Frederick J. Goldstein, Ph.D.

, FCP
ANTICONVULSANTS
I. Classification (Simplified) of Seizures
A. Generalized Seizures
Bilateral
Reduced (absence) or loss (tonic-clonic) of consciousness
1. Tonic-Clonic (Grand Mal)
Carbamazepine (TEGRETOL)
Phenobarbital*
Phenytoin (DILANTIN)
Primidone (MYSOLINE)
Topiramate (TOPAMAX)
Valproic Acid (DEPAKENE; DEPAKOTE)
2. Absence (Petit
Acetazolamide
Clonazepam
Ethosuximide
Trimethadione
Valproic Acid

Mal)
(DIAMOX)
(KLONOPIN)
(ZARONTIN)
(TRIDIONE)
(DEPAKENE; DEPAKOTE)

B. Partial Seizures (Focal)

Unilateral.
Occurs in one limb or group of muscles.
1. Simple Partial
No loss of consciousness.
Drugs: same as for tonic-clonic.
Felbamate
(FELBATOL)
Gabapentin
(NEURONTIN)
Lamotrigine
(LAMICTAL)
Levetiracetam (KEPPRA)
Oxcarbazepine (TRILEPTAL)
Tiagabine
(GABITRIL)
Topiramate
(TOPAMAX)
Vigabatrin
(SABRIL)
Zonisamide
(ZONEGRAN)

Frederick J. Goldstein, Ph.D., FCP

2. Complex Partial
Starts as simple: spreads to wider area.
Associated with confusion.
Drugs: same as for tonic-clonic.
__________________________________________________________________
* = may increase frequency of absence seizures
II. Seizure Production
A. Etiology
Primary: most cases
Secondary: various causes incl. head trauma & brain tumors
B. Seizure Focus
Always present
Abnormal EEG even in seizure-free periods; diagnostic value
Neurologist will try to find a balance between doses that will control
the seizure but not compromise cognitive function that much.
C. Triggering Factors
Changes in plasma electrolytes, pH and pCO2
Emotional stress
Visual changes (e.g., strobe lights, flickering TV screen)
D. Protective Effect of Anticonvulsants
Prevent spread of abnormal electrical stimuli
Stabilize neurons surrounding the seizure focus
III. Mechanisms of Actions (some current theories)
Dont memorize the table
Na+ Channel
Carbamazepine
Clonazepam
Diazepam
Ethosuximide
Felbamate
Gabapentin
Lamotrigine
Levetiracetam
Oxcarbazepine
Phenobarbital
Phenytoin
Pyrimidone
Tiagabine
Topiramate
Valproic Acid
Vigabatrin
Zonisamimde

Channel

Ca+2 GABA

X
X
X
X

X
X
X

X
X
X
X
X
X
2

X
X

X
X

X
X
X
X
X

Frederick J. Goldstein, Ph.D., FCP

Facilitate GABA Activity
1.Increase DURATION of Opening of GABA-A-Activated Cl- Channel
Barbiturates (e.g., phenobarbital) / Primidone
2.Increase FREQUENCY of Opening of GABA-A-Activated Cl- Channel
Benzodiazepines (e.g., clonazepam)
3. Increase Synaptic Concentration of GABA
Valproic Acid
Seizure focus can be picked up with EEG.
IV. Enzyme Inducers
Carbamazepine
Felbamate
Phenobarbital
Phenytoin
Primidone
Topiramate
V. Therapeutic Levels
Best correlation with efficacy:

free [unbound] plasma levels

Currently used: total (free + bound)

When reading papers: just know conclusions.
Therapeutic Level
(Free + Bound)
(ug/mL)
________________________________
Carbamazepine
5- 12
Clonazepam
10- 80
Ethosuximide
40-100
Phenobarbital
10- 40
Phenytoin
10- 20
Primidone
5- 15
+ phenobarbital (10-40)
Valproic Acid
50-100
________________________________
FREE fraction > normal in:
--------------------------- renal disease (esp. renal failure)
- liver disease

Frederick J. Goldstein, Ph.D., FCP

- critically ill trauma pts
- or any other condition associated with hypoalbuminemia

