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Clinical Epilepsy: Index

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Definitions and epidemiology Non-epileptic events


Physiologic
Evaluation of a first seizure Psychogenic

Choosing antiepileptic drugs Epilepsy monitoring units


Drug-drug interactions
Adverse effects Epilepsy safety
SUDEP
Epilepsy comorbidities
Pregnancy and epilepsy
Discontinuing antiepileptic drugs
Pediatric epilepsy and seizures
Alternative therapies
Appendix for nurses
Epilepsy surgery
Appendix for neurologists
Status Epilepticus

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Definitions

 Seizure: the clinical manifestation of


an abnormal, excessive excitation
and synchronization of a population
of cortical neurons

 Epilepsy: recurrent seizures (two or


more) which are not provoked by
systemic or acute neurologic insults

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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 Seizures


 Impaired consciousness
 Clinical manifestations vary Seizures
with site of origin and degree of
spread
• Presence and nature of aura
• Automatisms Partial Generalized
• Other motor activity
 Duration typically < 2 minutes

Complex
Partial

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Secondarily Generalized Seizures


 Begins focally, with or
without focal neurological
symptoms Seizures

 Variable symmetry,
intensity, and duration of
tonic (stiffening) and clonic
(jerking) phases Partial Generalized

 Typical duration 1-3


minutes
 Postictal confusion, Secondarily

somnolence, with or Generalized


without transient focal
deficit

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EEG: Partial Seizure

Right Frontal
seizure

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EEG: Partial Seizure

Continuation 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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Typical Absence 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
 EEG: Generalized 3 Hz spike-wave Absence
discharges

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EEG: Typical Absence Seizure

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Atypical Absence 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 Seizures

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Myoclonic Seizures

Seizures
Epileptic Myoclonus
 Brief, shock-like jerk of a muscle
or group of muscles

 Differentiate from benign, Partial Generalized


nonepileptic myoclonus (e.g., while
falling asleep)

 EEG: Generalized 4-6 Hz


polyspike-wave discharges
Myoclonic

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Myoclonic Seizures

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Tonic and Atonic 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 generalized
polyspike-wave. Seizures

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 minute
EEG – sudden diffuse attenuation or generalized Atonic
polyspike-wave

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Tonic and Atonic Seizures

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Generalized Tonic-Clonic Seizures


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

 EEG – generalized polyspikes Tonic-


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:
Bupropion
Tricyclics
 Neuroleptics
Phenothiazines
Clozapine
 Theophylline
 Isoniazid
 Penicillins
 Cyclosporin
 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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Choosing Antiepileptic Drugs


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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Choosing Antiepileptic Drugs


 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 depends largely on
drug side-effect profile and patient’s preference/concerns
 Choice of AED for generalized epilepsy depends on
predominant seizure type(s) as well as 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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Choosing Antiepileptic Drugs


Broad-Spectrum Agents Narrow-Spectrum Agents

Valproate Partial onset seizures


Felbamate Phenytoin
Lamotrigine Carbamazepine
Topiramate Oxcarbazepine
Zonisamide Gabapentin
Levetiracetam Pregabalin
Rufinamide* Tiagabine
Vigabatrin Lacosamide*

Absence
Ethosuximide

* New AEDs (approved 2008) categorization may change


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Choosing Antiepileptic
Drugs (cont.)
Monotherapy for Partial Seizures
Best evidence and FDA indication:
Carbamazepine, Oxcarbazepine, Phenytoin, Topiramate
Similar efficacy, likely better tolerated:
Lamotrigine, Gabapentin, Levetiracetam
Also shown to be effective:
Valproate, Phenobarbital, Felbamate, Lacosamide
Limited data but commonly used:
Zonisamide, Pregabalin

Azar NJ and BW Abou-Khalil. Seminars in Neurology. 2008; 28(3): 305-316. [PubMed]


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Choosing Antiepileptic
Drugs (cont.)

Monotherapy for Generalized-Onset


Tonic-Clonic Seizures
Best evidence and FDA Indication:
Valproate, Topiramate
Also shown to be effective:
Zonisamide, Levetiracetam
Phenytoin, Carbamazepine (may exacerbate absence and myoclonic sz )
Lamotrigine (may exacerbate myoclonic sz of symptomatic generalized epilepsies)

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Choosing Antiepileptic
Drugs (cont.)
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

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Choosing Antiepileptic
Drugs (cont.)

Myoclonic Seizures

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

Possibly effective:
Zonisamide, Topiramate

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Choosing Antiepileptic
Drugs (cont.)

