eMedicine Specialties > Neurology > Seizures and Epilepsy

Generalized Tonic-Clonic Seizures

David Y Ko, MD, Associate Professor, Department of Neurology, University of Southern California Keck School of Medicine
Soma Sahai-Srivastava, MD, Director of Neurology Ambulatory Care Services, LAC and USC Medical Center; Assistant Professor, Department of Neurology, University of Southern California

Updated: May 6, 2009

Introduction

Background

A seizure is an abnormal paroxysmal discharge of cerebral neurons due to cortical hyperexcitability. The International Classification of Seizures divides seizures into 2 categories: partial seizures (ie, focal or localization-related seizures) and generalized seizures.

Partial seizures result from a seizure discharge within a particular brain region or focus, and they manifest focal symptoms. Generalized seizures probably begin in the thalamus and other subcortical structures, but on scalp EEG recordings they may appear to start simultaneously in both cerebral hemispheres; therefore, they manifest symptoms bilaterally in the body and are always associated with loss of consciousness.

Partial seizures can generalize secondarily and result in tonic-clonic activity. Some partial seizures have very rapid generalization, and the partial phase of the seizure may not be readily apparent clinically or even on scalp EEG recordings. However, secondarily generalized partial seizures are not included in the category of generalized seizures, which includes only primary generalized seizures.

Generalized convulsive seizures can be classified as atonic, tonic, clonic, tonic-clonic, myoclonic, or absence on the basis of clinical symptoms and EEG abnormalities. Tonic seizure is the rigid contracture of muscles, including respiratory muscles, which is usually brief. The clonic component is the rhythmic shaking that occurs and is longer. Together, a generalized tonic-clonic seizure (GTCS) is also called a grand mal seizure and is one of the most dramatic of all medical conditions.

Several epilepsy syndromes have generalized seizures: benign neonatal convulsions, benign myoclonic epilepsy of infancy, childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and generalized tonic-clonic seizures upon awakening.

Pathophysiology

Generalized epilepsy is thought to be initiated by 3 different mechanisms: (1) abnormal response of hyperexcitable cortex to initially normal thalamic input, (2) primary subcortical trigger, and (3) abnormal cortical innervation from subcortical structures.

Physiologically, a seizure results from a paroxysmal high-voltage electrical discharge of susceptible neurons within an epileptogenic focus. These neurons are known to be hyperexcitable and, for unknown reasons, remain in a state of partial depolarization. The neurons surrounding the epileptogenic focus are GABA-ergic and hyperpolarized, and they inhibit the epileptogenic neurons. At times, when the epileptogenic neurons overcome the surrounding inhibitory influence, the seizure discharge spreads to neighboring cortical structures and then to subcortical and brainstem structures.

Various animal models of generalized epilepsy implicate brainstem structures in the pathogenesis of generalized seizures. These brainstem structures include (1) a lateral geniculate body, which produces a generalized tonic-clonic seizure when kindled in the cat; (2) ascending pathways through the mamillary bodies and anterior thalamus; and (3) the substantia nigra, including a nigrotectal GABA-ergic projection and locus ceruleus. The spread of excitability to subcortical, thalamic, brainstem, and spinal cord structures corresponds with the tonic phase of the seizure. Following this, an inhibitory impulse starts from the thalamus and interrupts the tonic phase into discontinuous bursts of electrical activity, known as the clonic phase.

Frequency

United States

The age-adjusted incidence of epilepsy (ie, recurrent unprovoked seizures) ranges from 24-53 per 100,000 per year. Approximately 20-25% of cases are classified as generalized seizures. Age-adjusted prevalence of epilepsy ranges from 4-8 per 1000 people.

International

Developing countries have similar incidences of epilepsy, ranging from 14-57 per 1000 people, based on World Health Organization statistics. Internationally, as in the United States, only a small proportion of seizures are generalized tonic-clonic seizures (20-25%); the majority are partial seizures.

