Temporal Lobe Epilepsy (TLE) is the most frequently diagnosed form of focal epilepsy in adults, with seizures originating in specific brain regions. The temporal lobes, situated behind the temples, manage memory, language, and emotion, which explains the varied symptoms experienced during a seizure. The underlying causes of TLE are complex and often remain unknown. Understanding TLE requires investigating both inherited predispositions and non-genetic structural changes.
Defining Temporal Lobe Epilepsy
Temporal Lobe Epilepsy is characterized by recurrent, unprovoked seizures that begin in the temporal lobe on one side of the brain. Seizures often start with a focal aware seizure (previously known as an aura), where the individual remains conscious but experiences unusual sensations. These sensations can include intense fear, a rising sensation in the stomach, or déjà vu.
Following this initial phase, the seizure can progress to a focal impaired awareness seizure, during which consciousness is altered or lost. Characteristic behaviors during this phase, known as automatisms, often involve repetitive, non-purposeful movements like lip-smacking, chewing, or picking at clothes. The seizure focus is frequently located in the mesial temporal lobe, involving structures like the hippocampus.
Genetic Contributions to TLE
The role of genetics in TLE is increasingly recognized, though the condition is not always inherited in a simple manner. Heritability can manifest through either single-gene mutations (monogenic inheritance) or complex interactions involving multiple genes and environmental factors.
Autosomal Dominant Partial Epilepsy with Auditory Features (ADPEAF)
One form, Autosomal Dominant Partial Epilepsy with Auditory Features (ADPEAF), is a rare, directly inherited monogenic type of TLE. This condition is often linked to mutations in the LGI1 gene, which encodes a protein involved in regulating neuronal communication. The inheritance pattern means a child has a 50% chance of inheriting the gene mutation from an affected parent, though the penetrance (likelihood of developing seizures) is incomplete.
Ion Channel Alterations
Another prominent genetic finding involves alterations in ion channel genes, leading to “channelopathies.” These protein channels control the flow of ions like sodium and potassium across nerve cell membranes, which is fundamental to generating electrical signals. Mutations in genes like SCN1A, which codes for a sodium channel subunit, are associated with various epilepsy syndromes and have been implicated in some mesial TLE cases.
Familial Mesial Temporal Lobe Epilepsy (FMTLE)
Familial Mesial Temporal Lobe Epilepsy (FMTLE) often displays an autosomal dominant pattern with incomplete penetrance. While no specific gene has been identified for all FMTLE cases, mutations in the DEPDC5 gene have been reported in some families. These genetic variants can make the brain hyperexcitable, lowering the seizure threshold and making the individual vulnerable to developing TLE, sometimes with a later trigger like a prolonged fever or head injury.
Acquired Causes of TLE
The majority of TLE cases are classified as acquired, resulting from structural damage or insults to the brain. The most frequent underlying cause for TLE that does not respond well to medication is Mesial Temporal Sclerosis (MTS). MTS involves the loss of nerve cells and the formation of scar tissue, primarily in the hippocampus.
MTS Development
The development of MTS is frequently linked to an initial injury or event that occurred early in life, often before the age of five. A significant risk factor for subsequent TLE with MTS is a history of prolonged or complicated febrile seizures during childhood. These seizures, occurring with a high fever, can lead to subtle damage in the hippocampus that may eventually manifest as TLE years later.
Other Causes
Beyond febrile seizures, other forms of damage to the temporal lobe tissue can lead to acquired TLE. Severe head trauma, particularly if it involves a loss of consciousness, is a known precursor. Brain infections such as encephalitis or meningitis can cause inflammation and subsequent scarring. Additionally, structural abnormalities like brain tumors, strokes, or vascular malformations can disrupt normal electrical activity, acting as a focal point for seizure generation.
Determining Etiology and Family Implications
Identifying the etiology of TLE is important for managing the condition and assessing future risks. Clinicians use diagnostic tools to differentiate between acquired structural causes and primary genetic forms. Magnetic Resonance Imaging (MRI) is the preferred neuroimaging method, as it provides detailed pictures of the brain structure and can reveal signs of acquired TLE, such as hippocampal atrophy or the scarring of MTS. An electroencephalogram (EEG) is also routinely performed to record the brain’s electrical activity and localize the seizure focus, but it cannot distinguish between a genetic and a structural cause. If imaging studies show no structural abnormality, genetic sequencing may be suggested, especially when there is a strong family history of seizures.
The determined etiology has significant implications for family counseling and risk assessment. For an individual with TLE caused by an acquired factor like head trauma or infection, the risk of their children or siblings developing the condition is generally considered low, similar to that of the general population. Conversely, a diagnosis of a monogenic genetic TLE, such as ADPEAF, means there is a higher, quantifiable risk for first-degree relatives. In these cases, genetic counseling can provide a more accurate assessment of inheritance patterns and inform family planning decisions.