Epilepsy and Personalised Medicine
Epilepsy, Neurology, Outcomes research, Genomics, Biomedical engineering, Translational medicine, Precision medicine, Pharmacogenetics
2021 group. L-R: Dr Jianxiong Chan, Dr Asanka Jayawardena, Professor Patrick Kwan, Ms Sher Maine Tan, Mr Abkar Sayad.
- Dr Alison Anderson – Bioinformatician
- Dr Zhibin (Ben) Chen – Biostatistician
- Dr Ana Antonic-Baker – Stem Cell biologist
- Dr Ben Rollo – Cell biologist
- Dr Jianxiong Chan – Molecular biologist
- Dr Anne McIntosh – Epidemiologist
- Dr Andrew Neal – Epilepsy Consultant
- Dr Emma Foster - Research Fellow, Epilepsy consultant
- Michael Gorman (co-supervisor, Swimburne University)
- Ofer Gonen (epilepsy fellow)
- Mubeen Janmohamed
- Muhammad Shahid Javaid
- John-Paul Nicolo (epilepsy fellow)
- Andreas Pattichis (neurosleep fellow)
- Abkar Sayad
- Lubna Shakhatreh (epilepsy fellow)
- Juliana Silva
- Shah Mukin Uddin
- Anna Willard (epilepsy fellow)
- Yukun Zhou
- Rashida Ali – Molecular biologist (Biobank Manager)
- Dr Asanka Jaywardena – Biomedical Engineer
- Ms Sher Maine Tan – Molecular Biologist
- Sameer Sharma (Casual)
- Dr Loretta Piccenna
To identify genetic, structural, metabolic and environmental factors that affect treatment outcomes in people with epilepsy and related neurological conditions (e.g. following stroke), and promote the translation of research findings into clinical practice using personalized medicine to improve treatment outcomes for patients.
Our group’s translational research covers a broad spectrum of areas in relation to neurological diseases such as epilepsy - ranging from basic discovery to clinical implementation and health economic analysis to provide the evidence necessary to improve patient outcomes. There is a strong focus on the use innovative approaches, e.g. pharmacogenomics, developing point of care diagnostic tools, clinical utility and cost-effectiveness, and the use of animal models to understand the effects of new treatments on patients with neurological diseases. Although the focus is on neurological diseases, particularly epilepsy, our work has broad relevance and extends to other disciplines.
Genomics of cutaneous adverse drug reactions
Many drugs, including antiepileptic drugs, antibiotics and anti-inflammatory drugs are associated with a range of skin related (cutaneous) side effects, including Stevens Johnson syndrome and toxic epidermal necrolysis. These reactions can be unpredictable and are associated with a high risk of mortality and morbidity. Exploring the genetic basis for these adverse drug reactions (ADRs) will have major impact on “personalised” drug selection, and the insights gained on the chemico-biological pathways will help future design of safer medications.
This project aims to effectively and efficiently discover the genetic variants involved in a unique subject cohort of patients with epilepsy (drug-exposed cases and controls) using the latest genotyping and sequencing platforms.
Clinical utility and cost-effectiveness of genomic sequencing for epilepsy
Genetic variants have been found to cause epilepsy as well as affect how people respond to treatment. Whole exome sequencing (WES) is a new method of genetic testing that has the advantage of being able to screen all the genes in a person. Currently, its use is mainly for research purposes only due to the high cost associated with performing the technique.
The purpose of this prospective study is to find out whether genomic sequencing offers value for money when used in the clinical setting to help diagnose people with epilepsy.
Development of a low cost, point-of-care diagnostic platform
Point-of-care (POC) testing provides diagnosis at the site of patient care, i.e. in real-time. It is done on patients conveniently and immediately which allows patients and doctors to receive the results quicker to enable faster clinical decisions to be made.
The aim of the project is to develop a novel rapid, ultrasensitive real-time POC platform targeting molecules in blood or saliva. Our study is divided into 3 main projects aimed at developing and validating 1) DNA-based, 2) Protein-based, and 3) Whole cell detection, from whole blood and saliva. This will be integrated on a single chip platform to facilitate a small, low-cost and reliable test device.
Wearable devices for non-invasive, ambulatory seizure monitoring and prediction
The development of reliable, accurate, non-invasive methodologies for continuous, long-term seizure monitoring is a critical part of the precision medicine approach in epilepsy management. While the gold standard for diagnosing and detecting seizures remains inpatient simultaneous electroencephalogram (EEG) and video recording, it is costly and impractical for extended use outside the hospital setting. Conventional outpatient seizure monitoring relies on seizure diaries to be completed by patients themselves, which is inexpensive but highly inaccurate. There is a need for novel technologies that combine low cost, non-invasiveness with reliability for extended seizure monitoring.
This project aims to develop an integrated wearable sensor system for the clinical management of seizures in patients with epilepsy. The device will be tested in patients admitted for inpatient video-EEG monitoring.
