Clinical Epilepsy

American Epilepsy Society

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 Clinical Epilepsy: Index
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Definitions and epidemiology Status Epilepticus

Evaluation of a first seizure Non-epileptic events

Choosing antiepileptic drugs Epilepsy monitoring units

Drug-drug interactions
Adverse effects SUDEP

Discontinuing antiepileptic drugs Driving

Epilepsy comorbidities Pregnancy and epilepsy

Epilepsy surgery
Appendix
Alternative therapies

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Definitions

•  Seizure: the manifestation of an abnormal,

hypersynchronous discharge of a population
of cortical neurons

•  Epilepsy: recurrent seizures (two or more)

which are not provoked by acute systemic
or neurologic insults

American Epilepsy Society 2015

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Epidemiology of
Seizures and Epilepsy

•  Seizures
• Incidence: 80/100,000 per year
• Lifetime incidence: 9%
(1/3 febrile convulsions)

•  Epilepsy
• Incidence: 45/100,000 per year
• Point prevalence: 0.5-1%
• Cumulative lifetime incidence: 3%

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ILAE Classification of
Seizures
Seizures

Partial Generalized

Simple Partial Absence

Complex Partial Myoclonic

Secondarily
Atonic
Generalized

Tonic

Tonic-Clonic
ILAE – International League Against Epilepsy
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ILAE Classification of
Seizures
Seizures

Partial Generalized

Simple Partial

Complex Partial

Secondarily Generalized

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ILAE Classification of
Seizures
Seizures

Partial Generalized

Simple Partial

With somatosensory
or special sensory symptoms

With motor signs

With autonomic
symptoms or signs

With psychic or
experiential symptoms

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 Complex Partial Return to index

Seizures
 Impaired consciousness Seizures

 Clinical manifestations vary

with site of origin and
degree of spread
• Presence and nature of aura Partial Generalized
• Automatisms
• Other motor activity

 Duration typically < 2

Complex
minutes Partial

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 Secondarily
Generalized Seizures
 Begins focally, with or Seizures
without focal
neurological symptoms
 Variable symmetry,
intensity, and duration Partial Generalized
of tonic (stiffening) and
clonic (jerking) phases
 Typical duration 1-3
minutes Secondarily
Generalized
 Postictal confusion,
somnolence, with or
without transient focal
deficit
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EEG: Partial Seizure

Right Frontal
seizure

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EEG: Partial Seizure

Continuatio
n of the
same
seizure
with
change in
amplitude
and
frequency

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EEG: Partial Seizure

Continuation of
the same
seizure with
spread to the
other
hemisphere

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EEG: Partial Seizure

Continuation of
the same
seizure with
spread to the
other
hemisphere

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ILAE Classification of
Seizures
Seizures

Partial Generalized

Absence

Myoclonic

Atonic

Tonic

Tonic-Clonic
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Seizures
 Brief staring spells (“petit mal”)
with impairment of awareness
Seizures
 3-20 seconds
 Sudden onset and sudden
resolution
 Often provoked by
hyperventilation
Partial Generalized
 Onset typically between 4 and
14 years of age
 Often resolve by 18 years of
age
 Normal development and
intelligence Absence
 EEG: Generalized 3 Hz spike-
wave discharges

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EEG: Typical Absence
Seizure

3Hz

spike/slow

wave

complexes
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 Atypical Absence Return to index

Seizures
 Brief staring spells with variably reduced
responsiveness
 5-30 seconds
 Gradual (seconds) onset and resolution
 Generally not provoked by hyperventilation
 Onset typically after 6 years of age

 Often in children with global cognitive impairment

 EEG: Generalized slow spike-wave complexes (<2.5
Hz)
 Patients often also have Atonic and Tonic seizures

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 Atypical Absence Return to index

Seizures

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Myoclonic Seizures

Seizures
Epileptic Myoclonus
 Brief, shock-like jerk of a
muscle or group of muscles
Partial Generalized
 Differentiate from benign,
nonepileptic myoclonus (e.g.,
while falling asleep)

 EEG: Generalized 4-6 Hz

polyspike-wave discharges Myoclonic

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Myoclonic Seizures
Generalized polyspike-slow-

wave discharges

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Seizures
Tonic seizures
•Symmetric, tonic muscle contraction of
extremities with tonic flexion of waist and neck

•Duration - 2-20 seconds.

•EEG – Sudden attenuation with generalized, low-

voltage fast activity (most common) or Seizures
generalized polyspike-wave.

Atonic seizures
Partial Generalized
•Sudden loss of postural tone
• When severe often results in falls

• When milder produces head nods or jaw drops.

Tonic
•Consciousness usually impaired

•Duration - usually seconds, rarely more than 1

Atonic
minute

•EEG – sudden diffuse attenuation or generalized

American polyspike-wave
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 Tonic and Atonic Return to index

Seizures

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 Generalized Tonic-Clonic Return to index

Seizures
 Associated with loss of
consciousness and post-ictal Seizures
confusion/lethargy
 Duration 30-120 seconds
 Tonic phase
 Stiffening and fall Partial Generalized
 Often associated with ictal cry

 Clonic Phase
 Rhythmic extremity jerking
Tonic-
 EEG – generalized polyspikes Clonic

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Epilepsy Syndromes

Epilepsy Syndrome
Grouping of patients that share similar:
• Seizure type(s)
• Age of onset
• Natural history/Prognosis
• EEG patterns
• Genetics
• Response to treatment

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Epilepsy Syndromes

Epilepsy

Partial Generalized

Idiopathic Symptomatic Idiopathic Symptomatic

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Etiology of Seizures and
Epilepsy
 Infancy and childhood
• Prenatal or birth injury
• Inborn error of metabolism
• Congenital malformation

 Childhood and adolescence

• Idiopathic/genetic syndrome
• CNS infection
• Trauma

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Etiology of Seizures and
Epilepsy
 Adolescence and young adult
• Head trauma
• Drug intoxication and withdrawal*

 Older adult
• Stroke
• Brain tumor
• Acute metabolic disturbances*
• Neurodegenerative

*causes of acute symptomatic seizures, not epilepsy

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Questions Raised by a First
Seizure
 Seizure or not?
 Provoked? (ie metabolic precipitant?)
 Seizure type? (focal vs. generalized)
 Evidence of interictal CNS dysfunction?
 Syndrome type?
 Which studies should be obtained?
 Should treatment be started?
 Which drug should be used?
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Evaluation of a First Seizure

 History, physical
 Blood tests: CBC, electrolytes, glucose, calcium,
magnesium, phosphate, hepatic and renal function

 Lumbar puncture
(only if meningitis or encephalitis suspected and potential for brain herniation is excluded)

 Blood or urine screen for drugs

 Electroencephalogram (EEG)
 CT or MR brain scan

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Seizure Precipitants

 Metabolic and Electrolyte Imbalance

 Stimulant/other proconvulsant intoxication
 Sedative or ethanol withdrawal
 Sleep deprivation
 Antiepileptic medication reduction or
inadequate
AED treatment
 Hormonal variations
 Stress
 Fever or systemic infection
 Concussion and/or closed head injury

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Seizure Precipitants (cont.)

