Delaying epilepsy onset could reduce impact on development

April 9, 2018 by Aisling Irwin, From Horizon Magazine, Horizon: The EU Research & Innovation Magazine
Keeping epilepsy from materialising at a young age could give young patients the chance for normal brain development. Credit: Pixnio, licensed under CC0 public domain

The case of a young boy with a rare genetic disorder over a decade ago has led to a multi-million Euro research project that is raising hopes of new approaches to childhood epilepsy.

It's part of a wave of interest in how to delay the emergence of epilepsy in children with rare diseases which scientists hope could shed light on the prevention of all epilepsies.

Some six months after he was born, the little boy was diagnosed with tuberous sclerosis, a genetic condition that causes benign tumours to sprout in various parts of the body. Before toddlerhood ends, most such patients have also developed epilepsy, mental impairment and autistic behaviours. But, due to a quirk of circumstance, doctors gave this boy epilepsy drugs long before he had any epilepsy – and the results have opened up a fruitful area of research.

For as long as the boy was on the drug, the anticipated epilepsy did not materialise. But, when it was stopped for fear of side effects, the first fit came within months. With it came autism and intellectual disabilities. It was a remarkable connection, and the specialists from the University of Cambridge, UK, wondered whether the epilepsy could actually have caused the other impairments.

Now, some 12 years later, a project called EPISTOP is in its final year exploring the ramifications of this finding and making discoveries that could be applicable to other childhood epilepsy disorders.

The theory is, that while some aspects of tuberous sclerosis are determined around the time of conception because of a genetic mutation, other elements – the mental disabilities – may not be caused directly by the gene but by those epileptic fits damaging the developing brain. If doctors can find a way of postponing the fits until beyond the age of two, they may allow the brain time to develop normally and keep the intellectual problems at bay for ever.

"When we developed the concept (of delaying epilepsy onset), such a word as prevention didn't exist, this word was forbidden," said Professor Sergiusz Jozwiak, a paediatric neurologist at the Medical University of Warsaw in Poland. "Most opinions were coming from adult epileptologists who don't face this problem because in adults the impact of epilepsy on mental development is not significant."

He said that delaying the first seizure can also make the epilepsy that does eventually develop simpler to treat. "It's like swimming against a current of water. The epilepsy wants to develop. But if it appears later it is easier to treat, we use much less epileptic drug."

Tell-tale

EPISTOP recruited 100 children, all diagnosed with tuberous sclerosis before birth, and monitored since then by electroencephalogram, or EEG, for the tell-tale signals that epilepsy is on its way.

Crucially, they were given drugs as soon as those signs appeared. They are awaiting the results.

The concept of an early window for action is also being explored in the DESIRE project, which is investigating many that lead to problems with behaviour, intellect, movement and eating – and all hallmarked by childhood epilepsy.

"This is a collection of a large number of that are cumulatively very relevant," said Professor Renzo Guerrini, child neurologist and psychiatrist at the University of Florence in Italy.

"For many of these conditions it is still not well understood whether epilepsy is in itself a factor which significantly worsens the clinical features, or whether it might just be an epiphenomen (appearing alongside the other conditions) which doesn't influence the overall outcome much.

"If you have a brain malformation … there is nothing you can do to reverse it. But … if you can prevent epilepsy from aggravating the situation you can improve the clinical status of these patients."

In other words, getting in quickly to stop those attacks could make life brighter on a number of fronts for some severely affected kids.

Genetics

One approach is of course to pin down the genetics behind these disorders. For EPISTOP, a team is taking blood samples of babies with tuberous sclerosis at four key moments – at birth, when the EEG first begins to pick up problems, when seizures begin and at two years of age. From those four genetic freeze-frames they can piece together the genetic backstory – when each gene becomes active and what their RNA apparatchiks are up to.

"We have a very, very unique situation," says Prof. Jozwiak. "For the first time we have access to the molecular story before epilepsy ... these results may help us to develop new drugs."

The DESIRE project, meanwhile, has found some genetic mutations for various patients, allowing them to name their disorders and thus link up with the often tiny numbers of fellow sufferers across Europe and beyond. Meanwhile scientists take that genetic knowledge and nurture brain cells in a laboratory that are engineered to harbour these defects and destined to develop in an abnormal way.

"Based on this it might be possible to devise molecules that can correct these defects," says Prof. Guerrini.

DESIRE scientists are homing in on conditions where only one discrete part of the brain develops abnormally, called focal cortical dysplasia. Different types of this dysplasia, it turns out, are characterised by different types of methylation of their DNA – methylation being one of the processes by which genes are switched on and off.

