Jay K. Varma, MD

DESCRIPTION

• Seizures and epilepsy syndromes can be broadly categorized into 2 groups: Partial (focal onset) and generalized. Generalized epilepsy syndromes are characterized by recurrent seizures arising from multiple, bilateral regions of the brain simultaneously. Partial epilepsy syndromes have seizures arising from a single focus often with secondary generalization or spread. A careful history, careful review of the EEG, and evaluation of seizure semiology with video-EEG recording can help distinguish between generalized and focal-onset epilepsies.
• Specific epilepsy syndromes that may manifest with generalized seizures include:
  • Childhood absence epilepsy (CAE) – characterized by typical absence seizures along with generalized tonic–clonic seizures in 40% of patients. Onset is between 3 years of age and puberty. Seizures may occur many times per day and can be elicited by hyperventilation. EEG shows characteristic generalized 3 Hz spike-and-wave discharges, up to 80% will have complete remission of seizures, typically by late adolescence.
  • Juvenile myoclonic epilepsy (JME) – characterized by myoclonic and generalized tonic–clonic seizures as well as absence seizures in 10–25% of patients. Age of onset is between age 7 and 30, but most typically in adolescence and symptoms may be lifelong. Myoclonic seizures and generalized tonic-clonic seizures tend to occur upon awakening. The EEG will reveal generalized spike-and-wave discharges, typically with a frequency greater than 3 Hz.
  • Juvenile absence epilepsy (JAE) – similar to CAE but with later age of onset (after puberty). Generalized tonic–clonic seizures are common (occurring in approximately 80% of patients) and remission is uncommon. Myoclonic seizures may occur in approximately 15% of patients but are less frequent and less conspicuous than in JME.
  • Lennox-Gastaut Syndrome (LGS) – characterized by multiple seizure types including tonic, atonic, atypical absence, generalized tonic–clonic, and myoclonic seizures. Age of onset is usually in childhood, typically before age 5. Developmental delay and/or static encephalopathy are typical, often preceding or following the onset of seizures. The interictal EEG will show slow spike-and-wave discharges (<2.5 Hz).
  • Generalized epilepsy with febrile seizures plus (GEFS+) – most patients present with febrile seizures in early childhood, approximately at the age of 1. They may present with generalized tonic–clonic seizures, absence seizures, myoclonic, atonic, or tonic seizures. Seizures persist beyond the age of 6 and into late adolescence but usually remit in the early teenage years. A positive family history of febrile seizures is key to the diagnosis. Genetic subtypes have been described; defined by mutations in the SCN1A, SCN1B, SCN2A, and GABRG2 genes.
  • Benign myoclonic epilepsy in infancy – a rare syndrome manifested as myoclonic jerks beginning at 5 months to 5 years. Myoclonic seizures may be triggered by tapping or auditory stimuli. EEG shows a normal background with generalized fast spike-and-wave or polyspike-and-wave discharges concomitant with myoclonic jerks.
  • Myoclonic-astatic epilepsy (MAE, Doose Syndrome) – seizures begin at ages of 7 months to 6 years and may be manifested by brief, symmetric jerks involving the neck, shoulders, arms, and legs resulting in head nodding, abduction of the arms, and flexion at the knees immediately followed by a loss of muscle tone causing falls. Patients may also have atonic seizures, tonic seizures, generalized tonic–clonic seizures, and atypical absence seizures.
  • Severe myoclonic epilepsy of infancy (SMEI, Dravet Syndrome) – typically presents with febrile and temperature-sensitive seizures. They may have many different seizure types including myoclonic seizures, generalized tonic–clonic seizures, atypical absence seizures, and focal seizures. The patients develop developmental delay (usually with normal development prior to onset of epilepsy), often with ataxia and upper motor neuron pattern weakness. Sodium-channel modulating drugs (carbamazepine, oxcarbazepine, lamotrigine, phenytoin) may exacerbate seizures and result in status epilepticus. Most commonly associated with SCN1A mutation.

EPIDEMIOLOGY

Incidence

The incidence of epilepsy is between 30 and 80 per 100,000 in developed nations and is significantly higher in developing nations.

Prevalence

The prevalence of epilepsy in developed nations, including generalized and focal epilepsies, is between 4 and 10 per 1,000. The prevalence is higher in developing nations.

