How can we bring refractory epilepsy under control?

Professor Ley Sander is a world-leading neurologist based at University College London and Medical Director at the Epilepsy Society. Ley specialises in epilepsy treatments and in his blog, he provides an overview of refractory epilepsy. Ley discussed why anti-seizure medications work for some but not all and how current research offers hope that more people will be able to bring their seizures under control in the future.

Anti-seizure medications (ASMs) were first developed over 100 years ago. However, with limited options available, it wasn’t until much later that we saw real progress in the area. The modern era of ASM development began in the mid-1970s. Since then, over 28,000 chemical compounds have been screened as potential new ASMs. We’ve also benefitted from considerable advances in clinical care for epilepsy, which has resulted in a growing list of new medications and treatment options. Despite this, one-third of people with epilepsy still have seizures that do not respond to treatment. Even if seizures are gone, many people continue to live with side effects from their ASMs, which can be just as debilitating as the seizures themselves.

When trials of two ASMs fail to control a person’s seizures, this is termed as drug-resistant or refractory epilepsy. This condition causes great worry and frustration for the people my colleagues and I see in our clinics – living with the unpredictability and uncertainty of when a seizure may occur. They are not alone. I was pleased to see the concerns of people with epilepsy reflected in the UK Epilepsy Priority Setting Partnership (PSP). Priority 9 asks, “What causes drug-resistant (refractory) epilepsy, and how can it be best treated?”. Uncontrolled seizures have a considerable impact not only on people with refractory epilepsy but their families, friends and carers too. People with drug-resistant epilepsy also have high psychiatric and physical comorbidities rates, with increased risk of injuries, poorer quality of life, and, worryingly, epilepsy-related death. This is why more research is urgently needed into the causes and underlying mechanisms of drug-resistant epilepsy to understand better how to treat it and, one day, perhaps even prevent it from occurring altogether.

So why do ASMs relieve some people of their seizures, but not everyone? In short, we don’t yet know. Epilepsy is a complex condition, with over 40 different types of seizures, each one impacting individuals in different ways. What works for one person may not work for another. The cause of epilepsy in almost two-thirds of people is also unknown. Not knowing the underlying mechanisms makes it much harder to find the correct treatment. The means of drug resistance are hugely variable and multifactorial – they could be related to the person’s epilepsy, the drug they are taking, or, indeed, their genetic blueprint.

Assessing the underlying mechanisms of drug resistance is essential to grouping people with refractory epilepsy and developing new therapeutic approaches. Potential underlying mechanisms for refractory epilepsy include:

• Target hypothesis: Drugs act by targeting a specific site on or inside a cell to change the behaviour of that cell. The target hypothesis suggests that epilepsy may cause alterations to the structure of the sites the drugs are targeting, rendering them ineffective at controlling seizures.
• Drug transporter hypothesis: Once drugs have reached a cell, they gain entry through the cell membrane via a channel or transporter. Studies on brain tissue obtained following epilepsy surgery found that some brain cells in some people with epilepsy have alterations, meaning that the concentration of ASM at the proposed target could be insufficient to control seizures.
• Pharmacokinetic hypothesis: ASMs must reach the brain and cross the blood-brain barrier (BBB) to treat epilepsy. The pharmacokinetic theory suggests that excess cellular transporters and channels in other parts of the body mean insufficient ASMs are reaching the brain tissue and crossing the BBB.
• Gene variant hypothesis: Research in the genetics of epilepsy and the popularity of whole genome sequencing has helped shed light on the role of genetics in epilepsy. More work is needed to define the drug resistance mechanisms associated with specific genetic epilepsies.
• Gut microbiome hypothesis: The role of the gut microbiome in brain health has recently attracted great attention. Some evidence suggests that the gut microbiome of people with drug-resistant epilepsy contains different bacteria than those with seizures that respond to ASMs. Some pilot research has demonstrated the efficacy of probiotics in reducing seizure frequency and improving quality of life; however, further studies are needed on the role of the gut microbiome in epilepsy and drug resistance.

Drug-resistant epilepsy represents vast challenges for researchers trying to find new treatments. The broad spectrum of epilepsies, each with its own mechanisms and clinical presentation, means that a ‘one size fits all’ approach is highly unlikely. Data-driven research across all types of epilepsy is urgently required to help us better understand the potential mechanisms so that we can develop better treatments.

Collaboration through multidisciplinary research involving clinical, lab-based and data researchers will be integral to better understanding and controlling refractory epilepsy. This is one of the many reasons I’m proud to be involved in the national research collaborative #Every1EndingEpilepsy alonside many epilepsy researchers across the UK. This programme is seeking £100 for every 1 in 100 people living with a diagnosis of epilepsy to advance epilepsy research radically through investment, collaboration and action. Collaboratives such as this will enable real progress to be made for the 30% of people with epilepsy who continue to experience seizures that do not respond to treatment.

Research is already providing hope for the over 200,000 people living with refractory epilepsy in the UK. New drugs are being trialled around the globe that could offer seizure freedom with fewer side effects. Personalised therapies that treat the cause of a person’s epilepsy – or even reverse it – could be used to treat people within the next decade, removing the need to use ASMs regularly. Advances in brain imaging and surgical techniques mean that epilepsy surgery can also be an option for more people.

Now more than ever, more investment in research is needed to accelerate these efforts and radically advance research so that more people live without the uncertainty and unpredictability of seizures.