromal fear, orolingual automatisms, dysautonomia.

– Memory compaints

• Parietal:

– Somatosensory symptoms, visual illusions/hallucinations, distortions of body image.

• Occipital:

– Forced eye deviation, visual hallucinations, visual perseverations (palinopsia).

• Medically refractory seizures with mental retardation; multiple etiologies.

• Onset early, usually age <5 years but case reports as late as age 14.

• 30% are idiopathic (genetic vs. unknown).

• 70% associated with prior insult or epileptic encephalopathy:– Encephalitis and/or meningitis

– Tuberous sclerosis

– Brain malformations (e.g., cortical dysplasias)

– Birth injury

– Hypoxic-ischemic injury

– Frontal lobe lesions

– Trauma

• 9-39% of cases are preceded by West Syndrome:– Infantile spasms

– Classic “hypsarrhythmia” EEG

– Mental retardation

• Three categories proposed by ILAE in 1989 and revised in

2010

1. Genetic (previously idiopathic): Presumed genetic basis,

usually onset in childhood but some in early adulthood.

2. Structural-metabolic (previously symptomatic): Related to

tumor, TBI, cortical dysplasia, infection, etc.

3. Unknown (previously cryptogenic)

http://blog.dentalplans.com/wp-content/uploads/2015/10/ski.png

HYPER-SYNCHRONIZATION OF CORTICAL NEURONS

– Increased excitatory post synaptic potentials (EPSPs)

• Glutamate*

• Aspartate

– Decreased inhibitory post synaptic potentials (IPSPs)

• GABA

– Changes in voltage gated ion channelsdepolarization

• Excessive inward Na+, Ca2+ currents

• Inadequate inward Cl-, outward K+ currents

• Mutations

1. Voltage-gated Na-channels: GEFS+ (SCN1A, SCN1B, SCN2A1)

2. Voltage-gated Cl-channels: JAE, JME (ClCN)2A

3. Voltage-gated K-channels: TLE (KCND2)

– Alteration of local ion concentrations

emedicine.comhttp://www.infantile-spasms.org/ www.thebarrow.org

• Isolated unprovoked generalized tonic-clonic seizure lasting < 3 minutes without localizing features:

– History

– CMP

– CBC

– Tox screen

– If no head trauma, no imaging necessary

– Driving restriction

– Reassurance

– EEG

– Pregnancy test

• Recurrent GTC, prolonged GTC or new onset seizure with focality, complete the above and:

– CT to r/o acute injury; if available, MRI.

– Initiation of AED therapy

• In any case in which history or EEG demonstrate focality, MRI is indicated.

• Psychiatric: (common), SSRIs/TCAs (rare),

clozapine

• Analgesic: (common),

• Antibiotics: PCN, Cephalosporins, Imipenem, Amphotericin

B

• Pulmonary: Aminophylline

• Immunologic: Cyclosporin

http://dailynewsdig.com/wp-content/uploads/2013/12/21-Hilarious-Quick-

Quotes-To-Describe-Your-Mother-In-Law-3.jpg

Borrowed from Joseph I. Sirven, AAN Fall Conference Epilepsy Uldate (10/2015)

AED MechanismsOf Action

• Mechanisms:1. Blockage of inward Na+

currents: CBZ, LTG, OXC,

PHT, TPM, VPA, ZNS

2. Enhancement of GABA-

mediated Cl- currents:

clonazepam, tiagabine.

3. Blockage of T-type calcium

channels: ETX

4. Blockage of glutamate-

mediated currents

• Many AEDs have

overlapping MOAs.

• Some without well-defined

MOAs (i.e. LEV).

www.aesnet.org

• Confirm a diagnosis of epilepsy (+/-)

• Determine seizure subtype (history, EEG, imaging)

• How quickly does medication needs to be introduced?

• Consider comorbid conditions, social circumstances,

finances, etc.

• Mechanism of action.

BROAD SPECTRUM NARROW SPECTRUM

OLDER • Clonazepam

• Valproic Acid/Divalproex *

• Carbamazepine

• Ethosuximide

• Phenobarbital

• Phenytoin

• Primidone

NEWER • Lamotrigine *

• Levetiracetam *

• Topiramate *

• Zonisamide

• Clobazam

• Eslicarbazepine

• Ezogabine

• Felbamate

• Gabapentin

• Lacosamide

• Oxcarbazepine *

• Perampanel

• Pregabalin

• Rufinamide

• Tiagabine

• Vigabatrin

* Available in once-daily extended release formulation

• Newer AEDs have fewer side-effects.

• Choose broad spectrum coverage if unsure of seizure subtype:

3. Valproic acid (better for generalized seizures)

4. Topiramate

5. Zonisamide (approved only as an adjunct in treatment of partial

seizures, though it does have broad-spectrum efficacy).

