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The University of Southampton
BRAIN UK

Lay Summaries of studies supported by BRAIN UK by category: Epilepsy

BRAIN UK Ref: 12/010
The brain in Sudden and Unexpected Death in Epilepsy (SUDEP): new insights from pathology
Dr M Thom, University College London 

Epilepsy is the most common serious neurological condition and SUDEP is the leading cause of premature death in people with epilepsy. The mechanisms are unknown and there are few neuropathology based studies. Our research in the last few years, utilising the tissue from Brain UK resources, has shown that in many patients with SUDEP there is an underlying lesion in the brain which has caused their seizures. This is called symptomatic epilepsy. In the first part of our study funded by CURE our aim was to look at acute changes in the brain which could occur in SUDEP using markers of inflammation (CD163, HLA-DR0, gliosis (GFAP), acute neuronal injury due to hypoxia (low oxygen levels) (HIF-1α) and blood brain barrier (BBB) disruption (IgG, Albumin) in regions of the brain that are vulnerable in epilepsy and that we know are important for autonomic functions (those that automatically regulate the heart rhythm and respiration). These included tissue samples from the hippocampus, mededlla and amygdala. We used tissue from our own resources and also from Brain UK and included 45 post mortem cases: 24 SUDEP, 5 epilepsy without SUDEP controls and 16 non-epileptic sudden death controls. Our initial studies have shown that their expression in SUDEP cases are not different from these seen in control groups. The second part of our study, which is funded by NIH and is part of the Centre for SUDEP Research (CSR), is addressing chronic alterations in these brain regions.

Project Status: Active

Research Outputs: Publication x 5; Abstract x 3; Presentation x 2; Poster x 2

DatePublication title
2016 Audit of Practice in Sudden Unexpected Death in Epilepsy (SUDEP) Post Mortems and Neuropathological Findings
2017 Neuropathology of SUDEP: Role of Inflammation, Blood-Brain Barrier Impairment, and Hypoxia
2018 The Ventrolateral Medulla and Medullary Raphe in Sudden Unexpected Death in Epilepsy
2019 Hippocampal Morphometry in Sudden and Unexpected Death in Epilepsy
2019 Characterisation of Medullary Astrocytic Populations in Respiratory Nuclei and Alterations in Sudden Unexpected Death in Epilepsy
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BRAIN UK Ref: 16/009
Evaluating mTOR pathway hyperactivity in intractable epilepsy
Dr Anurag Saxena, Cardiff University 

Epilepsy is a common neurological condition where patients have recurrent seizures. A small number of patients can have many seizures in a day and may require brain surgery to control them.

The “mechanistic target of rapamycin” (mTOR) pathway is a vital cellular pathway.  It is involved in many cellular functions, including cell growth and excitability in brain cells. Its overactivity may be responsible for making individuals prone to have epilepsy.

There is suggestion of increased activity of mTOR pathway in brain tissue of individuals who had brain surgery to control their epilepsy. We would like to evaluate if this overactive mTOR pathway is present in a wider variety of patients who need brain surgery for managing their seizures.

A group of medications known as mTOR inhibitors, such as Sirolimus (rapamycin) and Everolimus, have been effective in reducing seizures in animal models as well as clinical trials in conditions such as Tuberous sclerosis. Individuals with Tuberous sclerosis commonly have epilepsy, with high burden of seizures.

If the study suggests that the brain tissues of patients with difficult to control epilepsy have overactive mTOR pathway, it is likely we would be able to test if mTOR inhibitors can be used to manage these cases.

