Riding the Spikes and Waves: Epilepsy Update Epilepsy Update

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Riding the Spikes and Waves:
Epilepsy Update
Candida M. Brown, M.D.
Division of Neurology
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Definitions
Seizure
The abnormal discharge of an aggregate of neurons that result in a change in behavior or normal function.
More specifically, cortical neurons will be involved in a seizure.
Epilepsy
The condition of recurrent seizures. Epilepsy is a chronic condition, and a single seizure or several seizures
during a short period of time may or may not represent epilepsy. Numerous diseases result in epilepsy.
Seizures that are caused by toxins or other acute conditions and that do not occur at a later time do not
constitute epilepsy.
Ictus
Refers to a seizure.
Interictal refers to the period between seizure, and postictal refers to the period following a seizure.
Aura
The symptoms that occur at the beginning of a seizure. The aura is part of the seizure and represents the
consequence of an abnormal function of the neurons where the seizure begins. Aura comes from the Greek
word meaning breeze.
Automatism
A motor behavior occurring during a state of clouded consciousness either during or after a seizure.
Usually the patient is amnestic for this behavior. Automatisms may be a continuation of a pre-ictal activity
or a new activity. More common automatisms include chewing motion, walking or running behavior,
picking at clothing, and verbal behavior.
Impaired Consciousness
The inability to respond normally to exogenous stimuli.
Status Epilepticus
A seizure lasting longer than 30 minutes or intermittent seizures lasting longer than 30 minutes from which
the patient does not regain consciousness.
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Classification of Seizures
Need for classification
There are many different types of epileptic seizures, each of which has certain identifying characteristics.
There are also many epileptic syndromes that are characterized by the occurrence of a type (or types) of
seizure(s), together with other features, such as etiology, age of onset, and evidence of brain pathology.
The classification of epileptic seizures and epileptic syndromes is of more than theoretical interest.
Accurate diagnosis, which is aided by classification, allows the realization of such pragmatic goals as the
most appropriate utilization of treatment, the judicious withholding of treatment, and the prediction of
prognosis, which may lead to successful termination of treatment when appropriate. Of special importance
to the clinician engaged in managing the treatment of the patient with epilepsy is the way in which accurate
classification allows selection of the appropriate antiepileptic drug (AED) and the avoidance of
contraindicated medications.
Today, many experts rely on the classification systems and epileptic syndromes developed by commissions
organized by the International League Against Epilepsy (ILAE). Called the International Classification of
Epileptic Seizures (ICES) and the International Classification of Epilepsies (ICE), these two classification
systems are widely used and accepted.
Seizures
(Epilepsy=recurrent seizures)
Partial
Generalized
(EEG has d/c localized to specific
portion of brain during ictus)
Simple
(No impairment
of consciousness)
Complex
(Impairment of
consciousness)
(EEG has diffusely abnormal d/c
over entire brain during ictus)
Secondarily
Generalized
Absence
Myoclonic
Clonic
Tonic
Tonic Clonic
Atonic (Akinetic)
motor
somatosensory
autonomic
psychic
Trileptal
Valproic Acid
Phenobarbital
For all children < 2 years of age
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International Classification of Epilepsy and Epileptic Syndromes
Epileptic syndromes are defined by clusters of signs and symptoms that customarily occur together.
Features considered include predominant seizure type(s), age of onset, natural history, EEG, response to
AEDs, etiology, family history, and prognosis.
The International League Against Epilepsy Classification of Epilepsy Syndromes of
Childhood
Localization-Related Epilepsy Syndromes
Idiopathic (with age-related onset)
Benign childhood epilepsy with centrotemporal (rolandic) spikes
Childhood epilepsy with occipital paroxysms
Symptomatic or cryptogenic*
Chronic progressive epilepsia partialis continua of childhood
(Kojewnikow syndrome)
Topographic syndromes (temporal lobe, frontal lobe, etc.)
Generalized Epilepsy Syndromes
Idiopathic (with age-related onset)
Benign myoclonic epilepsy in infancy
Childhood absence epilepsy (pyknolepsy)
Juvenile absence epilepsy
Juvenile myoclonic epilepsy (Janz syndrome)
Epilepsy with grand mal seizures on awakening
Symptomatic or cryptogenic
West syndrome (infantile spasms)
Lennox Gastaut sydrome
Epilepsy with myoclonic-astatic syndrome (Doose syndrome)
Epilepsy with myoclonic absences
Epilepsy Syndromes Undetermined Whether Focal or Generalized
Severe myoclonic epilepsy in infancy (polymorphic epilepsy of infancy)
Epilpesy with continuous spikes and waves during slow wave sleep
Acquired epileptic aphasia (Landau-Kleffner syndrome)
Special Syndromes
Febrile Convulsions
*Cryptogenic epilepsies are presumed to be symptomatic and the etiology is unknown. They differ from the symptomatic epilepsies
by only the lack of precise etiologic evidence. They may, in fact, be difficult or impossible to separate from some idiopathic
epilepsies.
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Examples of Epileptic Syndromes
Infancy
West Syndrome
Triad: infantile spasms, arrested psychomotor development, hysarrythmia.
Male>female; onset 4-7 mos, always < 12 mos.
Childhood
Lennox-Gestaut Syndrome
Triad: mixed seizure disorder (tonic, atonic, atypical absence), myoclonic, GTC, partial), developmental
delay/MR, and abnormal EEG pattern.
Onset 1-8 years.
Symptomatic and/or idiopathic.
