eMedicine Specialties > Neurology > Seizures and Epilepsy
Generalized Tonic-Clonic Seizures: Treatment & Medication
Updated: May 6, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
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.
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
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)
Documented hypersensitivity; hepatic disease/dysfunction
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.
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
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
Documented hypersensitivity
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.
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
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)
Documented hypersensitivity
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.
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
Enzyme inducer, reduces levels of carbamazepine, valproate, lamotrigine, tiagabine, zonisamide, theophylline, warfarin, and cimetidine; valproate increases levels
Documented hypersensitivity
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.
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
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
Documented hypersensitivity
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.
Adult
100 mg/d PO bid initially, increase by 100 mg/d/wk to maintenance of 100-300 mg PO bid
Pediatric
Not established
May increase serum carbamazepine levels; carbamazepine may increase concentrations; phenobarbital may decrease levels
Documented hypersensitivity, history of urolithiasis
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.
Adult
600 mg PO tid initially, increase by 600-1200 mg/d each wk to maximum 1200-1600 mg PO tid
Pediatric
Not established
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
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
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.
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
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
Documented hypersensitivity
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.
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
None reported; does not inhibit CYP450 isoenzymes, epoxide hydrolase, or UDP-glucuronidation; probenecid inhibits renal clearance of ucb L057 (inactive levetiracetam metabolite)
Documented hypersensitivity
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.
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
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 Cmax of triazolam
Documented hypersensitivity; history of familial short QT syndrome; severe hepatic impairment
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
More on Generalized Tonic-Clonic Seizures |
| Overview: Generalized Tonic-Clonic Seizures |
| Differential Diagnoses & Workup: Generalized Tonic-Clonic Seizures |
 Treatment & Medication: Generalized Tonic-Clonic Seizures |
| Follow-up: Generalized Tonic-Clonic Seizures |
| References |
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References
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Morrell MJ. Differential diagnosis of seizures. Neurol Clin. Nov 1993;11(4):737-54. [Medline].
[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].
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].
Kluger G, Bauer B. Role of rufinamide in the management of Lennox-Gastaut syndrome (childhood epileptic encephalopathy). Neuropsychiatr Dis Treat. Feb 2007;3(1):3-11. [Medline].
[Best Evidence] Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology. May 20 2008;70(21):1950-8. [Medline].
Epilepsy and other seizure disorders. In: Ropper AH and Samuels M, eds. Adams and Victor's Principles of Neurology. 9th ed. New York: McGraw-Hill; 2009.
Clark S, Wilson WA. Mechanisms of epileptogenesis. Adv Neurol. 1999;79:607-30. [Medline].
Engel J, Pedley TA. Generalized convulsive seizures. In: Engel J, Pedley TA, eds. Epilepsy: A Comprehensive Textbook. 3 vol. Philadelphia: Lippincott-Raven; 1997:2417-2426.
Kerrigan JF, Fisher RS. Recurrent generalized and partial epilepsy. In: Current Therapy in Neurologic Disease. Philadelphia: BC Decker; 1997:52-53.
Further Reading
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