RISK FACTORS

A family history of epilepsy is a strong risk factor for generalized epilepsy. Children of patients with epilepsy are 3 times more likely to have epilepsy than the general population.

Genetics

• The genetic contribution to epilepsy is an area of active research. Genes have been implicated as a cause of epilepsy or increased susceptibility to seizures and also to medication response and development of adverse reactions to medications.
• Genetic variants of GABA receptors and nicotinic acetylcholine receptors have been associated with epilepsy as well as gene mutations encoding calcium, sodium, potassium, and chloride-ion channels. Non-ion channel mutations have also been associated with susceptibility to developing epilepsy.
• Genetic testing may be indicated in certain circumstances.

ETIOLOGY

• Idiopathic epilepsies are commonly thought to be genetic in origin.
• Symptomatic epilepsy syndromes are often associated with a structural lesion or inborn error of metabolism.

HISTORY

• The patient should report a history of recurrent episodes concerning generalized seizure types, described in further detail below:
  • Generalized tonic–clonic seizures – characterized by 2 phases, the tonic phase and the clonic phase. The tonic phase begins with loss of consciousness and often a loud vocalization (ictal cry) generated by activation of the respiratory musculature. The tonic phase is characterized by tonic stiffening of the limbs and is followed by the clonic phase. The clonic phase typically starts with rapid clonic movements of the limbs that slow down and often become larger in amplitude before ceasing. The patient may bite his or her tongue or sustain other injuries and experience bowel or bladder incontinence. The post-ictal state is often marked by confusion and lethargy. The tonic and clonic phases may recur, and the seizures may be accompanied by marked fluctuation in heart rate, respiratory rate, and blood pressure. The presence of an aura preceding a seizure suggests a focal onset as opposed to generalized onset.
  • Typical absence seizures – sudden loss of awareness and behavioral arrest, accompanied by staring, repetitive blinking, or eye flutter typically lasting less than 15 seconds. They may also be accompanied by motor or oral automatisms (lip smacking, purposeless, or pseudo-purposeful movements). EEG will reveal 3 Hz generalized spike-and-wave activity during the seizures, which can often be provoked by hyperventilation.
  • Atypical absence seizures – similar to typical absence seizures but accompanied by unusual features including atypical EEG findings, tonic posturing, prolonged duration, or post-ictal confusion.
  • Tonic seizures – sudden onset loss of awareness with tonic stiffening, often resulting in falls and head injury.
  • Atonic seizures – sudden loss of awareness and loss of muscle tone, often resulting in a fall with injury.
  • Myoclonic seizures – characterized by a brief jerking movement of the arms and trunk, typically without alteration of consciousness. They often occur in clusters in the morning.

PHYSICAL EXAM

• A thorough neurologic examination should be performed. Idiopathic generalized epilepsy syndromes are associated with a normal neurologic examination. Generalized seizures are common in individuals with structural abnormalities of the brain.
• Hyperventilation is a simple bedside maneuver that may induce an absence seizure and can clinch the diagnosis of CAE in suspected patients.

DIAGNOSTIC TESTS AND INTERPRETATION

Lab

Initial Lab Tests

Provoking factors should be ruled out in the evaluation of an initial seizure. Electrolytes including calcium, glucose, liver function tests, renal function tests, serum antiepileptic drug (AED) levels, serum and urine drug tests may help determine the cause of an initial seizure or breakthrough seizure.

Imaging

Initial Approach

Brain MRI is the imaging study of choice. Brain imaging may not be necessary if the physical examination is normal and the history and EEG are consistent with CAE or JME.

Diagnostic Procedures/Other

• EEG is often diagnostic; careful scrutiny should be made to distinguish between focal and generalized interictal activity.
• Video-EEG monitoring is the gold-standard test to diagnose and classify seizures if the diagnosis is unclear and also if the seizures are refractory to initial treatment.

DIFFERENTIAL DIAGNOSIS

• Psychogenic nonepileptic seizures can be confused with epileptic seizures. Video-EEG monitoring can help distinguish psychogenic spells from epileptic seizures.
• Tic disorders and other movement disorders may be confused for myoclonic or other seizures.