Metabolic and Electrolyte Imbalance

 Low blood glucose
(or high glucose, esp. w/ hyperosmolar state)
 Low sodium
 Low calcium
 Low magnesium

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Metabolic abnormalities and
seizures

Type Comment
Osmotic shifts, disrupted ionic balance, in anoxia w/
Hyponatremia
shutdown of Na-K pump
Hypo- or Rare to cause seizure. Sometimes through
hyperkalemia hypomagnesemia
Hypo- or Usually other seizures first, such as tetany or
hypercalcemia altered consciousness

Hypoglycemia BS <50, disrupted Na/K pump

May exacerbate epilepsy but rarely is de novo

Hyperthyroidism
cause
BS = blood sugar.

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Seizure Precipitants
(cont.)
Stimulants/Other Pro-convulsant Intoxication
 IV drug use
 Cocaine
 Ephedrine
 Other herbal remedies
 Medication reduction

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Seizure Precipitants (cont.)

Medications that can
lower seizure
threshold

 Antidepressants Isoniazid
Bupropion
Tricyclics
Penicillins
 Neuroleptics
Phenothiazines
Cyclosporin
Clozapine

 Theophylline
Meperidine
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EEG Abnormalities

 Background abnormalities: significant

asymmetries and/or degree of slowing
inappropriate for clinical state or age
 Interictal abnormalities associated with
seizures and epilepsy
• Spikes
• Sharp waves
• Spike-wave complexes
 May be focal, lateralized, generalized

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EEG Abnormalities

Interictal

left temporal

sharp wave

consistent

with a

diagnosis of

partial epilepsy

of left temporal

origin

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EEG Abnormalities

Interictal generalized

polyspike-wave

complex consistent

with a diaganosis of

idiopathic

generalized epilepsy

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Medical Treatment of First
Seizure
Whether to treat first seizure is controversial
 16-62% of unprovoked seizures will recur within 5 years
 Relapse rate may be reduced by antiepileptic drugs
 Relapse rate increased if:
 abnormal imaging
 abnormal neurological exam
 abnormal EEG
 family history
 Quality of life issues are important (ie driving)

First Seizure Trial Group. Neurology. 1993;43:478–483. [PubMed]

Camfield et al. Epilepsia. 2002;43:662–663. [PubMed]

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Antiepileptic Drug (AED)
Choice: Considerations
 Seizure type
 Epilepsy syndrome
 Efficacy
 Cost
 Pharmacokinetic profile
 Adverse effects
 Patient’s related medical conditions
(ie beneficial or deleterious effects on co-morbid
conditions)

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AED Choice: Attempt
Monotherapy
 Simplifies treatment

 Reduces adverse effects

 Conversion to monotherapy
• Eliminate sedative drugs first
• Withdraw antiepileptic drugs slowly over
several months

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AED Choice: More
Considerations
 Limited placebo-controlled trials available,
particularly of newer AEDs
 Several drugs are commonly used for indications
other than those for which they are officially
approved/recommended
 Choice of AED for partial epilepsy:
• drug side-effect profile and patient’s preference/concerns

 Choice of AED for generalized epilepsy:

• predominant seizure type(s)
• drug side-effect profile and patient’s preference/concerns

See appendix for

ILAE Summary Guidelines and Summary of AAN evidence-based guidelines

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AED Choice by Seizure
Type
Broad-Spectrum Agents Narrow-Spectrum
Agents
Valproate
Partial onset seizures
Felbamate Phenytoin
Carbamazepine
Lamotrigine
Oxcarbazepine
Topiramate Gabapentin
Pregabalin
Zonisamide Tiagabine
Lacosamide*
Levetiracetam Ezogabine*
Rufinamide* Absence
Ethosuximide
Vigabatrin*
Clobazam*

* New AEDs (approved since 2008)

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 AED Choice: Focal Onset Return to index

Seizures
Best evidence:
Carbamazepine**, phenytoin**, levetiracetam, zonisamide
Also shown to be effective, weaker evidence:
Valproate**, lamotrigine**, oxcarbazepine**, topiramate**,
phenobarbital**, gabapentin, vigabatrin
Limited or no data for monotherapy:
Pregabalin, lacosamide, rufinamide, ezogabine

** FDA approval for monotherapy

Glauser T, Ben-Menachem E, Bourgeois B et al. In Epilepsia, 54(3):551-563, 2013. C-Slide 45

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 AED Choice:
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Generalized-
Onset Tonic-Clonic
Seizures
Best evidence and FDA Indication:
Valproate**, topiramate**

Also shown to be effective:

Zonisamide, levetiracetam, oxcarbazepine

Phenytoin**, carbamazepine** (may exacerbate absence and myoclonic sz )

Lamotrigine (may exacerbate myoclonic sz of symptomatic generalized epilepsies)

** FDA approved for monotherapy

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AED Choice: Absence

Seizures
Best evidence:
Ethosuximide (limited spectrum, absence only), valproate

Also shown to be effective:

Lamotrigine

May be considered as second-line:

Zonisamide, levetiracetam, topiramate, felbamate, clonazepam

May precipitate or aggravate absence seizures:

Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, tiagabine,

vigabatrin

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AED Choice: Myoclonic

Seizures
Best evidence:
Valproate
Levetiracetam (FDA indication as adjunctive tx)
Clonazepam (FDA indication)

Possibly effective:
Zonisamide, topiramate

May Precipitate or Aggravate:

Carbamazepine, gabapentin, oxcarbazepine, phenytoin, tiagabine,
vigabatrin, and possibly lamotrigine (in JME)

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Lennox-Gastaut
Syndrome
Best evidence/FDA indication*:
Topiramate, felbamate, clonazepam, lamotrigine,
rufinamide, valproate, clobazam
* FDA approval is for adjunctive treatment for all
except clonazepam

Some evidence of efficacy:

Zonisamide, levetiracetam

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AED Mechanisms of
Action
Na+ Ca++ H-current Glutamate GABA Carbonic
AED Channel Channel enhance- Receptor Enhance- Anhydrase
Blockade Blockade ment Antagonism ment Inhibition
PHT X X (NMDA glycine)
CBZ, OXC X X (CBZ>OXC)

barb, benzo X (GABAA)

ESM X
VPA X X X
FBM X X X (NMDA) X
GBP X X X (NMDA glycine)
LTG X X X (kainate)
TPM X X X (AMPA,kainate) X X
TGB X (reuptake)
LEV X (kainate)
ZNS X X X
PGB X
LCM X (slow inact.)
RUF X
VGB X (metab.)

Modified from White HS and Rho JM, Mechanisms of Action of AEDs, 2010.

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AED Interactions: Mechanisms

 AEDs that may induce metabolism of other drugs:
 Broad spectrum inducers: carbamazepine, phenytoin,
phenobarbital, primidone
 Selective CYP3A (at higher doses): oxcarbazepine, topiramate,
felbamate
 AEDs that inhibit metabolism of other drugs:
 Valproate
 Selective CYP2C19: felbamate, topiramate and oxcarbazepine
 Can  concentrations of phenytoin and phenobarbital

 AEDs that are highly protein bound:

 Valproate, phenytoin, carbamazepine, tiagabine, ezogabine

 Other drugs may alter metabolism or protein binding

of antiepileptic drugs (especially antibiotics, chemotherapeutic
agents and antidepressants)

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AED Interactions:
Anticoagulation
Antiplatelet/
AED Anticoagulant Potential Clinical Effect
Phenytoin (PHT) 1. Warfarin 1. Increases INR*
2. Aspirin 2. Increases free PHT
Carbamazepine (CBZ) Warfarin Decreases INR

Phenobarbital (Pb) Warfarin Decreases INR

Primidone (PRM)

Valproic acid (VPA) 1. Warfarin 1. Slight decrease in INR

2. Aspirin 2. Increases free VPA

*AEDs increase metabolism of warfarin, but warfarin is 99% protein bound, and PHT and VPA increase warfarin’s

free fraction.