In their search for a way to repair that abnormal methylation the researchers are experimenting with a – one that is low in carbohydrates.

"There is some suggestion that the ketogenic diet might improve epilepsy in this category of patients," said Prof Guerrini. An eagerly awaited research paper is under review.

Surgery is an option for children with very severe epilepsy – and an accessible damaged brain region. One team is working on an instrument – which they have now patented – that picks up high frequency oscillations characteristic of the damaged areas, which increases the precision of the work.

Silencing

Other DESIRE scientists have identified epileptogenic cells that sit it in an odd position in the brain. The goal is to silence them without silencing their healthy counterparts. "You cannot make the whole brain silent or physical function would be annihilated," said Prof Guerrini.

In a rat model the team has developed a virus-based delivery system known as a vector that can recognise the abnormally located and epileptogenic cells, and silence them.

"It is a breakthrough," said Prof. Guerrini. "But of course we have to be cautious. This is an animal model."

Explore further: Simple blood test could reveal epilepsy risk

More information: Dmitry A. Sibarov et al, Functional Properties of Human NMDA Receptors Associated with Epilepsy-Related Mutations of GluN2A Subunit, Frontiers in Cellular Neuroscience (2017). DOI: 10.3389/fncel.2017.00155

Monika Słowińska et al. Early diagnosis of tuberous sclerosis complex: a race against time. How to make the diagnosis before seizures?, Orphanet Journal of Rare Diseases (2018). DOI: 10.1186/s13023-018-0764-z

Related Stories

Simple blood test could reveal epilepsy risk

February 12, 2018
A finger-prick blood test to diagnose epilepsy could be available within five years, according to scientists who are using tell-tale molecules called biomarkers to overcome current diagnostic problems and guide treatment.

Epileptic seizures and depression may share a common genetic cause, study suggests

January 10, 2018
From the time of Hippocrates, physicians have suspected a link between epilepsy and depression. Now, for the first time, scientists at Rutgers University-New Brunswick and Columbia University have found evidence that seizures ...

New study focuses on treatment for epilepsy caused by tuberous sclerosis

May 8, 2017
A clinical trial of a drug that researchers hope can prevent or delay the onset of epilepsy in children with tuberous sclerosis has begun at McGovern Medical School at The University of Texas Health Science Center at Houston ...

Some psychotic disorders may be induced by drugs designed to combat effects of epilepsy

August 9, 2016
Today Brain publishes a new study indicating that antiepileptic drugs designed to reduce seizures, may also induce psychotic disorders in some patients.

Childhood epilepsy not linked with later psychiatric disorders

September 21, 2015
For decades, experts have been studying potential links between childhood epilepsy and various behavioral and psychiatric conditions and some have hypothesized that that they are part of a larger spectrum of brain disorders ...

11 percent of stroke survivors struggle with epilepsy

December 5, 2016
(HealthDay)—More than one in 10 stroke survivors develop epilepsy, and the greater the brain damage caused by stroke, the higher the risk of seizures, a new study reports.

Recommended for you

New approach to treating chronic itch

August 15, 2018
Researchers at the University of Zurich have discovered a new approach to suppressing itch by targeting two receptors in the spinal cord with the right experimental drug. In a series of experiments in mice and dogs, they ...

Immune cells in the brain have surprising influence on sexual behavior

August 14, 2018
Researchers have found a surprising new explanation of how young brains are shaped for sexual behavior later in life.

Scientists pinpoint brain networks responsible for naming objects

August 14, 2018
Scientists at The University of Texas Health Science Center at Houston (UTHealth) have identified the brain networks that allow you to think of an object name and then verbalize that thought. The study appeared in the July ...

SMURF1 provides targeted approach to preventing cocaine addiction relapse

August 14, 2018
A class of proteins that has generated significant interest for its potential to treat diseases, has for the first time, been shown to be effective in reducing relapse, or drug-seeking behaviors, in a preclinical study.

Helping amputees feel as though their prosthetic limb belongs to their own body

August 14, 2018
The famous idiom "seeing is believing" is not enough to help amputees with the use of their prosthetic limb. Many amputees opt out of prolonged use of their prosthetic limb because their perception of their missing limb simply ...

Double discovery reveals insights behind brain degeneration

August 13, 2018
Research discoveries revealing the genetic causes of neurological degeneration could be a key to slowing the progression of devastating diseases.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.