Mortality/Morbidity

The morbidity for tonic-clonic seizure can be high because these patients get no aura and thus the seizure strikes without warning; minor injuries are frequent. Patients can have posterior shoulder dislocations and broken bones. Mortality for tonic-clonic seizures is low. The incidence of sudden death is 24 times higher in persons with epilepsy than in the general population. Some of the risk factors for sudden death in epilepsy (SUDEP) include high seizure frequency (specifically tonic-clonic type), younger age, mental retardation, and polytherapy.¹

Age

• Generalized convulsive seizures are uncommon in infants and rare in neonates.
• In elderly patients, generalized tonic-clonic seizures are usually due to secondary generalization of seizures emanating from localized brain lesions.

Clinical

History

• Prodromal symptoms
  • Patients with generalized tonic-clonic seizures may report having a prodrome, which comprises premonitory symptoms occurring hours or days before a seizure. Common prodromes include mood changes, sleep disturbances, lightheadedness, anxiety, irritability, difficulty concentrating and, rarely, an ecstatic feeling. Patients with generalized tonic-clonic seizures do not have auras. An aura represents a simple partial seizure, and a reliable history of aura identifies the seizure as partial and not generalized.
  • Other symptoms that have been described less consistently are abdominal pain, facial pallor, or headache. Most patients lose consciousness without any premonitory symptoms.

Physical

The patient may have completely nonfocal findings on neurologic examination when not having seizures. Seizures typically are divided into tonic, clonic, and postictal phases, which are described in detail in this section.

• Tonic phase
  • Generalized convulsive seizures may begin with myoclonic jerks or, rarely, with absences. The tonic phase begins with flexion of the trunk and elevation and abduction of the elbows. Subsequent extension of the back and neck is followed by extension of arms and legs. This can be accompanied by apnea, which is secondary to laryngeal spasm.
  • Autonomic signs are common during this phase and include increase in pulse rate and blood pressure, profuse sweating, and tracheobronchial hypersecretion.
  • Although urinary bladder pressure rises, voiding does not occur because of sphincter muscle contraction.
  • This stage lasts for 10-20 seconds.
• Clonic phase
  • The tonic stage gives way to clonic convulsive movements, in which the tonic muscles relax intermittently, lasting for a variable period of time.
  • During the clonic stage, a generalized tremor occurs at a rate of 8 tremors per second, which may slow down to about 4 tremors per second. This is because phases of atonia alternate with repeated violent flexor spasms. Each spasm is accompanied by pupillary contraction and dilation. Some patients may have tongue or cheek bites.
  • The atonic periods gradually become longer until the last spasm. Voiding may occur at the end of the clonic phase as sphincter muscles relax. The atonic period lasts about 30 seconds. The patient continues to be apneic during this phase.
  • The convulsion, including tonic and clonic phases, lasts for 1-2 minutes.
• Postictal state
  • The postictal state includes a variable period of unconsciousness during which the patient becomes quiet and breathing resumes.
  • The patient gradually awakens, often after a period of stupor or sleep, and often is confused, with some automatic behavior.
  • Headache and muscular pain are common. The patient does not recall the seizure itself.

Causes

• Most generalized epilepsies are idiopathic, but a definite genetic locus has been found for some of these generalized types of epilepsy.
• Benign familial neonatal convulsion is an autosomal dominant inherited condition with high penetrance, resulting from mutations in a voltage-gated potassium channel named KCNQ2 in chromosome 20. This gene is homologous to a gene (ie, KCNQ1) expressed in the heart, where mutations are responsible for one form of the long QT syndrome. A channelopathy in the sodium channel b1 subunit (SCN1B) is associated with generalized epilepsy with febrile convulsions.
• Unverricht-Lundborg disease, a progressive myoclonic epilepsy, is an autosomal recessive inherited disorder linked to chromosome arm 21q. The specific gene was identified recently as cystatin B, an intracellular protease inhibitor. For most of the other syndromes considered idiopathic generalized epilepsies, more than one gene is thought to be responsible.

