Although medications and other treatments for epilepsy can help many patients to better control or relieve their seizures, a significant number of people are resistant to treatment. Researchers at the Yale School of Medicine have started to delve deeper to better understand the reasons for this with their latest research.
The Research into Difficult to Treat Epilepsy
The researchers focused on two types of severe epilepsy disorders from two neurodevelopmental disorders—focal cortical dysplasia and tuberous sclerosis complex. These forms of biological epilepsy tend to be severe and they manifest in humans a short time after birth. This leads to sudden recurrent seizures and brain damage. These types of epilepsy are not easy to treat when utilizing anti-epilepsy medications.
Interestingly, the brain malformations that occur in humans are similar to what happens with the brains of mice. Studying mice has helped the researchers immensely. They were able to find a protein called HCN4, along with a molecular pathway called mTOR that are causing these epilepsies. This has helped them to get closer to finding a better way to treat the conditions.
Dennis Spencer of the Yale School of Medicine said, “About 35% to 40% of patients with epilepsy are resistant to medication. Epilepsy is very heterogeneous and so many patients who have epilepsy are resistant to medication and the medications that are used today are also quite heterogeneous.”
Because of the heterogeneous nature of these two epilepsy types, it was unknown what caused them to occur. It was also unknown why so many people that had those forms of epilepsy were resistant to the usual anti-epilepsy medication.
Angelique Bordey, a professor of Neurosurgery and Cellular and Molecular Physiology at the School of Medicine was a corresponding author of the study. She and her team tried to replicate the genetic mutations that were caused by epilepsy. To do this, they used the brains of mice who were still in the womb. When the mice were born, they had brain malformations that were similar to people who suffered from these two types of epilepsy.
The researchers looked at different sections of the brain using confocal microscopes. They found fluorescent cells affected by the mutations. They also found that the size of the cells in the malformations was usually larger than normal cells. The pathology was close to the pathologies found in humans who had these severe types of epilepsy.
They determined that the mTOR motor pathway and the forms of epilepsy were linked, as the motor pathway plays a role in cell growth. This led them to believe that the pathway was the cause for the epilepsy seizures. The HCN4 protein, as mentioned, was also an important element of why the seizures were happening. When they were able to prevent the HCN4 channel from opening in the brains of mice, the seizures stopped.
What Does This Mean For The Future?
While this is certainly a promising study and could provide much-needed relief for those who have these types of treatment-resistant epilepsy, more research needs to continue. Lena Nguyen, a postdoctoral fellow at the Yale School of Medicine and a contributor on the experiment said that they will continue their investigations into the mTOR signaling pathway and the HCN4 channel to better determine how they can use the treatment in humans.
Although it’s still early, there are estimates from Bordey that say the first trials of gene therapies to help with these types of epilepsy in people could start in 2023. They hope that gene therapy could eventually help to reduce the number of seizures a person has.