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emedicine.medscape.com

Generalized Tonic-Clonic
Seizures
Updated: Nov 27, 2017
Author: David Y Ko, MD; Chief Editor: Selim R Benbadis, MD

Overview

Background
A seizure is an abnormal paroxysmal discharge of cerebral neurons due to cortical hyperexcitability. The new
International Classification of Seizures divides seizures into 3 categories: generalized onset, focal onset (formerly
partial seizures) and unknown onset.[8] This article uses the term "partial seizures" throughout although the term focal
is now the official term. However, many patients and practitioners are using old terminology.

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 (now called bilateral tonic clonic, with the term
generalization reserved for primary generalized seizure only).[8] 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 (the new classification discourages the use of aura and suggests
the term simple focal seizure aware instead), but primary generalized seizures usually do not. However, secondarily
generalized partial seizures (now called focal with bilateral tonic clonic in the new classification) 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 may have generalized seizures:

Benign neonatal convulsions

Benign myoclonic epilepsy of infancy

Childhood absence epilepsy

Juvenile absence epilepsy

Juvenile myoclonic epilepsy

Generalized tonic-clonic seizures upon awakening

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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:

Abnormal response of hyperexcitable cortex to initially normal thalamic input

Primary subcortical trigger

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 (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:

A lateral geniculate body, which produces a generalized tonic-clonic seizure when kindled in the cat

Ascending pathways through the mamillary bodies and anterior thalamus

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.

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

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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:

Head trauma and trauma to the tongue, lips, and cheeks

Vertebral compression fractures

Aspiration pneumonia

Neurogenic pulmonary edema

Cardiac arrhythmias

Sudden death

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.

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Presentation

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/focal
aware 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 decreased consciousness during which the patient becomes quiet and

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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.

Complications
Seizures may lead to injuries, including falls, shoulder dislocation, burns, fractures, oral/tongue trauma, and urinary or
bowel incontinence. Loss of memory and postictal state and even brain injury may result, as well as aspiration
pneumonia, and if prolonged, rhabdomyolysis. If a seizure does not stop, it can lead to status epilepticus. There may
be an increased risk of Sudden Unexplained Death in Epilepsy (SUDEP).

DDx

Diagnostic Considerations
The following conditions should be considered in the assessment of patients with possible generalized tonic-clonic
seizures:

Hyperventilation and electrolyte imbalances

Prolonged QT syndrome and other arrhythmias

Dystonias including nocturnal paroxysmal dystonias

Paroxysmal dyskinesias[3]

Encephalopathies and metabolic disorders

Pseudoepileptic seizures or nonepileptic seizures

Nocturnal paroxysmal events (eg, sleep apnea, night terrors)[3]

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 spells[3]

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

Differential Diagnoses
Complex Partial Seizures

Confusional States and Acute Memory Disorders

Dizziness, Vertigo, and Imbalance

Frontal Lobe Epilepsy

Migraine Variants

Narcolepsy

Pediatric Febrile Seizures

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Pediatric Status Epilepticus

Syncope

Viral Encephalitis

Workup

Workup

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 if there is a suspicion of focal to bilateral tonic clonic seizures (the
secondarily generalized seizures).

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 may be normal. Hyperventilation, photic stimulation,
sleep-deprivation and/or prolonged 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:

Generalized bilaterally synchronous 3-Hz spike-and-wave complexes are associated with typical absence
attacks

Fast spike-and-wave activity at 4-5 Hz is associated most often with generalized tonic-clonic seizures

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.

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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:

Lissencephaly

Pachygyria

Band or laminar heterotopias

Subependymal heterotopias

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Focal cortical dysplasia polymicrogyria

Focal subependymal heterotopias

Schizencephaly

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.

Other Tests
If there is a strong family history, or semiology is consistent with certain epilepsy syndromes that are genetic, then
genetic testing may be useful. The genetic epilepsies are increasing and the testing costs are decreasing.

Procedures
The abliity to get ictal studies is increased with ambulatory video EEG and if the events are less frequent then inpatient
video EEG where AED can be reduced or withdrawn to induce typical seizue.

Treatment

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 has been considered the AED of 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] The selection of AED has to be

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personalized for each patient due to side-effect profile (e.g., valproic acid can cause weight gain, so if the patient is
obese it can worsen that medical issue).

Phenytoin and carbamazepine are reasonable second options among the older group of AEDs for partial to
secondarily generalized seizures (focal to bilateral tonic clonic seizures). However, the newer medications (e.g.,
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.

