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Epilepsy and Concussion

Research Team

Colin Doherty MD FRCPI  Director
Jennifer Williams –  MD PhD Student – Acute Brain Imaging In Epilepsy and Acute care in ED
Alex Gunko MD – MD Student – ESBACE project and National Acute Care Audit
Lilia Zaporojan – MD PhD student – Cognition and Epilepsy in HIV
Damien Fergusion MD PhD – student – Cognition in Hepatitis C
Eoin Kelly – MD PhD student – Concusion and Mild Traumatic Brain Injury
Claire Behan – Advanced Nurse practitioner – Patient education and TSC research
Cara Synott – Advanced Nurse Practitioner – Homeless projects
Denise Cunningham- Advanced Nurse Practitioner – Outreach programmes
Sinead Hynes Clinical Nurse Specialist – Epilepsy Surgery and Outreach programmes
Corrina Lynch – informatics and EPR

 

Collaborators across all Research Areas

Suzanne Norris (TCD) Hepatology
Colm Bergin (TCD) Infectious disease
Janice Redmond (TCD) Neurology
Jim Meaney (TCD) Imaging
Siobhan Hutchinson (TCD) Cognition
Eugene Wallace (TCD)
Norman Delanty  (RCSI)
Mary Fitzsimons (RCSI)
Gianpiero  Cavalieri (RCSI)
David Henshall (RCSI) Epilepsy
Matt Campbell (TCD) Genetics
Michael Molloy (UCC) Concussion
Fiona Wilson (TCD) Physiotherapy
Ciaran Simms (TCD) Engineering
Elizabeth Thiele Harvard (TSC)
Christine Lenihan (UCD)
Geralyn Hynes (TCD) Nursing
Dominic McCabe (TCD) Stroke

Research areas

Epilepsy

Epilepsy research in Academic Neurology encompasses a wide range of disciplines from Whole Exome Sequencing, through high field MR imaging after acute seizures, 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).

Exome sequencing

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.

Brain Imaging

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. Our project examines 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).

 

Fig 1 showing FLAIR signal abnormality in the acute periictal period which has not settled at 6 weeks but is associated with less oedema, acute diffusion restriction on DWI imaging at time point one which has disappeared at 6 weeks. T2 coronal views showing that there has been subsequent neuronal loss and possibly gliosis due to the ictal event.

 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.

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.

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.

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.

In 2016, the research team was awarded one of the Inaugural Global Brain Health Initiative (GBHI) awards for the development of a virtual Tool for exploring the role of historical concussion and head injury in dementia. The project funds a post-doc to work with researchers in UCSF to develop an App that can be deployed in dementia and memory clinics

Publications 2016/17

1. Williams, Jennifer; Petrov, George; Kennedy, Una; Halpenny, Joanie; Doherty, Colin P Moving evidence based guidelines for seizures into practice in the emergency department: What's stopping us? Epilepsy and Behaviour 2017; Vol 72 (72-77)
2. Williams JA, Bede PA, Doherty CP. An exploration of the spectrum of peri-ictal MRI change; a comprehensive literature review. Seizure 2017
3. Kinsella JA, Tobin W, Tierney S, Feeley TM, Egan B, Coughlan T, Ronan Collins D, O'Neill D, Harbison JA, Doherty CP, Madhavan P, Moore DJ, O'Neill SM, Colgan MP, Saqqur M, Murphy RP, Moran N, Hamilton G, McCabe DJH. Assessment of on-treatment platelet reactivity' and relationship with cerebral micro-embolic signals in asymptomatic and symptomatic carotid stenosis. J Neurol Sci. 2017 May 15;376:133-139. doi: 10.1016/j.jns.2017.03.015. Epub 2017 Mar 14. PubMed PMID: 28431600.
4. McNamara PH, Coen R, Redmond J, Doherty CP, Bergin C. A High Prevalence Rate of a Positive Screen for Cognitive Impairment in Patients With Human Immunodeficiency Virus Attending an Irish Clinic. Open Forum Infect Dis. 2016 Dec 27;4(1):ofw242. doi: 10.1093/ofid/ofw242. eCollection 2017 Winter. PubMed PMID: 28480240; PubMed Central PMCID: PMC5414021.
5. Lynn E, Lyons S, Langan Y, Craig S, Doherty C. The role of alcohol dependency in deaths among people with epilepsy recorded by the National Drug-Related Deaths Index (NDRDI) in Ireland, 2004-2013. Seizure. 2016 Nov 23;45:52-55. doi:10.1016/j.seizure.2016.11.014. [Epub ahead of print] PubMed PMID: 27919010.
6. McDermott A, Zaporojan L, McNamara P, Doherty CP, Redmond J, Forde C, Gormley J, Egaña M, Bergin C. The effects of a 16-week aerobic exercise programme on cognitive function in people living with HIV. AIDS Care. 2016 Nov 28:1-8. [Epub ahead of print] PubMed PMID: 27892704.
7. Doherty CP, O'Keefe E, Wallace E, Loftus T, Keaney J, Kealy J, Humphries MM, Molloy MG, Meaney JF, Farrell M, Campbell M. Blood-Brain Barrier Dysfunction as a Hallmark Pathology in Chronic Traumatic Encephalopathy. J Neuropathol Exp Neurol.2016 Jul;75(7):656-62. doi: 10.1093/jnen/nlw036. PubMed PMID: 27245243; PubMed Central PMCID: PMC4913433.
8. Omer, TA; Hutchinson, S; Doherty, C; Hardiman, O Deep phenotyping of Frontotemporal Dementia (ftd) and Ftd-mnd in Ireland: a clinic-based cohort longitudinal study. European Journal of Neurology, Vol 23 (370)
9. Murphy S, Bennett K, Doherty CP. Prescribing trends for Sodium Valproate in Ireland. Seizure 2016 Feb 17;36:44-48. doi: 10.1016/j.seizure.2016.01.019. [Epub ahead of print]