MEDICATION

• Phenytoin can be used to treat generalized tonic–clonic seizures, but may exacerbate myoclonic seizures. Signs of toxicity include midline ataxia and diplopia. Idiosyncratic effects include gingival hypertrophy, peripheral neuropathy, and hormonal disturbances.
• Carbamazepine is effective in treatment of generalized tonic–clonic seizures but may worsen absence seizures. It is prone to causing rash, particularly in East Asian patients.
• Ethosuximide is the drug of choice to treat typical absence seizures. It is ineffective in treatment of other seizure types.
• Valproic acid is the drug of choice for a wide array of generalized seizure types including absence and generalized tonic–clonic seizures. It carries a small risk of pancreatitis and hepatotoxicity. Idiosyncratic reactions include tremor, weight gain, hair loss, and hirsutism. Valproate has been associated with a higher rate of teratogenicity than other AEDs.
• Lamotrigine is often used as a second-line agent, or in women of childbearing age due to lower potential for teratogenicity than valproic acid. It may exacerbate myoclonic seizures. Rash is a serious side effect, especially when initiated as an adjunct to valproic acid.
• Phenobarbital is effective against most seizure types but can worsen absences. Mental slowing and drowsiness are common side effects.
• Levetiracetam is effective for a broad range of seizure types. It is often used as a first-line alternate therapy to valproic acid. Irritability and psychiatric side effects can occur. Levetiracetam has no drug–drug interactions and is renally metabolized.
• Topiramate is effective against a broad range of seizures and is considered a second-line therapy. Cognitive slowing, weight loss, hypohidrosis, nephrolithiasis, paresthesias, and GI upset are common adverse reactions.
• Zonisamide is similar in profile to topiramate and is effective against a broad range of seizures.
• Felbamate is effective in LGS and other refractory forms of epilepsy. Close monitoring for hepatic failure and aplastic anemia is necessary especially when initiating the medication.
• Vigabatrin is effective against a broad range of seizure types. Patients must be monitored for irreversible peripheral vision loss from retinal toxicity.
• Rufinamide is approved for treatment of LGS. Headache, dizziness, fatigue, and somnolence are the most common side effects.
• Clonazepam is effective in treating a wide range of seizures. Concurrent administration of clonazepam and valproic acid has been reported to induce absence status. Clonazepam may induce hypersalivation and should be used with caution in patients with respiratory weakness.
• Clobazam is a newly FDA-approved long-acting benzodiazepine for treatment of LGS. Somnolence and respiratory depression are potential adverse effects.

ADDITIONAL TREATMENT

General Measures

The goal of treatment is seizure-freedom without side effects. The patient and family must be educated about epilepsy and general safety measures and precautions for seizures.

Issues for Referral

All patients with epilepsy should be followed by a neurologist who can monitor and adjust AED therapy. Patients with refractory epilepsy may benefit from evaluation at a comprehensive epilepsy center.

Additional Therapies

A ketogenic diet may be an effective treatment in refractory epilepsy.

SURGERY/OTHER PROCEDURES

• Vagus nerve stimulation may reduce the frequency of seizures.
• Callosotomy may be considered as a palliative treatment in patients with severe refractory tonic, atonic, or generalized tonic–clonic seizures.

Pregnancy Considerations

Women of childbearing age should be counseled on the risk of teratogenic effects of AEDs, particularly valproic acid. The risk of major congenital malformations increases with increase in doses and increase in numbers of medications.

PATIENT EDUCATION

Patients with uncontrolled seizures should be counseled against driving and operating heavy machinery. State and local laws vary regarding mandatory reporting of a diagnosis of epilepsy to the authorities. They should take caution when standing at heights or when swimming or bathing. Patients with generalized tonic–clonic, tonic, and atonic seizures are at significant risk of injury from falling.

PROGNOSIS

Prognosis is highly dependent upon the epilepsy syndrome.

• Mantoan L, Walker M. Treatment options in juvenile myoclonic epilepsy. Curr Treat Options Neurol 2011;13(4):355–370.
• Mulley JC, Scheffer IE, Petrou S, et al. Channelopathies as a genetic cause of epilepsy. Curr Opin Neurol 2003;16:171–176.

ICD9

• 345.00 Generalized nonconvulsive epilepsy, without mention of intractable epilepsy
• 345.10 Generalized convulsive epilepsy, without mention of intractable epilepsy
• 345.90 Epilepsy, unspecified, without mention of intractable epilepsy

Careful determination of the type of generalized seizure syndrome assists in identification of efficacious therapy.