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Do women have it worse off when it comes to epilepsy outcomes?

A recent article in The Guardian highlighted the urgent need for research into sex-related differences in asthma mortality, claiming that the influence of sex hormones (like testosterone and oestrogen) on treatment response is being ignored. It is the latest example of women’s disadvantages in health, compounded by the national shortage of hormone replacement therapy or HRT. Here I will present our recent findings on the same theme showing that there are important differences between men and women in the prognosis (outcomes) for epilepsy that have not been recognised until now.

I am a paediatric neurologist with a research lab at King’s College London. We study the causes of epilepsy and the mechanisms of co-occurring conditions like behaviour and mood changes. We’re particularly interested in sleep and mental health. Find out more about our research here.

Photo by Tim Mossholder from Pexels

What is Epilepsy?

It’s the most common brain disorder in the world directly affecting 65 million people. People affected by epilepsy experience temporary interruptions in brain function, known as seizures, that may result in loss or impairment of consciousness, sensation, or control of movements. For most, it’s a chronic (long-lasting) condition incompletely treated with drugs that suppress seizures by reducing the electrical activity of the brain. At a personal level, epilepsy can have effects on mental health, social life, learning, work and relationships.

One particular common type of epilepsy starts in adolescence, known as juvenile myoclonic epilepsy or JME. In our group we are studying the genetic causes of JME. Like many neuropsychiatric conditions, we believe that a combination of genes and environment result in susceptibility to this type of epilepsy. And like many psychiatric conditions, about one in three people don’t respond to conventional anti-seizure drugs and so are termed “drug-resistant”.

To date, the dominant theory about drug resistance is that it is thought to be caused by genetic variants influencing how drugs are transported into the brain. However, there has been little scientific support for this theory over the past two decades. Instead, we hypothesised that there are probably different explanations of drug resistance for different groups of people with epilepsy.

Our research

We were lucky to have the world’s largest dataset of people recruited for research into JME. Because JME is more common in women, we had the idea from the outset of analysing factors that might affect drug resistance separately for men and for women — the first time anyone had thought to do this.

What we found was astonishing.

From previous studies, we knew that having absence seizures (brief blank spells lasting a few seconds) increased the risk of drug resistance , and we found this association in our dataset equally for men and for women. But what was really interesting was the relationship to stress.

Photo by Elisa Ventur on Unsplash

Stress is a well-known trigger for seizures and can take various forms: mental, physical or emotional. Common triggers for seizures include not sleeping well, drinking alcohol, mental stress or the hormonal changes of menstruation.

In our study, around a half of both men and women reported that their seizures were triggered by stress, and one in five told us that all their seizures were triggered by stress. What came as a surprise was that stress triggers made the prognosis of epilepsy worse in women but had no effect on men’s long-term outcomes. Menstrual cycle triggers increased the risk of drug resistance 15-fold, and other stress triggers increased the risk of drug resistance five-fold in women.

What this tells us in no uncertain terms is that the factors underlying drug resistance are different for women and men, and the data strongly suggest that mechanisms linking hormonal changes and stress response to brain activity are key to solving the problem of drug resistance.

Future work

This is a great opportunity to investigate how the menstrual cycle and stress response interact with seizure susceptibility. There are no current evidence-based interventions targeting stress or the menstrual cycle that reduce seizures. Perhaps this could be a stimulus to think about dedicated women’s epilepsy clinics? A forum for different therapies to come together to solve the challenges of stress reduction, sleep hygiene, sex and contraception, diet and drinking.

But what is it about women’s response to stress that makes their seizures worse?

The answer is not very clear.

Surprisingly, what we know about the classic descriptions of the fight or flight responses to stress, orchestrated by the sympathetic nervous system, are based exclusively on experiments on male rodents. Why? Because the old assumption in science was that variability in sex hormones would have made the interpretation of results in female animals “too confusing”! So things haven’t really changed much in a century.

Illustration by Hannah Moore/Northeastern University

Later work from the Stanford neuroscientist Shelley Taylor suggests that women may have alternative responses to stress mediated by the parasympathetic nervous system and the neurotransmitter (chemical messenger) oxytocin. Perhaps this is a clue to the sex difference in stress response and how it affects seizures. If we can unravel this mechanism, it may help many women experiencing conditions that vary with stress, like migraine, inflammatory bowel disease and depression.

Another interesting avenue of research is the role of inflammation in chronic epilepsy. Already a well-known link in depression, the concept that brain or peripheral (outside the central nervous system) inflammation may also affect response to anti-seizure drugs is slowly gaining ground. And as we know, chronic stress can result in a maladaptive inflammatory response. We hope to be able to investigate the connections between stress, inflammation and drug resistance in women with epilepsy in the near future.

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