Childhood Absence Epilpesy
Onset in childhood, before puberty, peak ages 6-7 years.
Seizures=absence, with or without clonic, atonic, tonic and autonomic components, and automatisms.
Development normal.
EEG=bilateral, synchronous, symmetric 3 Hz spike and wave activity: normal interictal background.
Frequency high: easily precipitated by hyperventilation.
Prognosis: good.
GTC components may develop in 40%.
Treatment: Ethosuximide, valproic acid (Preferred in GTC components present).
3 Hz Spike and Wave Activity characteristic of absence epilepsy
Benign Childhood Epilpesy with Central Temporal Spikes
Also known as Rolandic Epilepsy.
Onset: ages 3-13 years, peak at 9-10 years.
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Seizures=simple partial, often involving the face, frequently with associated somatosensory symptoms;
often generalized with nocturnal.
EEG=high-voltage central temporal spikes followed by slow waves, activated by sleep.
Genetic predisposition, male predominance.
Prognosis: excellent.
Acquired Epileptic Aphasia (Landau Kleffner Syndrome)
Childhood acquired aphasia=verbal auditory agnosia, rapid reduction of spontaneous speech.
Seizures=GTC, partial motor.
EEG=multifocal spikes, spike and wave discharges on EEG.
Prognosis: guarded; in general, seizures and EEG improve frequently before the age of 15.
Febrile Convulsions
Definition
Abnormal, sudden, excessive electrical discharge of neurons which propagates a neuronal process that
affects end organs in a clinically measurable fashion, associated with a fever.
Criteria
The first convulsion by a child is associated with a temperature of >38 degrees Centigrade (>100.4 degrees
Fahrenheit)
The child is less than 6 years old.
There is not evidence of CNS infection, inflammation, defined causes for the seizure, or metabolic disorder.
Classification
Simple
Lasts < 15 minutes.
No focal features present.
Occurrence of only one seizure in a 24 hour period.
Complex
Lasts > 15 minutes.
Focal features present.
Occurrence of a series with > one seizure in 24 hours.
Incidence
Occurs in 2-5% of all children.
Comprises 30% of all seizures occurring in children.
Age: 6 months to 5 years, with an average age of onset at 2 years.
Male>female; black>white.
Familial: 10% of parents of children with febrile seizures had a history of febrile seizures themselves, and
9% of siblings had at least one seizure in the past.
Relationship to meningitis
Most febrile seizures occur within the first 24 hours of onset of the fever.
If the seizure occurs more than 24 hours after the onset of the fever, suspect either meningitis or another
specific neurologic or metabolic cause.
5-6% of patients with meningitis present with febrile seizures.
1:300 patients with febrile seizures actually have meningitis.
Natural History
Overall, 33% if children with febrile seizures will have recurrence of seizures.
Factors to be considered:
Neurologic status prior to the onset of the seizure (Increased risk if abnormal).
Character of the seizures (Increase risk if partial).
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Family history of seizure disorders (Increased risk if family hx of epilepsy).
Age of onset of the disorder, which is considered to be the most important factor: 50% recurrence rate
when onset is < 1 year. 28% recurrence rate when onset > 1 year.
90% of the recurrences will take place within 30 months of the initial seizure, with 50-75% occurring
within the first year.
Risk of the development of epilepsy
In the general population: 0.5%.
Children who are developmentally normal with simple febrile seiures: 1.1%.
Children with neurologic deficits and complex febrile seizures: 15.4%.
Based on a study by Joffe and DeAngelis (AJDC, Dec. 1983), risk factors included: abnormal neurologic
status, family hx of epilepsy, and complex febrile seizures. The risk of developing epilepsy was dependent
on the number of risk factors in the history and on PE:
>2 factors: 13%
2 factors: 6%
1 factor: 3%
None: 2%
Neurologic sequelae
There are usually none.
One notable exception is complex febrile seizures that result in prolonged status epilepticus.
Neurological sequelae may include: motor or coordination difficulties, MR, learning disabilities, and
behavior problems.
Treatment
Prophylactic long-term maintenance therapy
THE USUAL RECOMMENDATION IS NOT TO TREAT.
Factors that need to be considered include the aforementioned risk factors and the frequency of recurrence
in an individual patient.
A patient with his/her first febrile seizure should NOT be considered for long-term therapy unless status
epilepticus was the presentation.
The drug of choice: Phenobarbitol
Doses: 5 mg/kg/d
Therapeutic levels: 15-40 mcg/ml
Decreases recurrences by 40-70%.
Other drugs: Valproic Acid
This drug has been found to be effective in Europe for prophylaxis management of febrile seizures.
However, it has not been formerly approved for this use in the US.
Acute intermittent treatment
Diazepam rectal gel (Diastat; pediatric formulation: 2.5 mg. 5 mg) approximately 0.5 mg/kg given at the
onset of a convulsion.
This form of treatment is especially useful in the child prone to complex febrile seizures consisting of status
epilepticus.
Use of low dose oral valium (0.2-0.33 mg/kg) has been studies without and with the use of antipyretic management. The results vary
but overall it is felt that the potential side effects of the valium (ataxia, lethargy, irritability at 39%) can obscure serious symptoms in a
patient who may develop a potentially serious infection such as meningitis.
Adolescence
Juvenile Myoclonic Epilepsy of Janz
Age of onset at or near puberty; male=female.
GTC sz or repeated myoclonic jerks upon awakening. Frequent myoclonic and absence spells during the
waking state, especially precipitated by sleep deprivation, ETOH use.