Lennox-Gastaut Syndrome
Best evidence/FDA indication*:
Topiramate, Felbamate, Clonazepam, Lamotrigine, Rufinamide, Valproate
* FDA approval is for adjunctive treatment for all except clonazepam

Some evidence of efficacy:


Zonisamide, Levetiracetam

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Antiepileptic Drug Monotherapy


 Simplifies treatment

 Reduces adverse effects

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

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Antiepileptic Drug Interactions


 AEDs that may induce metabolism of other drugs:
 carbamazepine, phenytoin, phenobarbital, primidone

 AEDs that inhibit metabolism of other drugs:


 valproate, felbamate

 AEDs that are highly protein bound:


 valproate, phenytoin, tiagabine
 carbamazepine, oxcarbazepine
 topiramate is moderately protein bound

 Other drugs may alter metabolism or protein binding of


antiepileptic drugs (especially antibiotics, chemotherapeutic agents and
antidepressants)

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AEDs and INR


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.

Boggs J. In: Ettinger AB, Devinsky O, eds. Managing Epilepsy and Co-Existing Disorders. Boston: Butterworth-Heinemann;
2002:39-47.

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Antiepileptic Drug Interactions


Drugs that may decrease the efficacy of
oral contraceptive pills:

• Phenytoin
• Carbamazepine
• Phenobarbital
• Topiramate*
• Oxcarbazepine*
• Felbamate*
*at high doses

“High-dose” birth control pills are recommended for patients taking


these medications.

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Antiepileptic Drug Interactions


 Lamotrigine and hormonal contraception:

 Oral contraceptive pills can decrease lamotrigine levels


by 50%
 Lamotrigine levels will increase significantly during the
placebo week, possibly leading to toxicity
 Lamotrigine can decrease progesterone levels. Patients
using Depo-provera may need shorter intervals
between injections.

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AED 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.

Table: Summary of ILAE guidelines on therapeutic drug levels


Patsalos et al. Epilepsia. 2008;49:1239–1276. [PubMed]
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Adverse Effects of AEDs: Common


Typically dose-related:
Dizziness , Fatigue , Ataxia, Diplopia
 all AEDs

Irritability
 levetiracetam

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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Adverse Effects of AEDs: Serious


Typically Idiosyncratic:

Renal stones
 topiramate, zonisamide

Anhydrosis, heat stroke


 topiramate

Acute closed-angle glaucoma


 topiramate

Hyponatremia
 carbamazepine, oxcarbazepine

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Adverse Effects of AEDs: Serious


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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Adverse Effects of AEDs: 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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Adverse Effects of AEDs: 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 Return to index

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)
▼= trend towards significantly lower than average rash rate of all other AEDs (0.003<p<0.05)

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


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Adverse Effects of AEDs: Rash

Drugs rarely associated with rash


 Valproate
 Gabapentin
 Pregabalin
 Levetiracetam
 Topiramate

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AED-related rash in Return to index

Asian patients
FDA alert 12/2007

Risk of “dangerous or even fatal skin reactions” such as Steven-Johnson Syndrome


and Toxic epidermal necrolysis is incrased 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 AEDs (phenytoin)

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Epilepsy Comorbidities and AEDs


Osteoporosis
• Mostly worsened by the enzyme inducers: phenytoin,
phenobarbital, primidone. Carbamazepine data equivocal.
• Equivocal data with valproate, unavailable for other non- inducers.
• Patients should take calcium 1000-1500/day; Vit D 400-4000/day
Pack AM Neurology. 2008;70:1586–1593. [PubMed]

Migraine
• Consider topiramate, valproate

Depression
• Can be exacerbated by levetiracetam (and less so zonisamide)
• Can be helped by lamotrigine and possibly gabapentin, pregabalin
(and vagus nerve stimulator)

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Depression in Epilepsy

 Prodromal, peri-ictal, interictal


 20% to 60% in many series
 Suicide rate 5 times higher than that of
general population

Ettinger AB, et al. J Epilepsy. 1998;11:20-24.


Barraclough BM. The suicide rate of epilepsy. Acta Psychiatr Scand. 1987 Oct;76(4):339–345. [PubMed]

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Depression in Epilepsy

Score Cutpoints: Major Depression > 21; Mod/mild Depression = 15-21; No Depression < 15
CES-D. overall group effect (p 0.001), comparison between epilepsy and asthma groups (p 0.05).
Ettinger A, Reed M, Cramer J. Neurology. 2004;63:1008–1014. [PubMed]

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Bipolar Depression in Epilepsy

12.2% Bipolar symptoms


in epilepsy and
other chronic
conditions
7.2%
5.9%

3.2%

1.7%

Epilepsy Migraine Asthma Diabetes Controls


Ettinger AB et al. Neurology. 2005;65:535–540. [PubMed]

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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
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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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Non-Drug Treatment/
Lifestyle Modifications

 Adequate sleep

 Avoidance of alcohol, stimulants, etc.

