Introduction

The temporal lobes are brain structures found behind the temples and cheekbones. They are responsible for processing hearing, language, memory, and emotions. Therefore, any complications to this region of the brain would be detrimental. Disruptions to the temporal lobe can be brought about by a seizure, which is called temporal lobe epilepsy (TLE).¹ 

The aetiology of a disease refers to its cause(s), and understanding it is crucial to ensure appropriate preventative and management strategies are taken. TLE must be especially monitored as it is the most common seizure disorder in adults. The most common causes can be categorised into structural, genetic, and idiopathic, for example:

• Hippocampal sclerosis 
• Infections 
• Tumors 
• Traumatic brain injury
• Vascular anomalies 
• Genetic causes
• Cryptogenic (unknown) causes

This article will explore these three causes and the corresponding management and treatment.

Structural causes of TLE

The anatomy of the brain is complex, and each section is responsible for different functions. Changes to each section can impact others due to the brain’s interconnectedness, and structural changes can lead to a specific type of TLE known as mesial temporal lobe epilepsy (MTLE) – mesial refers to the middle section of the brain involving the hippocampus. These are the inner parts of the brain, with the hippocampus found between the temporal lobes.² In MTLE, also known as hippocampal sclerosis, the hippocampus is slowly broken down. The hippocampus is a known site of epileptic activity caused by the reduction of its mass. 

Volume abnormalities are found in other regions of the brain, which contribute to TLE. The grey matter and white matter in the brain and spinal cord are vital for many brain functions. Grey matter, which contains neuronal cell bodies, is primarily involved in processing and integrating information, while white matter consists of myelinated axons that facilitate communication between different regions of the brain. Changes to them in the brain are both a cause and a consequence of TLE. It was found that the volume of grey matter impacted the structural connectivity of white matter, which influenced the occurrence of TLE. The thalamus, parahippocampal gyrus, and temporal gyri are further examples of structures that experience volume abnormalities contributing to TLE.³

Additionally, traumatic brain injury (TBI) can induce TLE. It disrupts the intricate connections between cells in the temporal lobe, specifically, damaging the neurons and the neurotransmitter function. This leads to heightened levels of excitatory signalling and consequently lowers a person’s tolerance to TLE. Furthermore, the severity and location of TBI determine the likelihood of TLE.⁴ There are several mechanisms which influence this outcome:

• Excitotoxicity: Excess excitatory neurotransmitters (glutamate) overstimulate the cells, forcing cell death. This is disruptive for neural circuits 
• Direct tissue damage: Physical damage to the temporal lobe, specifically the hippocampus, is detrimental to neural activity. The lack of regulation by the hippocampus causes abnormal neuronal connections
• Neuroinflammation: The inflammatory response following TBI can activate glial cells. These cells normally ensure that nerve cells are held in place and function properly, but excess activity further damages the neurons by releasing excess chemicals
• Axonal sprouting: The damaged neurons from TBI can produce new abnormal connections. These new pathways can be susceptible to seizure activity
• Impaired inhibition: The impaired balance between excitatory and inhibitory pathways can promote TLE⁴

Brain tumours have a similar role in causing TLE as TBI. The presence of a tumour physically disrupts the usual electrical activity in the temporal lobe. A low-grade tumour (slow-growing) has a higher chance of causing TLE than a high-grade (fast-growing) tumour. This is due to the slow, progressive irritation of brain tissue. Further consequences include:

• Inflammation
• Changes in neurotransmitter balance around the tumour
• The proximity of the tumour to the temporal lobe influences the likelihood of TLE
• The surrounding tissue can be altered, which disturbs connections and cellular activity of neurons
• Blood-brain barrier disruptions prevent the controlled movement of substances across the barrier. This can lead to harmful substances entering the brain⁵

Additionally, infection and autoimmune responses can bring about seizures. Encephalitis is a condition that causes inflammation of the brain through viral or autoimmune pathways. Viral encephalitis occurs due to viruses such as:

• Measles 
• Rubella 
• Zika virus 
• West Nile virus 

When a person’s immune system attacks the brain, the condition is called autoimmune encephalitis. The antibodies target proteins and receptors in the brain, and the specific kind of protein targeted determines the type of autoimmune encephalitis. There are 3 main types:

• Anti-NMDA receptor encephalitis, where the immune system attacks the NMDA receptors in the brain
• VGKC-complex antibody encephalitis, where the immune system targets the VGKC complex in the brain
• GABA-A/B receptors can also be targeted

Conditions like this disrupt the temporal lobe activity, triggering TLE.⁶

Genetic causes of TLE

TLE is usually polygenic, meaning more than two genes influence this condition. Few reports show monogenic cases of TLE, but numerous studies have shown links between them, suggesting a familial pattern. Patients with TLE usually have relatives who are also at risk of the condition. Affected genes, combined with environmental factors, make a person more susceptible to TLE. 

