Epilepsy is a disorder that consists of recurrent seizures. Epilepsy occurs in 1 to 2 percent of the general popula- tion. The incidence of epilepsy is highest in infancy. It decreases during childhood and is lowest in adoles- cence. The incidence markedly increases in elderly patients.
I. Clinical evaluation
A. Epileptic seizures are behavioral changes resulting
from paroxysmal, excessive electrical discharges from the brain. Not all jerks, shakes, and episodic behaviors are seizures. For example, tics, tremors, dystonia, and attention-deficit disorder can imitate epileptic seizures.
B. Once a paroxysmal behavioral event is identified as
a seizure, the next step is to determine whether it is epilepsy or a secondary effect of hypoxia, hypoglycemia, infection, fever, and toxic substance abuse (eg, alcohol withdrawal, cocaine use).
Epilepsy is characterized by recurrent seizures (ie, at least two seizures are needed for diagnosis).
C. Epilepsy can result from either inherited or acquired
factors. Head injury, stroke, brain tumor, cortical dysplasia, and infection are common causes of both seizures. In many cases, the cause of epilepsy remains unknown.
Nonepileptic paroxysmal disorders that can mimic epileptic seizure
Syncope
! Reflex (vasovagal, carotid sinus, glossopharyngeal, cough)
! Decreased cardiac output
! Decreased left ventricular filling (hypovolemia, orthostatic hypotension, pulmonary embolism) ! Cardiac arrhythmia
Migraine with auras, basilar migraine, confusional migraine Transient ischemic attack
Periodic paralysis
Sleep disorders (parasomnias, daytime amnestic episodes) Gastrointestinal disorders (reflux, motility disorders) Movement disorders (tics, Tourette's syndrome, nonepileptic myoclonus, paroxysmal choreoathetosis, shuddering attacks)
Psychiatric disorders (panic, somatization, dissociation, conversion [nonepileptic psychogenic seizures]) Drug toxicity and substance abuse
Breath-holding spells
II. Features of epileptic seizures
A. Epileptic seizures are divided into two broad cate-
gories--generalized and partial. Generalized sei- zures arise from both sides of the brain simulta- neously. Partial (ie, focal) seizures occur within one or more restricted regions of the brain.
Classification of epileptic seizures
Generalized Partial Absence Myoclonic Tonic Atonic Clonic
Tonic-clonic (grand mal seizure)
Simple partial (conscious- ness not impaired) Complex partial (con- sciousness impaired) Partial with secondary gen- eralization (can be tonic-clonic, tonic, or clonic)
B. Partial seizures are further classified as simple,
complex, or secondarily generalized. Simple partial seizures alter behavior but do not impair conscious- ness. Complex partial seizures alter conscious- ness. Partial seizures can also become secondarily generalized, causing tonic and clonic movements.
C. History of the event. A witnessed, 90-second
episode that involved loss of consciousness, stiffening, and jerking of the extremities followed by muscle soreness, headache, and the need to sleep for several hours afterwards strongly suggests a tonic-clonic seizure.
History of a suspected seizure Before the event
Unusual stress (eg, severe emotional trauma) Sleep deprivation
Recent illness
Unusual stimuli (eg, flickering lights)Use of medications and drugs
Activity immediately before event (eg, change in posture, exercise)
During the event
Symptoms at onset (eg, aura)
Temporal mode of onset: gradual versus sudden Duration: brief (ictal phase <5 min) versus prolonged Stereotypy: duration and features of episodes nearly identi- cal versus frequently changing
Time of day: related to sleep or occurring on awakening Ability to talk and respond appropriately
Ability to comprehend
Ability to recall events during the seizure
Abnormal movements of the eyes, mouth, face, head, arms, and legs
Bowel or bladder incontinence Bodily injury
After the event
Confusion Lethargy Abnormal speech
Focal weakness or sensory loss (ie, Todd's paralysis) Headache, muscle soreness, or physical injury
D. A witness should answer the following ques- tions:
1. What was the patient doing at the onset? Did the
or repetitive actions? Evidence of any focal rhythmic behavior of the face or extremities at the onset suggests partial epilepsy.