INR = international normalized ratio.

American Epilepsy Society 2015 C-Slide 53

Boggs J. In: Ettinger AB, Devinsky O, eds. Managing Epilepsy and Co-Existing Disorders. Boston: Butterworth-
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AED Interactions:
Hormonal Contraception
Enzyme-inducing AEDs that may decrease the efficacy of
hormonal contraception:
Carbamazepine (Tegretol, Carbatrol)
Clobazam (Onfi)
Eslicarbazepine (Aptiom)
Felbamate (Felbatol)
Oxcarbazepine (Trileptal)
Perampanel (Fycompa)
IUD is the
Phenobarbital (Phenobarbital, Primidone) preferred
Phenytoin (Dilantin) contraceptive
method for
Rufinamide (Banzel)
women taking
Topiramate (Topamax) enzyme-inducing
Gaffield ME et al. Contraception 2011; 83:16–29 . [PubM
AEDs.
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AED Interactions:
Lamotrigine and oral contraception

 Lamotrigine clearance is increased significantly by

estrogen, particularly synthetic estrogens.

 Oral contraceptive pills can decrease lamotrigine levels

by up to 50%

 Lamotrigine levels may increase significantly during the

placebo week

 IUD is the contraceptive method of choice for women

taking lamotrigine
Gaffield ME et al. Contraception 2011; 83:16–29 . [PubM
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AEDs: Serum
Concentrations
 AED serum concentrations are to be used as a
guide, not dictate clinical decision making.
 Serum concentrations are useful when optimizing
AED therapy, assessing compliance, monitoring
during pregnancy or oral contraceptive use, or
teasing out drug-drug interactions.
 Individual patients define their own “therapeutic”
and “toxic” ranges.

Patsalos et al. Epilepsia. 2008;49:1239–1276. [PubMed

]
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AEDs: Common Adverse
Effects
Typically dose-related:

Dizziness , Fatigue , Ataxia, Diplopia

 all AEDs

Irritability, neuropsychiatric side effects

 Levetiracetam, ezogabine

Word-finding difficulty
 Topiramate

Weight loss/anorexia
 Topiramate, zonisamide, felbamate

Weight gain
 Valproate (also associated with polycystic ovarian syndrome )
 Carbamazepine, gabapentin, pregabalin

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AEDs: Serious Adverse
Effects
Typically Idiosyncratic:
Renal stones
 Topiramate, zonisamide

Anhydrosis, heat stroke

 Topiramate, Zonisamide

Acute closed-angle glaucoma

 Topiramate

Hyponatremia
 Carbamazepine, oxcarbazepine

Urinary Retention
 Ezogabine

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AEDs: Serious Adverse
Effects
Typically Idiosyncratic:

Aplastic anemia
 Felbamate, zonisamide, valproate, carbamazepine

Hepatic Failure
 Valproate, felbamate, lamotrigine, phenobarbital

Peripheral vision loss

 Vigabatrin

Rash
 Phenytoin, lamotrigine, zonisamide, carbamazepine

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AEDs: Adverse Effects -
Rash
 15.9% patients experienced a rash attributed
to an AED

 Average rate of AED-related rash for a given

AED 2.8%, 2.1% causing AED discontinuation.

 Predictors significant in multivariate analysis:

 occurrence of another AED-rash

Arif H. et al. Neurology. 2007;68:1701–1709. [PubMed]

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AED Adverse Effects -
Rash
Stevens-Johnson Syndrome (SJS) and
Toxic Epidermal Necrolysis (TENS)
 Severe life threatening allergic reaction

 Blisters and erosions of the skin, particularly

palms/soles and mucous membranes

 Fever and malaise

 Rare: severe risk roughly 1-10/10,000 for many AEDs

 Rapid titration of lamotrigine especially in
combination with valproate increases risk

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AED-related rash in
adult patients with epilepsy

▲▲= rash rate significantly greater than average of all other AEDs (p<0.003)

▼▼= rash rate significantly lower than average of all other AEDs (p<0.003)

▲= trend towards significantly higher than average rash rate of all other AEDs (0.003<p<0.05)
Arif H. et al. Neurology. 2007;68:1701–1709. [PubMed]
▼= trend towards significantly lower than average rash rate of all other AEDs (0.003<p<0.05)
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AEDs: Adverse Effects -
Rash
Drugs rarely associated with rash
 Valproate
 Gabapentin
 Pregabalin
 Levetiracetam
 Topiramate

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AED-related rash in
Asian patients
 FDA alert 12/2007: Risk of “dangerous or
even fatal skin reactions” such as Steven-
Johnson Syndrome and Toxic epidermal
necrolysis is increased in patients with HLA-
B*1502 allele
 Estimated absolute risk for those with the allele: 5%
 This allele is almost exclusively found in Asians
 10-15% of population in China, Thailand, Malaysia,
Indonesia, Phillipines and Taiwan
 2-4% in India
 <1% in Japan and Korea
 59/60 Asian patients w/ SJS/TEN had this allele vs
4% of CBZ tolerant patients
 Asians “should be screened for the HLA-B*1502
allele before starting treatment with
carbamazepine”
 These patients may also be at risk with other
www.fda.gov
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Possible suicide risk with
AEDs
Recent FDA alert (1/2008):
• Meta-analysis of 199 placebo-controlled add-on tx trials
(44,000 patients)
• Suicidality with adjunct AEDs than adjunct placebo:
• 0.43% vs 0.22%
• Extra 2.1 patients per 1000 more patients will have suicidality
• 4 suicides with AEDs vs 0 with placebo
• “generally consistent across the 11 AEDs”

Data analysis is controversial and overall difference is very small

Further investigation is needed

Clinicians should be aware of potential risk and screen for

depression/suicidality
www.fda.gov
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Starting AEDs
 Discuss likely adverse effects

 Discuss unlikely but important adverse effects

 Discuss likelihood of success

 Discuss recording/reporting seizures, adverse

effects, potential precipitants

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Discontinuing AEDs
 Seizure freedom for 2 years
implies overall >60% chance of successful
withdrawal in some epilepsy syndromes
 Favorable factors
• Control achieved easily on one drug at low dose
• No previous unsuccessful attempts at withdrawal
• Normal neurologic exam and EEG
• Primary generalized seizures except JME
• “Benign” syndrome

 Consider relative risks/benefits (e.g., driving,

pregnancy)

Practice parameter. Neurology. 1996;47:600–602. [PubMed]

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Evaluation After Seizure

Recurrence
 Progressive pathology?
 Avoidable precipitant?
 If on AED
• Problem with compliance?
• Pharmacokinetic factor?
• Increase dose?
• Change medication?
 If not on AED
• Start therapy?