Warnings for Antiepileptic Medications

FDA now requires warnings about increased risk of suicidal thoughts and
behavior be added to labeling for ALL antiepileptic medications,
including those used to treat psychiatric disorders, migraine
headaches, and other conditions. Manufacturers of these medications
will also be required to submit a risk evaluation and mitigation
strategy, including a Medication Guide, for each product, which will
explain approved information about the risks of suicidality associated
with this class of drugs. These actions are based on FDA review of
clinical trials in which patients receiving antiepileptic drugs had
almost 2X risk of suicidal behavior or thoughts compared to placebo.
INAL CONTRIBUTION

How Seizure Detection by Continuous Electroencephalographic

Monitoring
Affects
the
Prescribing
of
Antiepileptic
Medications
Ronan D. Kilbride, MD, MRCPI; Daniel J. Costello, MD, MRCPI; Keith H.
Chiappa, MD
Objectives: To assess effect of continuous electroencephalographic
monitoring on the decision to treat seizures in the inpatient setting,
particularly in the ICU.
Design: Retrospective cohort study.
Setting: Medical and neuroscience ICUs and neurological wards.
Patients: Three hundred consecutive nonelective continuous EEG
monitoring studies, performed on 287 individual inpatients over a 27month period.
Main Outcome Measures: Epileptiform EEG abnormalities and changes in
antiepileptic drug (AED) therapy based on EEG findings.
Results: Findings from continuous EEG monitoring led to a change in AED
prescribing in 52% of all studies with initiation of an AED therapy in

Frederick J. Goldstein, Ph.D., FCP

14%, modification of AED therapy in 33%, and discontinuation of AED
therapy in 5% of all studies. Specifically, the detection of EEG
seizures led to a change in AED therapy in 28% of all studies.
Conclusions: Findings of continuous EEG monitoring resulted in a change
in AED prescribing during or after half of the studies performed. Most
AED changes were made as a result of the detection of EEG seizures.
Arch Neurol. 2009;66(6):723-728

BARBITURATES-are enzyme inducers. Can cause vitamin D deficiency,

folic acid defic. Vitamin K defic. (can cause osteomalaciasoftening of
bones due to lack of vitamin D).
Phenobarbital
Metharbital (GEMONIL) [N-methyl barbital barbital]
Mephobarbital (MEBARAL) [N-methyl phenobarbital phenobarbital]
ADRs
Sedation
Confusion
Dizziness
Ataxia (muscle incoordination)
Blurred vision
Anxiety
Insomnia
Agitation
Hyperkinesia (increased activity)

Frederick J. Goldstein, Ph.D., FCP

Rash
Vitamin D deficiency
Osteomalacia
Rickets
Folic Acid Deficiency
Anemia
Vitamin K Deficiency (in neonate born to mother taking these drugs)
Increased bleeding

Barbiturate-Related
Primidone (MYSOLINE)
Parent compound (primidone) is active; also two active metabolites:
- phenylethylmalonamide [PEMA]
- phenobarbital
Uses
Similar to barbiturates
ADRs
Similar to barbiturates
HYDANTOINS
Phenytoin (DILANTIN)
Mephenytoin (MESANTOIN)
Ethotoin (PEGANONE)
Less sedative effects than barbiturates
Also used as anti-arrhythmic agent
ADRs
Blurred vision
Weakness / Dizziness / Confusion / Drowsiness
----------------------------------------------------------

Frederick J. Goldstein, Ph.D., FCP

Nystagmus:
> 20 ug/mL plasma*
Ataxia:
> 30 ug/mL plasma*
Lethargy:
> 40 ug/mL plasma*
* at these levels, biotransformation becomes zero order:
- a small increase in dose will produce a much larger
elevation of plasma level (very disproportionate)
---------------------------------------------------------Nystagmus: Looking straight ahead and you look to the side and your
pupils will stagger. Pupils are not steady. Means they are on a CNS
depressant.
Hallucinations / Hyperactivity
Peripheral neuropathy
Gingival hyperplasia (drug withdrawal does not cause reversal)
Hirsutism
N & V

