Epilepsy and Concussion
Epilepsy and Brain Injury Research (E-BIR) Team
Colin Doherty MD FRCPI Chair in Epileptology and Head of School of Medicine
Declan Brennan MD (SPR) and PhD Student - Concussion and Brain Injury
Claire Behan – ANP (Epilepsy) and PhD Student - Seizure Biomarkers
Mary Vasseghi – RN and PhD Student - Tuberous Sclerosis Complex
Elisabeth Doran MD – Consultant Neurologist/Senior Lecturer Academic Unit of Neurology, Clinical Medicine, TCD and Director of Epilepsy Service, St James’s - Inclusion Health Projects
Damien Ferguson MD PhD Consultant Neurologist/Senior Lecturer, Academic Unit of Neurology, Clinical Medicine, TCD -Cognition in Hepatitis C
Cara Synott – ANP (Epilepsy) – Slaintecare/Inclusion health projects
Denise Cunningham- Advanced Nurse Practitioner – Outreach programmes
Sinead Hynes ANP (Epilepsy) – Epilepsy Surgery
Laura Healy PhD – Nutrition and Ketogenic Diet
Corrina Lynch – informatics and EPR and Sodium Valproate
Anne Gough (ANP) epilepsy – Ketogenic Diet
Aisling Cope – Medicinal Cannabis and Epilepsy Treatment
PI Collaborators across all Research Areas
Matt Campbell (TCD genetics) Blood Brain Barrier, Epilepsy, Concussion and COVID
Orla Hardiman (TCD neurology ) – ICT/digital platforms
Hugh Kearney (TCD Neurology ) MS and Blood Brain Barrier
Aoife Laffan (TCD Neurology) functional neurology/ COVID and Blood Brain Barrier
Suzanne Norris (TCD Hepatology) Hep C and Cognition
Colm Bergin (TCD Infectious disease) HIV, Hep C & Cognition
Jim Meaney (TCD) Imaging
Peter Bede (TCD) Imaging
Siobhan Hutchinson (TCD Neurology) Cognition
Norman Delanty (RCSI Neurology) genomics
Peter Widdes Walsh (RCSI Neurology) Clinical epileptology
Gianpiero Cavalieri (RCSI genomics) genomics and digital health
Kathleen Bennett (RCSI – Data Science) (Data Analytics)
David Henshall (RCSI - Physiology) Epilepsy biomarkers
Michael Molloy (UCC- Rheumatology) Concussion
Fiona Wilson (TCD Physiotherapy) – Concussion
Elizabeth Thiele Harvard (Harvard Neurology) - TSC
Robert Forster – (DCU electrochemistry) biomarkers
Rob Argent (RCSI Physiotherapy) Digital medicine
Christine Lenehan (UCD Disability) Epidemiology of Epilepsy
Dominic McCabe (TCD Neurology) Stroke
The Epilepsy and Brain Injury Research Group
Epilepsy and brain injury research in Academic Neurology encompasses a wide range of Research areas from Whole Exome Sequencing in Epilepsy, micro RNA and Blood Brain Barrier biomarkers of seizures, through high field MR imaging to health service research and innovation; Integrated seizure pathway development; Electronic Patient Records (EPR); Patient centeredness and stigma in epilepsy; epilepsy related death and Chronic Disease Management (CDM).
As part of government funded research programme known as ‘The Lighthouse Project’ through the Chief Information Officer in the HSE, the Epilepsy EPR, has been funded to marry State of the Art exome sequencing in people with severe epilepsy and learning disability with a collaborative process after a genetic diagnosis is given and the sharing of information electronically between families, the medical team and international bioinformatics resources to aid in management.
