AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 are associated with generalized epilepsy: 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 (GTCS) 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 GTCSs (20-25%); the majority are partial seizures.

Mortality/Morbidity

The morbidity and mortality for tonic-clonic seizure is high because these patients get no aura and thus the seizure strikes without warning. Patients can have posterior shoulder dislocations and broken bones. 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.

Age

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

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Prodromal symptoms
• • Patients with GTCSs 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 GTCSs 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. The majority of 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.
  • 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Hyperventilation and electrolyte imbalances
Prolonged QT syndrome and other arrhythmias
Dystonias including nocturnal paroxysmal dystonias
Paroxysmal dyskinesias
Encephalopathies and metabolic disorders
Pseudoepileptic seizures
Nocturnal paroxysmal events (eg, sleep apnea, night terrors)
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

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Plasma prolactin levels, if investigated within 10-20 minutes of a GTC 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 found in 10% of patients with primary GTCSs. 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 GTCSs, except if the diagnosis of primary generalized seizure itself is in doubt.

Other Tests

• Interictal EEG
• • The awake EEG of patients with GTCS 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 GTCSs; (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 GTCSs 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

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

A number of medications are used for the treatment of GTCSs. 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 since it treats a broad spectrum of seizure types, including myoclonic seizures.
• 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, and zonisamide 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.

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 GTCS respond well. No other surgical option exists for pure GTCS.

Diet

A ketogenic diet is recommended to improve seizure control. 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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Drug Category: Anticonvulsant agents

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Complications

• 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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal 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 phenytoin, especially because it is a strong teratogenic agent.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Adams RD, Ropper VM. Epilepsy and other seizure disorders. In: Adams RD, Victor M, Ropper AH, eds. Principles of Neurology. 6th ed. New York: McGraw-Hill;. 1997:315-328.
• 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.
• Morrell MJ. Differential diagnosis of seizures. Neurol Clin. Nov 1993;11(4):737-54. [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].
• Walczak TS, Leppik IE, D''Amelio M. Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study. Neurology. Feb 27 2001;56(4):519-25. [Medline].

Article Last Updated: Apr 5, 2007