2. What was the patient doing during the event?
Signs may include: tonic movements or postur- ing seen as stiffening, most often of the extremi- ties or axial body; clonic movements; a rhythmic flexion-extension movement of the extremities; loss of consciousness; incontinence; and tongue biting.
3. What was the duration of the ictal event? This
information can differentiate true seizure from psychogenic events, which often last longer.
4. What was the patient doing after the ictal event?
Focal deficits and Todd's paralysis are common findings. The presence of postictal confusion may help differentiate between seizure and syncope.
III.Past medical history
A. Meningitis, encephalitis, head trauma, cancer, or
cerebrovascular disease suggests the cause of epilepsy focus. In diabetic patients, hypoglycemia (glucose less than 40 mg/dL) or hyperglycemia (glucose higher than 300 mg/dL) may precipitate seizures. Hyponatremia, hypocalcemia, hypomag- nesemia, hypoparathyroidism, hypothyroidism also may cause seizures.
B. Medications. Theophylline, meperidine (Demerol),
isoniazid, antipsychotic drugs (clozapine [Clozaril], phenothiazines), radiocontrast dyes, alkylating agents, and ß-lactam antibiotics are among the most commonly implicated medications in seizure. Other medications include lidocaine, anesthetics, tricyclic antidepressants, selective serotonin reuptake inhibitors, bupropion (Wellbutrin), acyclovir (Zovirax), ß-blockers, and decongestants (eg, phenylpropanolamine). Seizures can be provoked by alcohol withdrawal, cocaine, phencyclidine (PCP), and 3,4-methylenedioxy- methamphetamine (MDMA, "ecstasy").
IV. Physical examination
A. Findings may include trauma, infection, malig-
nancy, congenital anomalies, and focal weakness or spasticity suggesting previous stroke.
B. Vital signs should be measured and a general
medical examination performed.
1. Examine the patient for injuries from the seizure
or fall.
2. Check oxygen saturation and auscultate the
chest for aspiration.
3. Measure heart rhythm and rate, blood pressure,
and orthostatic changes for assessment of syncope.
4. Auscultate for carotid murmurs or carotid bruits
and sources of embolic stroke.
5. Check for rapid pulses, which are often present
after seizure and may help in evaluation of psychogenic seizures.
C. Neurologic examination
1. Patients should be observed for fluency of
language, facial asymmetry, gaze preferences, and pupillary asymmetry. The last presents in patients who have herniation from brain swelling caused by parenchymal or epidural bleeding and in those who have a rapidly growing brain tumor.
2. Sensory deficits suggest parietal lobe dysfunc-
tion. An extensor plantar response may be noted after a seizure and is not necessarily a patho- logic finding.
V. Diagnostic testing
A. Measurement of glucose, calcium, magnesium,
thyroid hormone, liver enzyme levels, and toxicol- ogy screening (including blood alcohol levels) may reveal common medical causes of seizures. A complete blood cell count may suggest infection, anemia, or sickle cell disease.
B. Lumbar puncture should be performed in patients
suspected to have had an infection or a fever after assessment of the possible risks of the procedure (eg, coagulopathy, mass lesion). Patients who are immunocompromised because of corticosteroid use, recent transplantation or HIV infection should undergo cerebrospinal fluid evaluation to detect possible fungal, bacterial, or viral infection.
C. Computed tomography can detect the presence
of bleeding or gross structural lesions immediately after a seizure. However, magnetic resonance imaging is the study of choice because it is more sensitive and specific for evaluating structural lesions.
D. Electroencephalogram (EEG) can help establish
the presence and type of epilepsy, although its value is limited. An estimated 0.4% of adults and 2.8% of children who have never had a seizure may have interictal epileptiform discharges. A normal EEG does not refute the diagnosis of epilepsy. The initial EEG reveals epileptiform
activity in only 40% of the patients with probable epilepsy. The yield of the test is enhanced by using sleep deprivation, hyperventilation, and photic stimulation.