In the field of brain imaging in epilepsy, a wide spectrum of abnormalities have been described in patients who have undergone MRI in the peri-ictal seizure period. These qualitative studies suggested that these observable changes can either persist or reverse. The exact rates of imaging changes in patients and what clinical and semiological characteristics govern such changes remains unclear. This project examined the biological impact of even single seizures using quantitative techniques through DTI in the acute period and follow these patients longitudinally. Patients were recruited within 72hrs of ictus and underwent high quality 3T neuroimaging and repeat after 6 weeks (fig 1).
Figure 1. Voxel based Morphometry: Coloured areas shows statistically significant changes in volume in left Hippocampus, anterior cingulate and bilateral temporal cortex in HIV patients with Cognitive impairment
Blood-brain barrier Imaging and biomarkers in Epilepsy
Disruption to the blood-brain barrier (BBB) is commonly observed in experimental models of epilepsy and in resected brain tissue from patients with treatment resistant temporal lobe epilepsy. While previous studies have shown associations between BBB dysfunction and seizure activity in epilepsy, there is a paucity of investigations exploring the underlying molecular mechanisms that drive microvascular dysfunction in the condition. Patients with treatment resistant temporal lobe epilepsy were recruited for pre- and post-surgical dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Hippocampal and cortical brain tissue samples were used for histological and transcriptomic analysis of BBB integrity. Seizures were induced in mice via systemic or unilateral intrahippocampal injection of kainic acid and blood-brain barrier integrity was assessed by perfusion of different molecular weight tracer molecules. DCE-MRI revealed widespread BBB disruption in pre-surgical patients with temporal lobe epilepsy which was subsequently ameliorated following surgical resection of affected regions. Molecular analysis of resected tissue uncovered breakdown of the endothelial cell tight junction proteins, leakage of plasma proteins into the brain parenchyma and extensive neuroinflammation characterised by microglial activation and astrogliosis. Correlation analysis revealed strong associations between markers of inflammation and disease severity and the incidence of psychiatric comorbidities. In rodents, intrahippocampal injection of kainic acid disrupted the tight junction proteins claudin-5, occludin and ZO-1. In mice heterozygous for claudin-5 there was increased vulnerability to evoked seizures and more extensive BBB disruption and neuroinflammation compared to wild-type mice. Finally, in an inducible claudin-5 knockdown mouse model, loss of claudin-5 resulted in spontaneous recurrent seizures, astrogliosis and increased mortality. Our findings suggest that epilepsy can alter BBB integrity by modulating the tight junction protein claudin-5. Surgical resection of affected brain regions attenuated BBB disruption which suggests that microvascular stabilisation is important for seizure freedom. In mice, kainic acid induced seizures resulted in loss of the tight junction protein claudin-5. While loss of claudin-5 is lethal with severe neuroinflammation and recurrent seizures occurring, haploinsufficiency is sufficient to reduce the threshold for the induction of convulsive seizures. This data complements decades of research showing that BBB breakdown is sufficient to induce epileptiform activity (figure 2)
Figure 2: BBB disruption and seizures
Infectious Diseases Related Neurodegeneration
Research in the domain of infectious diseases related cognitive impairment is a relatively new but growing area in Academic Neurology. To date there has been one finalised study which evaluated the prevalence and both: neuropsychological and imaging pattern of HIV related cognitive impairment in a St James’s Hospital based HIV positive population cohort. This project ended with a successful PhD submission.
Currently, there is an ongoing study assessing follow up neuropsychological and imaging features of HIV associated cognitive impairment 2 years after the baseline data acquisition. More recently, a HRB funded project in collaboration with the Departments of Infectious Diseases and Hepatology aims at screening for Hepatitis C (HCV) related cognitive impairment.
Cognitive Impairment in HIV
At least 50% of HIV infected patients suffer from cognitive impairments, ranging from minor cognitive disorder to HIV-associated dementia (HAD). These patients may experience symptoms such as forgetfulness, language difficulties and changes in personality. These symptoms may have serious implications in the patients’ daily life as well as their clinical care. Despite the introduction of Highly Active Anti-Retroviral Therapy, the subtler forms of HIV-associated neurocognitive disorders (HAND) remain frequent.