 Avoidance of known precipitants

 Stress reduction — specific techniques

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Patient Selection for 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
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 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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Status Epilepticus

 Definition
• More than 10 minutes of continuous 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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SE Treatment Algorithm
One commonly used treatment algorithm is:
First 5 minutes:
• 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).
Arif H, Hirsch LJ. Semin Neurol. 2008;28:342–354. [PubMed]

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SE Treatment Algorithm

6-10 minutes
• Thiamine 100 mg IV; 50 ml of D50 IV unless
adequate glucose known.
• Lorazepam 4 mg IV over 2 mins; if still seizing, repeat
X 1 in 5 mins.
• If no rapid IV access give diazepam 20 mg PR or
midazolam 10 mg intranasally, buccally or IM.

Arif H, Hirsch LJ. Semin Neurol. 2008;28:342–354. [PubMed]

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SE Treatment Algorithm

10-20 minutes:
• If seizures persist, begin fosphenytoin 20 mg/kg IV
at 150 mg/min, with blood pressure and EKG
monitoring.
• Reasonable to bypass this step, or perform
subsequent step simultaneous with fosphenytoin
loading

Arif H, Hirsch LJ. Semin Neurol. 2008;28:342–354. [PubMed]

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SE Treatment Algorithm
10-60 minutes: one (or more) of the following 4 options:
(intubation usually necessary except for valproate)

• Continuous IV midazolam: Load: 0.2 mg/kg; repeat 0.2-0.4 mg/kg


boluses every 5 minutes until seizures stop, up to a maximum total
loading dose of 2 mg/kg. Initial rate: 0.1 mg/kg/hr. cIV dose range:
0.05 – 2.9 mg/kg/hr.
OR
• Continuous IV propofol: Load: 1 mg/kg; repeat 1-2 mg/kg boluses
every 3-5 minutes until seizures stop, up to maximum total loading
dose of 10 mg/kg. Initial cIV rate: 2 mg/kg/h. cIV dose range: 1-15
mg/kg/hr. Avoid >48 hrs of >5 mg/kg/h (increased risk of propofol
infusion syndrome).
OR
• IV valproate: 40 mg/kg over ~10 minutes. If still seizing, additional
20 mg/kg over ~5 minutes.
OR
• IV phenobarbital: 20 mg/kg IV at 50-100 mg/min.

Arif H, Hirsch LJ. Semin Neurol. 2008;28:342–354. [PubMed]


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SE Treatment Algorithm
Arif H, Hirsch LJ. Semin Neurol. 2008;28:342–354. [PubMed]

60 minutes:
• Continous IV Pentobarbital. Load: 5 mg/kg at up
to 50 mg/min; repeat 5 mg/kg boluses until
seizures stop. Initial cIV rate: 1 mg/kg/hr.
cIV-dose range: 0.5-10 mg/kg/hr; traditionally
titrated to suppression-burst on EEG.

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
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
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 phase »
Movements
or brief tonic rhythmic clonic
posturing mvmts

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 spell


Syncope Seizure

Confusion/ Common;
disorientation Rare; <30 secs several mins or
longer
Rare, brief,
Common,
Diffuse myalgias usually
hours-days
shoulders/chest

Creatine kinase
Rare Common
elevation
Hirsch et al, Merritt’s Textbook of Neurology, 2007
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Features That Are Not Helpful in
Differentiating Syncope from Seizure

 Incontinence  Injury other than


 Prolactin level lateral tongue 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- Important Caveats
epileptic seizures

Thrashing, struggling, crying, pelvic Bizarre complex automatisms can


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

Preserved consciousness with bilateral Frontal lobe seizures may have


tonic or clonic mts bilateral 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 occur after epileptic seizures

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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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Sudden Unexplained Death in
Epilepsy: SUDEP
Definition:
“sudden, unexpected, witnessed or
unwitnessed, nontraumatic and non-
drowning death in a patient with epilepsy
where the postmortem examination does
not reveal a toxicologic or anatomic cause
of death, with or without evidence of a
seizure and excluding documented status
epilepticus.”