Differential Diagnoses

Other Problems to Be Considered

Hyperventilation and electrolyte imbalances
Prolonged QT syndrome and other arrhythmias
Dystonias including nocturnal paroxysmal dystonias
Paroxysmal dyskinesias²
Encephalopathies and metabolic disorders
Pseudoepileptic seizures
Nocturnal paroxysmal events (eg, sleep apnea, night terrors)²
Paroxysmal abnormalities of tone (eg, opisthotonic posturing and clonus)
In infants, apneic syndromes including gastroesophageal reflux and jitteriness of the newborn
In toddlers and young school-aged children, simple faints and breath-holding spells²

Workup

Laboratory Studies

• Plasma prolactin levels, if investigated within 10-20 minutes of a generalized tonic-clonic seizure, are elevated 5-30 times the baseline values. The plasma prolactin level is a useful diagnostic tool to exclude pseudoseizures if the seizure looks like a tonic-clonic seizure. Prolactin level may not be elevated in absence and myoclonic seizures and in simple and brief complex partial seizures.
• Serum adrenocorticotropic hormone (ACTH), cortisol, vasopressin, growth hormone, and beta-endorphin levels also are increased postictally but for a very brief duration; therefore, they are not useful clinically.
• In 15% of patients, especially after a prolonged seizure, cerebrospinal fluid (CSF) pleocytosis may be found (commonly 10 cells/mm³ and rarely as many as 50 cells/mm³).
• Metabolic acidosis and elevated levels of serum lactate and creatine kinase are common findings after a seizure.

Imaging Studies

• Imaging studies may not be necessary in a small subgroup of patients with a clear history of myoclonic epilepsy and absence, with classic 4- to 5-Hz polyspike and wave and EEG from which the diagnosis of a generalized epilepsy syndrome like juvenile myoclonic epilepsy can be made with reasonable certainty (along with other supporting evidence, nonfocal neurologic examination findings and a family history of seizures), because the likelihood of finding an abnormality on imaging is very low. In practice, however, complete certainty is not possible; therefore, brain imaging is the next step in the workup of patients with epilepsy.
• An abnormality on CT scans is rare in patients with primary generalized tonic-clonic seizures. Because CT will not detect most types of congenital structural brain abnormalities, MRI is the imaging modality of choice.
• Neuronal migration disorders that may be diagnosed on MRI include lissencephaly, pachygyria, band or laminar heterotopia, subependymal heterotopias, focal cortical dysplasia polymicrogyria, focal subependymal heterotopias, and schizencephaly.
• Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) scans have no role in the workup of generalized tonic-clonic seizures, except if the diagnosis of primary generalized seizure itself is in doubt.

Other Tests

• Interictal EEG
  • The awake EEG of patients with generalized tonic-clonic seizure is often normal. Interictal abnormalities include spikes, sharp waves, polyspikes, and polyspike or spike-and-wave complexes.
  • Hyperventilation, photic stimulation, and sleep-deprived EEG can increase the likelihood of finding an abnormality on EEG.
  • Paroxysmal frontal intermittent rhythmic delta activity (FIRDA) may be found in some patients, especially those with a history of absences, but this is a nonspecific abnormality that is not considered epileptiform.
  • Certain specific interictal EEG patterns can be distinctive of generalized epilepsy syndromes: (1) generalized bilaterally synchronous 3-Hz spike-and-wave complexes are associated with typical absence attacks; (2) fast spike-and-wave activity at 4-5 Hz is associated most often with generalized tonic-clonic seizures; (3) polyspikes or polyspike and slow-wave complexes usually are seen with juvenile myoclonic epilepsy.
• Ictal EEG
  • The tonic phase of convulsion is characterized by progressively higher amplitude and lower frequency discharge pattern observed simultaneously in both cortical hemispheres, reaching a maximum of 10 Hz.
  • This then becomes slower and mixed with bilateral high-amplitude spikes and a progressively greater amount of high-amplitude rhythmic delta activity. These are slow, developing progressively into repetitive complexes of high-amplitude spike-and-slow-wave activity in the clonic phase.
• Postictal EEG: The postictal EEG may be isoelectric or may show diffuse, very low-amplitude, slow delta activity. This corresponds to sustained hyperpolarization.
• Patients with generalized tonic-clonic seizures and idiopathic generalized epilepsy typically have no evidence of any localized, regional, or diffuse brain abnormality on history, physical, or neurologic examination; clinical laboratory testing; or imaging studies.