E. Ambulatory 24-hour EEG recordings can be
useful for patients in whom epileptic seizure is a relatively strong possibility when the standard EEG is normal.
VI. Treatment of epilepsy
A. After a single tonic-clonic seizure, recurrence rates
are 15 to 60%. After two tonic-clonic seizures, the risk of a third seizure is 85%.
B. Treatment should be started with one drug and
then increase the dose gradually until the patient is seizure-free or experiences significant side effects.
Initial treatment for partial and generalized epilepsies Type of epilepsy First-line agents Second-line agents Partial Carbamazepine, oxcarbazepine (Trileptal), phenytoin (Dilan- tin) Divalproex (Depakote), felbamate (Felbatol), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), tiagabine (Gabitril Filmtabs), topiramate (Topamax), valproate (Depakene), zonisamide (Zonegran) Generalized Absence seizures Ethosuximide (Zarontin), valproate Lamotrigine, levetiracetam
Idiopathic Lamotrigine,valproate Topiramate,zonisamide
Symptom- atic Lamotrigine, topiramate, valproate, zonisamide Barbiturates, benzodiazepines
VII. Therapy for localization-related partial epilepsy A. About 70% of adult patients with epilepsy have
partial-onset seizures, which encompass simple partial, complex partial, and secondarily general- ized tonic-clonic seizures. About 50% of patients have both partial seizures and secondarily general- ized tonic-clonic seizures.
B. For the majority of patients with newly diagnosed
partial epilepsy, initial treatment consists of carbamazepine (Tegretol), oxcarbazepine (Trileptal), or phenytoin (Dilantin). Alternative choices include divalproex (Depakote), felbamate (Felbatol), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), tiagabine (Gabitril), topiramate (Topamax), and zonisamide (Zonegran).
Antiepileptic Drugs Adult dos-
age Children(per kg of body weight) Dosing intervals Carbamaz epine (Tegretol) 600 to
1,600 mg 20 to 40mg Three orfour times per day Ethosuximi
de (Zarontin)
750 to
1,5000 mg 4 to 5 mg Twice perday
Gabapenti n (Neurontin) 900 mg up to 6,000 mg Three or four times per day Lamotrigin e (Lamictal) 200 to 800
mg Twice perday
Levetiracet am (Keppra).
500 and
1500 mg Once ortwice per day Phenobar-
bital (Solfoton)
1 to 4 mg
per kg 2 to 5 mg Once ortwice per day
Adult dos- age Children (per kg of body weight) Dosing intervals Phenytoin (Dilantin) 200 to 500 mg 5 mg up to a maxi- mum of 300 mg Once or twice per day Primidone
(Mysoline) 500 to1,000 mg 10 to 20mg Three orfour times per day Tiagabine
(Gabitril Filmtabs)
32 to 56
mg Three orfour times per day Topiramate
(Topamax) 400 to 800mg Twice perday Valproic acid (Depakene , Depakote) 15 to 60 mg per kg 15 to 60 mg Three or four times per day Zonisamid e (Zonegran) 100 and 600 mg per day Once per day
C. Carbamazepine (Tegretol) usual starting dose is
200 mg twice per day, with weekly increases of 200 mg per day and a usual daily maintenance dose of 600 to 1,200 mg. The long-acting formulations of carbamazepine improve compliance because they can be taken twice daily and are better tolerated. Carbamazepine is a strong inducer of some of hepatic cytochrome P-450 and is associated with a number of significant drug-drug interactions. In addition, carbamazepine induces its own metabo- lism. The usual therapeutic range for serum carbamazepine levels is 6 to 12 mg/L.
D. Oxcarbazepine (Trileptal) is approved for initial
monotherapy. This drug has significant efficacy as monotherapy in patients newly diagnosed as having partial epilepsy as well as patients whose condition is refractory. Oxcarbazepine is more tolerable and associated with less frequent rashes than carbamazepine. Oxcarbazepine is initiated at 150 mg twice a day, with weekly increments of 300 mg per day and a target dose of 900 to 1,200 mg. Compared with carbamazepine, oxcarbazepine is associated with substantially fewer drug-drug interactions and does not undergo autoinduction.