Treatment: VPA. High risk of recurrence without rx, estimated to be 85%.
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The First Non-Febrile Seizure
Clinical Dilemma
Distinguishing true seizures from non-epileptiform paroxysmal disorders of childhood.
Appropriate evaluation.
Whether to start treatment.
Differential Diagnosis of Seizures
Neonatal
Apnea
Hypoglycemia
Brainstem release phenomenon
Benign myoclonus
Infancy and Early Childhood
Breathholding spells
Spasmus nutans
Benign paroxysmal vertigo
Night terrors, sleep walking
Cyclic vomiting
Shuddering attacks
Masturbation
Sandifer’s syndrome
Acute choreoathetosis
School Age
Migraine
Syncope
Tics
Paroxysmal Choreoathetosis
Dystonia
Episodic dyscontrol
Pseudoseizures
Physical and Neurological Examination
Signs Suggesting an Etiology for Seizures
System
General examination
Sign
Dysmorphic features
Disorder
Brain malformation, storage
disease, syndrome, chromosomal
abnormality
Head
Macrocephaly
Storage disease, phakomatoses,
syndrome, obstructive hydoceph.
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Microcephaly
Hx of congenital infection,
syndrome, hx of previous CNS
injury, acquired
neurodegenerative process
Hair
Broken, alopecia
Menkes disease, biotin
deficiency, arginsuccinic aciduria
Skin
Hypopigmented macules, caféus-lait spots, upper eyelid
hemangioma, petechiae, rash
Tuberous sclerosis,
neurofibromatosis, Stuge-Weber,
blood dyscrasias, meningitis,
sepsis, autoimmune disorder
Neck
Nuchal rigidity
Meningitis, subarachnoid
hemorrage, posterior fossa mass
Fundi
Papilledema. Hemorrhage
Tumor, trauma, child abuse,
hypertensive encephalopathy
Choreoretinitis, retinal lesions
Intrauterine infection,
degenerative disease, tuberous
sclerosis
Abdomen
Organomegaly
Storage disease
Nervous System
Altered mental status
Post-ictal vs metabolic disorders,
systemic disorders, drug
intoxication
Focal neurologic findings
Tumor, hemorrhage, Todd’s
paralysis, stroke, head injury
Laboratory Evaluation
The following laboratory studies should be considered when a patient presents to the ER after a first time
seizure, especially if the patient has not yet returned to his/her baseline:
CBC with differential
Lytes, Cr, Glu, Ca
Consider, if clinically appropriate to presentation:
LFT, Ammonia
TFTs
Urine toxicology screen
Serum amino acids, urine organic acids
Lumbar puncture: infection, subarachnoid hemorrhage
EEG
Should be arranged as an outpatient within two to four weeks after presentation.
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Imaging studies
A CT scan is NOT always necessary in the patient who presents with his/her first seizure.
A CT scan in the ER should be considered in patients who:
Remain post-ictal or encephalopathic,
Had any focal features to the presentation of their seizure, or
Have any focality noted on neurologic examination.
Otherwise, arrangements for an EEG should be made within the next two weeks. Further imaging studies
can then be arranged if the EEG demonstrates any focality.
In general, when imaging studies are necessary in patients with seizures, Magnetic Resonance Image (MRI)
is the preferred study.
Risk of recurrence after the first seizure
The percentage varies in the literature, but tends to fall in the range of 35-60%.
Factors that increase the risk of recurrence include:
A clinical description of partial seizures
Presence of a focal abnormality detected by neurologic exam or CT/MRI
Presence of epilpetiform activity on EEG
A strong family history of epilepsy.
The majority of seizures (75%) will recur within 6 months, 87% within 1 year, and 96% within 2 years.
Treatment
The first afebrile seizure is usually NOT treated with AEDs.
However, an EEG is always ordered.
A formal consult with a neurologist is usually not necessary.
Factors to consider in the decision to initiate treatment include:
Age of the patient
Type of seizure
Predisposing factors
Psychologic and social consequences of further seizures
Change of recurrence of seizures
Risks of treatment: labeling, cost, side effects.
Limitations of activities
Driving
Varies from state to state.
In California, when a patient 14 years of age or older presents to a physician with any form of alteration of
consciousness, including partial complex and generalized seizures, that physician is bound by law to report
the incident to the State of California Department of Motor Vehicles. Failure to do so can result in a
significant fine ($10,000).
The report can be done by completing the Confidential Morbidity Report Form obtained from the
Department of Public Health Services within the local county. The report can also be provided by filling
out a Driver Medical Evaluation Form obtained from the DMV< or sending a letter directly to the local
DMV office.
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The power to suspend a license is under the jurisdiction of the California DMV. In most cases, the license
is suspended until the physician feels it is safe for the patient to drive. The Driver Medical Evaluation
Form is obtained by the patient from the DMV and completed by the physician. In California, there is no
absolute time that a patient must be seizure-free, although most neurologists use the time frame of 6
months.
If the patient does undergo successful treatment with AEDs, he/she must also demonstrate compliance with
medication by proof of appropriate refills, drug levels, and keeping appointments.
Other activities
Since the risk of recurrence is highest during the first six months after the first seizure, some “common
sense” precautions should be followed:
The patient should shower/bath in the house only when someone is in the home in the event the seizure
would result in alteration/loss of consciousness.
The patient should not swim or use a hot tub without supervision.
The patient should limit activities that require him/her to climb high places, when possible.
Helmets should be worm when biking or rollerblading.