Treatment

Medical Care

A number of medications are used for the treatment of generalized tonic-clonic seizures. The choice of drug should be tailored to the individual patient and to the epilepsy syndrome and not only to the seizure type.

• Valproic acid is considered the agent of first choice (except in female patients with reproductive capability) since it treats a broad spectrum of seizure types, including myoclonic seizures. The unblinded, randomized, controlled Standard Antiepileptic and New Antiepileptic Drug (SANAD) study on the effectiveness of valproate, lamotrigine, or topiramate for generalized and unclassifiable epilepsy gave the nod to valproate.³
• Phenytoin and carbamazepine are reasonable second options among the older group of medications, but the newer medications tend to work equally well if not better and have better side effect profiles, especially long-term side effect.
• Among the newer medications, lamotrigine, topiramate, zonisamide⁴ and levetiracetam are other broad-spectrum drugs that are relatively well tolerated.
• Phenobarbital is still used by many neurologists, though its adverse cognitive effects have led to a decline in its use.
• For refractory generalized epilepsy, felbamate also is used as an agent of last resort and is very effective. The adverse effects of felbamate necessitate very careful monitoring of blood counts and liver function tests.
• The agent rufinamide (Banzel) has been approved as adjunctive therapy for seizures associated with Lennox-Gastaut syndrome.^5,6

Surgical Care

Preliminary data show that vagus nerve stimulation (VNS) is effective in generalized epilepsy. The US Food and Drug Administration (FDA) has approved VNS only for the treatment of partial seizures. Open label VNS registry results have also shown some patients with generalized tonic-clonic seizures respond well. No other surgical option exists for pure generalized tonic-clonic seizures. Patients must be carefully evaluated because some partial seizures with quick secondary bilaterally synchrony may be labeled as primary generalized tonic-clonic.

Diet

A ketogenic diet can be tried to improve seizure control in younger patients who are refractory. The ketogenic diet was developed at the Mayo Clinic and John Hopkins Institute, and it was based on the observation that seizures improved during periods of starvation. The exact mechanism by which this diet works is not known. This diet produces a ketotic state but provides adequate calories for nutrition from proteins and fat. It is used for intractable epilepsy, especially in childhood. It is less commonly prescribed for adults because the diet, being very restrictive, is very difficult to maintain. Studies have shown a substantial reduction in seizure frequency in 50% of patients placed on the diet. Side effects are mainly GI and include bloating, constipation, renal stones, and bone and weight loss. The diet typically contains a fat-to-carbohydrate ratio of 4:1. Urinary ketones are checked daily and need to be greater than 4.

Medication

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Anticonvulsant agents

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

Valproate (Depakote, Depakote ER, Depakene, Depacon)

Considered drug of first choice for primary generalized epilepsy. Has very wide spectrum and is effective in most seizure types, including myoclonic seizures. Has multiple mechanisms of anticonvulsant effects including increasing GABA levels in brain as well as T-type calcium channel activity. The ER formulation allows for once-a-day administration.

