Generalized Tonic-Clonic Seizures

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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 and may progress to secondarily generalized seizure. Primary generalized seizures probably begin in the thalamus and other subcortical structures, but on scalp electroencephalographic (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. Some partial seizures may have an aura, but primary generalized seizures usually do not. However, secondarily generalized partial seizures are not included in the category of generalized seizures, which includes only primary generalized seizures.

Generalized 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.

The following epilepsy syndromes have generalized seizures:

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. The awake EEG of patients with generalized tonic-clonic seizure may be normal; however, certain specific interictal EEG patterns can be distinctive of generalized epilepsy syndromes (see Workup). In generalized seizure patients, the activation of photic stimulation and/or hyperventilation during an EEG may produce spikes or even seizures.

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, not only to the seizure type (see Treatment and Management, as well as Medication).

Go to Epilepsy and Seizures, First Adult Seizure, and First Pediatric Seizure for an overview of these topics.

Pathophysiology

Generalized epilepsy is thought to be initiated by 3 different mechanisms:

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 (ie, they release gamma-aminobutyric acid) 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 the following:

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.

Etiology

Most generalized epilepsies are idiopathic. However, a definite genetic locus has been found for some of these generalized types of epilepsy.

Benign familial neonatal convulsion is an autosomal dominant condition with high penetrance, resulting from mutations in a voltage-gated potassium channel gene, named KCNQ2, in chromosome 20. This gene is homologous to a gene (ie, KCNQ1) expressed in the heart, mutations of which 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.

Epidemiology

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

Developing countries have similar incidences of epilepsy, ranging from 14-57 cases per 1000 population, based on World Health Organization statistics. Internationally, as in the United States, partial seizures are the most common, but generalized tonic-clonic seizures still make up a significant percentage of seizures (20-25%).

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.

Prognosis

The morbidity for tonic-clonic seizure can be high because these patients experience no aura and thus the seizure strikes without warning; minor injuries are frequent. Patients can have posterior shoulder dislocations and broken bones.

Potential complications of generalized tonic-clonic seizures include the following:

Mortality rates for seizures are low, but, amongst the epilepsies, rates for tonic-clonic seizures are higher. 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]

Patient Education

For patient education information, see the Brain and Nervous System Center, as well as Epilepsy.

History

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. For seizures that arise out of sleep (nocturnal seizures), it may be hard to distinguish a primary generalized seizure from a partial seizure with secondary generalization.

Other symptoms that have been described less consistently are abdominal pain, facial pallor, or headache. Witnesses of a patient's seizure should be asked about the stereotypical ictal cry, which is strongly associated with generalized tonic-clonic seizures.[2]

Physical Examination

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

This stage lasts for 10-20 seconds. 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.

Clonic phase

The tonic stage gives way to clonic convulsive movements, in which the tonic muscles relax intermittently for a variable period of time.

During the clonic stage, a generalized movement occurs at a rate of about 4-8 Hz. This is because phases of atonia alternate with repeated violent flexor spasms. Each spasm is accompanied by pupillary contraction and dilation. Some patients may bite their tongue or cheek.

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 around 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.

Approach Considerations

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.

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 such as 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 may be obtained in the workup of patients with primary generalized epilepsy.

Go to EEG in Common Epilepsy Syndromes, Epileptiform Normal Variants on EEG, and Generalized Epilepsies on EEG for information on these topics.

Electroencephalography

Interictal EEG

The awake EEG of patients with generalized tonic-clonic seizure is often normal. Hyperventilation, photic stimulation, and sleep-deprived EEG can increase the likelihood of finding an abnormality on EEG.

Interictal abnormalities include usually generalized spikes, sharp waves, polyspikes, and polyspike or spike-and-wave complexes. 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, as follows:

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.

Prolactin Study

Plasma prolactin levels, if measured within 10-20 minutes of a generalized tonic-clonic seizure, are elevated to 5-30 times the baseline values. The baseline level is obtained at the same time of day when the patient is not seizing. The plasma prolactin level is a useful diagnostic tool to exclude pseudoseizures if the seizure looks like a tonic-clonic seizure. The prolactin level may not be elevated in absence and myoclonic seizures and in simple and brief complex partial seizures.