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Medical Comorbidities of
Epilepsy
 Most medical conditions occur with
increased incidence in patients with
epilepsy compared to patients without it
 Some of these may be pathophysiologically
related (stroke) and some may be less so
 Recurrent seizures may be feature of a
cryptogenic condition that has myriad
downstream manifestations (?auto-immune
illness)

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Medical/Neuro Comorbidities of
Epilepsy
(CDC Novmeber 2013)
no epilepsy % any epilepsy %

Heart 11.3 18.3

HTN 29 34

Stroke 2.4 4.3

Arthritis 21.4 30.9

Face Pain 4.8 14.2

HA/Migraine 16.2 34.7

Ulcer 28.9 47.1

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 Return to index
Psychiatric Comorbidities
of Epilepsy
 Anxiety
 Generalized Anxiety Disorder
 Panic Attacks

 Affective
 Unipolar Depression
 Bipolar Disorder

 Psychosis
 Post-ictal
 Chronic Interictal/Schizophrenia-like

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Anxiety and Epilepsy

 With rigorous diagnostic criteria prevalance of

anxiety disorders in epilepsy patients in the
community are between 14.8 - 25% (Edeh ‘87 and
Jacoby ‘96)

 Pariente in 1991 reported an incidence of 21% of

panic attacks in French Epilepsy patients compared
to 3% of controls

 Hospital based studies show similar rates as

community (Perino ‘96, Gureje ‘91)

 In epilepsy surgery candidates rates have been

found as high as 31% (Manchanda ‘96)

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Affective Disorders and
Epilepsy
 Major Depression

 Bipolar Disorder

 Subsyndromal Symptoms

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Major Depression and
Epilepsy
 Conservative estimates state that 20% of
Epilepsy patients will develop Depression
 Some estimates as high as 50 - 80%
 Women with significantly higher rates
 Rates vary regionally
 Studies have consistently shown that
Depression increases the risk of developing
Epilepsy, suggesting a common stem etiology

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Bipolar Disorder and
Epilepsy
 Lifetime prevalence of Bipolar Disorder in
Epilepsy patients is 1.5 - 2%
 Much less common than Depression
 Notably, post-ictal psychosis can have a
bipolar flavor, schizophreniform but with
preserved affect and mild hypomania
 Many AED’s are mood stabilizers, most
notably: Lamictal, Depakote, Tegretol,
Trileptal

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 Sub-Syndromal Return to index

Symptoms
 The most common presentation of Affective
Disorders in Epilepsy patients is sub-
syndromal depression
 They don’t meet criteria for Major Depressive
Episode but can be significantly symptomatic
 Depressive symptoms have been shown to
correlate with quality of life consistently, even
when seizure frequency, type, etc. have not

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Psychosis and Epilepsy

 Ictal

 Post-Ictal

 Interictal

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Ictal Psychosis

 Can range from a sense of being followed over

the contralateral shoulder (amygdaloid focus)
with mild paranoia to hallucinations of all sorts
(auditory, visual, olfactory, tactile)
 Can be associated with EEG changes, though
not frequently if awareness is unaltered
 Fluctuating awareness and
paranoia/hallucinations with lability are
hallmarks of non-convulsive status epilepticus

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Post-Ictal Psychosis
 Often after a lucid period of 24 - 36 hours.

 Bizarre in nature often, religious at times,

schizophreniform in content
 Affect often preserved with irritability or hypomania

 Can last hours to days to even weeks

 Treating with anti-psychotics for a few weeks limits

intensity and duration
 RF include, prolonged seizures, seizures with l.o.c.,
bitemporal foci, clusters of seizures, GTC’s, family
history of mood disorders, and longer duration of
epilespy

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Interictal Psychosis

 Most commonly seen in Temporal Lobe Epilepsy of

long duration with poor seizure control

 Post-Ictal Psychoses increase in frequency and

duration and then become chronic interictal
psychosis without return to baseline

 Very schizophreniform looking with paranoid, bizarre,

religious delusional systems

 Require chronic anti-psychotic pharmacologic and

psychosocial interventions

 Can occur de novo after Epilepsy Surgery

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Diagnosis of Psychiatric Symptoms
in Epilepsy

 Every visit with a provider should include a

discussion of psychiatric symptoms with patient
and family
 Remember that sub-syndromal symptoms can
significantly impact quality of life and respond to
treatment
 Know when to refer to psychiatrist or therapist for
ongoing treatment
 Depression and Anxiety should always be explored
 Screen for post-ictal psychosis

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 Psychosocial ConcernsReturn to index

and Quality of Life in

Epilepsy

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 Patient Selection for
Return to index

Surgery
 Epilepsy syndrome not responsive to
medical management
• Unacceptable seizure control despite maximum
tolerated doses of 2-3 appropriate drugs as
monotherapy

 Epilepsy syndrome amenable to surgical

treatment

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Evaluation for Surgery

History and Exam: consistency, localization of
seizure onset and progression
3Telsa MRI: 1.5 mm coronal cuts with sequences
sensitive to gray-white differentiation and to gliosis
Other neuroimaging options: PET, ictal SPECT
EEG: ictal and interictal, special electrodes
Magnetoencephalography (MEG): interictal, mapping
Neuropsychological battery
Psychosocial evaluation
Intracarotid amobarbital test (Wada)

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Surgical Treatment
 Potentially curative
• Resection of epileptogenic region (“focus”)
avoiding significant new neurologic deficit

 Palliative
• Partial resection of epileptogenic region
• Disconnection procedure to prevent seizure
spread
• Callosotomy
• Multiple subpial transections

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Epilepsy Surgery
Outcomes
Anterior Neocortical
Temporal Resection
Resection
Seizure Free 66% 49%
(except auras) (possibly higher with mesial (63% if lesional)
temporal sclerosis)

Improved 21% 30%

Not improved 14% 21%

Engel J, Jr, et al. Neurology. 2003;60:538–547. [PubMed]

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Epilepsy Surgery
Corpus Callosotomy
 Palliative surgery for intractable epilepsies with drop attacks
(i.e. Lennox-Gastaut Syndrome)
 Up to 75% have > 75% reduction in atonic seizures
 Risk of disconnection syndromes

Hemispherectomy
 Indicated for catastrophic hemispheric epilepsies, usually presenting in children (i.e.
Rasmussen’s encepalitis, hemimegalencephaly)
 43-79% seizure free (varies by etiology)
 “Functional hemispherectomy” (disconnection without removal) now more commonly
performed

Multiple Subpial Transections

 Cuts horizontal cortical-cortical connections
 Generally reserved for epileptogenic regions in functional cortex

Spencer SS and L Huh. Lancet Neurol. (2008), 525–537. [Pubmed]

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 Vagus Nerve Return to index

Stimulator
 Intermittent programmed electrical stimulation of left
vagus nerve
 Option of magnet activated stimulation
 Adverse effects local, related to stimulus
(hoarseness, throat discomfort, dyspnea)

 Mechanism unknown
 Clinical trials show that 35% of patients have a 50%
reduction in seizure frequency and 20% experience a
75% reduction after 18 months of therapy.
 May improve mood and allow AED reduction
 FDA approved for refractory partial onset seizures and
refractory depression

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Non-Drug Treatment/
Lifestyle Modifications
 Adequate sleep

 Avoidance of alcohol, stimulants, etc.