Dosing

Adult

Depacon IV (100-mg/mL vials): 10-15 mg/kg/d initially, increase by 5-20 mg/kg/wk to maximum of 60 mg/kg/d or as tolerated; IV administration rate should be 20 mg/min
Depakene capsule, tablet, sprinkle, or syrup: Administer PO dose as in IV dose (extended-release dosage form is 8-20% lower in bioequivalence to delayed-release form)

Pediatric

Initial dose: 20 mg/kg/d IV
Maintenance dose: 30-60 mg/kg/d IV

Interactions

Cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may significantly reduce levels; salicylates decrease protein binding and metabolism of valproate in children; may result in variable changes of carbamazepine concentrations with possible loss of seizure control; may increase diazepam and ethosuximide toxicity (monitor closely)

May increase phenobarbital and phenytoin levels while either may decrease valproate levels; may displace warfarin from protein-binding sites (monitor coagulation tests); may increase zidovudine levels in HIV-seropositive patients; increases elimination half-life of lamotrigine by 165% (dose should be reduced)

Contraindications

Documented hypersensitivity; hepatic disease/dysfunction

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Dose-related hepatic dysfunction occurs commonly during first 6 mo of therapy, usually manifested by symptoms of nausea, vomiting, weakness, lethargy, and facial edema; asymptomatic hyperammonemia also may occur; patients aged <2 y with history of liver problems, congenital metabolic disorders, severe seizure disorder, or mental retardation are at increased risk of toxicity; thrombocytopenia and inhibition of secondary phase of platelet aggregation may occur; pancreatitis

Phenytoin (Dilantin)

Does work for tonic-clonic seizures and often used because can be administered once a day. Long-term side effects of osteopenia and cerebellar ataxia now temper its use by neurologists. One of the most difficult AEDs to use due to zero-order kinetics and narrow therapeutic index. Can have significant bidirectional drug interactions.

Dosing

Adult

Loading dose: 15-20 mg/kg/d PO/IV
Maintenance dose: 5 mg/kg/d PO/IV when IV rate does not exceed 50 mg/kg

Pediatric

Initial dose: 5-7 mg/kg/d PO/IV
Maintenance dose: 5-7 mg/kg/d PO/IV

Interactions

Carbamazepine, felbamate, cimetidine, warfarin, chloramphenicol, isoniazid, and disulfiram increase levels; rifampin, antacids, and valproate decrease levels; lowers levels of carbamazepine, felbamate, valproic acid, lamotrigine, tiagabine, zonisamide, oxcarbazepine, oral contraceptives, methadone, and theophylline; increases levels of warfarin, leading to increase in prothrombin time

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Carefully monitor level in hepatic insufficiency; common adverse effects include nystagmus, ataxia, dysarthria, and sedation
Adverse effects that are not as well known include choreiform movements; external ophthalmoplegia; rash; Stevens-Johnson syndrome; aplastic anemia; hepatitis; nephritis; thyroiditis; systemic lupus erythematosus (SLE); hyperglycemia; gingival hyperplasia; coarsening of facial features; deficiency of vitamin D, K, folic acid, and immunoglobulin A
Decreased bone density, decreased motor nerve conduction velocity, and increased plasma alkaline phosphatase reported

Carbamazepine (Tegretol, Tegretol XR, Carbatrol, Epitol)

Older antiepileptic drug used as second-choice agent along with phenytoin. Has active metabolite 10-11 epoxide. Like phenytoin has been associated with osteopenia.

Dosing

Adult

400-1200 mg/d PO divided tid; extended-release form given bid

Pediatric

Initial dose: 5 mg/kg/d PO
Maintenance dose: 15-20 mg/kg/d PO

Interactions

Danazol administration within 30 d may increase serum levels significantly (avoid whenever possible); do not coadminister with MAO inhibitors; cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; may decrease primidone and phenobarbital levels (their coadministration may increase carbamazepine levels)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Atypical absence seizures may worsen in frequency; obtain CBCs and serum iron at baseline (ie, prior to treatment), during first 2 mo, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision—caution while driving or performing other tasks requiring alertness

Phenobarbital (Barbita, Luminal, Solfoton)

One of first major antiepileptics in use since early 1900s. Now increasingly recognized that phenobarbital can cause some major adverse cognitive effects; therefore, falling in disfavor with neurologists. Major advantage is once daily dosing, which is possible because of very long half-life. Major drawback is the issue of tolerance and possibility of abuse.

