Symptomatic Generalized Epilepsy

Symptomatic generalized epilepsy (SGE) encompasses a group of challenging epilepsy syndromes. As a group, SGE has 3 main features: (1) multiple seizure types, especially generalized tonic and atonic seizures; (2) brain dysfunction other than the seizures, in the intellectual domain (mental retardation or developmental delay) and in the motor domain (cerebral palsy); and (3) EEG evidence of diffuse brain abnormality.

The following are examples of epilepsy syndromes that are included in the category of SGE:

• Early myoclonic encephalopathy

• Early infantine epileptic encephalopathy with suppression bursts or Ohtahara syndrome

• West syndrome

• Epilepsy with myoclonic atonic seizures

• Epilepsy with myoclonic absence

• Lennox-Gastaut syndrome

• Progressive myoclonic epilepsies

See the following Medscape Reference epilepsy topics for more information on these conditions:

• Absence Seizures

• Benign Childhood Epilepsy

• Complex Partial Seizures

• Epilepsy and Seizures

• Juvenile Myoclonic Epilepsy

• Lennox-Gastaut Syndrome

• Myoclonic Epilepsy Beginning in Infancy or Early Childhood

• Partial Epilepsies

• Reflex Epilepsy

Overall, seizures are a paroxysm of high-frequency or synchronous low-frequency high-voltage electrical discharges that cause a sudden alteration in the CNS. Three conditions are involved: (1) population of pathologically excitable neurons, (2) an increase in excitatory glutaminergic activity, and (3) reduction of inhibitory GABAergic projections.[1] In symptomatic generalized epilepsy, an underlying structural or metabolic derangement is also present. EEG findings reflect age-related changes as the brain matures.[2]

Frequency

Assessing the frequency of symptomatic generalized epilepsy (SGE) is difficult because the definition varies and can be more or less inclusive.

In a study by Ohtahara and Yamatogi, 12 of 16 patients with Ohtahara syndrome developed into West syndrome or infantile spasms between ages 3 and 6 months as defined by EEG findings.[3] Infantile spasms affect 1 in 2000 infants.[4] Lennox-Gastaut syndrome has an incidence of 1.9-2.1 cases per 100,000 children and accounts for 6-7% of intractable pediatric epilepsy; however, this depends of the definition used for Lennox-Gastaut syndrome.

Mortality/Morbidity

A study of social outcomes in a Nova Scotia study found that 20 years after diagnosis of childhood-onset symptomatic generalized epilepsy (SGE), 25% die. All survivors have mental retardation and depend on parents and institutions in terms of living and finances.[5] Most patients with SGE grow up to have intractable epilepsy, with a small percentage who are seizure free with no antiepileptic drugs.[5] In a follow-up study of 14 patients with Ohtahara syndrome, 4 died early and the remaining 10 were severely handicapped.[6]

Age

These refer to age at onset. In adulthood, most patients with symptomatic generalized epilepsy (SGE) have a less well-defined syndrome that still has the characteristics of SGE and is closest to a Lennox-Gastaut syndrome (intractable multiple seizure types, mental retardation, and cerebral palsy). Note the following progression:

• Neonates - Early myoclonic encephalopathy, early infantine epileptic encephalopathy with suppression bursts, or Ohtahara syndrome

• Infancy - West syndrome

• Childhood - Epilepsy with myoclonic atonic seizures, epilepsy with myoclonic absence, Lennox-Gastaut syndrome

• Adolescence-adults - Progressive myoclonic epilepsies

The history is the most important diagnostic tool and should include the following:

• Birth, mother’s pregnancy, and developmental history

• CNS infections

• Head trauma

• Family history of seizures

• Seizure description by witness

The following are types of seizures seen in symptomatic generalized epilepsy (SGE):

• Myoclonic - Brief muscle jerks, single or in clusters, affecting any group of muscles, usually in the trunks and limbs

• Clonic - Repetitive and rhythmic jerking of limbs, neck, or face

• Tonic - Symmetric or asymmetric stiffening or posturing

• Atonic - Abrupt loss of muscle tone, usually truncal and resulting in a head drop or a fall

• Atypical absence - Similar to absence seizure but longer and with less clear onset and end

• Generalized tonic-clonic seizures

Epilepsy syndromes that are included in the category of SGE are discussed below.