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Principle of Anticonvulsant Management
Anti-epileptic drugs (AEDs) should only be considered in a patient who has had more than one seizure in
the afebrile state and in patients with febrile seizures who have been considered to be at high risk for
recurrence.
Choice of medication depends on the seizure type and epileptic syndrome.
The monotherapy “game plan.”
Once a medication has been chosen, start the medication at the recommended starting dose and interval (see
drug charts). Obtain baseline labs prior to starting medication.
Obtain serum blood levels and labs that need to be monitored after five half-lives of the individual drug.
Achieve therapeutic levels; adjust accordingly.
Continue to increase the does of the medication as needed to either achieve therapeutic benefit (i.e. seizurefree status) or drug toxicity occurs. Unacceptable side effects should include behavior and cognitive
changes that might compromise the patient’s quality of life.
Once an acceptable dose and therapeutic level has been achieved, monitor levels and labs every three
months for the first year and every six months the second year.
When polytherapy is needed.
If the patient continues to have seizures despite high therapeutic drug levels, then a second drug should be
added.
Begin the second drug at the recommended starting does and interval, while continuing the first drug. The
first drug may need to be reduced slightly in does if anticipated side effects occur due to drug-drug
interactions (see chart below). For example, adding valproic acid to a patient already on phenobarbital will
usually increase the phenobarbital levels, causing unacceptable side effects such as sedation.
Pharmacokinetic drug interactions of antiepileptic drugs commonly encountered in practice
Original Drug
Carbanazepine
Added Drug
Phenobarbital
Phenytoin
Primidone
Effect of added drug on serum
concentration of original drug
↓
↓
↓
Phenobarbital
Carbamazepine
Methsuximide
Phenytoin
Valproic Acid
No change
↑
↑
↑
Phenytoin
Carbamazepine
Methsuximide
Phenobarbital
Primidone
Valproic Acid
↑
↑
No change
No change
↓
Primidone
Carbamazepine
Phenytoin
Valproic Acid
↑of derived Phenobarbital
↑of derived Phenobarbital
↑
Valproic Acid
Carbamazepine
Phenobarbital
Phenytoin
Primidone
↓
↓
↓
↓
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Wait five half-lives for the second drug, re-check blood levels and labs, and if the new drug is therapeutic
and patient is seizure-free, begin wean of first drug. Re-check levels after patient is completely off first
drug.
If seizures continue on two drugs, push the second until therapeutic benefit is achieved or side effects
become unacceptable.
If a patient has been unsuccessfully managed on two different medications, a neurologist should be
consulted
Who is a candidate for weaning off medication?
Any patient who has remained seizure free for at least two years.
Neonatal seizures are an exception. The patient can be considered for a wean off medication if seizure free
any time during the first year. The earlier the better, depending on the neurologic status of the child and the
cause of the neonatal seizure.
How to wean medication.
Withdrawal of medication should be done slowly.
One should try to reduce at a rate no faster than 1 tablet every five half-lives.
Designing a reduction plan that is easy for the patient to remember and comply is always best, i.e.
descreasing by one tablet every other Monday until off.
What is the patient’s risk of recurrence?
This is dependent on the type of seizure, the type of epileptic syndrome and other factors that include the
neurologic status of the patient, the MRI results, and the EEG results at the time weaning is considered.
In general, the risk of recurrence is estimated to be at approximately 25-30%.
The risk of recurrence is higher in patients with partial seizures than in patients with primary generalized
epilepsies.
The risk is higher in some forms of epileptic syndromes such as Juvenile Myoclonic Absence or Lennox
Gestaut, and lower in others such as Childhood Absence and Rolandic Epilepsy.
The risk is also higher in patients with symptomatic epilepsies: i.e. Tuberous Sclerosis, Sturge Weber
Disease, congenital migrational malformations such as heterotopias, schizencephaly, etc.
Finally, the risk is higher in patients with EEG abnormalities that are epileptiform at the time of
consideration for withdrawal. However, an EEG should not be the basis for the decision to wean
medication, not should it be ordered prior to wean unless the information is to be used to help make the
decision.
What to instruct the patient while weaning medication.
The risk of recurrence is highest during the first six months after coming off the medication. Therefore,
certain “common sense precautions should be followed:
If the patient is of driving age, he/she should be instructed not to drive for six months.
The patient should shower/bath in the house only when someone is in the home in the event a seizure that
would result in alteration of consciousness occurs.
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The patient should not perform activities that require him/her to climb high places.
Helmets should be worn when biking, rollerblading, or skateboarding.
The patient should not swim or enter a hot tub without supervision.
Treatment Options in Patients with Epilepsy
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Anticonvulsant Drugs
Banzel
Barbituates: Phenobarbital, Primidone
Dilantin
Tegretol
Valproic Acid
Benzodiazepines: Valium, Ativan, Clonopin, Tranxene, Nitrazepam
Ethosuccimide
Methsuximide
Gabapentin
Lamotigine
Topiramate
Levatiracetam
Oxcarbazepine
Zonisamide
Felbamate
Vigabatrin
Vimpat
Adjunctive medications
Acetazolamide
Used occasionally for refractory generalized epilepsies, especially atypical absence, myoclonic, and
akinetic spells, always in conjunction with other medication.
Dose: 250-1000 mg/day ÷ BID to TID
Tablets: 125, 250mg
Capsules: 500 mg
Steroids
ACTH
The first drug of choice for infantile spasms.
Treatment per protocol (consult a neurologist).
Acthar gel preferred over lyophilized powder.
