As early as 3 months of age, infants with a severe form of epilepsy called Dravet syndrome start having convulsive seizures, during which their arms and legs jerk repeatedly. As they become toddlers, another type of seizure begins to appear. These seizures do not cause obvious convulsions, but disrupt consciousness and can occur more than 50 times every single day. A challenge to detect and difficult to treat, these non-convulsive seizures often go unnoticed by parents and physicians.
A recent study, published in the journal Cell Reports, characterizes these silent seizures in a mouse model of Dravet syndrome and identifies the brain area that could be targeted to stop them. Nearly 8 in 10 patients with Dravet syndrome have a genetic mutation that causes both developmental delays and seizures, which can even lead to sudden death. Affected children also have cognitive deficits, sleeping difficulties and autism-like behaviors.
Previous animal studies had shown that convulsive seizures are caused when inhibitory cells are not sufficiently active in a brain region called the cerebral cortex. Since then, the scientific field has focused on finding treatments to enhance the function of those cells. The laboratory on the other hand, studied a different region of the brain: the thalamus. This region plays a major role in cognition, sleep, attention, and consciousness.
"All of these elements are altered in patients with Dravet syndrome in a way that is unlikely to be caused only by changes in the cerebral cortex," explained the senior author. "We wanted to see what happens in this brain region and how its cells might be altered in the context of this syndrome."
The researchers were expecting inhibitory cells in the thalamus to be less active, similarly to those in the cerebral cortex. Surprisingly, they saw the opposite. "We found that the inhibitory cells in the thalamus were quite active in mouse models of Dravet syndrome," said, one of the lead authors of the study.
The researchers used electroencephalography, or EEG, to record brain waves and detect abnormalities in brain activity in mice with Dravet syndrome. They also observed that these non-convulsive seizures were much more frequent than convulsive seizures, occurring hundreds of times each day in some mice.
The non-convulsive seizures are in some cases called "atypical absence seizures." Atypical, because they last longer--10 to 30 seconds on average--than those seen in children with typical absence epilepsy. Absence, because the patients appear as if they are mentally absent during the attacks, as they lose consciousness but without collapsing. These seizures as "silent" given that they can go unnoticed without an EEG recording.
When a child is experiencing an absence seizure, she or he will seem absent-minded, staring blankly into space. This can be perceived as the child not paying attention, but can have many detrimental effects in daily life. "Imagine you have several 20-second blanks while I'm talking; you'll get a sense of what I'm saying, but you won't understand all of it," explained another author. "Although they may not be as dramatic as convulsions, these interruptions can happen regularly throughout the day, so they really impair learning."
Non-convulsive seizures in patients with Dravet syndrome are particularly difficult to treat compared to other types of seizures. Even the latest treatments are not effective in preventing or stopping them. For instance, cannabis-based drugs can reduce the number of convulsive seizures, but have little impact on the frequency of silent seizures.
In the new study, the authors identified two ways to stop non-convulsive seizures in mice. First, the team manipulated the activity of specific neurons in the mouse brain using optogenetics, an approach that makes it possible to control the activity of neurons with laser light. They developed methods to detect seizures, and upon detection, quickly changed the activity of neurons in the thalamus to stop the seizures.
"This approach allowed us to identify the specific cells and brain activity required for initiating and aborting non-convulsive seizures in models of Dravet syndrome," said the senior author. "It had been difficult to do this in the past, because seizures involve a very large network of cells that ping-pong signals all around the brain within milliseconds. So, it was crucial for us to detect them immediately at their place of origin."
Optogenetics cannot be used in humans yet, so the authors looked for a pharmacological drug that could achieve the same result. They found that a drug named EBIO1 reduced the firing of inhibitory cells in the thalamus. When Dravet model mice were treated with this drug, their seizures were markedly reduced and, in some cases, even stopped.
"It is very exciting that an FDA-approved drug already exists that targets the very brain activity we found to cause non-convulsive seizures," said the senior author. "To our knowledge, it has never been used in epilepsy, but no side effects were reported when it was used in clinical trials for movement disorders."
When a drug has already been approved for safety by the US Food and Drug Administration (FDA), it can be made available to patients much more quickly. The study by the team identified a drug that treats non-convulsive seizures through its action on the thalamus, and may explain why anti-seizure medications that do not reduce thalamic activity are not effective in stopping these seizures.
Treating Silent Seizures in Children
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