Dosing

Adult

90 mg PO qd, increase by 30 mg/d every mo to usual maintenance dose of 90-120 mg/d

Pediatric

Initial dose: 3-5 mg/kg/d PO
Maintenance dose: 3-5 mg/kg/d PO

Interactions

Enzyme inducer, reduces levels of carbamazepine, valproate, lamotrigine, tiagabine, zonisamide, theophylline, warfarin, and cimetidine; valproate increases levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Adjust dose in patients with hepatic or renal insufficiency; idiosyncratic reactions include rash, granulocytosis, aplastic anemia, and hepatitis; folic acid, vitamin K, and vitamin D deficiency may occur with long-term use; adverse cognitive effects include sedation, irritability, hyperactivity, slowed mentation, and ataxia

Lamotrigine (Lamictal)

Newer antiepileptic drug with very broad spectrum of activity, like valproate. FDA approved for both primary generalized and partial-onset epilepsy. Has several mechanisms of action that may account for effectiveness. Major disadvantage is that dose has to be increased very slowly over several weeks to minimize chance of rash especially if patient is on valproic acid.

Dosing

Adult

Week 1 and 2: 50 mg/d PO; if coadministered with valproic acid (VPA), then start with 25 mg qod
Week 3 and 4: 100 mg/d PO in divided doses; if coadministered with VPA, then 25 mg/d
Increase by 100 mg/d qwk; if coadministered with VPA, increase by 25-50 mg every other wk
Maintenance dose without VPA: 300-500 mg PO in divided doses
Maintenance dose with VPA: 100-200 mg/d PO

Pediatric

Initial dose: 1-2 mg/kg/d PO
Maintenance dose: 5-10 mg/kg/d PO
FDA approved only for Lennox-Gastaut syndrome in patients <16 y

Interactions

Acetaminophen increases renal clearance of medication, decreasing effects; similarly, phenobarbital and phenytoin increase lamotrigine metabolism, causing decrease in lamotrigine levels; valproic acid increases half-life; oral contraceptives (OCPs) can increase lamotrigine metabolism, but the 7 d of no hormonal medications in OCPs can cause 40% increase in lamotrigine levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in impaired renal or hepatic function; severe rash may occur within 2-8 wk of starting treatment (1% in children and 0.3% in adults) and can progress to Stevens-Johnson syndrome

Zonisamide (Zonegran)

One of newer antiepileptics recently introduced in US markets. Has been studied extensively in Japan and Korea and seems to have broad spectrum properties. Blocks T-type calcium channels, prolongs sodium channel inactivation, and is a carbonic anhydrase inhibitor.

Dosing

Adult

100 mg/d PO bid initially, increase by 100 mg/d/wk to maintenance of 100-300 mg PO bid

Pediatric

Not established

Interactions

May increase serum carbamazepine levels; carbamazepine may increase concentrations; phenobarbital may decrease levels

Contraindications

Documented hypersensitivity, history of urolithiasis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Associated with 2-3.5% risk of urolithiasis; anorexia, nausea, ataxia, impaired concentration, and other adverse cognitive effects reported
Cleared by hepatic conjugation and oxidation (reduce dose in hepatic insufficiency)

Felbamate (Felbatol)

Approved by FDA for medically refractory partial seizures and Lennox-Gastaut syndrome. Has multiple mechanisms of action, including (1) inhibition of NMDA-associated sodium channels, (2) potentiation of GABA-ergic activity, and (3) inhibition of voltage-sensitive sodium channels. Used only as drug of last resort in medically refractory cases because of risk of aplastic anemia and hepatic toxicity, thereby necessitating regular blood tests.