Perampanel (Fycompa) is approved as adjunctive treatment for primary generalized tonic-clonic seizures in adults and
children aged 12 years or older. Perampanel has also shown good efficacy in reducing partial seizures with secondary
generalization.

The AED rufinamide (Banzel) has been approved as adjunctive therapy for seizures associated with Lennox-Gastaut
syndrome (LGS).[6, 7] Another AED, clobazam (Onfi/Frisium), has been useful in seizures associated with LGS as
well in the United States, but worldwide use of this drug for many years also suggests good coverage for primary
generalized tonic-clonic seizures.

For refractory generalized epilepsy, felbamate also is used as an agent of last resort and is very effective. The
potential adverse effects of felbamate necessitate very careful monitoring of blood counts and liver function tests.

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 (e.g., phenytoin, carbamazepine, phenobarbital, valproic acid, and topiramate) have a
teratogenic risk that needs to be considered.

Vagus Nerve Stimulation

The US Food and Drug Administration (FDA) approval for vagus nerve stimulation (VNS) is for the adjunctive
treatment of refractory partial seizures. Open-label VNS registry results have also shown that some patients with
generalized tonic-clonic seizures respond well. In more than 20 years of clinical use in the United States, VNS has
helped reduce seizures in many patients with primary generalized seizures.

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 popularized at Johns Hopkins and spread widely. 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 low-carbohydrate diet is

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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 affecting safe driving 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. Cooking with open flame may be dangerous,
leading to burn injuries.

Surgical Care
Surgical options for primary generalized seizures are limited to vagus nerve stimulation (VNS).

Diet
Epileptic individuals should avoid alcohol due to its potential to interact with AEDs. Alcohol use, if sufficient, can also
lower the seizure threshold.

Medication

Medication Summary
The goals of pharmacotherapy are to reduce seizure frequency, severity, and morbidity and prevent complications with
the least side effects. The agents used for tonic-clonic seizures include anticonvulsants such as valproate, lamotrigine,
levetiracetam, felbamate, topiramate, zonisamide, clobazam, and perampanel.

Anticonvulsant Agents

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

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

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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, which
is important for absence seizures. The extended-release (ER) formulation allows for once-a-day administration.

Ethotoin (Peganone)
Ethotoin may act in the motor cortex, where it may stabilize the seizure threshold and inhibit the 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)

Phenytoin is effective in the treatment of tonic-clonic seizures and is often used because it can be administered once a
day if the extended release formulation is administered (there is also an IV formulation). Acute adverse
effects include rash and a remote risk of SJS. Long-term use may cause osteopenia and cerebellar ataxia, which has
caused practitioners to prescribe it less often. It is one of the most difficult AEDs to use due to its zero-order kinetics
and narrow therapeutic index. Recent studies have reported different serum levels when patients use the brand and
generic phenytek. In addition, it can have significant drug interactions. The need to monitor liver function, CBC, and
drug levels (including free fraction in those with altered protein) add to the cost of using this AED.

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

This AED is used as a second-choice agent along with phenytoin. It has active metabolite 10-11 epoxide. Like
phenytoin, carbamazepine has been associated with rash and osteopenia. The rash can progress to SJS and has an
HLA-B1502 marker, which needs to be tested on Asian patients. An IV formulation that is to be used for 7 days or less,
when oral administration is temporarily not feasible, has been recently approved and has received orphan designation.
The manufacturer plans to make it available in 2017.

Lamotrigine (Lamictal, Lamictal ODT, Lamictal XR)

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)
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)
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, Quedexy, Trokendi XR, Topamax Sprinkle)

An AED with a broad spectrum of antiepileptic activity, topiramate is approved for generalized tonic-clonic seizures. It

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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, Roweepra, Spritam)

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)
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)
Primidone decreases neuron excitability and increases the seizure threshold.

Perampanel (Fycompa)
Perampanel is a noncompetitive antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
glutamate receptor. It is indicated as adjunctive treatment for primary generalized tonic-clonic seizures and for partial-
onset seizures (with or without secondary generalized seizures) in adults and children aged 12 years or older.

Clobazam (ONFI)
Clobazam is a 1,5-benzodiazepine that possesses potent anticonvulsant properties. May enhance the inhibitory effect
of GABA on neuronal excitability by increasing neuronal membrane permeability to chloride ions. Has been approved
as adjunct treatment for refractory epilepsy, specifically LGS, in pediatric and adult patients.

Questions & Answers

Overview

What are generalized tonic-clonic seizures (GTCS)?

Which epilepsy syndromes are associated with generalized tonic-clonic seizures?