Early myoclonic encephalopathy and early infantile epileptic encephalopathy with suppression burst/Ohtahara syndrome

As implied in the name, this has early onset (< 28 d). The first seizure can occur a few hours after birth and persist in both sleeping and waking hours. Early myoclonic encephalopathy has an erratic focal myoclonus, which can migrate throughout the infant's body. In Ohtahara syndrome, tonic spasms are the dominant seizure type, with little to no myoclonic seizures.[7, 8] As the brain continues in development, 40-60% of these infants have movements that can then evolve into flexor or extensor spasms seen in infantile spasm or West syndrome.

West syndrome

This consists of the characteristic triad of infantile spasms, mental retardation, and an EEG pattern of hypsarrhythmia. The infantile spasms can have a cluster of tonic flexion (transient neck, trunk, and extremity contraction) or extension of the axial body and limbs (backward extension of head and trunk and abduction of extremities). Focal cortical dysplasia can cause specific features such as focal tonic stiffening or focal movements such as head or eye deviation.[9]

Lennox-Gastaut syndrome

This consists of the characteristic triad of multiple seizure types, mental retardation, and EEG findings that include slow diffuse spike-wave complexes less than 2.5 Hz.[10, 11] Onset of symptoms begins approximately at age 2-6 years, with continuation into adult life. Of the various seizure types involved, atonic and tonic are most characteristic. Cognitive decline occurs within the first year of onset of seizures or can precede seizure onset.[2] The nosologic borders of Lennox-Gastaut syndrome are imprecise and somewhat arbitrary. "Lumpers" include virtually any type of SGE, whereas "splitters" require slow spike-wave complexes to make a diagnosis of Lennox-Gastaut syndrome.

Epilepsy with myoclonic atonic status and epilepsy with myoclonic absence

These can essentially be viewed as variants of Lennox-Gastaut syndrome. Both have a similar triad of multiple seizure types, mental retardation, and EEG findings with a 2-3 Hz spike-wave complex (slightly faster than Lennox-Gastaut syndrome). Age of onset is approximately 2 years, with first seizure type as generalized tonic-clonic. Later, the seizures predominately become myoclonic, atonic, and absence. The absence seizures involved in this syndrome are often prolonged, with bilateral limb myoclonus, differentiating it from idiopathic childhood absence seizures, for which seizure duration involves seconds and can be accompanied with only mild jerks of eyes, eyelids, or eyebrows.

Progressive myoclonic epilepsy

This is a group of epilepsies secondary to metabolic and neurodegenerative conditions. This consists of a triad of multiple seizure types, cerebellar impairment, and cognitive deterioration. The seizure onset is often in childhood and is characterized by intractable myoclonic jerks with tonic-clonic seizures and massive myoclonic seizures.[12, 13] The myoclonic jerks are multifocal and fragmentary, precipitated by posture or external stimuli such as sound, light, or touch.[14] Cerebellar degeneration presents as ataxia, dysarthria, and tremor. Dementia follows seizure onset and is progressive. Specific syndromes of progressive myoclonic epilepsy with key clinical features include Unverricht-Lundborg disease (Baltic myoclonus), myoclonus epilepsy with ragged red fibers (MERRF), neuronal ceroid lipofuscinoses (Batten disease), and sialidoses (cherry-red spot myoclonus syndrome).

It is important to recognize that many patients with SGE do not fit precisely into one of the above syndromes. In fact, beyond childhood, probably the majority of such patients have changed both clinically and based on EEG findings, so that they cannot be pigeon-holed into a named syndrome. These patients still belong under the broad category of SGE, and it is important for general neurologists to recognize this. Patients with Lennox-Gastaut, for example, when they grow up, do not become patients with complex partial seizures, an often-used wastebasket diagnosis. They are better categorized as having an SGE or "grown-up" Lennox-Gastaut syndrome. Now that medications have been approved with an indication for Lennox-Gastaut syndrome, this becomes more than a semantic or theoretical issue.