 Avoidance of known precipitants

 Stress reduction — specific techniques

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Non-Drug Treatment/
Ketogenic Diet
 Main experience with children, especially with
multiple seizure types
 Likely anti-seizure effect of ketosis (beta
hydroxybutyrate), but other mechanisms also
may be responsible for beneficial effects
 Low carbohydrate, adequate protein, high fat
 50% with a >50% seizure reduction
 30% with >90% reduction
 Side effects include kidney stones, weight
loss, acidosis, dyslipidemia

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Non-Drug Treatment/
Alternative Diets
 Modified Atkins diet
• 10 g/day carbohydrates to start, fats encouraged
• No protein, calorie, fluid restriction
• 3 reports to date from Johns Hopkins, 1 from South
Korea
– 47% all children with >50% seizure reduction
– Studies underway for adults

 Low-glycemic index treatment

• 40-60 g/day low-glycemic carbohydrates
• Portions generally controlled
• Single report from Massachusetts General
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Status Epilepticus
 Definition
• More than 5 minutes of continuous clinical
or electrographic seizure activity
or
• Two or more sequential seizures without full
recovery between seizures

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Status Epilepticus (SE)

 A medical emergency
• Adverse consequences can include hypoxia,
hypotension, acidosis, hyperthermia,
rhabdomyolysis and neuronal injury
• Know the recommended sequential protocol
for treatment and distribute a written protocol
to emergency rooms, ICUs and housestaff.
• Goal: stop seizures as soon as possible

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Mortality of SE by Age
70

60
50
% Mortality

40

30

20

10

0
16-20 20-29 30-39 40-49 50-59 60-69 70-79 80+

Age Group (Years)

Towne AR et al. Epilepsia. 1994;35:27-34.
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Mortality of SE by
duration
50

40
% Mortality

30

20

10

0
0:30-0:59 1:00-1:59 2-4 5-10 11-23 24+

Seizure Duration (Hours)

Towne AR et al. Epilepsia. 1994;35:27-34.
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 SE Treatment Return to index

Algorithm
• Check emergency ABC’s
• Give O2
• Obtain IV access
• Begin EKG monitoring
• Check fingerstick glucose
• Draw blood for Chem-7, Magnesium,
Calcium, Phosphate, CBC, LFTs, AED levels,
ABG, troponin
• Toxicology screen (urine and blood).
• Thiamine 100 mg IV; 50 ml of D50 IV unless
adequate glucose known.
Arif H, Hirsch LJ. Semin Neurol. 2008;28:342–354. [PubMed]

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Status Epilepticus:
First-line Treatment Options
Class &
Benzodiazepin Rout Maximum Level of
Dosing
e e Dose Evidenc
e
4mg @
2mg/min Class I
LORAZEPAM IV 0.1mg/kg May repeat x1 Level A
in 5-10 min
IM
Nasal Class I
MIDAZOLAM 0.2mg/kg 10mg
Bucca Level A
l
Class IIa,
DIAZEPAM PR 0.2mg/kg 20mg
Level A
Brophy GM et al. Neurocrit. Care 2012; 17:3–23 [
PubMed]
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Status Epilepticus: Second-
line Treatment Options
Maximu
Class &
Rou m Additional
AED Dosing Level of
te Rate of Dose
Evidence
Infusion
5 PE/kg ,
10 min
Fosphenyto 20 150 Class IIa
IV after
in PE/kg PE/min Level B
loading
dose
5-10mg/kg,
10 min
20mg/k 50mg/mi Class IIa
Phenytoin IV after
g n Level B
loading
dose
20mg/kg,
3-6
Brophy GM et al. 102012;
Neurocrit. Care min17:3–23 [
Valproate 20-40
PubMed] Class IIa
American Epilepsy Society 2015 IV mg/kg/m after C-Slide 100

Sodium mg/kg Level A

 Refractory Status Return to index

Epilepticus:
Treatment Options
Class &
Continuous Adverse
Infusions Initial Dose Level of
Infusion Effects
Evidence
Respiratory
0.2mg/kg Class IIa depression
Midazolam 0.05-2mg/kg/hr
@ 2mg/min Level B Hypotension

Respiratory
1-2mg/kg Depression
30-200 Class IIb Hypotension*
Propofol @ Propofol infusion
mcg/kg/min Level B
20mcg/kg/min syndrome
Renal Failure
Respiratory
depression
Hypotension
Pentobarbita 5-15 mg/kg Class IIb
0.5-5mg/kg/hr Cardiac depression
l @ ≤ 50mg/min Level B Paralytic Ileus
Prolonged mental
status depression
American Epilepsy Society 2015 Brophy GM et al. Neurocrit. Care 2012; 17:3–23 [ C-Slide 101

PubMed]
 Return to index

SE Treatment Algorithm

Begin EEG monitoring ASAP if patient does not

rapidly awaken, or if any CIV treatment is used.
~20% of those patients successfully treated
clinical for status will still be seizing on EEG.

Treiman et al. N Engl J Med. 1998;339:792–8. [PubMed]

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 Differential Diagnosis of Return to index

Non-epileptic Events:
Physiologic
 Syncope
 Cardiac (Arrhythmia)
 Non-Cardiac Syncope (Vasovagal, Dysautonomic)

 Metabolic (Hypoglycemia)
 Migraine
 Sleep Disorders (Narcolepsy)
 Movement Disorders (Paroxysmal Dyskinesia)
 Transient Ischemic Attacks

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 Differential Diagnosis of Return to index

Non-epileptic Events:
Psychogenic
 Psychogenic Seizures

 Malingering

 Panic Attacks

 Intermittent Explosive Disorder

 Breath-holding Spells

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Syncope

 Characteristic warning, usually gradual

(except with cardiac arrhythmia)
 Typical precipitants (except with cardiac
arrhythmia)
 Minimal to no postictal confusion/somnolence
 Convulsive syncope — tonic>clonic
manifestations, usually < 30 sec; usually from
disinhibited brainstem structures (only rarely
from cortical hypersynchronous activity)

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Syncope vs Seizure:
Before Spell
Syncope Seizure

Trigger
Common Rare
(position, emotion, Valsalva)

Sweating & nausea Common Rare

Aura (e.g. déjà vu, smell)

Rare Common
or unilateral symptoms

Hirsch et al, Merritt’s Textbook of Neurology, 2007

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Syncope vs Seizure:
During Spell
Syncope Seizure

Pallor Common Rare

Cyanosis Rare Common

Loss of consciousness <20 secs >60 secs

Hirsch et al, Merritt’s Textbook of Neurology, 2007

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Syncope vs Seizure:
During Spell
Syncope Seizure

Automatisms Occasional Common

Tongue biting, lateral Rare Occasional

Frothing/hyper-salivation Rare Common

Hirsch et al, Merritt’s Textbook of Neurology, 2007

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Syncope vs Seizure:
During Spell
Syncope Seizure
Few clonic or
Prolonged tonic
myoclonic jerks or
Movements phase » rhythmic
brief tonic
clonic mvmts
posturing

Duration < 15 seconds 30 -120 seconds

Frothing/hyper-
Rare Common
salivation
Hirsch et al, Merritt’s Textbook of Neurology, 2007
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 Syncope vs Seizure: After Return to index

spell
Syncope Seizure

Confusion/ Common;
disorientation Rare; <30 secs several mins or
longer

Rare, brief, usually Common,

Diffuse myalgias
shoulders/chest hours-days

Creatine kinase
Rare Common
elevation
Hirsch et al, Merritt’s Textbook of Neurology, 2007
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 Features That Are Not HelpfulReturn
in to index
Differentiating Syncope from
Seizure
 Incontinence  Injury other than
lateral tongue
 Prolactin level
biting
 Dizziness
 Eye movements
 Fear (rolling back)