Other Laboratory Studies

In 15% of patients, especially after a prolonged seizure, cerebrospinal fluid (CSF) pleocytosis may be found (commonly 10 cells/μL and rarely as many as 50 cells/μL).

Metabolic acidosis and elevated levels of serum lactate and creatine kinase are common findings after a seizure.

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.

Computed Tomography

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.

Magnetic Resonance Imaging

Classically, MRIs are normal in primary generalized tonic-clonic seizures. Neuronal migration disorders that may be associated with partial seizures and that may be diagnosed on MRI include the following:

Positron Emission Tomography

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 and usually only when resective surgery is being considered, but that is not a therapy for this type of epilepsy.

Approach Considerations

A number of antiepileptic drugs (AEDs) 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, not to the seizure type only.

Go to Epilepsy and Seizures, First Adult Seizure, and First Pediatric Seizure for an overview of these topics.

Anticonvulsant Therapy

Valproic acid is considered the agent of first choice for patients who have multiple seizure types, including generalized tonic-clonic seizures (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 supported the primacy of valproate.[4]

Phenytoin and carbamazepine are reasonable second options among the older group of AEDs. However, the newer medications (eg, lamotrigine, topiramate, zonisamide,[5] levetiracetam) tend to work as well if not better and have better side-effect profiles, especially regarding long-term side effects. 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.[6, 7]

Special considerations

Certain AEDs 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 agents such as phenytoin, carbamazepine, and phenobarbital.

The older first-generation AEDs (eg, phenytoin, carbamazepine, phenobarbital, valproic acid) are all known teratogenic agents.

Vagus Nerve Stimulation

The US Food and Drug Administration (FDA) has approved vagus nerve stimulation (VNS) only for the treatment of partial seizures. Open-label VNS registry results have also shown that some patients with generalized tonic-clonic seizures respond well. In many years of clinical use of VNS, many patients with primary generalized seizures have had seizure reduction.

No other surgical option exists for pure generalized tonic-clonic seizures. Patients must be carefully evaluated and may necessitate video-EEG because some partial seizures with quick secondary bilateral synchrony may be labeled as primary generalized tonic-clonic.

Ketogenic Diet

A ketogenic diet can be tried to improve seizure control in younger patients whose condition is refractory. The ketogenic diet was developed at the Mayo Clinic and Johns Hopkins Institute, and it was based on the observation that seizures improved during periods of starvation. Studies have shown a substantial reduction in seizure frequency in 50% of patients placed on the diet.

The exact mechanism by which this diet works is not known. The diet typically contains a fat-to-carbohydrate ratio of 4:1. This diet produces a ketotic state but provides adequate calories for nutrition from proteins and fat.

The ketogenic diet 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. In adults, a high-protein diet is being studied.

Adverse effects are mainly gastrointestinal and include bloating, constipation, renal stones, and bone and weight loss. Urinary ketones are checked daily and need to be greater than 4+ (80-160 mg/dL.

In general related to diet, avoid excessive amounts of stimulants such as energy drinks.

Activity Restriction

Driving is restricted if patients are still having seizures as per particular state laws. In addition, common-sense restrictions for patients with epilepsy should be followed, such as not operating dangerous equipment, not swimming alone, and not taking baths unsupervised, among others.

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications. The agents used for tonic-clonic seizures include anticonvulsants such as valproate, lamotrigine, levetiracetam, phenytoin, felbamate, topiramate, and carbamazepine.

Valproate (Depakote, Depakote ER, Depakene, Depacon, Stavzor)

Clinical Context:  Considered the drug of first choice for primary generalized epilepsy, valproate has a very wide spectrum and is effective in most seizure types, including myoclonic seizures. It has multiple mechanisms of anticonvulsant effects, including increasing gamma-aminobutyric acid (GABA) levels in brain as well as T-type calcium channel activity. The extended-release (ER) formulation allows for once-a-day administration.

Ethotoin (Peganone)

Clinical Context:  Ethotoin may act in the motor cortex, where it may the inhibit spread of seizure activity. The activity of the brain stem centers responsible for the tonic phase of grand mal seizures may also be inhibited.

Phenytoin (Dilantin, Phenytek)

Clinical Context:  Phenytoin works for tonic-clonic seizures and is often used because it can be administered once a day. Long-term side effects of osteopenia and cerebellar ataxia now temper its use by neurologists. This agent is one of the most difficult antiepileptic drugs (AEDs) to use, due to its zero-order kinetics and narrow therapeutic index. In addition, it can have significant bidirectional drug interactions.