Most patients with symptomatic generalized epilepsy (SGE) have neurological findings that reflect other abnormalities, including cognitive (mental retardation or development delay) and motor (cerebral palsy).[1, 7, 8]

Symptomatic generalized epilepsy (SGE) is defined as epilepsy secondary to an underlying etiology, either known (symptomatic) or presumed (cryptogenic). The insult associated with SGE can be prenatal (genetic or extrinsic), perinatal (birth trauma or anoxia), or postnatal (eg, trauma, infection).

Causes include specific entities such as metabolic disorders, chromosomal abnormalities, white matter disease, and obvious structural lesions.

The following studies are intended to determine the etiology:

• Electrolyte evaluation

• CBC count

• Metabolic testing

• Genetic testing

MRI of the brain is also used to determine the etiology.

EEG

The EEG in symptomatic generalized epilepsy (SGE) typically reveals epileptiform abnormalities and other evidence of diffuse brain dysfunction (various degrees of slowing). As the brain develops from neonate to adolescent, the epileptiform abnormalities can also change.

In neonates with SGE, early myoclonic encephalopathy and Ohtahara syndrome have EEG findings with a suppression-burst pattern. The myoclonic jerks of early myoclonic encephalopathy correlate with the burst of spikes, sharp waves, and slow waves lasting 1-5 seconds on EEG, with periods of suppression of 3-10 seconds with no normal background.[7, 15]

The EEG in Ohtahara syndrome shows bursts of 2-6 seconds of wide amplitude spikes and polyspikes that alternate with 3-8 seconds of suppressed electrical activity. Later in infancy, the burst-suppression pattern is replaced by continuous multifocal spikes and slow waves of large amplitude or hypsarrhythmia, as is seen in infantile spasm.[1] The hypsarrhythmia represents spread of epileptic activity when the brain has not developed inhibition.[9]

As the brain continues to mature, EEG patterns in children with SGE can evolve into a generalized, high-amplitude, synchronous, slow spike, polyspike, and slow wave discharges of 1.5-2.5 Hz, as is seen in Lennox-Gastaut syndrome.[6] The interictal EEG shows a generalized slow spike-wave pattern, further activated by drowsiness and sleep.[16]

EEG findings progressive myoclonic epilepsy reveal a specific pattern unique to the syndrome. EEG in Lafora disease reveals occipital spikes in 50% of patients.

Unverricht-Lundborg disease EEG findings reveal background slowing in theta frequency, with a 3-5 Hz polyspike, and waves discharge with sporadic focal spikes and wave discharges.

EEG in patients with sialidosis reveals progressive slowing of background activity with bilateral spike and wave activity, which is photosensitive.

Beyond early childhood and almost regardless of etiology, the typical EEG of SGE includes slow (< 2.5 Hz) spike and wave complexes and multifocal spikes. Ictal patterns are described in EEG-video monitoring.

For more information, see EEG in Common Epilepsy Syndromes and Generalized Epilepsies on EEG.

No procedures are indicated, except for in specific neurodegenerative diseases that are typically investigated during childhood. If the latter conditions are suspected, then cerebrospinal fluid analysis should be performed. If a specific genetic condition is suspected, then chromosomal analysis or skin biopsy for electron microscopy may be diagnostic.

Symptomatic generalized epilepsy (SGE) is often intractable to antiepileptic medications, and no consensus has been reached on how it should be treated. Usually, many drug trials are needed to achieve reasonable seizure control. When neonates and infants as old as 1 year initially present with intractable seizures, a trial of intravenous (IV) pyridoxine should be administered in case the neonate has a pyridine-dependent seizure. When seizures remain uncontrolled with antiepileptic drugs, nonpharmacologic options should be considered, such as ketogenic diet, vagus nerve stimulation, and surgical options.

Antiepileptic medication

Myoclonic encephalopathy is found to respond to pyridoxine and benzoate. Ohtahara syndrome is found to respond to phenobarbital and zonisamide. Case reports have shown that corticotropin (ACTH) has not been useful in decreasing seizure frequency.