Acquired epilepsy in Alzheimer’s disease
Alzheimer's disease (AD) patients are 10 times more likely to develop epilepsy compared with age-matched controls. The treatment of recurrent seizures with conventional antiepileptic drugs may exacerbate cognitive decline. There are currently no treatments that prevent epilepsy in AD patients and the pathological basis for the increased risk of epilepsy is largely unknown. Understanding the mechanisms of epileptogenesis in AD is crucial in identifying effective therapeutic strategies. This will help to prevent the development of epilepsy in this high risk and vulnerable population. This project aims to directly address the mechanisms of epileptogenesis in AD through the study of animal models of AD and acquired epilepsy.
The aims will be achieved by subjecting transgenic AD models reflecting the pathological hallmarks to acquired epileptogenesis and treating them novel compounds. The phenotypic changes will be correlated with the molecular and cellular changes in these pathways.
Stroke and epilepsy
Stroke is one of the leading causes of acquired epilepsy in industrialised countries. Seizures are a major complication in stroke survivors and are associated with increased mortality and poorer functional recovery. Patients with post-stroke seizures have an increased risk of in-hospital complications, leading to prolonged hospitalisation. Conversely, patients with epilepsy also have an increased risk of de novo stroke, the reasons for which are unclear.
This project is focused on identifying biomarkers of patients at risk of developing post-stroke epilepsy, using advanced imaging and genetic approaches, and evaluating novel compounds to prevent the development of post-stroke epilepsy.
Management and prognosis of first seizure and newly diagnosed epilepsy
To formulate rational treatment plans, it is important to understand the different clinical courses and patterns of response to antiepileptic drugs, ideally by following outcomes from the point of treatment initiation.
This project will perform an analysis focusing on patients presenting with a first seizure and their response to the initial therapies and their relationship with long-term treatment outcomes and the development of drug resistance in newly treated epilepsy patients.
Long-term Prognosis of Antiepileptic Drug Therapy in People with Newly Diagnosed and Treated Epilepsy
Antiepileptic drug therapy constitutes first line treatment for seizure management. Our previous research has demonstrated that approximately one-third of patients do not respond to drug treatment and continue to have seizures. Those who have failed two or more antiepileptic drug therapies are considered to have drug-resistant epilepsy and a high risk of having uncontrollable seizures. However, the long-term outcomes of epilepsy are poorly understood, hampering the selection of a rational and effective management plan. Our recent study showed that despite the increasing use of the new drugs, the overall treatment outcomes in people with new onset epilepsy has not improved.
This project aims to develop and validate a model (algorithm) and scoring system based on our unique access to some of the world’s largest databases of people with newly diagnosed epilepsy to provide a better indication of long-term outcomes.
Treatment Gap in People with Newly Diagnosed Epilepsy in Australia
Antiepileptic drugs (AEDs) are the mainstay of treatment for epilepsy and can render two-thirds of the treated patients seizure-free. However, many patients with epilepsy are not receiving AEDs for a variety of reasons. Our research has estimated the epilepsy “treatment gap” in Western Australia, where 22% of individuals newly diagnosed with epilepsy remained untreated by the end of follow-up, and 33% of the treated patients had not actually commenced on AED treatment until a further seizure. People with epilepsy are known as having higher mortality and an associated range of physical and psychological comorbidities. However, whether the mortality and morbidity risks in the untreated epilepsy patients are significantly different from those treated with AED therapies has not been well studied. Moreover, there is scant knowledge regarding the health economics effect of the “treatment gap” and whether it is cost-effective to narrow the “gap”.
Current Project Funding
- Kwan, P, Armstrong, M, Flynn, D, Chan, J, John, K. Designing a Point of Care diagnostic device for clinical management of patients with epilepsy - a single test and single visit approach. Victorian Medical Research Acceleration Fund – R3 (The Alfred Hospital). Collaboration with Monash Art, Design & Architecture (MADA)
- Kwan, P, Marzbanrad, F, Yap, L, Gong, S, Wang, Y, Zhai, Q and Cheng, W. Automated seizure detection for patients with epilepsy. 2018 Monash Institute of Medical Engineering (MIME) Seed Fund
- Kwan, P, O’Brien, T, Cloud, G, Hand, P, Yan, B, Nicolo, J, Wright, D. Brain glutamate imaging by ultra-high-field MRI for prediction of post-stroke epilepsy. Victorian Medical Research Acceleration Fund – R2 (The Alfred Hospital). Collaboration with Royal Melbourne Hospital
- Scheffer, I, O’Brien, T, Kwan, KLP (Executive lead). Sanming Project. Shenzhen Children’s Hospital
- Kwan KLP, Petrovski S, Ratcliffe J, Winship IM & Mullen SA. NHMRC project grant APP1143934. Clinical utility and cost-effectiveness of genome sequencing for refractory epilepsy in children and adults: a multicentre randomised controlled trial. Collaboration with the University of Melbourne
- Naganur VD, Kusmakar S, Chen Z, Palaniswami MS, Kwan P, O'Brien TJ. The utility of an automated and ambulatory device for detecting and differentiating epileptic and psychogenic non-epileptic seizures. Epilepsia Open. 2019 May 13;4(2):309-317. doi: 10.1002/epi4.12327.