Carbamazepine (Tegretol, Tegretol XR, Carbatrol, Epitol, Equetro)

Clinical Context:  This older antiepileptic drug is used as a second-choice agent along with phenytoin. It has active metabolite 10-11 epoxide. Like phenytoin, carbamazepine has been associated with osteopenia.

Lamotrigine (Lamictal, Lamictal ODT, Lamictal XR)

Clinical Context:  Lamotrigine is a newer antiepileptic drug with a very broad spectrum of activity, like valproate. It is FDA approved for both primary generalized and partial-onset epilepsy.

Lamotrigine has several mechanisms of action that may account for its effectiveness. A major disadvantage is that the dose has to be increased very slowly over several weeks to minimize the chance of rash, especially if the patient is on valproic acid.

Zonisamide (Zonegran)

Clinical Context:  One of newer antiepileptics recently introduced in the US market, zonisamide has been studied extensively in Japan and Korea and seems to have broad-spectrum properties. It blocks T-type calcium channels, prolongs sodium channel inactivation, and is a carbonic anhydrase inhibitor.

Felbamate (Felbatol)

Clinical Context:  Felbamate is approved by the FDA for medically refractory partial seizures and Lennox-Gastaut syndrome. This agent 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. It is used only as drug of last resort in medically refractory cases because of the risk of aplastic anemia and hepatic toxicity, which necessitates regular blood tests.

Topiramate (Topamax)

Clinical Context:  An AED with a broad spectrum of antiepileptic activity, topiramate is approved for generalized tonic-clonic seizures. It has multiple mechanisms of action, including state-dependent sodium channel blocking action; it also potentiates inhibitory activity of the neurotransmitter GABA. It may block glutamate activity and is a carbonic anhydrase inhibitor.

Levetiracetam (Keppra, Keppra XR)

Clinical Context:  Levetiracetam is 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.

Rufinamide (Banzel)

Clinical Context:  An AED that is structurally unrelated to current antiepileptics, rufinamide modulates sodium channel activity, particularly prolongation of the channel's inactive state. It significantly slows sodium channel recovery and limits sustained repetitive firing of sodium-dependent action potentials. Rufinamide is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome.

Primidone (Mysoline)

Clinical Context:  Primidone decreases neuron excitability and increases the seizure threshold.

Class Summary

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

Author

David Y Ko, MD, Associate Professor of Clinical Neurology, Associate Director, USC Adult Epilepsy Program, Keck School of Medicine of the University of Southern California

Disclosure: GSK Honoraria Speaking and teaching; UCB Honoraria Speaking and teaching; Lundbeck Consulting fee Consulting; Westward Consulting fee Consulting; Esai Consulting fee Consulting; Supernus Consulting fee Consulting

Coauthor(s)

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

Disclosure: Nothing to disclose.

Specialty Editors

Ramon Diaz-Arrastia, MD, PhD, Professor, Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Southwestern Medical School; Director, North Texas TBI Research Center, Comprehensive Epilepsy Center, Parkland Memorial Hospital

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Jose E Cavazos, MD, PhD, FAAN, FANA, FACNS, Professor with Tenure, Departments of Neurology, Pharmacology, and Physiology, Assistant Dean for the MD/PhD Program, Program Director of the Clinical Neurophysiology Fellowship, University of Texas School of Medicine at San Antonio; Co-Director, South Texas Comprehensive Epilepsy Center, University Hospital System; Director, San Antonio Veterans Affairs Epilepsy Center of Excellence and Neurodiagnostic Centers, Audie L Murphy Veterans Affairs Medical Center

Disclosure: LGCH, Inc Ownership interest Consulting

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Speaking, consulting; Sunovion Consulting fee None

References

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  2. Elzawahry H, Do CS, Lin K, Benbadis SR. The diagnostic utility of the ictal cry. Epilepsy Behav. Jul 2010;18(3):306-7. [View Abstract]
  3. Morrell MJ. Differential diagnosis of seizures. Neurol Clin. Nov 1993;11(4):737-54. [View Abstract]
  4. [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. [View Abstract]
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  7. [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. [View Abstract]