Dosing

Adult

600 mg PO tid initially, increase by 600-1200 mg/d each wk to maximum 1200-1600 mg PO tid

Pediatric

Not established

Interactions

May increase steady-state phenytoin levels, necessitating 40% reduction of phenytoin dose in some patients; phenytoin may double clearance, resulting in more than 45% decrease in steady-state levels; may cause increase in phenobarbital plasma concentrations; phenobarbital may reduce plasma levels; may decrease steady-state carbamazepine levels and increase steady-state carbamazepine metabolite levels; may increase steady-state valproic acid levels

Contraindications

Patients with past history of drug dyscrasias, significant hepatic disease, or autoimmune disease; avoid in patients with past history of significant idiosyncratic toxicity to other AEDs

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Common adverse effects include weight loss, insomnia, and psychiatric disturbances; felbamate-associated hepatic toxicity is estimated to occur in 1 in 30,000 individuals, and that of aplastic anemia is estimated to occur in 1 in 5000 individuals

Topiramate (Topamax)

AED with broad spectrum of antiepileptic activity including approval for primary generalized tonic-clonic seizures. Has multiple mechanisms of action including state-dependent sodium channel blocking action, potentiates inhibitory activity of neurotransmitter GABA. May block glutamate activity and also is a carbonic anhydrase inhibitor.

Dosing

Adult

50 mg/d PO; titrate by 50 mg/d at 1-wk intervals to target dose of 200 mg bid

Pediatric

25 mg or 50 mg/d PO initially; titrate to dosage of 6 mg/kg/d

Interactions

Phenytoin, carbamazepine, and valproic acid can decrease levels significantly; reduces digoxin and norethindrone levels; carbonic anhydrase inhibitors may increase risk of renal stone formation and should be avoided; use CNS depressants with extreme caution since topiramate may have additive effect in CNS depression, as well as other adverse cognitive or neuropsychiatric events

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Risk of kidney stone formation increased 2-4 times that of untreated population; risk may be reduced by increasing fluid intake; caution in renal or hepatic impairment; some patients may be at risk of metabolic acidosis (serum bicarbonate level can be measured)

Levetiracetam (Keppra)

Indicated for primary generalized tonic-clonic seizures in adults and children aged 6 years or older, as well as for use in juvenile myoclonic epilepsy and for partial seizures.

Dosing

Adult

500 mg PO bid initially; may increase daily dose by 1000-mg/d increments q2wk, not to exceed 1500 mg bid

Pediatric

<6 years: Not established
6-15 years: 10 mg/kg PO bid; may increase daily dose by 20-mg/kg increments q2wk, not to exceed 30 mg/kg bid
>16 years: Administer as in adults

Interactions

None reported; does not inhibit CYP450 isoenzymes, epoxide hydrolase, or UDP-glucuronidation; probenecid inhibits renal clearance of ucb L057 (inactive levetiracetam metabolite)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal impairment (reduce dose); major side effects include somnolence, asthenia, incoordination, mild leukopenia (3%) and behavioral changes such as anxiety, hostility, emotional lability, depression and psychosis (1-2%), and depersonalization; seizure frequency may increase following discontinuing drug (discontinue gradually); statistically significant decreases in RBCs and WBCs have been observed

Rufinamide (Banzel)

Antiepileptic agent. Structurally unrelated to current antiepileptics. Modulates sodium channel activity, particularly prolongation of the channel's inactive state. Significantly slows sodium channel recovery and limits sustained repetitive firing of sodium-dependent action potentials. Indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome.

Dosing

Adult

400-800 mg/d PO divided bid initially; increase in 400- 800-mg/d increments q2d; not to exceed 3200 mg/d; administer with food
Adding to valproate: Initiate at dose <400 mg/d PO divided bid

Pediatric

<4 years: Not established
>4 years: 10 mg/kg/d PO divided bid initially, may increase in 10-mg/kg increments qod; not to exceed 45 mg/kg/d or 3200 mg/d; administer with food

Interactions

Weak inhibitor of CYP2E1 and weak inducer of CYP3A4; serum levels may decrease when coadministered with carbamazepine, phenobarbital, phenytoin, and primidone; serum levels may increase when coadministered with valproate (if on valproate, initiate rufinamide therapy at dose <400 mg/d); conversely, concurrent use can decrease carbamazepine and lamotrigine serum levels and increase serum levels of phenobarbital and phenytoin (because of nonlinear kinetics); may decrease serum levels of ethinyl estradiol and norethindrone when coadministered (oral contraception users should use additional nonhormonal contraception); decreases AUC and C_max of triazolam