ACTH is now an orphan drug; thus to obtain ACTH one must now contact NORD regarding their Acthar
Gel Limited Access Program. It may take up to three days to obtain the drug.
NORD Acthar Gel Program: 1-800-459-7599
Prednisone
Preferred to ACTH by some epileptologists for infantile spasms.
Rarely and occasionally used in certain refractory epilepsies such as Landau Kleffner Syndrome, and
Epilepsia Partialis Continua.
1-2 mg/kg
Given for 4-6 weeks; should be gradually discontinued over several weeks.
Ketogenic Diet
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Currently the diet is utilized in children with any type of seizure disorder, especially when traditional
medication in combination have proved ineffective or the side effects intolerable.
The ketogenic diet is a rigid, mathematically calculated, and doctor supervised diet. The diet is planned to
produce ketosis by reversing the usual ratio of dietary carbohydrate and fat.
The diet is generally not used in children less than 1 year of age due to the difficulty in maintaining ketosis
and euglycemia.
The diet most likely would not work for a child who has access to food or has very specific food
preferences. The diet would also not work for a child whose meals are prepared and eaten outside the
home.
Kaiser Permanente of Northern California has a Ketogenic Diet Program, which is implemented by the
child neurologist and requires initial hospitalization in Hayward. The patient will then need closed followup by the pediatric neurologist, pediatrician, and dietician in charge of the program.
Vagus Nerve Stimulation
A vagus nerve stimulator is surgically implanted into the patient by either an ENT physician or
neurosurgeon. The voltage of the stimulator is gradually increased over time by either a neurologist or
epileptologist. The stimulator gives the vagus nerve electrical stimulation at fixed intervals (i.e. every five
minutes) and fixed voltage.
This treatment has been studied and used for children and adults with refractory generalized and partial
epilepsy, and with drop attacks and Lennox—Gestaut Syndrome. The mean reduction in seizures averages
about 58%, with 21% of the patients having a > 90% reduction in sz frequency.
Surgical Treatment of Epilepsy
Surgery is sometimes recommended for children with epilepsy that in intractable to optimal anticonvulsant
therapy. Surgery is never a substitute for good medical therapy, and anticonvulsant drugs are often needed
after surgery is performed.
Three procedures are often used: hemispherectomy, interhemispheric commissurotomy, and temporal
lobectomy.
Evaluation for such procedures is extensive, requiring the services of a specific epilepsy center.
Such evaluation may include hospitalized telemetry monitoring of seizures, placement of sphenoidal and
subdural transcortical electrodes, PET scanning, and extensive neuropsychological testing.
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Anticonvulsant Medications
DRUG
Carbamazepine
(Tegretol)
FORMS
100 mg/5 ml
100 mg chew. tab
200 mg tab
Tegretol XR
100, 200, 400 mg
tabs
Carbatrol
200 & 300 mg
extended release
capsules
Valproic Acid
(Depakene)
Divalproex
(Depakote)
250 mg/5cc
125 mg sprinkle
250 mg & 500 mg
tabs
DAILY DOSAGE
10-30 mg/kg/d up
to 800-200 mg/kg/d
divided bid-qid
LABS
CBC, Na, SGPT,
trough level 1
week after starting;
then q 3-6 mos
USES
Simple and
complex partial sz,
GTC sz
SIDE EFFECTS
Drowsiness, GI
upset, ataxia,
diplopia, dizziness,
leukopenia,
hepatotoxicity,
hyponatremia,
vestibulopathy,
rash/allergy, aplastic
anemia.
COMMENTS
Can make absence
seizures worse. Avoid
EES, theophylline,
cimetidine,
clarithrmycin,
fluoxetine, isoniazid,
verapamil—will ↑ CBZ
level.
Troughs: 4-12
PO
12-60 mg/kg/d up
to 1000-2000 mg/d
divided bid-quid.
CBC, SGPT, Cr
Trough level 1
week after starting;
then q 3-6 mos
GTC, absence,
akinetic,
myoclonic, and
partial szs
GI upset, diarrhea,
weight gain, tremor,
hair loss,
macrocytosis,
thrombocytopenia,
pancytopenia, plt
dysfunction,
hepatotoxicity,
hyperammonaemia,
teratogenic—most
common= spina
bifida
In all children < 2yrs,
use with L-carnitor 100
mg/kg/d up to 1000
mg/d.
Thrombocytopenia risk
with infections,
responsive to ↓ dose.
Trough: 40-150 (usually
70-100)
Rectal
Use syrup diluted
1:1 with water,
given PR as
retention enema.
Depakon
(IV form)
100mg/cc in 5ml
vials; infuse at 20
mg/min over 60
min.
Use same po daily
dose ÷ q 6 hours.
Convert back to po
as soon as possible.
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Rufinamide
(Banzel)
200 mg tabs
400 mg tabs
45 mg/kg/d divided
BID
None
Lennox-Gestaut
Syndrome
Depression,
behavioral changes,
suicidality; s/sx
hypersensitivy
reaction if rash
develops;
leucopenia,
Somnolence,
vomiting, headache,
fatigue, dizziness,
nausea, tremor,
nystagmus, blurred
vision
Modulates the activity
and prolongs the
inactivity of the sodium
channel
CBC, SGPT, tough
level 1-2 wks after
starting and q 3-6
mos
Simple and
complex partial,
GTC.
Sedation, gingival
hyperplasia, hirsutism,
ataxia, dizziness,
nystagmus,
hepatotoxicity,
leukopenia,
adenopathy, lupus-like
syndrome, neuropathy
0 order kinetics and
erratic absorption and
metabolism make dosing
in children difficult.