How are generalized tonic-clonic seizures diagnosed and treated?

Which mechanisms initiate generalized tonic-clonic seizures?

What is the pathophysiology of generalized tonic-clonic seizures?

What is the role of the brainstem in the pathogenesis of generalized tonic-clonic seizures?

What causes generalized tonic-clonic seizures?

What is the prevalence of generalized tonic-clonic seizures?

What is the morbidity associated with generalized tonic-clonic seizures?

What are the mortality rates for generalized tonic-clonic seizures?

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What are sources of patient education for generalized tonic-clonic seizures?

Presentation

Which clinical history findings are characteristic of generalized tonic-clonic seizures?

Which physical findings are characteristic of generalized tonic-clonic seizures?

What are the signs and symptoms of the tonic phase of generalized tonic-clonic seizures?

What are the signs and symptoms of the clonic phase of generalized tonic-clonic seizures?

What are the signs and symptoms of the postictal state of generalized tonic-clonic seizures?

What are the possible complications of generalized tonic-clonic seizures?

DDX

Which conditions should be included in the differential diagnoses of generalized tonic-clonic seizures?

What are the differential diagnoses for Generalized Tonic-Clonic Seizures?

Workup

Which tests are performed in the workup of generalized tonic-clonic seizures?

Which interictal EEG findings suggest generalized tonic-clonic seizures?

Which ictal EEG findings suggest generalized tonic-clonic seizures?

Which postictal EEG findings suggest generalized tonic-clonic seizures?

What is the role of prolactin studies in the workup of generalized tonic-clonic seizures?

What is the role of lab testing in the workup of generalized tonic-clonic seizures?

What is the role of CT scanning in the workup of generalized tonic-clonic seizures?

What is the role of MRI in the workup of generalized tonic-clonic seizures?

What is the role of PET scanning in the workup of generalized tonic-clonic seizures?

What is the role of genetic testing in the workup of generalized tonic-clonic seizures?

What is the role of ambulatory video EEG in the workup of generalized tonic-clonic seizures?

Treatment

How are generalized tonic-clonic seizures treated?

What is the role of anticonvulsants in the treatment of generalized tonic-clonic seizures?

What are possible adverse effects of anticonvulsants for the treatment of generalized tonic-clonic seizures?

What is the role of vagus nerve stimulation in the treatment of generalized tonic-clonic seizures?

What is the role of ketogenic diet in the treatment of generalized tonic-clonic seizures?

Which activity modifications are used in the treatment of generalized tonic-clonic seizures?

Which surgical procedures are used in the treatment of generalized tonic-clonic seizures?

Which dietary modifications are used in the treatment of generalized tonic-clonic seizures?

Medications

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What are goals of drug treatment for generalized tonic-clonic seizures?

Which medications in the drug class Anticonvulsant Agents are used in the treatment of Generalized Tonic-Clonic
Seizures?

Contributor Information and Disclosures

Author

David Y Ko, MD Associate Professor of Clinical Neurology, Loma Linda University School of Medicine

David Y Ko, MD is a member of the following medical societies: American Academy of Neurology, American Clinical
Neurophysiology Society, American Epilepsy Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: SK<br/>Serve(d) as a
speaker or a member of a speakers bureau for: Eisai, Lundbeck, Sunovion, Supernus, UCB.

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

Soma Sahai-Srivastava, MD is a member of the following medical societies: American Academy of Neurology,
American Medical Association, American Headache Society

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Disclosure: Received salary from Medscape for employment. for: Medscape.

Jose E Cavazos, MD, PhD, FAAN, FANA, FACNS, FAES Professor with Tenure, Departments of Neurology,
Neuroscience, 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

Jose E Cavazos, MD, PhD, FAAN, FANA, FACNS, FAES is a member of the following medical societies: American
Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, American Neurological
Association, Society for Neuroscience

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Brain Sentinel,
consultant.<br/>Stakeholder (<5%), Co-founder for: Brain Sentinel.

Chief Editor

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

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, American
Medical Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Ceribell, Eisai,
Greenwich, Growhealthy, LivaNova, Neuropace, SK biopharmaceuticals, Sunovion<br/>Serve(d) as a speaker or a
member of a speakers bureau for: Eisai, Greenwich, LivaNova, Sunovion<br/>Received research grant from: Cavion,
LivaNova, Greenwich, Sunovion, SK biopharmaceuticals, Takeda, UCB.

Additional Contributors

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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

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, Phi Beta Kappa

Disclosure: Nothing to disclose.

References

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