 Brief automatisms

Hirsch et al, Merritt’s Textbook of Neurology, 2007

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Migraine aura vs. occipital seizure

Migraine Occipital Seizure

Duration 5-20 min 0.5-5 min

Typical B&W; straight lines; Color, round, variable

Content slow spread spread

Laterality Either side Always same side

(contralateral)
Associated Altered awareness,
Features automatisms

Hirsch et al, Merritt’s Textbook of Neurology, 2007

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Psychogenic Non-epileptic
Seizures
 10-45% of patients referred for intractable spells
 Females > males
 Psychiatric mechanism — dissociation, conversion
 Common association with physical, emotional, or sexual abuse
 Spells with non-epileptic etiology
 No obvious ictal eeg correlation
(classically normal awake background during episode of impaired
consciousness)

Caveats: Diagnosis can be complicated

 The majority of simple partial seizures have no EEG correlation
 Frontal lobe seizures may have unusual semiology and no discernable
EEG correlation

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Psychogenic Non-epileptic
Seizures
FEATURES SUGGESTIVE OF NONEPILEPTIC PSYCHOGENIC
SEIZURES

 Eye Closure
 Pelvic thrusting
 Opisthotonus
 Side-to-side head shaking
 Prolonged duration (>4 minutes)
 Stopping and starting
 Suggestibility

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Psychogenic Non-epileptic Seizures

Features suggestive of Non-epileptic Important Caveats

seizures

Thrashing, struggling, crying, pelvic thrusting, Bizarre complex automatisms can occur

side-to-side rolling, wild movements with frontal lobe seizures

Preserved consciousness with bilateral Frontal lobe seizures may have bilateral

tonic or clonic mts convulsive movements without impairment

of consciousness

Lack of postictal confusion Posti-ictal confusion is often absent after

frontal lobe seizures

Postictal crying or shouting Aggressive and emotional behavior can

American Epilepsy Society 2015 occur after epileptic seizures C-Slide 116
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Psychogenic Non-epileptic
Seizures
 Represents psychiatric disease
 Once recognized, approximately 50%
respond well to specific psychiatric
treatment
 Epileptic and nonepileptic seizures may co-
exist
 Video-EEG monitoring often required for
diagnosis

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Utility of epilepsy
video/EEG monitoring units
Epilepsy Monitoring Unit (EMU):

 Inpatient unit with specialized personnel

 Continuous video and EEG recording

 Utility:
 Differentiate between epileptic and non-epileptic spells
 Identification of unrecognized seizures
 Recording seizures for presurgical evaluation

NAEC Guidelines for EMU evaluation:

 Treatment failure of 1 year

 Failure of 2-3 AEDs

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 Utility of epilepsy video/EEG
Return to index

monitoring units: Non-epileptic

spells
Study of 213 EMU admissions
• 21% had purely nonepileptic events
• Treated as if epilepsy for a mean of 9 yrs
• Half treated w/ >3 AEDs
• EMU yielded definitive diagnosis in 88%

Smolowitz et al. American Journal of Medical Quality. 2007;22(2):117–122. [PubMed]

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 Utility of epilepsy video/EEG
Return to index

monitoring units (EMU):

Epilepsy
Early Identification of Refractory Epilepsy n=525
Kwan P and MJ Brodie. N Engl J Med. 342 (2000), 314-9. [Pubmed]
• 192 (37%) patients were refractory.
• Only 11% of patients became seizure-free if the first
drug was ineffective.
• Suggests need for early pre-surgical evaluation

Patient awareness of seizures n=31

Blum DE et al. Neurology. 1996;47:260–4. [PubMed]
• 30% patients deny all seizures
• Only 23% were aware of all seizures

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Sudden Unexplained Death
in Epilepsy: SUDEP
Definition:
“Sudden, unexpected, witnessed or unwitnessed,
nontraumatic and nondrowning death, occurring
in benign circumstances, in an individual with
epilepsy, with or without evidence for a seizure
and excluding documented status epilepticus
(seizure duration >30 min or seizures without
recovery in between), in which postmortem
examination does not reveal a cause of death”

Nashef, et al. Epilepsia 2012; 53: 227 [PMID: 22191982]

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SUDEP Definitions -
Updated
• SUDEP definitions updated in 2012 to
recognized that:
• Some cases of sudden death have insufficient
information to determine cause of death
• Some patients with SUDEP have coexisting
conditions that may (in conjunction to seizure)
contribute to death (e.g. long QT syndrome)
• Recognize the concept of near-SUDEP, a patient
resuscitated after a probable SUDEP

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Epidemiology of SUDEP
SUDEP
• Represents about 2-18% of deaths among the
general population of patients with epilepsy
Forsgren et al, Epilepsia 2005;46 Suppl 11:18
• Likely most common disease-related cause of death in
refractory epilepsy

• Risk of sudden death in epilepsy patients 24 X

that of general population. Ficker et al, Neurology 1998;
51:1270

• Epilepsy is a significant risk factor for sudden

death in population-based studies. Holst et al,
Epilepsia 2013; 29:1–8.

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SUDEP Incidence
 100 fold range in SUDEP incidence
 Rates depend on the population
studied:
• Incidence cohort of newly
diagnosed epilepsy: 0.09 per 1000
person-years
• Refractory epilepsy patients: 2.2-
6.0 per 1000 p-y
• Surgical patients : 6.3-9.3 per
1000 p-y
• Low rates in children but higher
rates in adults with childhood
onset epilepsy
Devinsky NEJM 2011

Reviewed in Tomson, et al. Lancet neurol 2008; 7: 1021 [PMID:

18805738], Devinsky N Engl J Med 2011; 365: [PMID: 22070477]

American Epilepsy Society 2015

 Return to index
Sudden Unexplained Death
in Epilepsy: SUDEP
Witnessed SUDEP Langan Y et al. JNNP 2000;68:211–213. [PubMed]

• 15/135 SUDEP cases were witnessed.

• 12/15 were associated with a convulsive seizure.

• One collapse occurred 5 minutes after a GTC seizure and one

after an aura.

• One patient died in a probable postictal state.

• 12/15 were noted to have experienced respiratory difficulties .

• Suggests that respiratory dysfunction may be an important

contributing factor in SUDEP.
• Suggests that positioning or stimulation of respiration may be
important in the prevention of SUDEP.

