Idiopathic generalized epilepsy (IGE) is a group of four types of epilepsy with genetic causes. IGE is common and accounts for 15 percent to 40 percent of all cases of epilepsy. IGEs are part of a larger group of epileptic disorders called genetic generalized epilepsy.
The International League Against Epilepsy defines four subtypes of IGE:
Each subtype of IGE is characterized by the age of onset and the main seizure type they cause. IGE causes specific types of generalized onset seizures (which involve both sides of the brain):
Many people with IGE experience more than one of these types of seizures at some point in their lives.
Although the different types of IGE affect people of different ages and cause different types of seizures, they all have certain features in common:
IGE usually occurs in healthy individuals with no other neurological disorders but may occur alongside depression, anxiety, attention deficit hyperactivity disorder (ADHD), and learning difficulties. IGE is usually not associated with developmental abnormalities, except in cases of specific genetic syndromes.
All forms of IGE are believed to have a genetic cause, but only some of the specific genetic causes have been identified. IGE is associated with mutations (or variants) of individual genes as well as chromosomal abnormalities. These genetic changes can be inherited mutations (passed down through families) or they can be new (or “spontaneous”) mutations.
Unlike some genetic diseases (hemophilia A, for example), IGE is not usually caused by mutations in a single gene. The way that genetic mutations cause IGE is not fully understood, but it is believed to involve a perfect storm of genes interacting with one another to cause disease. IGE can sometimes run in families, with multiple first-degree relatives (parents, children, and siblings) having related generalized seizure disorders.
Some types of IGE are associated with specific chromosomal abnormalities. DNA in human cells is organized into 23 pairs of chromosomes. Deleted or repeated parts of chromosomes can cause a variety of genetic disorders like Down syndrome and Klinefelter syndrome, and these syndromes can predispose individuals to epilepsy and seizures.
Specific mutations in genes, called gene variants, are also associated with IGE. Although some genes associated with IGE have been identified, research has not identified all of the genes potentially responsible for IGE. Some of the genes that have been identified so far are involved in the function of ion channels and GABA receptors. Ion channels are responsible for moving ions like sodium and calcium in and out of neurons (brain cells), which allows them to produce an electrical charge. When genetic mutations produce abnormal ion channels, it can lead to abnormal electrical discharges in the brain, causing seizures.
GABA receptors play a key role in how the brain regulates itself. GABA — short for gamma-aminobutyric acid — is a neurotransmitter, a chemical that is released by a neuron to interact with other neurons. GABA normally inhibits (or lowers) the activity of other neurons. Abnormal GABA receptor function can result in abnormal brain activity and seizures.
Diagnosing IGE involves a careful personal and family medical history, provided by a parent or caregiver in children, as well as a physical exam and EEG. The ways seizures look and occur are important for proper diagnosis. Seizures are typically described by a parent, caregiver, or other witnesses, and video documentation of seizures can be very helpful for diagnosis. Neurological testing results are usually normal. Brain imaging studies (like CTs and MRIs) and genetic testing are not usually used to diagnose IGE —unless there are unusual features, such as atypical seizures or intellectual disability, that can indicate other causes of epilepsy.
EEG testing helps determine the type of epilepsy disorder a person has. An EEG is a test that measures the electrical activity in the brain using many small electrodes attached to the scalp. EEG recordings done while a person with IGE is having a seizure show seizure activity affecting both sides of the brain.
Abnormal EEG findings in IGE can often be provoked by sleep deprivation and can sometimes occur during sleep. Some people with IGE can have seizures with exposure to flashing lights and patterns, and some types of seizures can be provoked with hyperventilation (rapid breathing).
The main treatment for IGE is broad-spectrum antiseizure medications. Broad-spectrum medications are used to treat all types of seizure disorders. IGE does not typically respond to more narrow-spectrum, or specific, antiseizure medications. Drugs that affect sodium channels and GABA receptors can worsen seizures.
Commonly prescribed medications for IGE include:
IGE may require lifelong treatment with antiseizure medication. Childhood epilepsy syndromes may resolve as a person gets older, but they may also evolve into other types of IGE.
A ketogenic diet can help reduce seizures in children with IGE, especially if medications do not adequately control seizures. The diet restricts carbohydrate (sugar) intake and increases fat intake to maintain high levels of ketones in the blood. Although it is effective, the ketogenic diet is a very restricted diet that can be difficult to maintain.
There are several types of idiopathic generalized epilepsy.