Traditionally, infantile spasm/West syndrome is treated with ACTH, corticosteroids, or benzodiazepines (Clonazepam). A Cochrane Database Systematic Review found strong evidence that high-dose hormonal treatments of prednisolone alleviates spasms faster and improves long-term developmental delay compared with vigabatrin for infantile spasms of no underlying cause.[17, 18] West syndrome associated with tuberous sclerosis responds best to vigabatrin,[4] and, in this setting, vigabatrin has become the drug of choice in many countries.

Lennox-Gastaut syndrome treatment involves valproate, lamotrigine, topiramate, rufinamide, and felbamate.[2] Risk factors associated with felbamate include aplastic anemia and hepatoxicity. Antiepileptic drugs to avoid include carbamazepine, oxcarbazepine, phenytoin, and vigabatrin.

Myoclonic atonic treatment involves valproic acid, lamotrigine, and benzodiazepine.[2] Seizures are worsened by carbamazepine, oxcarbazepine, phenytoin, vigabatrin, and phenobarbital.[2]

Myoclonic absence treatment involves a combination of ethosuximide and valproate.

Progressive myoclonic epilepsy treatment involves a combination of valproic acid, ethosuximide, benzodiazepines, phenobarbital, zonisamide, and lamotrigine.[19] Antiepileptic drugs to avoid because they may exacerbate myoclonus include phenytoin, carbamazepine, vigabatrin, and tiagabine. Lamotrigine should be used with caution as it can exacerbate myoclonus. Zonisamide as add-on therapy was been found to be useful in a study by Kyllerman and Ben-Menachem in which 7 patients with progressive myoclonic epilepsy who had intractable seizures on a regimen of valproic acid and benzodiazepine had reduction of seizures after the addition of zonisamide.[20]

Go to Antiepileptic Drugs for more information.

Ketogenic diet

The ketogenic diet is used in children aged 1-10 years and consists of 90% of daily calories coming from fat. Typically, the diet is initiated in a hospital setting because the child must undergo 1-2 days of starvation to induce the ketosis. Then, the ketogenic diet is started. Approximately 10% of children who undergo the ketogenic diet have complications of nephrolithiasis; the risk is higher in children on topiramate. Several reviews have concluded there are benefits with the ketogenic diet as treatment for intractable pediatric epilepsy, which is often symptomatic generalized epilepsy (SGE).[21]

A review by Lefevre and Aronson found a reduction of seizure frequency in two thirds of the children, which subsequently permitted a reduction in their seizure medication.[22] In a study examining the long-term effects after cessation of the ketogenic diet on pediatric patients with epilepsy, 60% with SGE, the most common adverse effect was less than tenth percentile for height.[4] A ketogenic diet was the most effective treatment in decreasing seizures in a pediatric group of 23 myoclonic astatic epilepsy patients.[23]

Vagus nerve stimulation

The vagal nerve stimulator is a pacemakerlike device implanted in the chest with stimulating electrodes that connect to the vagus nerve at the left carotid bifurcation. The stimulator is found to decrease as much as 25% of seizures in intractable partial or secondarily generalized seizures.[1]

The mechanism of action is unknown, and its use is still considered experimental. In a retrospective trial of 46 patients with Lennox-Gastaut syndrome, vagus nerve stimulation resulted in 43 patients having a 58.2% median seizure reduction in 3 months.[24] The most common adverse effect reported was coughing during the stimulation and voice alteration.

Go to Vagus Nerve Stimulation for more information.

Corpus callosotomy is a surgical option for patients with drop attacks and atonic and tonic seizures and has also reduced the rates of generalized tonic-clonic seizures.[25] In patients with Lennox-Gastaut syndrome, patients with atonic or tonic seizures as the primary seizure type have the option of resection of the complete corpus callosum or just the anterior portion. If the patient has mental retardation, the recommendation is a 90-100% (complete) corpus callosotomy. If the patient has no mental retardation, then an anterior 75% corpus callosotomy is recommended. Vagus nerve stimulation should be attempted before surgery.

Consultation with a neurosurgeon may be needed.

See Ketogenic diet in Medical Care.

Pediatric patients who present with seizures require close follow-up because epilepsy syndromes transform into other syndromes as the patient grows older.

