Autism and epilepsy: why the overlap?

Two different conditions

Autism is a neurodevelopmental condition: a different way in which the brain develops and processes information, expressed in communication and social interaction, in repetitive or highly focused interests and behaviors, and often in a particular way of perceiving sensory input. Epilepsy, on the other hand, is a disease of the brain characterized by a tendency to have recurrent epileptic seizures (you can read more in What is epilepsy?).

They are different conditions: most autistic people do not have epilepsy, and most people with epilepsy are not autistic. But when we look at large groups of people, the two appear together much more often than chance would explain.

How often do they occur together?

• About 1 in 10 autistic people has epilepsy, compared with fewer than 1 in 100 people in the general population.1
• The risk is higher in autistic people who also have an intellectual disability: in one meta-analysis, about 21% of them had epilepsy, compared with 8% of those without.2
• Epilepsy is proportionally more common in autistic girls and women than in autistic boys and men.1,2
• The frequency increases with age, and adolescence is a period when seizures can appear for the first time.1,4
• In the other direction, about 6% of people with epilepsy are autistic, and the figure is much higher in some early-onset epilepsy syndromes: about 1 in 5 children with infantile spasms, and almost half of those with Dravet syndrome.3

Why does it happen?

There is no single answer, and different explanations most likely apply to different people. Here are three main ideas, which are not mutually exclusive.

1. Shared genetic causes

Some genetic conditions raise the risk of both autism and epilepsy. Well-known examples are tuberous sclerosis complex, fragile X syndrome and Dravet syndrome. In these cases, the same change in brain development can give rise to both conditions, without one causing the other.3,4

2. The balance between excitation and inhibition

Like a car with an accelerator and a brake, brain circuits depend on a balance between signals that activate neurons (excitation) and signals that calm them (inhibition). An influential hypothesis proposes that, in some autistic people, this balance tips slightly toward excitation during development. That same imbalance, if large enough, is what makes epileptic seizures more likely. It is important to say that this is an actively researched hypothesis, not an established fact for all autistic people.

3. Chloride and GABA during development

GABA is the brain's main "brake", but its effect depends on the amount of chloride inside neurons. In the immature brain, neurons contain a lot of chloride — because a protein called NKCC1 brings it in and another, KCC2, is not yet able to pump it out — and GABA excites instead of braking. As the brain matures, this balance reverses and GABA becomes a brake.5 If that switch is delayed or incomplete, circuits could remain more excitable and develop differently: a scenario compatible with both autism and epilepsy.

In our lab we study this idea in an animal model based on prenatal exposure to valproic acid. We use this model because, in people, exposure to valproate during pregnancy has been found to increase the risk of autism in children: in a large Danish study, the risk rose from about 1.5% in the general population to about 4.4% in exposed children.6

Is there a treatment that targets this mechanism?

The chloride idea led to testing bumetanide, a diuretic that blocks NKCC1, in autistic children and adolescents. After encouraging results in small studies, two large international clinical trials (with more than 400 participants in total) found no difference between bumetanide and placebo, and its development for autism was discontinued.7

This result is a good example of how science works: an attractive hypothesis in the lab has to be tested carefully in people, and sometimes it is not confirmed. It does not mean the chloride mechanism is irrelevant, but that the relationship between that mechanism and autistic experience is more complex than was thought. Understanding that complexity better is precisely the goal of basic research.

What does this mean for families?

Because epilepsy is more common in autistic people, it is worth knowing its signs. Some seizures are subtle — a fixed stare lasting a few seconds, unusual repetitive movements, or episodes of disconnection — and can be mistaken for autistic behaviors. It has also been described that, in some children, a loss of previously acquired skills can be accompanied by abnormal electrical activity in the brain, although the exact relationship is still debated.4 If you notice something that worries you, mention it to your health team: an electroencephalogram (EEG) can help clarify it.

What we study

Our work seeks to understand, in animal models, how the excitability of hippocampal neurons changes in autism and what role NKCC1 plays in the appearance of seizures. You can read more on our autism research page, or explore some of these ideas interactively in our simulators.

References

1. Liu X, et al. Prevalence of epilepsy in autism spectrum disorders: a systematic review and meta-analysis. Autism. 2022;26(1):33–50. doi:10.1177/13623613211045029
2. Amiet C, et al. Epilepsy in autism is associated with intellectual disability and gender: evidence from a meta-analysis. Biol Psychiatry. 2008;64(7):577–582. doi:10.1016/j.biopsych.2008.04.030
3. Strasser L, Downes M, Kung J, Cross JH, De Haan M. Prevalence and risk factors for autism spectrum disorder in epilepsy: a systematic review and meta-analysis. Dev Med Child Neurol. 2018;60(1):19–29. doi:10.1111/dmcn.13598
4. Tuchman R, Rapin I. Epilepsy in autism. Lancet Neurol. 2002;1(6):352–358. doi:10.1016/s1474-4422(02)00160-6
5. Kaila K, Price TJ, Payne JA, Puskarjov M, Voipio J. Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat Rev Neurosci. 2014;15(10):637–654. doi:10.1038/nrn3819
6. Christensen J, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013;309(16):1696–1703. doi:10.1001/jama.2013.2270
7. Fuentes J, et al. Bumetanide oral solution for the treatment of children and adolescents with autism spectrum disorder: results from two randomized phase III studies. Autism Res. 2023;16(10):2021–2034. doi:10.1002/aur.3005

This text is for educational purposes and does not replace assessment by a health professional.