CAE usually starts from ages 2 to 12 and makes up about 18 percent of cases of childhood epilepsy. CAE causes absence seizures, which can include a blank stare, suddenly stopping activity, and brief confusion when emerging from the seizure. Absence seizures usually last less than 10 to 15 seconds but may last longer.
Children with CAE have one or more seizures every day and may also have generalized tonic-clonic seizures, which cause a loss of consciousness and convulsions. CAE resolves by adolescence in most cases (60 percent), but it can evolve into one of the other types of IGE.
Several mutations in GABA receptor genes (GABRG2 and GABRA1) have been identified that are linked to CAE. A chromosomal abnormality called 15q13.3 microdeletion syndrome, which causes a variety of physical and developmental defects is associated with CAE. Another gene involved in CAE, SLC2A1, is associated with glucose transporter 1 deficiency syndrome. This disorder prevents glucose (blood sugar) from entering the brain, causing a variety of neurological symptoms, including seizures that begin in infancy or very early childhood.
JAE is very similar to CAE but is less common. JAE affects children and young adults between the ages of 8 and 20 years old and rarely begins later in adulthood. Absence seizures in JAE are less frequent than in CAE, occurring less than once a day. Absence seizures seen in people with JAE also last slightly longer (5 to 30 seconds) with only partial loss of awareness.
More than 90 percent of people with JAE also have generalized tonic-clonic seizures. CAE can evolve into JAE as a person gets older but unlike CAE, JAE usually requires lifelong treatment with antiseizure medications.
Gene mutations associated with JAE are seen in the GABRG2, GABRA1, and SLC2A1 genes (all of which are also seen in CAE) as well as CACNA1A, a calcium channel subunit gene. Calcium channels are an important type of ion channel involved in allowing neurons to “fire,” or produce electrical discharges.
JME is a common type of IGE, accounting for almost 10 percent of all cases of epilepsy and usually starts between the ages of 8 and 40. Up to 15 percent of cases of JME evolve from CAE. JME causes myoclonic seizures, which are sudden, brief, uncontrollable muscle jerks affecting a single muscle or muscle group but do not cause a change in awareness or consciousness.
Myoclonic seizures in JME occur most commonly within an hour of waking or when a person is tired or sleep deprived. About one-third of people with JME have absence seizures, but they tend to be milder and less frequent than those seen with CAE or JAE. More than 90 percent of people with JME experience generalized tonic-clonic seizures. These may occur after a series of progressively worsening myoclonic seizures. JME usually requires lifelong treatment with medication to prevent seizures.
JME is associated with mutations in several different genes. For example, the GABA receptor genes GABRA1 and GABRD are associated with JME. JME is also associated with the chloride channel gene CLCN2 and the calcium channel genes CACNB4 and EFHC1. JME is also linked to chromosomal abnormalities including microdeletions 15q13.3 and 15q11.2 and microduplication 16p13.11.
As the name implies, epilepsy with generalized tonic-clonic seizures alone causes generalized tonic-clonic seizures without any other types of seizures. This IGE syndrome can occur in people from 5 to 40 years old, but 80 percent of cases develop in people in their 20s. Seizures vary in frequency — they may occur less than once a year but can occur more than once a month in about 20 percent of cases. In some individuals, this syndrome evolves from CAE.
Generalized tonic-clonic seizures include a tonic phase of muscle stiffening followed by a clonic phase of rhythmic jerking or twitching along with a loss of consciousness. Generalized tonic-clonic seizures involve the entire body. Seizures almost always occur within two hours of waking up, but other factors like fatigue, sleep deprivation, and alcohol consumption can all make seizures more likely to occur. This type of epilepsy requires lifelong treatment.
Epilepsy with generalized tonic-clonic seizures alone is strongly associated with a family history of seizure disorders. About 20 percent of people have a family history of generalized tonic-clonic seizures alone, and about 10 percent have a family history of febrile seizures (seizures brought on by fever). The CLCN2 gene is also associated with this type of IGE.
The outlook for IGE depends, in part, on which subtype a person has. CAE improves with age in most cases but can also evolve into other types of IGE. JAE and JME can improve over time but may require lifelong treatment. Epilepsy with generalized tonic-clonic seizures alone usually requires lifelong treatment to prevent seizures, although seizures can be infrequent with this disorder. Proper diagnosis of IGE is vital to determine the appropriate treatment. IGE responds well to treatment with broad-spectrum antiepileptic drugs but can be worsened when the wrong medications are used.
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