Patients with symptomatic generalized epilepsy (SGE) often have long-term complications from antiepileptic drug adverse effects; thus, maximizing all treatment options such as ketogenic diet and vagus nerve stimulation are encouraged.

The seizures in symptomatic generalized epilepsy (SGE) are often intractable, and patients require continued supportive management of their underlying brain lesions.

The goals of pharmacotherapy are to prevent epileptic seizures, reduce morbidity, and prevent complications. Antiepileptic drugs, corticotropin ACTH, and vigabatrin are indicated.

Class Summary

Vitamins are used to meet dietary requirements and are used in metabolic pathways, as well as in DNA and protein synthesis.

Pyridoxine (Aminoxin, Pyri-500)

Involved in synthesis of GABA within the CNS.

Class Summary

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

Zonisamide (Zonegran)

Indicated for adjunctive treatment of partial seizures with or without secondary generalization. Evidence indicates it is also effective in myoclonic and other generalized seizure types.

Phenobarbital

Important to use minimal amount required and to wait for anticonvulsant effect to develop before giving second dose. Start with loading dose and continue with maintenance dosage.

Clonazepam (Klonopin)

Long-acting benzodiazepine that increases presynaptic GABA inhibition and reduces monosynaptic and polysynaptic reflexes. Suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters. Has multiple indications, including suppression of myoclonic, akinetic, or petit mal seizure activity and focal or generalized dystonias (eg, tardive dystonia). Reaches peak plasma concentration at 2-4 h after oral or rectal administration.

Vigabatrin (Sabril)

This agent inhibits GABA transaminase, which increases levels of the inhibitory molecule GABA within the brain.

Valproic acid (Depacon, Depakene, Stavzor)

Chemically unrelated to other drugs that treat seizure disorders. Although mechanism of action is not established, activity may be related to increased brain levels of GABA or enhanced GABA action. Valproate may also potentiate postsynaptic GABA responses, affect potassium channel, or have a direct membrane-stabilizing effect.

For conversion to monotherapy, concomitant antiepilepsy drug dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may start at initiation of therapy or can be delayed by 1-2 weeks if there is concern that seizures may occur with a reduction. Monitor patients closely during this period for increased seizure frequency.

As adjunctive therapy, divalproex sodium may be added to the patient's regimen at 10-15 mg/kg/d. May increase by 5-10 mg/kg/wk to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses of less than 60 mg/kg/d.

Lamotrigine (Lamictal)

Efficacy as adjunctive therapy against seizures associated with Lennox-Gastaut syndrome was demonstrated in 2 controlled trials and multiple open-label studies. Valuable for patients with Lennox-Gastaut syndrome despite risk of idiosyncratic dermatologic reactions. Consider for use as soon as diagnosis of Lennox-Gastaut syndrome is made. Proper attention to concomitant medications, low starting dose, and very slow titration can minimize risk of dermatologic reactions. Initial dose, maintenance dose, titration intervals, and titration increments depend on concomitant medications.

Topiramate (Topamax)

In a multicenter, double-blind, placebo-controlled trial, found to be safe and effective as adjunctive therapy (target dose 6 mg/kg/d) for patients with Lennox-Gastaut syndrome. In a long-term open-label extension portion of this trial (mean dosage 10 mg/kg/d), drop attacks were reduced by more than half in 55% of patients, and 15% of patients were free of drop attacks for longer than 6 months at the last visit.

Rufinamide (Banzel)

Antiepileptic agent but structurally unrelated to current antiepileptics. Modulates sodium channel activity, particularly prolongation of the channel's inactive state. Significantly slows sodium channel recovery and limits sustained repetitive firing of sodium-dependent action potentials. Indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome.

Felbamate (Felbatol)

Oral antiepileptic agent with weak inhibitory effects on GABA-receptor binding and benzodiazepine receptor binding. Has little activity at MK-801 receptor-binding site of NMDA receptor-ionophore complex. However, felbamate is antagonist at strychnine-insensitive glycine recognition site of NMDA receptor-ionophore complex. Not indicated as first-line antiepileptic treatment. Recommended for use only in patients whose epilepsy is so severe that benefits outweigh risks of aplastic anemia or liver failure. Most adverse effects during adjunctive therapy may resolve as dosage of concomitant antiepileptic drugs decrease.