Epigastric pain /

Anorexia

Decreased insulin secretion = hyperglycemia & glycosuria

Osteomalacia:
hypocalcemia due to induced Vitamin D deficiency
(via enzyme induction)
Hypersensitivity reaction: Stevens-Johnson Syndrome
- severe--can be fatal--form of erythema multiforme
- if this rash occurs, must D/C immediately
Hematological Reactions
Leukopenia
Thrombocytopenia
Anemia
Hypoprothrombinemia due to induced Vitamin K deficiency
Liver damage

HYDANTOINS

(continued)

Enzyme Induction
Chronic administration usually produces enzyme induction:

Frederick J. Goldstein, Ph.D., FCP

- plasma levels decrease
- pt experiences increased frequency of seizures
- small increase in dose may re-establish therapeutic level
Monitoring
Plasma levels of free phenytoin provide best parameter for
management of pts.
Levels in brain correlate more reliably to concentations of free
phenytoin in plasma than to total phenytoin in plasma.
Use of only the total phenytoin level may cause intoxication.

Pediatric monitoring
Can use saliva levels:
- very low protein
- no albumin
Excellent correlation with free phenytoin levels
Saliva phenytoin
---------------Plasma phenytoin

1.39
---1.00

- higher levels in saliva due possibly to active transport of

phenytoin from blood ---> saliva
Advantages for pediatric monitoring include:
- can be performed at home
- daily measurement
- no trauma
- improvement in compliance
- enhanced pt-doctor relationship

Frederick J. Goldstein, Ph.D., FCP

SUCCINIMIDES
Ethosuximide (ZARONTIN)
Methsuximide (CELONTIN)
Phensuximide (MILONTIN)
ADRs
CNS depression similar to barbiturates
Parkinson-like reactions
Photophobia (increased sensitivity to light)
Anemia
___________________________________________________________________
BENZODIAZEPINES-cannot have a holiday.
Clonazepam (KLONOPIN)
Clorazepate (TRAXENE)
Diazepam (VALIUM)
Development of tolerance limits use
ADRs
CNS depression similar to--but less intense than--barbiturates
Wider margin of safety
Generally less respiratory depression than barbiturates
___________________________________________________________________
Carbamazepine (TEGRETOL)
Regarded by many neurologists as DOC in partial seizures
Also used in:
- pain (tic doulourex)
- psychiatric disorders (e.g., schizophrenia, bipolar)
ADRs
CNS depression:
Ataxia
Double vision

similar to barbiturates

Frederick J. Goldstein, Ph.D., FCP

Agranulocytosis
Rash
Hypertension (possibly due to water retention)

Acetazolamide (DIAMOX)
ADRs
Drowsiness
Parenthesias (sensations in skin [e.g. tingling, burning])
Limited use due to rapid development of tolerance
___________________________________________________________________
Phenacemide (PHENURONE)
Limited clinical use due to severe ADRs:
- aplastic anemia
- hepatitis
- nephritis
___________________________________________________________________
Trimethadione (TRIDIONE)
Previous DOC for absence seizures
Limited use due to severe ADRs:
- hemeralopia:
- reduced vision; pt sees whitish objects
- no evidence of permanent optic nerve damage
- hepatitis
- nephritis
- bone marrow damage
___________________________________________________________________
Felbamate (FELBATOL)
Newer Agent

10

Frederick J. Goldstein, Ph.D., FCP

Effective in partial seizures: monotherapy + polytherapy (phenytoin
or carbamazepine)
- induces enzymes
- lowers carbamazepine & phenytoin levels
Also efficacious in pts with Lennox-Gastaut syndrome
- occurs in childhood
- multiple seizure types + mental retardation
- refractory to standard anticonvulsant drugs
ADRs
Double / blurred vision
N & V / anorexia
Insomnia
Keppra (levetiracetam)
Ethyl-2-oxo-1-pyrrolidine acetamide.
Chemically unrelated to existing antiepileptic drugs (AEDs).
Mechanism of Action
Precise mechanism(s) by which levetiracetam exerts its
antiepileptic effect is unknown.
In vitro and in vivo recordings of epileptiform activity from
hippocampus show it inhibits burst firing without affecting normal
neuronal excitability may selectively prevent both:
hypersynchronization of epileptiform burst firing
propagation of seizure activity.
Did not demonstrate binding affinity for variety of known
receptors:
GABA
Glycine
NMDA (N-methyl-D-aspartate)
No effect on neuronal voltage-gated sodium or T-type calcium
currents
Shown to block negative modulators of GABA- and glycine-gated
currents.