- Alsfouk BA, Alsfouk AA, Chen Z, Kwan P, Brodie MJ. Pharmacological outcomes in teenagers with newly diagnosed epilepsy: A 30-year cohort study. Epilepsia. 2019 Jun;60(6):1083-1090. doi: 10.1111/epi.15664.
- Foster E, Holper S, Chen Z, Kwan P. Presentation and management of community-onset vs hospital-onset first seizures. Neurol Clin Pract. 2018 Oct;8(5):421-428. doi: 10.1212/CPJ.0000000000000524.
- Wong JKL, Gui H, Kwok M, Ng PW, Lui CHT, Baum L, Sham PC, Kwan P, Cherny SS. Rare variants and de novo variants in mesial temporal lobe epilepsy with hippocampal sclerosis. Neurol Genet. 2018 Jun 11;4(3):e245. doi: 10.1212/NXG.0000000000000245.
- Krauss GL, Perucca E, Kwan P, Ben-Menachem E, Wang X-F, Shih JJ, Patten A, Yang H, Williams B, Laurenza A. Final safety, tolerability, and seizure outcomes in patients with focal epilepsy treated with adjunctive perampanel for up to 4 years in an open-label extension of phase III randomized trials: Study 307. Epilepsia. 2018; 59 (4): 866 – 876.
- Sivathamboo S, Perucca P, Velakoulis D, Jones NC, Goldin J, Kwan P, O’Brien TJ. Sleep disordered breathing in epilepsy: Epidemiology, mechanisms and treatment. Sleep. 2018; doi: 10.1093/sleep/zsy015. [Epub ahead of print].
- Thevathasan A, Naylor J, Churilov L, Mitchell PJ, Dowling RJ, Yan B, Kwan P. Association between hemorrhagic transformation after endovascular therapy and poststroke seizures. Epilepsia. 2018; 59 (2): 403-409.
- Chen Z, Churilov L, Chen Z, Naylor J, Koome M, Yan B, Kwan P. Association between implementation of a code stroke system and poststroke epilepsy. Neurology. 2018; 90(13): e1126-e1133. doi: 10.1212/WNL.0000000000005212.
- McCormack M…..EPIGEN Consortium;, Pirmohamed M, Carleton BC; Canadian Pharmacogenomics Network for Drug Safety;, Cendes F, Lopes-Cendes I, Liao WP, O'Brien TJ, Sisodiya SM; EpiPGX Consortium;, Cherny S, Kwan P, Baum L; International League Against Epilepsy Consortium on Complex Epilepsies;, Cavalleri GL. Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients. Neurology. 2018; 90(4):e332-e341. doi: 10.1212/WNL.0000000000004853.
- Soraya GV, Chan J, Nguyen TC, Hyunh DC, Abeyrathne CD, Chana G, Todaro M, Skafidas E, Kwan P. An Interdigitated Electrode Biosensor Platform for Rapid HLA-B*15:02 Genotyping for Prevention of Drug Hypersensitivity. Biosensors Bioelectronics. 2018; 111:174-183. doi: 10.1016/j.bios.2018.01.063.
- Chen, Z., Brodie, M.J., Liew, D., Kwan, P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs a 30-year longitudinal cohort study. JAMA Neurology. 2018; 75(3):279-286. doi: 10.1001/jamaneurol.2017.3949.
- Liu S, Shen Y, Shultz SR, Nguyen A, Hovens C, Adlard PA, Bush AI, Chan J, Kwan P, O’Brien TJ, Jones NC. Accelerated kindling epileptogenesis in Tg4510 tau transgenic mice, but not in tau knockout mice. Epilepsia. Accepted 20 June 2017.
- Shi YW, Min FL, Zhou D, Qin B, Wang J, Hu FY, Cheung YK, Zhou JH, Hu XS, Zhou JQ, Zhou LM, Zheng ZZ, Pan J, He N, Liu ZS, Hou YQ, Lim KS, Ou YM, Hui-Ping Khor A, Ng CC, Mao BJ, Liu XR, Li BM, Kuan YY, Yi YH, He XL, Deng XY, Su T, Kwan P, Liao WP. HLA-A*24:02 as a common risk factor for antiepileptic drug-induced cutaneous adverse reactions. Neurology. 2017; 88(23):2183-2191. doi: 10.1212/WNL.0000000000004008.
- Perucca P, Scheffer IE, Harvey AS, James PA, Lunke S, Thorne N, Gaff C, Regan BM, Damiano JA, Hildebrand MS, Berkovic SF, O'Brien TJ, Kwan P. Real-world utility of whole exome sequencing with targeted gene analysis for focal epilepsy. Epilepsy Res. 2017; 131:1-8. doi: 10.1016/j.eplepsyres.2017.02.001.
- Chen Z, Liew D, Kwan P. Real-world cost-effectiveness of pharmacogenetic screening for epilepsy treatment. Neurology 2016; 86(12), 1086-94.
- Chan J, Jones NC, Bush AI, O’Brien TJ and Kwan P. A mouse model of Alzheimer's disease displays increased susceptibility to kindling and seizure-associated death. Epilepsia. 2015; 56(6): e73-7. doi: 10.1111/epi.12993.