Found to be safe and effective in patients with Lennox-Gastaut syndrome in randomized, double-blind, placebo-controlled adjunctive therapy trial; 12-month follow-up study in patients who completed controlled part of study confirmed long-term efficacy; although effective, significant risk of idiosyncratic reactions associated with use make it third-line or fourth-line drug for Lennox-Gastaut syndrome.

Carbamazepine (Carbatrol, Equetro, Epitol, Tegretol)

Anticonvulsant action may involve depressing activity in nucleus ventralis anterior of thalamus, resulting in reduction of polysynaptic responses and blocking posttetanic potentiation. Reduces sustained high-frequency repetitive neural firing. Potent enzyme inducer that can induce own metabolism. Due to potentially serious blood dyscrasias, undertake benefit-to-risk evaluation before drug instituted. Therapeutic plasma levels are between 4-12 mcg/mL for analgesic and antiseizure response. Peak serum levels in 4-5 h. Half-life (serum) in 12-17 h with repeated doses. Metabolized in liver to active metabolite (ie, epoxide derivative) with half-life of 5-8 h. Metabolites excreted through feces and urine.

Indicated for complex partial seizures and trigeminal neuralgia. Following a therapeutic response, may reduce dose to minimum effective level or discontinue treatment at least once every 3 months.

Oxcarbazepine (Trileptal)

The pharmacological activity of oxcarbazepine is primarily by the 10-monohydroxy metabolite (MHD) of oxcarbazepine. May block voltage-sensitive sodium channels, inhibit repetitive neuronal firing, and impair synaptic impulse propagation. This drug's anticonvulsant effect may also occur by affecting potassium conductance and high-voltage activated calcium channels. Drug pharmacokinetics are similar in older children (>8 y) and adults. Young children (< 8 y) have a 30-40% increased clearance compared with older children and adults. Children younger than 2 years have not been studied in controlled clinical trials.

Phenytoin (Dilantin, Phenytek)

May act in motor cortex, where may inhibit spread of seizure activity. Activity of brain stem centers responsible for tonic phase of grand mal seizures may also be inhibited.

Individualize dose. Administer larger dose before bedtime if dose cannot be divided equally.

Ethosuximide (Zarontin)

Effective only against absence seizures. Has no effect on generalized tonic-clonic, atonic-akinetic, or partial seizures. Mechanism of action is based on reducing current in T-type calcium channels found on thalamic neurons. Spike-and-wave pattern during petit mal seizures thought to be initiated in thalamocortical relays by activation of these channels.

Clobazam

Benzodiazepine that binds to benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the CNS, including the limbic system and reticular formation. GABA inhibits neuronal excitability by increasing neuronal membrane permeability to chloride ions. This increase in permeability results in hyperpolarization of the neuronal membrane and causes the membrane to become more stable.

Class Summary

These agents have profound and varied metabolic effects.

Corticotropin (H.P. Acthar)

Stimulates adrenal cortex to produce and secrete adrenocortical hormones.

Used in infants with infantile spasms (West syndrome). Estimated overall efficacy (percentage of infants with infantile spasms due to any cause reaching seizure freedom) is 50-67%. Associated with serious, potentially life-threatening adverse effects.

Must be administered IM, which is painful to infant and unpleasant for parent to perform. Daily dosages expressed as U/d (most common), U/m2/d, or U/kg/d.

Prospective single-blind study demonstrated no difference in effectiveness of high-dose, long-duration corticotropin (150 U/m2/d for 3 wk, tapering over 9 wk) versus low-dose, short-duration corticotropin (20-30 U/d for 2-6 wk, tapering over 1 wk) with respect to spasm cessation and improvement in patient's EEG. Hypertension was more common with larger doses.

Precise mechanism for infantile spasms unknown. Theorized that corticotropin suppresses corticotropin-releasing hormone (CRH), which is an excitatory neuropeptide. Infants with infantile spasms may have increased CRH.

Prednisolone (Millipred, Orapred, Prelone)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability. May be beneficial in the treatment of carpal tunnel syndrome