Trinity College Dublin: Brain tumour related epilepsy: merging basic science with clinical practice

About 380 people are diagnosed with primary brain tumours each year in Ireland, a devastating diagnosis for patients and their families. Seizures are common in patients with glioma, a particular type of tumour that occurs in the glial cells that support the neurons of the brain. The epileptic seizures that occur due to glioma are known as brain tumour related epilepsy (BTRE) and are debilitating and difficult to control.

The seizures are closely related to recurrence and progress of the brain tumour. Seizures result in reduced mobility for patients (due to loss of their driving license, for example) and increases the risk of death due to uncontrollable seizures. Seizures are the first presenting symptom in 65-85% of patients with low grade gliomas (LGG) and 68% of patients with glioblastoma multiforme (GBM).

In 2018, Professor Cunningham was appointed to the Ellen Mayston Bates Professorship of Neurophysiology of Epilepsy in Discipline of Physiology, School of Medicine at Trinity College. This position was founded due to an endowment from Ellen Mayston Bates which led to establishment of a major epilepsy research programme which is enabling discoveries to benefit people all over the world suffering from this serious brain disorder. Although his work is inherently laboratory-based, Professor Cunningham puts patients at the core of his research. He says:

“One particular quote from a patient stays in my mind: ‘Every time I have a seizure, it reminds me of the tumour inside my brain’.

“For patients, treatment options include surgery, radiotherapy, chemotherapy and anti-seizure medication (ASM). However, 37.5% of patients with LGG continue to experience seizures following surgery and, whilst early radiotherapy and upfront chemotherapy reduces seizure frequency, many patients continue to experience seizures.

Increasing seizure burden and ASM use is associated with reduced cognitive performance and patients with seizures report reduced physical and mental health. Given the limited efficacy of surgical, oncological and pharmacological treatments for BTRE and its impact on quality of life, there is an urgency to expedite novel therapies. My research investigates if we can improve treatments of seizures associated with tumours by exploring novel drugs and therapy approaches which are specific to the disease processes in this condition.”

Under normal conditions in the brain neurotransmitters, such as glutamate, allow brain cells to talk to one another. Glutamate does this by exciting brain cells. Around the tumour is an area of brain tissue called the peritumoural region. This contains tumour cells trying to invade the surrounding normal brain tissue. These invading tumour cells use the neurotransmitter, glutamate, to help them move and grow in the brain. The tumour cells release glutamate so that the transmitter reaches very high levels around the tumour. Glutamate acts to produce hyper-excitability in the brain by activating a particular receptor, the AMPA receptor, and to alter normal brain cells around the tumour. Thus, the tumour ‘hi-jacks’ the glutamate system for its own ends.

Professor Cunningham has extensive experience is working with human peri-tumour tissue, keeping this tissue alive so that he can study the electrical activity of neurons as they generate seizure activity. The work is highly collaborative, as Professor Cunningham explains:

“We collaborate with colleagues from Beaumont Hospital (Mr Donncha O’Brien, Mr Stephen McNally, and Mr Kieron Sweeney, all of the Department of Neurosurgery) and plan to collect human tissue to study the effectiveness of novel drugs and other therapies in stopping seizure activity in the peri-tumoural tissue. We also work with researchers from the Royal College of Surgeons, University College Dublin, St James’s Hospital, and University College London.”

The impact of this work is evident in two key areas: in the improvement of clinical management and in advancing Ireland’s national research priorities and strategies. For clinical practice, the long-term impact is to fast track discoveries into tangible benefits for patients. The project will provide benefits to a variety of end-users in healthcare with people with BTRE as primary beneficiaries of the research.

Moreover, this work provides opportunities for neurologists, neurosurgeons and oncologists involved in the treatment of patients with BTRE to make optimal clinical decisions, and in the advancement of crucial clinical trials. The research will also impact policy by informing government-level reports related to practice and the economic cost of BTRE.

Although there is no cure for the condition, Professor Cunningham’s lab is the first in Trinity to focus entirely on epilepsy, a topic traditionally under-resourced in the field of Neuroscience.

Described as the ‘brains’ behind Trinity’s epilepsy research, Professor Cunningham’s unique work represents real hope of more effective and targeted treatment for this poorly understood disease.

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