Up until recently the prevalence and pattern of HAND in Irish HIV positive population was unknown. In our Department’s original cross sectional study, we did a brief cognitive testing on 604 patients attending the St. James’s Hospital HIV services. 51.5% of the initial screening study participants had a positive screen for cognitive impairment. Then, a subset of 104 patients who screened positive for cognitive impairment, underwent detailed cognitive testing to underpin the pattern of cognitive impairment in HIV.
A cross-sectional study which assessed brain atrophy in patients with cognitive impairment secondary to HIV was also carried out. Participants included 50 HIV positive patients, who had a positive screen for cognitive impairment. The findings of this study showed dysexecutive amnestic picture on neuropsychological testing correlated with involvement of the anterior cingulate, temporal cortices and hippocampus on imaging which supports our hypothesis of a neurodegenerative continuum from acute to chronic infection.
The aim of our second study is demonstrate the progressive nature of the decline in cognition due to a presumed neurodegenerative process using neuropsychological testing and brain imaging 18 months -2 years after initial testing of our original cohort.
Cognitive Impairment in HCV
As many people are infected with HCV as are with HIV, or about 3.3% of world’s population. HCV infection becomes chronic in approximately 75%–85% of cases; 1–5% will die from the consequences of chronic infection - liver cancer or cirrhosis; but 13–50% of individuals with chronic HCV infection will develop cognitive dysfunction.
There is growing evidence that approximately one-third of people with chronic HCV experience cognitive impairment even in the absence of cirrhosis and that its occurrence is unrelated to other indices of liver function.
Our study of HCV will determine the prevalence of HCV related cognitive impairment in the HCV positive cohort as well as neuropsychological pattern with the use of detailed psychological testing. A sub cohort of 50 participants will have their brain MRI acquired as part of this project to assess for possible MRI disease markers.
Traumatic Brain Injury
Traumatic brain injury (TBI) is the leading cause of death in children and young adults in Ireland. Malignant brain swelling has a major role in the pathophysiology that evolves after severe TBI. Therapeutic strategies to prevent cerebral oedema are limited and, if brain swelling persists, the risks of permanent brain damage or mortality are greatly exacerbated. While major brain injury is a risk in modern contact sports, the number of deaths and major disability emanating from sports related head injury appears at first glance to be small. A far greater challenge is the occurrence of what has become known as mild TBI (mTBI).
A recent collaboration between the Smurfit Institute of Genetics, TCD and St James' Hospital Dublin has led to the establishment of a multidisciplinary project focused on elucidating the underlying pathophysiology of concussive brain injuries in young sports men and women. A combined clinical and basic research programme investigating the role of the blood-brain barrier (BBB) in the context of mTBI observed in rugby players was initiated in September 2015. With the growing awareness of concussive and sub-concussive brain injuries in sports, this work will lead to a better understanding of the mechanism of injury at play. Additionally, this work has the potential to lead to improved management of mTBI in general. Current research involves the imaging and cognitive and neuropsychiatric outcomes off athletes who have at least 10 years exposure to high level contact. At least 40 players have been recruited so far.
In collaboration with the Dublin Brain Bank, the research programme is also focused on elucidating the role of the BBB in the onset of chronic traumatic encephalopathy (CTE). Much attention has focused on emerging evidence linking the development of CTE to concussive injuries in athletes and military personnel. However, the underlying molecular pathobiology of CTE is far from clear and it can only be diagnosed post-mortem. Recently, our group was the first to observe evidence that the BBB is significantly disrupted in CTE and these results may lead to new forms of "in-life" diagnosis of the condition which can only be diagnosed post-mortem at present (Fig 1). Cumulatively, our research programme focusing on the role of the cerebrovasculature in neurological conditions such as mTBI and CTE will lead to improved treatment paradigms for patients in the future.