Nashef L, Brown S. Lancet. 1996;348(9038):1324–1325. [PubMed]

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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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Epidemiology of SUDEP

SUDEP
• Represents about 2-18% of deaths among the
general population of patients with epilepsy.
• Risk of sudden death in epilepsy patients 24 X
that of general population.
• Mean SUDEP incidence: 3.7/1000 people per
year.
• Higher in patients referred for epilepsy
surgery (up to 1 per 100 per year).

Walczak TS et al. Neurology. 2001;56:519–25. [PubMed]

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Epidemiology of SUDEP

SUDEP Risk Factors

• History of and number of GTCS


• Frequent seizures
• Subtherapeutic AED levels
• Young adults
• Long epilepsy duration; early epilepsy onset
• AED polytherapy
• Frequent AED changes
• IQ <70
Tomson et al. Epilepsia. 2005;46(Suppl 11):54–61. [PubMed]

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Recommendations for SUDEP prevention


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
• Consider epilepsy surgery at that point
• Maximize compliance with AEDs

Use the least number of AEDs needed to control seizures


• Add AED with the aim of replacing the current AED in a
timely fashion (But not at the expense of worsening of
seizure control)

Educate patients and families

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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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Pregnancy and Epilepsy:
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
 Neural tube defects
 Cardiac defects
 Genitourinary defects
 Oral clefts
 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)

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


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Pregnancy and Epilepsy


 96% of pregnancies in mothers with epilepsy produce
normal children
 Spontaneous abortions and pre-term birth are more
common in women with epilepsy
 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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Pregnancy and Epilepsy:
Major Congenital Malformation and AEDs

Valproate consistently associated with poorer outcomes


 MCM rate with valproate monotherapy 6.2-13.2%
across 5 registries
 Most studies show dose- related increase in risk with
doses > 1000mg/day
 Polytherapy regimens including valproate also
substantially increased risk of MCM
 Valproate associated with lower IQs in exposed
children

Phenobarbital probably also poses higher risk of MCM


compared with other monotherapy regimens.

Meador KJ, Pennell PB, Harden CL, Gordon JC, Tomson T, Kaplan PW, Holmes GL, French JA, Hauser WA, Wells PG, Cramer JA., HOPE Work
Group. Pregnancy registries in epilepsy: A consensus statement on health outcomes. Neurology. 2008;71:1109–1117. [PubMed]
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Pregnancy and Epilepsy:
Major Congenital Malformation and AEDs

MCM rate similar among other studied AEDs in monotherapy,


but not enough data to show significant difference between
them
 Levetiracetam
 Early data promising (0% in monotherapy, 2.7% in polytx)
 Carbamazepine (2.2-3.9%)
 Substantial data available, relatively good track record
 Lamotrigine (1.4-4.4%)
 Increased risk (5.4%) with doses > 400/day
 Gabapentin (0-3.2%)
 Topiramate (0-4.8%)
 Phenytoin (3.2-6.7%)
 Zonisamide, Pregabalin
 Limited monotherapy data
Meador KJ, Pennell PB, Harden CL, Gordon JC, Tomson T, Kaplan PW, Holmes GL, French JA, Hauser WA, Wells PG, Cramer JA., HOPE Work
Group. Pregnancy registries in epilepsy: A consensus statement on health outcomes. Neurology. 2008;71:1109–1117. [PubMed]
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Pregnancy and Epilepsy
Guidelines for Management

All women of child-bearing potential should


receive education and carefully considered
management before and during pregnancy
to optimize the chances of a good outcome
for both mother and child.

Reference: Liporace J, D’Abreu. Epilepsy and Women’s Health: Family Planning, Bone Health,
Menopause, and Menstrual Related Seizures. Mayo Clinic Proceedings 2003; 78: 497-506.

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Pregnancy and Epilepsy
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
• 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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Pregnancy and Epilepsy
Guidelines for Management
Before pregnancy
• 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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Pregnancy and Epilepsy
Guidelines for Management
During pregnancy
• Monitor AED dose requirements to maximize
seizure control
– Particularly with lamotrigine (levels fall > 50%
and sz increase)
– Also increased clearance of levetiracetam,
oxcarbazepine, phenobarbital and phenytoin
• Continue folate supplementation
• High-risk OB care, consider prenatal diagnosis of
malformations, level II ultrasound
• Consider Vit K (10 mg/day orally) starting at 36
weeks

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Breast Feeding and Epilepsy


Breastfeeding should be encouraged unless clear risk posed

Probably safe:
• Carbamazepine
• Phenytoin
• Valproate
• Lamotrigine
“Use with caution” in lactating women:
• Primidone
• Phenobarbital
• Ethosuximide

Pennell et al. Epilepsy and Behavior. 2007. 11: 263-9 [crossref]


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