↑ szs with toxicity.
Trough levels: 10-20.
May be administered IV
or IM; fewer
administration adverse
effects; expensive.
Start 10 mg/kg/d
po BID, increasing
by 10 mg/kg qod to
45 mg/kg/d divided
BID
Max: 1600 mg
BID
Phenytoin
(Dilantin)
30 mg/5cc
125 mg/5cc
50 mg chew tab
30 & 100 mg cap
4-8 mg/kg/d up to
300-500 mg/d
divided qd-tid
Fosphenytoin
(Cerebrex)
50 mg phenytoin
equivalent (75 mg
fosphenytoin)/1 cc
(2, 10 ml)
All doses are
expressed as
phenytoin sodium
equivalents (PE): 1
mg phenytoin = 1
mg PE.
Phenobarbital
20 mg/5cc
10, 30, 60 & 100
4-8 mg/kg/d up to
90-120 mg/d
Fosphenytoin
Use with caution in
patients with prophyria.
Consider amount of
phosphate delivered in
pts with phosphate
restrictions.
May see hypokalemia
with rapid IV infusion.
CBC, SGPT, tough
level 1-2 wks after
GTC & partial szs,
non-myoclonic szs
Sedation,
paradoxical
Behavioral side effects
limit use over age 2.
19
mg tabs
¼, ½, 1 grain tabs
divided qd-bid.
starting, then q 3-6
mos.
in infancy.
hyperkinesis, mild
reversible cognitive
impairment, rash,
ataxia
Level rises when VPA
added. Trough: 15-40.
Primidone
(Mysoline)
250 mg/5cc
50 & 250 mg tabs
10-25 mg/kg/d up
to 500 mg/d
divided bid-tid
CBC, SGPT,
phenobarb trough
level 2-3 wks after
starting, then q 3-6
mos.
Same as
Phenobarbital.
Same as
Phenobarbital,
headache, slowed
speech.
Metabolized to
Phenobarbital & PEMA,
rapid & slow
metabolizers. Trough:
same as phenobarb.
Ethosuximide
(Zarontin)
250 mg/ 5 ml
250 mg tab
10-30 mg/kg/d up
to 1000 mg/d
divided bid-tid
CBC, trough level
1-2 wks after
starting, then q 3-6
mos.
Absence epilepsy
without GTC szs.
GI upset, rash,
lupus-like
syndrome,
headache.
Increase slowly to avoid
GI upset. Trough: 40100.
Methsuccimide
(Celontin)
150 mg, 300 mg
Kapseals
Children PO
10-15 mg/kg/24
hours ÷ q 6-8 hrs.
Increase weekly to
max 30 mg/kg per
24 hrs.
CBC, LFTs, UA
About 1 wk after
steady state and
then q 3-6 mos.
Refractory absence
epilepsy
GI symptoms, blood
dyscrasias, mental
status changes,
periorbital edema,
drowsiness,
Stevens-Johnson
syndrome.
Therapeutic range: 1040 mg/L.
Measure therapeutic
range for metabolite, Ndesmethylmethsuximide.
Adults PO
300 mg/24 hr ÷
BID-QID for 1 wk.
May ↑ by 300
mg/24 hr to max
dose of 1.2 gm/24
hr ÷ BID-QID.
20
Benzodiazepines
(Valium, Ativan,
Klonopin,
Tranxene,
Nitrazepam)
Varies by specific
compound
Varies by specific
compound
Diastat
(rectal valium)
All doses rounded
to nearest available
dosage strength.
2-5 yrs: 0.5 mg/kg
6-11 yrs: 0.3 mg/kg
> 12 yrs: 0.2 mg/kg
Gabapentin
(Neurontin)
Pediatric rectal gel
2.5, 5, 10 mg
(5mg/ml
concentration with
4.4 cm rectal tip
delivery system)
Adult rectal gel
10, 15, 20 mg (5
mg/ml
concentration with
6 cm rectal tip
delivery system)
100, 300 & 400 mg
tabs
600-900 mg/d
divided tid
None
2nd line drug for
partial szs.
? monotherapy for
Rolandic Epilepsy.
Levetiracetam
(Keppra)
250, 500, 750 mg
tablets
In children:
consult a
neurologist.
None
Adjunctive rx for
partial szs
In adults:
1000 mg/d divided
bid; may increase
by 1000 mg/d q 2
If needed, trough
level 1-3 wks after
starting, then prn.
Add on for
myoclonic, akinetic
and mixed szs; may
try in refractory
partial szs; most
helpful with status
epilepticus.
Sedation,
tachyphylaxis,
dependence, excess
drooling
Usefulness often limited
by side effects.
Expensive.
Dizziness, GI upset,
ataxia,
aggressiveness,
hyperactivity,
irritability,
somnolence,
nystagmus, weight
gain.
Asthenia, headache,
infection, pain,
dizzuness,
somnolence
Side effects rare. Does
not alter
pharmacokinetics of
other AEDs, expensive.
Reduce dosage in
patients with renal
impairment.
Does not affect the
plasma concentration of
existing AEDs.
21
wks to max dose of
3000 mg/d
Lamotrigine
(Lamictal)
25 mg chew tabs
25 & 100 mg tabs
1-20 mg/kg/d up to
200-600 mg/d
divided tid.
Tricky: consult a
neurologist.
CBC & SGPT q 36 mos.
2nd line drug for
partial szs, absence
szs, LennoxGestaut, GTC,
myoclonic, atonic.