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SUDEP Risk Factors

Factors associated with Factors associated with

increased SUDEP risk decreased SUDEP risk
Frequent GTCs*** Seizure freedom
Symptomatic etiology Sharing bedroom/monitoring
Nocturnal seizures*
Subtherapeutic AED levels
AED polytherapy**
carbamazepine use
lamotrigine use
Early age of epilepsy
onset/longer duration of
epilepsy**
•
Male sex Risk factors found in multiple studies

Mental retardation

Reviewed in Tomson, et al. Lancet neurol 2008; 7: 1021-31 [PMID: 18805738]; Hesdorffer, et al. Epilepsia 2012; 53:

249-52 [PMID: 22191685]

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SUDEP: Mechanisms
 Witnessed, EMU-recorded,
and post-mortem studies all
support a seizure, typically
GTC, as the terminal event
 Three main mechanism
emerge from observed cases:
• Primary respiratory causes: central
or obstructive apnea
• Cerebral shutdown: diffuse post-
ictal suppression of EEG preceding
EKG or respiratory changes
• Cardiac arrhythmias/autonomic
failure
Friedman, et al. JCI 2013; 123: 1415 [PMID: 23524959]

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SUDEP Prevention
Evidence suggests seizure control reduces SUDEP risk
• Meta-analysis showed subjects randomized to effective dose of an AED had
7-fold reduction in risk of SUDEP during the observation period compared to
placebo in add-on studies . Ryvlin et al. Lancet neurol. 2011; PMID:
21937278

Optimize seizure control as promptly as possible

• Re-evaluate epilepsy diagnosis and treatment as soon as 2 AEDs have
failed, or when GTC szs are frequent despite initial AED treatment
• Evaluate for other therapies: surgery, VNS, diet therapy
• Maximize adherence to AEDs
• Address seizure-provocative lifestyle factors (alcohol use, sleep
deprivation)

Educate patients and families

Seizure alert devices
• Several devices (watches, bed motion detectors) exist to alert
caregivers for GTC sz
• Caution: none are FDA approved or proven to prevent SUDEP or other
complications of seizures.

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First Aid
Tonic-Clonic Seizure
 After seizure ends, turn person on side with
face turned toward ground to keep airway
clear, protect from nearby hazards

 Transfer to hospital needed for:

• Multiple seizures or status epilepticus
• Person is pregnant, injured, diabetic
• New onset seizures

 DO NOT put any object in mouth or restrain

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Driving and Epilepsy

 Regulation varies state by state regarding:
• Reporting requirements
• Required seizure-free period
• Favorable/unfavorable modifiers

 Insurance issues
 Employment issues
Resource: www.efa.org

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Guidelines for
Management
- 50% of pregnancies in women with epilepsy
are unplanned
- All women with epilepsy of reproductive
age should be counseled about the effects
of epilepsy and AEDs on a future pregnancy
- Pregnancy planning starts with the first
AED prescription for a woman of
childbearing age and drug changes should
be made a year before conception when
possible

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Pregnancy and Epilepsy

 96% of pregnancies in mothers with epilepsy
produce normal children
 There is an increased rate of fetal malformations
associated with antiepileptic drug exposure
 Seizures during pregnancy may be harmful
 Tonic-clonic seizures associated with intracranial
hemorrhage, fetal bradycardia and lower IQ in
children
 Status associated with increased fetal and maternal
mortality in some studies
 Insufficient data on non-convulsive seizures

Harden CL et al. Neurology. 2009 Jul 14;73(2):133-41. [PubMed]

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Major Congenital Malformation and

AEDs
Most available data on risk of AEDs comes from
pregnancy registries
 Main outcome variable of most registries are major
congenital malformations (MCM)
 MCM = malformation that affects physiologic
function or requires surgery. Examples:
 Neural tube defects
 Cardiac defects
 Genitourinary defects
 Oral clefts
 Recent prospective studies have also investigated
the effects of AEDs on cognitive development of
exposed children

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Major Congenital Malformation and
AEDs
 MCMs are more common with AED
exposure
 MCM risk in general population 1.6-2.1%
 MCM risk with AED monotherapy 4.5% (OR 2.6)
 MCM risk with Polytherapy 8.6% (OR 5.1)
 Polytherapy risk may be related to specific
combinations of drugs, particularly combinations
with valproic acid
 MCM risk seems to be dose-related for most drugs

Holmes et al. N Engl J Med. 2001;344:1132–1138. [PubMed]

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Major Congenital Malformation and
AEDs
Valproate has been consistently
associated with poorer outcomes
 MCM rate with valproate monotherapy 6.2-16.3%
across 5 registries
 Most studies show dose- related increase in risk with
doses > 750mg/day
 Polytherapy regimens including valproate also
substantially increased risk of MCM
 Valproate is associated with lower IQs in exposed
children compared with other AEDs (10pts on average)
 Valproate is associated with an increased risk of
autism and autism spectrum disorder in exposed
children

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AEDs in Pregnancy
 Probably safest AEDs (range of published MCM rates)
• Lamotrigine (2-5.2%)
• Levetiracetam (3%)
• Carbamazepine (2.2-6.3%)
• Phenytoin (2.9-6.7%)
 Probably have risk lower than valproate
(more data needed)
• Oxcarbazepine
• Zonisamide
• Gabapentin

 Have significant risk greater than some other AEDs

• Topiramate
• Phenobarbital
• Valproate

Adapted from Harden CL: Continuum.

2014; 20:60–79 [PubMed]
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Guidelines for
Management
Education
• Most women with epilepsy have normal children
• Risk of fetal malformations is increased with AED
exposure
• AED teratogenicity is related to exposure in the first
trimester of pregnancy
• Effects on cognitive development likely occur
throughout pregnancy but particularly in 3rd trimester
• Planning should begin well before pregnancy
• Seizures may be deleterious to the fetus
• Compliance with AED treatment is important
• Prenatal diagnosis of fetal malformations is possible

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Guidelines for
Management
Before pregnancy

• Confirm epilepsy diagnosis (exclude non-epileptic

seizures)
• Attempt AED monotherapy with lowest effective
dose
• Consider switching AEDs prior to pregnancy,
particularly if on valproate
• Establish baseline therapeutic levels
• Folate supplementation
• 0.4 – 5 mg/day

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Guidelines for
Management
During pregnancy
• Continue folate supplementation
• Recommend level II ultrasound
• Monitor AED levels at least monthly and adjust dose
accordingly
• Lamotrigine clearance increases dramatically
over the course of pregnancy
• Metabolism also increased for levetiracetam,
oxcarbazepine, phenobarbital and phenytoin
• Carbamazepine levels may be relatively
stable, but depends on the individual patient
• Patients need a post-partum dosing plan to
avoid toxicity post-partum

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Breast Feeding and
Epilepsy
• Breastfeeding should be encouraged for most women
with epilepsy
• Known benefits of breastfeeding likely outweigh
theoretical risks of medication exposure for most drugs
• Six-year old breastfed children of mothers taking
carbamazepine, lamotrigine, phenytoin or valproic acid
monotherapy had higher IQs and verbal abilities than
children who were not breastfed. No adverse effects
were noted
• Some recommendations advise caution with drugs with
longer half-lives including ethosuxamide, phenobarbital
and zonisamide but concerns are mostly theoretical.
More data is needed on these drugs

Meador KJ et al JAMA Pediatr. 2014; 168:729–736 [

PubMed]
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Appendix:
References for Neurologists
Epidemiology and classification

 Herman ST. Classification of Epileptic Seizures. Continuum Neurol.

2007; 13(4): 13-47.