• Focal epilepsy agents (CBZ, OXC, ESL, GBP, PRG) may worsen

generalized epilepsies.

• Generalized seizures only: Levetiracetam, lamotrigine, valproic

acid, sometimes topiramate.

• Focal onset: Levetiracetam, lamotrigine, oxcarbazepine,

lacosamide, carbamazepine.

• Comorbid mood disorder?

– Consider LTG, VPA, OXC (focal epilepsy only

– Avoid LEV

• Neuropathic pain?

– GBP, PRG, CBZ, OXC

• Migraine?

– TPM, VPA, GBP, PRG

• Hepatic dysfunction?

– LEV

• Poor compliance or wearing off?

– Consider XR formulations

• Stevens Johnson Syndrome with lamotrigine

– Most often associated with rapid initiation.

– Increased risk with co-administration of VPA.

• PHT, CBZ, PHB, PRM, and VPA hasten bone loss.

– Assess for vitamin D deficiency.

– Supplement vitamin D at least 2,000 IU per day.

– DEXA

• VPA: weight gain, tremor, hair loss, GI upset,

hematologic, hepatic/pancreatic dysfunction, osteoporosis

• Patients on warfarin: Avoid VPA, PHT, PHB, CBZ, and

primidone if possible.

• TPM: Cognitive slowing, kidney stones, weight loss, rare acute

angle closure glaucoma.

• LEV: Irritability, mood changes, rare overt psychosis. Renally

cleared; needs re-dosing after dialysis.

• Patients of Asian decent with HLA-B*1502 have increased risk

of Stevens Johnson Syndrome with CBZ, OXC, ESL.

• CBZ, OXC, ESL: hyponatremia

• Felbatol: Aplastic anemia

• Newer AEDs- Clobazam, lacosamide, rufinamide,

eslicarbazepine, perampanel.

• XR formulations are expensive, require prior authorization.

• All AEDs carry small increased risk of suicide.

• Perampanel: Increased homicidal ideation.

– PHT: Gingival hyperplasia, osteoporosis, hepatic dysfunction, hirsutism, weight gain,

dermatitis, neuropathy, cerebellar atrophy.

– At high doses, beware of dramatic changes in serum levels with small change in dose.

– Phenytoin metabolism is dose dependent.

• Low drug concentrations:

– Elimination follows first-order kinetics

– Fixed percentage of drug metabolized during a per unit time

• High drug concentrations:

– Zero-order kinetics

– Fixed quantity of drug metabolized per unit time

– Due to saturation of metabolic pathways.

http://www.boomer.org/c/p1/Ch20/Ch2003.html

• Women of childbearing age

– Potential for teratogenicity of ALL AEDs.

– Newer AEDs better than older AEDs.

– Consider urine pregnancy test prior to initiation.

– Folic acid in ALL women of childbearing potential.

– LTG and LEV levels drop in pregnancy.

– Other AEDs: Possible reduction in contraceptive efficacy;

secondary contraception should be used.

• Women of all ages

– LTG: Estrogen-containing OCPs increases LTG clearance

and may decrease levels by as much as 50%.

– VPA: Hirsutism, weight gain

• No uniform definition for status epilepticus exists. Recent data

recommends aggressive treatment following 5 minutes of

convulsion.

• Rationale for early treatment:

– Permanent neurological damage occurs following 30 minutes

of seizure activity.

– “Seizures beget seizures”: Persistent seizures produce

physiologic changes that potentiate further seizure activity.

• Synapses increase through axonal “sprouting”

• Apoptosis of inhibitory neurons

• Loss of excitatory input to inhibitory neurons

• Local changes in ion channels and conductivity

• Seizures persisting > 5 minutes becoming progressively

intractable to AEDs.

• Beware of subclinical seizure and non-convulsive status

epilepticus.

– Continuous EEG monitoring

• Adverse consequences include hypoxia, hypotension,

cardiac arrhythmia, acidosis, aspiration pneumonia,

rhabdomyolysis, hyperthermia, and death.

• “SUDEP has been defined as the sudden, unexpected, witnessed or unwitnessed, non-traumatic, and nondrowning death in patients with epilepsy, with or without evidence for a seizure, with exclusion of documented status epilepticus, and when post-mortem examination does not reveal a structural or toxicological cause for death” (Nashef, 1997).

• 20-30-fold risk of sudden death in epileptic patients relative to the general population.