RASH in 10-12%,
life threatening rash
in 1:1000 adults and
1:100-200 children,
(↑ risk with rapid
titration and adding
to VPA), GI upset,
fatigue, ataxia,
dizziness, diplopia,
headache, nausea,
vomiting.
Prolongs t1/2 of VPA;
need to increase slowly
by 5-10 mg/kg;
expensive; complicated
pharmacokinetics with
other AEDS which ↓
clearance of LMG—
consult a neurologist.
Oxcarbazepine
(Trileptal)
150, 300, 600 mg
tablets
300 mg/ 5 cc
In adults:
600 mg/d divided
bid; increase to
max of 1200 mg/d
divided bid
None
Adjunctive rx, and
monotherapy for
partial szs in adults;
Adjunctive rx for
partial szs in
children ages 4-16
yrs.
Dizziness, vomiting,
fatigue, ataxia,
double vision,
nausea, GI distress,
hyponatremia,
headache,
somnolence
Pts with allergic rxn to
CBZ have 25-30% risk
of same rxn with
Trileptal.
Partial szs, LennixGestaut, infantile
spasms.
Behavioral adverse
effects, anorexia,
sleep disorders,
somnolence,
dizziness, fatigue,
headache, diplopia,
Nephrolithiasis reported
in adult pts caused by
ability of drug to inhibit
carbonic anhydrase.
Use with caution in
children on ketogenic
Topiramate
(Topomax)
25, 100, 200 mg tab
25 mg sprinkles
In children:
Start with 8-10
mg/kg/d divided
bid; increase to
max according to
wt:
20-29 kg: 900 mg/d
30-39 kg: 1200
mg/d
>40 kg: 1800 mg/d
1 mg/kg/d up to 310 mg/kg/d ÷ bid.
None
Can effect other AED
levels; when added as
2nd agent, need to
monitor levels of initial
AED.
22
Zonisamide
(Zonegran)
100 mg capsules
Children < 16 yrs:
Consult neurologist
Vigabatrin
(Sabril)
600 mg/5 cc
400 & 600 mg tabs
500 mg sachets
45 mg/kg/d up to
3600 mg/d divided
bid-tid.
10-30 mg/kg/d
divided tid.
diet or taking
acetazolamide.
None
Adjunctive rx for
partial seizures
Headache,
abdominal pain,
anorexia, nausea,
dizziness,
somnolence, fatigue,
speech
abnormalities,
diplopia
Has long t ½; may take
up to 2 weeks to achieve
steady state;
Classified as a
sulfonamide, therefore if
allergic to sulfa meds,
contraindicated.
CBC, SGPT
monthly.
Partial sz, atonic
szs, LennoxGestaut, infantile
spasms.
Anorexia, weight
loss, vomiting,
insomnia, headache,
dizziness,
somnolence,
hepatoxicity,
aplastic anemia.
Relatively high risk of
aplastic anemia and
hepatotoxicity severely
restricts use to refractory
cases.
Gi upset, headache,
Hyperactivity,
weight gain, facial
edema, drowsiness,
insomnia, ataxia,
stupor.
Retinopathy with
longterm use.
Not available in USA.
Recently did not receive
FDA approval due to
visual field defects with
long-term use.
Some parents able to
obtain outside of
country.
May be resubmitted for
orphan drug status for
Adults:
100 mg/d; may
increase q 2 weeks
by 100 mg to max
of 400 mg/d
Felbamate
(Felbatol)
ataxia, psychomotor
slowing, nystagmus,
impaired
concentration,
weight loss,
nephrolithiasis.
None
Myoclonic,
generalized, partial
szs, infantile
spasms; Lennox
Gestaut.
Found to be
especially effective
in pts with infantile
spasms & tuberous
Inhibits metabolism of
PHT, VPA, CBZ; need
to ↓ other AEDs by 2030%.
23
sclerosis.
for rx of infantile
spasms.
Tiagabine
(Gabatril)
4, 12, 16, 20 mg
tabs
0.1mg/kg/d; titrate
upward as needed
by 0.1 mg/kg every
two weeks to max
of 1.5 mg/kg/d ÷
bid to tid.
None
Partial szs; GTC;
absence; atonic;
myoclonic.
Somnolence,
dizziness, headache,
ataxia, depression.
Non-convulsive status or
twilight state reported in
adults receiving higher
doses of tiagabine (4860 mg/d).
Little interaction with
other AEDs.
Lacosamine
(Vimpat)
50, 100, 150, 250
mg tablets
50 mg po/IV bid,
increase by 100
mg/day
Max: 400 mg/day
Baseline
Creatinine
Baseline EKG if
known conduction
abnl
Partial seizure
disorders
Multi-organ
hypersensitivity rxn;
PR prolongation;
Syncope; atrial
fibrillation and atrial
flutter; suicidality;
dizziness, headache,
diplopia, N/V
Exact MOA unknown;
Enhances slow
inactivation of voltagesensitive Na channels;
stabilizes neuronal
membranes, inhibiting
repetitive firing
Per protocol.
Starting doses are:
ACTH 150 u/m2/d,
Prednisone 2
mg/kg/d; Consult a
neurologist.
Per protocol;
consult a
neurologist.
Infantile spasms,
myoclonic szs,
refractory epilepsy,
Landau-Kleffner
Syndrome.
HTN,
immunosuppression,
hyperglycemia,
hyperactivity,
osteopenia.
Use in closely
supervised protocols
with neurologist; use
limited to 3-6 mos.