 Engel J et al. A Proposed Diagnostic Scheme for People with

Epileptic Seizures and with Epilepsy: Report of the ILAE Task Force
on Classification and Terminology. Epilepsia 2001; 42(6): 796-803. [
PubMed]

 Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and

unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia.
1993;34(3):453–468. [PubMed]

 French, JA and Pedley, TA. Management of Epilepsy. N Engl J Med

2008 359: 166-176 [PubMed]

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Appendix:
References for Neurologists
Evaluation of a first seizure

 First Seizure Trial Group. Randomized clinical trial on the efficacy of

antiepileptic drugs in reducing the risk of relapse after a first unprovoked
tonic-clonic seizure. Neurology. 1993;43:478–483. [PubMed]

 Camfield P, Camfield C, Smith S, Dooley J, Smith E. Long-term outcome is

unchanged by antiepileptic drug treatment after a first seizure: a 15-year
follow-up from a randomized trial in childhood. Epilepsia. 2002;43:662–663.
[PubMed]

 Krumholz A, Wiebe S, Gronseth G, et al. Quality Standards Subcommittee of

the American Academy of Neurology; American Epilepsy Society. Practice
parameter: evaluating an apparent unprovoked first seizure in adults (an
evidence-based review) Neurology. 2007;69(21):1996–2007. [PubMed]

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Appendix:
References for Neurologists

Anti-epileptic drugs

 French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the
new antiepileptic drugs Neurology. 2004a; 62:1252–60. [PubMed]
2004b;62:1261–73. [PubMed]

 Glauser T, Ben-Menachem, Bourgeois B et al. Updated ILAE evidence

review of antiepileptic drug efficacy and effectiveness as initial
monotherapy for epileptic seizures and syndromes. Epilepsia 2013;
54(3): 551-563. [PubMed]

 Patsalos PN, Berry DJ, Bourgeois BF, Cloyd JC, Glauser TA, Johannessen
SI, Leppik IE, Tomson T, Perucca E. Antiepileptic drugs–best practice
guidelines for therapeutic drug monitoring: A position paper by the
Subcommission on therapeutic drug monitoring, ILAE Commission on
therapeutic strategies. Epilepsia. 2008;49:1239–1276. [PubMed]

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Appendix:
References for Neurologists
Anti-epileptic drugs in special populations
 Harden CL et al. Practice parameter update: management issues for
women with epilepsy. Neurology. 2009 Jul 14;73(2):133-41. [PubMed]

 Harden CL: Pregnancy and epilepsy. Continuum (Minneap. Minn). 2014;

20:60–79 [PubMed]

 Rowan AJ et al. New onset geriatric epilepsy: a randomized study of

gabapentin, lamotrigine, and carbamazepine. Neurology. 2005 Jun
14;64(11):1868-73. [PubMed]

 Azar NJ and BW Abou-Khalil. Considerations in the Choice of an

Antiepileptic Drug in the Treatment of Epilepsy. Seminars in
Neurology. 2008; 28(3): 305-316. [PubMed]

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Appendix:
References for Neurologists
Discontinuing antiepileptic drugs

 Berg AT, Shinnar S. Relapse following discontinuation of

antiepileptic drugs: a meta-analysis. Neurology
1994;44:601-608. [PubMed]

 Practice parameter: a guideline for discontinuing

antiepileptic drugs in seizure-free patients-summary
statement. Report of the Quality Standards Subcommittee
of the American Academy of Neurology. Neurology.
1996;47:600–602. [PubMed]

 Specchio LM et al. Discontinuing antiepileptic drugs in

patients who are seizure free on monotherapy. J Neurol
Neurosurg Psychiatry 2002 72: 22-25 [PubMed]

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Appendix:
References for Neurologists
Intractable epilepsy and epilepsy surgery

 Kwan P and MJ Brodie. Early Identification of Intractable Epilepsy.

N Engl J Med. 342 (2000), 314-9. [Pubmed]

 Wiebe S et al. A randomized, controlled trial of surgery for

temporal-lobe epilepsy, N Engl J Med 345 (2001), 311–318
[Pubmed]

 Engel J et al. Practice parameter: temporal lobe and localized

neocortical resections for epilepsy: report of the Quality
Standards Subcommittee of the American Academy of Neurology,
in association with the American Epilepsy Society and the
American Association of Neurological Surgeons, Neurology 60
(2003), 538–547 [Pubmed]

 Spencer SS and L Huh, Outcomes of epilepsy surgery in adults

and children . Lancet Neurol. (2008), 525–537. [Pubmed]
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Appendix:
References for Neurologists
Management of status epilepticus

 Arif H, Hirsch LJ. Treatment of status epilepticus. Semin Neurol. 2008;28:342–

354. doi: 10.1055/s-2008-1079339. [PubMed]

 Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, Laroche SM,
Riviello JJ, Shutter L, Sperling MR, Treiman DM, Vespa PM: Guidelines for the
evaluation and management of status epilepticus. Neurocrit. Care 2012; 17:3–23
[PubMed]

 Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, Handforth
A, Faught E, Callabresi VP, Uthman BM, Ramsay RE, Mamdani MB. A
comparison of four treatments for generalized convulsive status epilepticus. N
Engl J Med. 1998;339:792–8. [PubMed]

 Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, Gottwald MD,
O'Neil N, Neuhaus JM, Segal MR, Lowestein DH. A comparison of lorazepam,
diazepam and placebo for the treatment of out-of-hospital status epilepticus. N
Engl J Med. 2001;345:631–7. [PubMed]
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ILAE Summary Guidelines
Seizure type or Class Class Class Level of efficacy and effectiveness evidence
epilepsy syndrome I II III (in alphabetic order)

Adults with partial-onset 4 1 34 Level A: CBZ, LEV, PHT, ZNS

seizures Level B: VPA
Level C: GBP, LTG, OXC, PB, TPM, VGB

Children with partial-onset 1 0 19 Level A: OXC

Seizures Level B: None
Level C: CBZ, PB, PHT, TPM, VPA, VGB

Elderly adults with partial- 1 1 3 Level A: GBP, LTG

onset seizures Level B: None
Level C: CBZ

Adults with generalized 0 0 27 Level A: None

onset tonic–clonic Level B: None
seizures Level C: CBZ, LTG, OXC, PB, PHT, TPM, VPA

Children with generalized 0 0 14 Level A: None

onset tonic–clonic Level B: None
seizures Level C: CBZ, PB, PHT, TPM, VPA

Children with absence 1 0 7 Level A: ESM, VPA

Seizures Level B: None
Level C: LTG

BECTS 0 0 3 Level A: None

Level B: None
Level C: CBZ, VPA

JME 0 0 1 Levels A, B, C: None

Glauser et al. Epilepsia 2013; 54(3): 551-563.

[PubMed]
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Levels
Level Established as useful/predictive or not useful/predictive for the given condition in
A= the specified population.

Level Probably useful/predictive or not useful/predictive for the given condition in the
B= specified population.

Level Possibly useful/predictive or not useful/predictive for the given condition in the
C= specified population.

Level Data inadequate or conflicting. Given current knowledge, test, predictor is

U= unproven.

French et al. Neurology. 2004a; 62:1252–60. [PubMed] 2004b;62:1261–73. [PubMed]

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 Clinical Epilepsy
Workgroup
 Daniel Friedman, MD (chair)

 Elizabeth E. Gerard, MD (past chair)

 Ed Garcia, MD

 Sara Inati, MD

 Mirret El-Hagrassy, MD

 David Ko, MD

 Siddhartha Nadkarni, MD

Prior members:

Larry Hirsch, MD (past chair)

Alan Ettinger, MD

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