Project Status: Active

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BRAIN UK Ref: 16/016
Epilepsy: What is the significance of the density of ectopic neurons in the white matter of temporal, parietal and frontal lobe, and are they normal or pathological?
Dr Azzam Ismail, University of Leeds School of Medicine 

Epilepsy is the fourth most common neurological disorder, and in the U.K. approximately 1 in 30 people develop it as some stage in their life. Drug resistant epilepsy can have serious implications on quality of life and increase risk of memory loss, mood difficulties and death, observed in patients with frequent untreated seizures [1]. Our research investigates the significance of densities of ectopic (abnormal) neurons in the white matter of three lobes of the brain: temporal, parietal and frontal. Ectopic neurons in the white matter of these lobes are noted in variable number in normal and epilepsy patients. It is not clear what is the normal or abnormal density of these ectopic neurons. Therefore, we look to compare the density of these neurons between epilepsy patients and normal. Autopsy brain samples of patients who died of sudden unexplained death in epilepsy (SUDEP) and non-epileptic samples will be used. Temporal, parietal and frontal lobe slides will be gathered from two populations (non-epileptic and SUDEP patients) from patients autopsied. Results will be documented and matched with the clinical history of the patient. Our research hopes to enhance the understanding of the pathogenesis of epilepsy and ultimately provide improved management strategies. 

1. http://www.epilepsy.com/learn/types-epilepsy-syndromes/temporal-lobe-epilepsy

Project status: Closed

Research Outputs: Presentation x 2

BRAIN UK Ref: 18/002
Understanding the neural substrates of visuospatial memory and how this is affected by epilepsy and Alzheimer’s Disease.
Mr Massawer Butt, University of Bristol

“Pattern Separation” is your brain’s ability to differentiate similar but distinct objects or arrangements of objects (e.g. ‘where I put my keys today’ vs ‘where I put them yesterday’). It is dependent on a particular set of cells in the memory region of the brain and is important for the encoding and recollection of memories. Animal studies have shown that the seizures associated with epilepsy cause heavy loss of one of the types of cell that are activated during this task.  It is also known that the region of the brain where these cells are found is affected by ageing and by the processes that lead to dementia, suggesting that the same cells that are affected by epileptic seizures may also be affected by Alzheimer’s Disease.  The aim of this study is to analyze the area associated with memories in human brain tissue, to establish if there is a difference in various cell populations in participants with epilepsy and Alzheimer’s.  This will later be used as a critical input to future studies characterizing the pattern separation performance of people with and without epilepsy.

Project status; Active

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BRAIN UK Ref: 18/010
Identification of Differentially Expressed Proteins and Genes Impacting Seizures and Risk of SUDEP in Dravet Syndrome
Dr Orrin Devinsky, New York University

Dravet Syndrome is a severe form of epilepsy that is associated with an increased risk of sudden unexpected death in epilepsy (SUDEP). Although a gene mutation has been identified in 80% of patients, seizures generally remain drug resistant. Defects of various neurotransmitter signals in the brain have been implicated in Dravet Syndrome, however the processes that lead to seizures are still not well understood. We aim to evaluate these processes by identifying pathological differences in the proteins and genes of involved areas of the brain (hippocampus and brainstem). This will be done in Dravet Syndrome patients and compared to patients with and without epilepsy. We aim to improve our understanding of the processes associated with seizures in these brain regions. This will provide insight into potential therapeutic strategies for improving seizure management in Dravet Syndrome, reducing SUDEP risk and understanding of other forms of epilepsy.

Project Status: Active

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BRAIN UK Ref: 19/011
The purinergic P2X7 receptor as drug target for refractory status epilepticus
Dr Tobias Engel, Royal College of Surgeons in Ireland

Severe seizures, which last for more than 5 minutes, are known as status epilepticus. This is a medical emergency and the priority is stopping the seizure activity. Approximately 30% of patients, however, are resistant to drugs designed for stopping seizures. We have found that, in mice, a particular receptor - P2X7 - contributes to this drug resistance. Further, we have also shown that P2X7 is increased in conditions that are often related to increased resistance to anti-seizure drugs, such as inflammation in the body. It is unclear, however, whether the findings in mice are also true for humans. The first step towards investigating this is to see whether patients who showed resistance to anti-seizure drugs have a higher than normal amount of P2X7. This would suggest that P2X7 is also involved in drug-resistance in humans and would back the idea that developing treatments targeted at P2X7 may be useful for breaking drug-resistance in these patients.

Project Status: Active

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BRAIN UK Ref: 19/016
Investigating cellular identity in childhood epilepsy
Prof. Tom Jacques, UCL Great Ormond Street Institute of Child Health 

Not yet available 

Project Status: Pre-Approval

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