• Proposed mechanisms:– Apnea/Hypoventilation (central or obstructive)hypoxia

– Dysautonomia

– Ictal changes in brain perfusion resulting in increased intracranial pressure

• Highest risk in patients with:

– Poor seizure control

– Intractability

– Multiple AEDs (unclear if AEDs are the cause or multiple AEDs are a marker of intractability)

Sudden Unexplained Death In Epilepsy. Shorvon. The Lancet, Volume 378, issue 9808 (December 10 - 16 2011), p. 2028-2038

• Elective (usually) admission for diagnostic purposes, seizure classification, and/or pre-surgical evaluation

• Should be considered in patients with continued seizures despite therapeutic levels of AEDs

• Continuous video EEG monitoring

• Added stresses to provoke events in question:

– Reduced/discontinuation of medications

– Sleep deprivation

– Hyperventilation

– Photic stimulation

– Exposure to agents known to provokes seizures in individual patients

• Important to capture ALL of the patient’s events-some patients may have epileptic and nonepileptic events.

• 21 y.o. Caucasian female with history of MVA and

concussion.

• ROS: Headaches, poor concentration, anxiety, depression,

anhedonia, unexplained weight loss confusion.

• Only epilepsy risk factor is MVA.

• SH: 5 cigarettes per day, “medical marijuana, schooled

through grade 10, unemployed, partnered with 2 children

under age 2.

• FH: NC

• Prior w/u: 3 EEGs and MRI all normal.

• PNEE, spells, fits, pseudoseizures, convulsions

• +/- prior psychiatric diagnoses

• Common co-morbidities:

– Anxiety

– Depression

– Bipolar disorder

– Hx/o multiple life stressors, psychosocial trauma, etc.

– Other diagnoses with strong somatic components: IBS, complex regional pain syndrome, reflex sympathetic dystrophy, fibromyalgia.

• Conversion/somatization disorder.

• No AEDs indicated unless accompanied by true epileptic seizures (e.g. lamotrigine for bipolar disorder).

• Reassurance, referral to psychiatry/mental health specialists (cognitive behavioral therapy).

• Psychiatric comorbidities are more common in epileptic

patients than in the general population- 50% of epilepsy

patients.

• Depression is VERY common.

– Physical: Seizures, subclinical hyper-synchronous neural

discharges and some antiepileptic drugs may cause acute

states of depressive mood on a purely neurobiological basis.

– Psychosocial: Socioeconomic hardship, impact on

employment, disruption in family life, etc.

• Failure to address and treat psychiatric symptoms results in

poor seizure control.

• 53 y.o. AA male with predominantly nocturnal convulsions

preceded by a lapse in awareness and a “joker grin.”

• Prodromal irritability, per wife.

• Continued seizures with trials of PHT and LEV

monotherapy (some non-adherence).

• PMH: OSA, remote head trauma with LOC, GERD, asthma,

HTN

• SH: Engineer, married.

• FH: NC

• EMU data and semiology consistent with left temporal lobe

epilepsy.

• Seizure free on LEV XR 750/1500; OXC 300/300 since

10/2014.

Prolonged stay in a weightless environment, sequela (X52.XXXS)

http://concordispracticemgmt.com/

• ~1/3 epileptic patients.

• International League Against Epilepsy (ILAE):

– When a person has failed to become (and stay) seizure free

with adequate trials of two seizure medications.

– Antiepileptic medications (AEDs) must be appropriate for

seizure subtype and utilized in dosages sufficient to treat

seizures.

• Evaluate reasons for poor seizure control:

– Is the diagnosis correct?

– Are the prescribed medications appropriate?

– Are medications being taken as directed?

– Are there other factors that may be contributing to seizure

control?

• Excessive stress

• Poor sleep

• Effects of other health

conditions

• Missed medication doses

• Alcohol, illicit substances

• Drug-drug interactions

• Concurrent use of

medications that “lower

the seizure threshold”

All patients with medically

refractory seizure disorder should

be referred to an Epilepsy Center.

Surgical Resection

Neuromodulation

Neuroablation

Epilepsy Diet

• Who?

– Focal seizure disorder

– Failure of 2 or more seizure medications

• Favorable candidates:

– All seizures “look similar”/arise from one focus

– Temporal lobe epilepsy

– Underlying lesion (cortical dysplasia, tumor)

– No involvement of “eloquent areas”

– Electrophysiologic and imaging data are concordant

Low-grade glioma

T1

FLAIR

Cortical Dysplasia

Mesial Temporal Sclerosis

Vagal Nerve Stimulation

Responsive Neurostimulation

External Trigeminal Nerve Stimulation

Deep Brain Stimulation

• Both generalized and focal epilepsies.

• Pacemaker-sized generator implanted

during minor day-surgery.

• Generator connects to a tiny electrode

in the neck via thin wire.

• Electrode envelops the vagus nerve in

the neck and is programmed to deliver

pulses to the vagus nerve in regular

intervals.