E. Phenytoin (Dilantin), the usual starting dose is
300 mg daily (4 to 5 mg/kg per day), with a mainte- nance dose of 200 to 500 mg per day. A loading dose of phenytoin at 18 to 20 mg/kg can be given orally or intravenously. Phenytoin can be given once daily, although it is often administered two or three times per day to minimize side effects. The therapeutic serum range of phenytoin is 10 to 20 mg/L. Phenytoin is a strong hepatic enzyme in- ducer and is prone to drug-drug interactions.
F. Divalproex (Depakote) is usually started at 250 to
500 mg twice daily (10 to 15 mg/kg per day), with weekly increments of 250 to 500 mg per day (5 to 10 mg/kg per day) and a range in daily dose from 1,000 to 3,000 mg. An intravenous formulation is available. The therapeutic serum range is 50 to 150 mg/L.
G. Monotherapy versus polytherapy
1. About 47% of patients with newly diagnosed
epilepsy became seizure-free during treatment with their first AED and 14% became sei- zure-free during treatment with a second or third drug.
2. Felbamate (Felbatol) is an effective drug, but its
use has been severely restricted because of its association with life-threatening aplastic anemia and fulminant hepatic failure. It should not be used as first-line therapy.
3. Gabapentin (Neurontin) has the advantages of
safety, tolerability, favorable pharmacokinetic profile, and ease of use. It has been used mostly as adjunctive therapy in patients with refractory seizures but is an attractive agent as monotherapy in patients with severe hepatic disease, cutaneous allergies, porphyria, or acquired immunodeficiency disease and in elderly patients who take a number of medica- tions. The effective dose is 900 to 4,800 mg per day, divided into three doses.
4. Lamotrigine (Lamictal) is approved as adjunc-
tive therapy and as second-line monotherapy. It is sometimes used as initial monotherapy be- cause it has a similar efficacy as phenytoin or carbamazepine and is better tolerated than carbamazepine.
5. Tiagabine (Gabitril) exerts its effect by inhibiting
efficacy two times daily or four times daily. This drug is used as adjunctive therapy, with a usual starting dose of 4 mg per day, weekly increments of 4 mg per day, and a target daily dose between 32 and 64 mg.
6. Topiramate (Topamax) has significant efficacy
when used as adjunctive therapy. Because of potential adverse cognitive events, it should be started at a low dose, with gradual adjustment. Starting dose is 25 or 50 mg per day with weekly increments of 25 to 50 mg per day. The usual target dose for adjunctive therapy is 400 mg taken twice daily, with a dose range between 100 and 1,000 mg per day.
7. Levetiracetam (Keppra) is an attractive AED
because of tolerability and ease of use. The starting dose is 500 mg at bedtime, with weekly increments of 500 mg and a total target daily dose between 1,000 and 3,000 mg divided into two doses. It can be used in monotherapy.
8. Zonisamide (Zonegran) is approved as adjunc-
tive therapy. It should be avoided in patients with sulfa allergies. Zonisamide can be associated with a rash in 3%; rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur. The recommended start- ing dose is 100 mg taken once a day, with incre- ments of 100 mg every 2 weeks if needed, with a target dose between 100 and 600 mg per day.
VIII. Therapy for generalized epilepsies
A. For patients who have multiple seizure types, it is
necessary to choose a broad-spectrum anticonvulsant with efficacy against multiple seizure types.
B. Valproate remains a mainstay treatment for these
patients, but lamotrigine, topiramate, and zonisamide, are also efficacious against multiple seizure types and can be considered as alternative agents. Because of its tolerability, some physicians select lamotrigine rather than valproate as the initial drug of choice.
IX. Discontinuation of therapy. Patients who remain
seizure-free for at least 2 years should be consid- ered candidates for tapering and discontinuing AED treatment. About two-thirds of patients remain seizure-free following discontinuation of treatment. References, see page 282.