Contraindications

Documented hypersensitivity; history of familial short QT syndrome; severe hepatic impairment

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May shorten QT interval; may cause multiorgan hypersensitivity reaction; withdrawal; status epilepticus; caution with mild-to-moderate hepatic impairment; common adverse effects include somnolence, fatigue, dizziness, ataxia, nausea, vomiting, and headache; like other antiepileptic drugs, discontinue gradually; monitor for emergence or worsening of depression, suicidal thoughts, or suicidal behavior

Follow-up

Complications

Complications of generalized tonic-clonic seizures include the following:

• Head trauma and trauma to the tongue, lips, and cheeks
• Vertebral compression fractures
• Aspiration pneumonia
• Neurogenic pulmonary edema
• Cardiac arrhythmias
• Sudden death

Patient Education

For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Epilepsy.

Miscellaneous

Medicolegal Pitfalls

• Certain antiepileptic agents are enzyme inducers and decrease the levels of oral contraceptive agents. Warn patients of this and advise them to use additional contraceptive precaution while on enzyme-inducing medications like phenytoin, carbamazepine, and phenobarbital. 
• The older first generation AEDs such as phenytoin, carbamazepine, phenobarbital, and valproic acid are all known teratogenic agents.
• Driving is restricted if patients are still having seizures as per each state laws.

References

1. Walczak TS, Leppik IE, D'Amelio M, Rarick J, So E, Ahman P, et al. Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study. Neurology. Feb 27 2001;56(4):519-25. [Medline].

2. Morrell MJ. Differential diagnosis of seizures. Neurol Clin. Nov 1993;11(4):737-54. [Medline].

3. [Best Evidence] Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet. Mar 24 2007;369(9566):1016-26. [Medline].

4. Peters DH, Sorkin EM. Zonisamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy. Drugs. May 1993;45(5):760-87. [Medline].

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Keywords

partial seizures, tonic-clonic activity, tonic-clonic seizures, generalized tonic-clonic seizure, GTCS, epilepsy, generalized seizures, seizure treatment, focal seizures, localization-related seizures, sudden death in epilepsy, SUDEP, generalized convulsive seizures, grand mal seizure

Contributor Information and Disclosures

Author

David Y Ko, MD, Associate Professor, Department of Neurology, University of Southern California Keck School of Medicine
David Y Ko, MD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Medical Association, and California Medical Association
Disclosure: Pfizer Honoraria Speaking and teaching; UCB Grant/research funds clinical trials; Johnson and Johnson Grant/research funds clinical trials

Coauthor(s)

Soma Sahai-Srivastava, MD, Director of Neurology Ambulatory Care Services, LAC and USC Medical Center; Assistant Professor, Department of Neurology, University of Southern California
Soma Sahai-Srivastava, MD is a member of the following medical societies: American Academy of Neurology, American Headache Society, and American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Ramon Diaz-Arrastia, MD, PhD, Assistant Professor, Department of Neurology, Comprehensive Epilepsy Center, University of Texas Southwestern
Ramon Diaz-Arrastia, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, New York Academy of Sciences, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Jose E Cavazos, MD, PhD, FAAN, Associate Professor with Tenure, Departments of Neurology, Pharmacology, and Physiology, University of Texas Health Science Center at San Antonio; Co-Director, South Texas Comprehensive Epilepsy Center; Director of the Epilepsy Center, Audie L Murphy Veterans Affairs Medical Center
Jose E Cavazos, MD, PhD, FAAN is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and Society for Neuroscience
Disclosure: Glaxo-SmithKline Honoraria Consulting; Ortho-McNeil Neurologics Honoraria Consulting; UCB Pharma Honoraria Consulting

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

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