The LGI1 gene is involved in developing the central nervous system (CNS) and is involved in the function of glial cells. Mutations of this gene were studied, and several were linked to TLE. It particularly impacted the auditory symptoms of their seizures, causing buzzing, ringing, or clicking. The mechanism of how this gene mutation causes TLE is unknown.⁷ 

The SCN1A gene causes multiple types of epilepsy, including TLE. This gene provides the blueprint for sodium ion channels, which ensure the transmission of electrical signals in the brain. The SCN1A mutation can be random or inherited, and the type of mutation itself can vary.⁸

PRRT2 is a transmembrane protein mainly made up of proline. This protein is involved in the CNS and controls other protein functions, specifically, the proteins mediating calcium ions' release from cells. There is a range of mutations which may occur with this gene:

• Nonsense – a mutation which produces an early stop codon 
• Missense – a change in a single amino acid in the protein
• Deletion – deletion of an amino acid

These lead to the gene not producing its usual effect. As a result, the control of proteins is impaired, and the excess neurotransmitters released due to calcium influx can lead to TLE.⁹ Damage to ion channel functions increases the hyperexcitability of neurons, which interferes with electrical signals in the brain and thus increases the risk of TLE. 

Other genetic links have been found in epilepsy. Some studies presented the genetic mechanisms which cause repeated damage to the hippocampus and contribute to TLE occurrence. For example, familial temporal lobe epilepsy is a form of familial TLE, which comes in two types: mesial or lateral. The more common mesial form involves the GATOR1 complex genes. The lateral form is associated with the LGI1 gene, as previously discussed.¹⁰

Idiopathic causes of TLE

Idiopathic causes refer to when the reason for the seizure is unknown. In this case, the cause of TLE is unclear and occurs randomly. This produces the challenge of identifying the characteristics of the idiopathic tendencies of the TLE. The main problem which arises in idiopathic TLE is identification. The brain may appear normal on an MRI scan due to only subtle lesions or injuries in the brain. Doctors will have two potential routes of diagnosis: genetic history and family history. A particular unknown gene mutation may be linked to TLE, and additionally, family history is a common place to start when looking for the causes of TLE.¹¹

Diagnostic approaches in determining aetiology

TLE is diagnosed through neuro-imaging techniques: MRI, PET and SPECT. This is crucial for identifying abnormalities in the brain structure, indicating TLE. In the scans, the doctors look for:

• Changes in vascular structures
• Tumours 
• Changes in hippocampus size 

MRI is the preferred method of diagnosis, as it is sensitive to hippocampal changes and provides high-resolution images. However, MRI comes with its limitations. The information extracted from the image may be interpreted differently among experts. Despite MRI’s high-resolution imagery, it cannot pick up all lesions that may be present. PET and SPECT are done if MRI scans show inconclusive results.²

EEG (electroencephalogram) monitors the electrical activity of the brain and is used for all patients suspected of having TLE. The electrical signals are recorded using electrodes, which locate the epileptic focus. However, differentiating between TLE types through wave patterns is difficult, as they can be similar.¹

If no structural indicators are apparent, doctors turn to genetic testing for TLE. Genetically linked TLE is diagnosed through different methods. A gene panel analysis is carried out. Here, the suspected genes involved in epilepsy are reviewed. However, due to TLE’s complexity, genetic testing alone is insufficient. Strong family history is taken into account along with other associated risk factors. 

Treatment and management 

The intensity of a seizure correlates with increased neuronal decline. Therefore, it is essential to control neurodegeneration to reduce seizure frequency. This regulation is key to maintaining a patient’s quality of life. 

At initial diagnosis, the patient is prescribed medicine to manage the condition. These include:

• Phenytoin
• Valproate
• Carbamazepine 
• Phenobarbital

The side effects of these drugs vary depending on the patient and their type of TLE. Optimal seizure control involves a combined surgical and pharmaceutical approach, and the two most common surgical interventions are:

• Anterior temporal lobe surgery: Resection of the anterior (front) temporal lobe and hippocampus
• Amygdalohippocampectomy: Targeting the mesial structures¹

Future of TLE management

Gene therapies are being utilised to develop personalised medicine, which allows doctors to tailor treatment and management to each patient. Furthermore, the role of psychiatry has been recognised in TLE. For example, neurologists now consider depression and anxiety when devising treatment plans. Meanwhile, social support groups can help individuals cope better with TLE. All these factors hold great promise for the future of TLE management.²

Summary

Temporal lobe epilepsy (TLE) is caused by seizures which occur in the temporal lobe of the brain. The temporal lobe is responsible for various functions, such as processing hearing, language, memory, and emotions. The causes can typically be categorised into structural, genetic, and idiopathic causes. TLE is diagnosed through neuroimaging techniques, with MRI being the preferred method for diagnosis. EEG is done to monitor the electrical activity in the brain, and genetic tests may be carried out if no structural abnormalities are detected in the imaging investigations.

Treatment is with anti epileptic medications. Sometimes, optimal seizure control involves a combined surgical and pharmaceutical approach. Other factors, that may help in this condition, include gene therapy, the role of psychiatry, and support groups to help individuals cope better. Tailor-made and personalised treatment plans always show more promise and effective patient care and management.