• Mechanism poorly understood.

• Patient modulates through magnet swipe.

• Noninvasive programming in the office.

• Efficacy similar to addition of another medication.

• Side effects: Cough, voice change, tickling at the back of the

throat, changes in heart rate rarely vocal cord paralysis.

• Battery life up to ~10 years.

• MRI limitations.

Magnet

• Who?:

– >18 years old with medically refractory focal epilepsies who are not candidates

for surgical resection.

– Seizure foci (up to 2) must be clearly identified.

• What? - Device is implanted within a small

window taken out of the skull.

- Electrodes are placed near the seizure

focus.

- Efficacy Similar to VNS.

- No head-to-head trials between VNS

and RNS.

• How?- Detects early changes in brain activity

and deliver stimulation to prevent

propagation of a seizure.

- Programmed noninvasively by

physician.

1. Deep Brain Stimulation

• Relatively new and experimental in the US (approved in

Europe)

• Subcortical stimulation paradigms involving the anterior and

centromedian thalamic nuclei, the subthalamic nucleus, the

caudate, and the cerebellum

2. Cortical Stimulation: Primarily targeting the hippocampi. Very

much experimental.

3. Transcranial Magnetic Stimulation: Little data. Few case reports

suggest some benefit.

• MRI-guided thermal laser ablation

– New indication for epilepsy

– Uses laser contained within cooling sheath to target focal lesions

while preserving surrounding tissue.

– MRI-guided, less invasive (small hole in skull)

• Applications: - Focus not easily accessed

with more conventional

surgery.

- Multiple foci (tubers,

cortical dysplasias).

https://www.dellchildrens.net/services_and_programs/comprehensive_epilepsy_program/epilepsy_laser_surgery

Ketogenic Diet

Modified Atkins Diet

Low Glycemic Index Diet

All diets must be monitored by a

dietitian/nutritionist and your

doctor

• Epilepsy is common.

• All that shakes is not seizure.

• All seizures do not shake.

• 2/3 of patients with epilepsy are well-controlled with antiepileptic medications.

• Medications should be carefully selected based on seizure subtype and medical/psychiatric comorbidities.

• Poor seizure control can result in permanent neurological sequelae and increases the risk for sudden death.

• Use of the EMU to differentiate between epileptic and non-epileptic events is imperative to providing patients with appropriate treatment.

• Non-epileptic events do not preclude the coexistence of epileptic seizures.

• Medically refractory epilepsy = failure of 2 or more AEDs.

• All medically refractory patients should be referred to an

epilepsy center as soon as intractability is evident.

• Optimization of seizure control has a tremendous impact on

patients’ quality of life.

Bizarre personal appearance (R46.1)

http://40.media.tumblr.com

• Berg, etal. New concepts in classification of the epilepsies: Entering the 21st century inEpilepsia, 52(6):1058–1062, 2011.

• Bodde, NMG et.al. Psychogenic Non-Epileptic Seizures-Diagnostic Issues: A Critical Reviewin Clinical Neurology and Neurosurgery 111(2009) 1-9.

• Fattore, Cinzia; Perucca, Emilio. Novel Medications for Epilepsy. Drugs 2011: 71 (16) 2151-2178.

• Fischer, et al. A practical Definition of Epilepsy in Epilepsia, 55(4):475–482, 2014.

• Knake, Susanne et.al. Status Epilepticus: A Critical Review in Epilepsy and Behavior 15 (2009) 10-14.

• Kohrman, Michael H. What Is Epilepsy? Clinical Perspectives in the Diagnosis and Treatment in J Clin Neurophysiol 2007;24: 87-95.

• Noachtar, S et. al. Epilepsy surgery: a critical review. Epilepsy Behavior. 2009 May;15(1):66-72. Epub 2009 Feb 21.

• Pitkanen, et. al. Mechanisms of epileptogenesis and potential treatment targets. The Lancet Neurology, Vol. 10, February 2011.

• Rabinstein, Alejandro. Management of Status Epilepticus in Adults in Neurol Clin 28(2010) 853-862.

• Rosetti, A and Lowenstein, D. Management of refractory status epilepticus in adults: still more questions than answers in Lancet Neurology 2011; 10: 922-930.

• Schmidt, Dieter. Drug Treatment of Epilepsy: Options and Limitations in Epilepsy and Behavior 15 (2009) 56-65

• Shorvon. Sudden Unexplained Death In Epilepsy.The Lancet, Volume 378, issue 9808 (December 10 - 16 2011), p. 2028-2038

• www.epilepsyfoundation.org

• www.epilepsy.com

• www.aesnet.org

• www.emedicine.com

• www.uptodate.com