11

Frederick J. Goldstein, Ph.D., FCP

Partially inhibits N-type calcium currents in neuronal cells.
Effective as adjunctive therapy in adult patients with refractory
partial onset seizures with or without secondary generalization.

Dose Adjustment Regimen For Adult Pts With Impaired Renal Function
Creatinine Clearance
(mL/min)
Normal
> 80
Mild
50 80
Moderate
30 50
Severe
< 30
ESRD patients using dialysis ----

Dosage
(mg)
500 to 1,500
500 to 1,000
250 to 750
250 to 500
500 to 1,000

Group

Frequency
Every 12 h
Every 12 h
Every 12 h
Every 12 h
Every 24 h1

1- Following dialysis, a 250 to 500 mg supplemental dose is recommended.

Valproic Acid (DEPAKENE)

DEPAKOTE: enteric-coated product
Mechanisms:Molecular structure is similar to GABA so it functions
as an alternative substrate. There is more GABA that is free.
1. Blockade of Na+ channel-Reduces cell function
2. Inhibition of GABA transaminase (catabolic GABA enzyme)
CH2-CH2-CH2-COOH
|
NH2

CH3-CH2-CH2
\
CH-COOH
/
CH3-CH2-CH2

GABA
VALPROIC ACID
______________________________________________________________
ADRs
Sedation / Ataxia
Tremor

12

Frederick J. Goldstein, Ph.D., FCP

N & V / Anorexia
Hepatotoxicity:
- can be fatal!
- > 60 deaths have already occurred
- generally occurs within six months of initiation of therapy
- may be reversible if therapy terminated in time
Plasma Protein Binding-because it is protein bound=MORE of the
drug, or can compete with other drugs like aspirin. Causes levels of
valp. To rise=increased CNS sedation and more risk of hepatotoxicity.
Valproic acid is highly protein bound.
Free levels increase:
- as dose increases (disproportionate)
- when competing drugs are added to therapy (e.g., ASA)
WITHDRAWAL of ANTICONVULSANT THERAPY
Can be considered for some pts if seizure-free for at least 2 years.
Must be withdrawn SLOWLY (i.e., over a 6-month period).
% of children remaining seizure-free(70-90%) > % of adults(60-65%)
Best chance of success includes pt with:
- no mental retardation
- monotherapy
TERATOGENICITY-if somebody on two or more of these drugs you
increase teratogenicity.
Anticonvulsant-treated epileptic > non-treated epileptic > normal
Teratogens include:
- benzodiazepines (possible "Fetal Benzodiazepine Syndrome")
- phenytoin ("Fetal Hydantoin Syndrome")
- valproic acid ("Fetal Valproate Syndrome")
Valproic Acid > benzodiazepines
Polytherapy (2 or more anticonvulsant drugs)
>
monotherapy
- benzodazepines may enhance valproate teratogenicity

13

Frederick J. Goldstein, Ph.D., FCP

Valproic Acid Cases
1. At 12 weeks gestation:
- serum alpha-fetoprotein [AFP] level = 90 mmol/L [N = < 20]
- AFP is plasma protein produced by fetal tisues (e.g.,
liver, GI)
- also by neoplastic tissue in adults (can be employed
to monitor efficacy of chemotherapy)
- during pregnancy, some AFP normally crosses placental
barrier
- AFP levels are elevated in amniotic fluid and maternal
blood when fetus has neural tube defect
- some states in USA mandate that a pregnant woman is to
be notified of possible neural tube defect
At 33 weeks gestation:
- myelomeningocele & hydrocephalus verified by ultrasound
- parents rejected option of abortion
At 38 weeks gestation:
- C-section delivery
- open lumbosacral myelomeningocele
- sensorimotor deficits from L-3 down
- hydrocephalus required ventriculo-peritoneal shunt (day 7)
- dysmorphic features (chromosomal investigation was normal)
At two years of age:
- severe psychomotor retardation with autistic traits
- no speech development
2. Similar profile to Case #1:
At six years of age: severe motor dysfunction; wheelchair bound
STATUS EPILEPTICUS
According to the Epilepsy Foundation of America, status epilepticus
is more than 30 minutes of:
1. "continuous seizure activity"
or

