Lennox-Gastaut Syndrome: Unseen Challenges and the Need for Greater Awareness

Melanie Huntley, PhD

Lennox-Gastaut syndrome (LGS) is a severe form of epilepsy that typically becomes apparent during infancy or early childhood. Children, adolescents, and adults living with the condition may experience multiple types of seizures, including tonic, atonic, myoclonic, generalized, and atypical. Although not always present at the onset of seizures, most people with LGS experience some degree of impaired intellectual functioning or information processing, along with developmental delays and behavioral disturbances.

LGS impacts approximately 48,000 children and adults in the US. Each year, on November 1st, the clinical and patient communities come together for International LGS Awareness Day, an event dedicated to raising awareness and bringing together families affected by the disease. The day acts as a kickoff to Epilepsy Awareness Month, celebrated annually in November, to continue awareness efforts towards epileptic and seizure disorders. This year, the LGS Foundation is bringing forth a few different initiatives, including its “30 Ways in 30 Days” campaign to raise awareness of LGS, as well as its annual awareness dinner, which takes place November 2nd, the day after International LGS Awareness day.

In efforts to continue to raise awareness for LGS, NeurologyLive® sat down with Melanie Huntley, PhD, a principal data scientist for Roche and a mother of a daughter living with the disease. In the discussion, Huntley discussed the all-encompassing aspects of LGS, including its profound effects on brain development, resulting in severe cognitive, behavioral, and physical challenges. In addition, she discussed the limitations of current treatments, which primarily address seizures but fail to manage other symptoms. Huntley also highlighted emerging research concepts like neurostimulation and genetics, as well as the need for better support systems for families and the inclusion of neurodevelopmental outcomes in clinical trials.

NeurologyLive: What aspects of LGS need greater awareness?

Melanie Huntley, PhD: I think what most people don't realize, even though there are medications on the market for LGS, is that most individuals with LGS are still suffering from daily, uncontrolled seizures. These seizures can strike at any time, leading to falls, injuries, and even aspiration or choking. LGS is a condition that requires caregivers to be ready to respond 24 hours a day, which takes a huge toll on the support systems of families affected by LGS. These families need a lot of help, so I'd love to bring more attention to the need for better support for these families, with wraparound care for all the needs of those with LGS and the impact on their caregivers.

Additionally, I think people don’t realize that LGS is not just about seizures. The relentless, uncontrolled seizures interfere with brain development, leading to a range of other symptoms. Many people with LGS require lifelong, complete support for activities of daily living, like toileting, dressing, feeding, and moving around. Many become non-verbal and experience cognitive and developmental delays, with some requiring wheelchairs and feeding tubes. They also often experience serious sleep disruption and, unfortunately, develop challenging behaviors. So, it’s not just about seizures; the symptoms associated with LGS are broad and complex.

How would you currently characterize the treatment of LGS? Where do we excel, and where do we fall short?

Generally, we treat the most obvious symptom of LGS, which is seizures. That's probably where our greatest strengths are right now in treating LGS. But, as we discussed, addressing only the seizures doesn’t cover all the symptoms that impact quality of life, like behavioral issues, cognitive delays, and loss of the ability to speak. Many of these kids were either typically developing or had some language before the seizures started, and then they lose the ability to speak and express themselves.

Because we don’t fully understand the cause of LGS, treatment is often trial and error to find out what seizure treatments may offer relief. Unfortunately, we can’t yet predict which patients will respond well to which treatments, and that’s one of our weaknesses.

How is our management of the neurodevelopmental issues of LGS?

First, we’re making some progress in understanding where these neurodevelopmental issues arise in LGS. Human brains have many different networks and states. One state allows us to focus on tasks, while another lets us relax or even daydream. In LGS, unfortunately, both the active and inactive states are happening simultaneously, which has a huge impact on learning and can lead to neurodevelopmental issues.

So, what progress are we making in managing these neurodevelopmental issues? There are things that caregivers can do to help address some of the behavioral issues. A popular workshop at the LGS Foundation’s conference this summer, led by Aline Devine, focused on managing challenging behaviors from a "brain-first" perspective. I’d highly encourage caregivers to seek out this kind of information and support.

In terms of other neurodevelopmental aspects, some patients benefit from surgical interventions, which can reduce seizure frequency. Reducing seizures can improve sleep and quality of life, which may positively impact neurodevelopment. For medications, we currently don’t have any specifically targeting neurodevelopmental issues, but the LGS community is actively working with pharma companies and regulators, like the FDA, to ensure that neurodevelopmental symptoms are measured and addressed in clinical trials, so we’re not just counting seizures.

What promising treatment approaches are in the pipeline for LGS?

I'm particularly excited about potential treatments that address both the underlying causes of LGS and the non-seizure symptoms, like sleep and behavioral issues. One of the most promising areas here is neurostimulation-based treatments. With LGS, the dysfunction or dysregulation in brain networks causes both active and default mode networks to be on simultaneously. There may be opportunities to intervene precisely in specific brain regions to improve overall functioning, although it’s challenging to achieve this specificity with drugs alone. Since the brain communicates with electrical signals, neurostimulation could potentially help, but it’s an invasive treatment involving the placement of probes in the brain, so it’s not an option for everyone.

At the same time, we still need new drugs that can offer better seizure control. With current treatments, many patients with LGS continue to experience hundreds of seizures daily.

In terms of genetics of LGS, how has research advanced in this area?

We know there’s no single gene mutation that causes LGS. Mutations in over 150 epilepsy-related genes are considered risk factors, but the genetic cause remains unknown for many patients. Research is focused on expanding the genetic databases of patients with LGS and understanding why some people with these risk factors develop LGS, while others don’t.

Where the LGS community is most excited is in exploring how different mutations or risk factors converge to cause LGS, and targeting that convergence in treatments. This understanding could also help us intervene earlier, preventing LGS from evolving and potentially reversing some neurodevelopmental damage. That would be an incredible outcome for everyone.