Per protocol
Refractory
Epilepsy or
alternative to AEDs
when requested by
parents.
Malnutrition, GI
upset, lethargy,
hypoglycemia,
difficult to maintain
in ambulatory
Use in closely
supervised protocols
with neurologist and
dietician for 1-2 years.
200 mg/20mL IV
Steroids (ACTH &
prednisone)
Ketogenic diet
ACTH (Acthar) gel
80 u/ml
Prednisone: many
24
children.
Vagus Nerve
Stimulation
Surgical
implantation of a
vagus nerve
stimulator.
Stimulator is
adjusted to specific
voltage at regular
intervals by
neurologist or
epileptologist.
Refractory Partial
Szs
Postulated effects:
synchronization of brain
activity; inhibition of
epileptogenic structures;
monoaminergic
modulation of sz
threshold; reduction of
activity in the solitary
nucleus.
Summary of Current Treatment Options
Partial
Generalized
Simple
Complex
Secondarily Generalized
Tonic-Clonic
Tonic
Myoclonic
PHT, CBZ, PB
GBP, TGB, VGB, VMP
Atonic
Infantile Spasms
ACTH, VGB
VPA, LTG, TOP
(FBM)
Absence
ESX
25
Status Epilepticus
A common pediatric neurologic emergency.
Affects 25-50,000 children in US each year.
Definition
A single seizure that lasts for at least 30 minutes, or recurrent seizures lasting for more than 30 minutes without the patient regaining consciousness.
Goals




Ensure adequate cardiorespiratory function.
Stop seizure activity.
Prevent recurrence of seizures.
Identify and treat the etiology.
Suggested Timetable for the Treatment of Status Epilepticus
Time (in minutes) from the onset of the seizure
or arrival in ER
0-5
Action
Diagnose status epilepticus by observing the sz
activity or if one additional sz has occurred without
recovery in between.
Administer oxygen by nasal cannula or mask;
position the patient’s head for optimal airway
patency; consider intubation if respiratory assistance
is needed.
Obtain and record vital signs at onset of care and
26
periodically thereafter; control any abnormalities as
necessary; establish EKG monitoring.
Establish IV access; draw venous blood samples for
glucose level, serum electrolytes, Ca, Mg, CBC.
Consider anticonvulsant levels, LFTs, blood
cultures, toxicology screen, NH3 when clinically
appropriate.
Assess oxygenation with oximetry or periodic
arterial blood gas determinations.
6-9
10-20
For established hypoglycemia or an unavailable
blood glucose level, administer glucose: in adults:
give 100 mg thiamine, followed by 50 mg of 50%
glucose by direct IVP; in children: give 2 ml/kg of
25% glucose.
Administer either 0.1 mg/kg of lorazepam (Ativan)
at 2 mg/min up to 4 mg total dose in adults.
Less preferred alternative: 0.2 mg/kg of diazepam
(valium) at 5 mg/min IV up to 20 mg maximum in
adults.
20+
If diazepam used, can be repeated if seizure
continues after 5 minutes. Diazepam use must be
followed by loading with phenytoin.
If status persists, administer fosphenytoin 20 mg PE
(phenytoin equivalents)/kg at 3 mg/ kg/min (150 mg
PE min/min maximum); if seizures continue,
fosphenytoin 5-10 mg PE/kg up to maximum of 30
mg/kg.
Alternative: Administer 20 mg/kg phenytoin no
faster than 50 mg/min in adults and 1 mg/kg/min in
children by IV; monitor electrocardiogram and
blood pressure during infusion. IV fluid must be
27
0.9% saline without glucose.
NOTE: Phenobarbital, rather than phenytoin, may
be used as the first AED of choice in children, 2
years old.
≥ 60
If status continues, give additional phenytoin or
fosphenytoin at boluses of 5mg/kg (PE) to
maximum of 30 mg/kg
If status persists, give 20 mg/kg of Phenobarbital IV
at max. rate of 60 mg/min in adults, 30 mg/min in
children. When Phenobarbital is given after a
benzodiazepine, the risk of apnea or hyopnea is
great and assisted ventilation is usually required.
If status persists, then combined aggressive therapy
and thorough neurological evaluation are required.
Such a patient requires admission to an ICU, urgent
EEG recording, and administration of an
intravenous anesthetic agent. Drugs available for
such use include barbiturates, midazolam, and
propofol. Intubation & ventilation is required, and
vasopressors are frequently used.
Midazolam anesthesia is initiated by 0.2 mg/kg IV
that is followed by maintenance at 0.75 to 10
µg/kg/min. This dose variation is caused by
tachyphylaxis. Both phenytoin and phenobarbital
maintenance should be continued. Assessments
with clinical evaluation and EEG must be
performed at regular intervals.
Barbituates are potent but associated with profound
systemic effects. Sodium pentobarbital loading
dose is 15 mg/kg OV given slowly over 1-2 hours,
then continuous IV at 0.5-1.0 mg/kg/hr. During
28
hours 0-6, may give additional loading doses of 5
mg/kg q 2 hours until a burst-suppression pattern on
EEG is achieved.
Propofol anesthesia is initiated with 1-2 mg/kg and
then between 2-10 mg/kg/hr. Doses are adjusted
based on effects of drug on EEG. Acute treatment
endpoints are spike suppression or a pattern of
burst-suppression with interburst intervals more
than 1 second.
Modified from: Willmore, L.J., “Epilepsy Emergencies: The First Seizure and Status Epilepticus,” Neurology, 1998; 51 5 Suppl 4): S34-S38.