14

Frederick J. Goldstein, Ph.D., FCP

2. "two or more sequential seizures without full recovery
of consciousness between seizures."
___________________________________________________________________
Causes
Include--but NOT limited to--the following:
- medication change
- fever/infection (children > adult)
- CNS infection (children > adults)
- drug (includes alcohol) related (adults > children)
- head trauma
- brain tumors (adults > children)
Treatment
1. Oxygenation
2. Muscle paralysis
- only acute use of short-acting neuromuscular blocker
- NOT effective in terminating seizure activity in brain:
- abnormally increased CNS activity continues
- can result in permanent brain damage if not stopped
3. Glucose
- usually hyperglycemia occurs first
- induces secretion of insulin
- secondary hypoglycemia (usually > 2 hrs after attack begins)
- need determination of blood glucose level
- if hypoglycemia is present--or glucose level can not be
determined--glucose should be administered
4. Blood Pressure
- usually hypertension occurs first (first 30-45 min)
- hypotension may occur later
- may lead to reduced cerebral perfusion
- potentiation of excitotoxic brain damage
- support BP (if necessary with vasopressors)
STATUS EPILEPTICUS

(continued)

15

Frederick J. Goldstein, Ph.D., FCP

5. Anticonvulsants
Benzodiazepines
DOC if pt is currently convulsing (acute management)
Diazepam*
High lipid solubility ----> rapid entrance into brain
Rapid redistribution: brain & plasma levels fall
quickly
Seizures can recur within 10-20 minutes
May cause respiratory depression & hypotension
Can be given by rectal solution (not suppository) when
seizures begin at home.
Lorazepam*
Less lipid soluble
Longer duration of action
Clinical study indicated that efficacy = diazepam
Same ADRs
Midazolam
High frequency of respiratory depression
Rapid & complete absorption after IM administration
Phenytoin*
DOC if pt has stopped convulsing
Can be added to benzodiazepines
Longer onset and duration of action than benzodiazepines
ADRs include:
- hypotension
- cardiac disturbances
- less respiratory depression & sedation than
benzodiazepines and phenobarbital
Phenobarbital
Older drug used for many years
Efficacy = combination of diazepam + phenytoin
ADRs include:
- significant sedation
"
respiratory depression
"
hypotension
______________________________________________________________

16

Frederick J. Goldstein, Ph.D., FCP

* IM routes of administration for certain benzodiazepines and
phenytoin are unreliable; therefore, NOT recommended.
NEUROLOGICAL REVIEW
Frequency and Prognosis of Convulsive Status Epilepticus of Different Causes Systematic Review
Aidan Neligan, MSc, MRCP; Simon D. Shorvon, MD, MA, FRCP
A systematic review was conducted of all studies of status epilepticus (SE) with more than 30
patients published between January 1, 1990, and December 31, 2008, to determine the
frequencies of the common underlying causes and the extent to which the underlying causes
affect the prognosis of an episode of SE.
The frequencies of underlying causes vary among studies and show marked geographic
differences, but in most studies, the most common underlying causes were cerebrovascular
disease and low antiepileptic drug levels.
A relatively good prognosis of SE is found when the underlying cause is associated with low
antiepileptic drug levels or alcohol abuse, and a relatively poor outcome occurs when the
underlying cause is cerebrovascular disease, particularly in the case of SE due to acute cerebral
anoxia, but in most conditions, the reported prognosis is variable.
Also, when SE occurs in the context of an acute cerebral insult, such as cerebral infection or
cerebrovascular disease, the prognosis of the acute cerebral event is worsened.
Arch Neurol. 2010;67(8):931-940

17