EpLink: The Epilepsy Integrated Discovery Project

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By: Jabir Mohamed

Epilepsy as a Long-Standing Public Health Concern

Epilepsy is a significant health concern. Among chronic brain disorders, epilepsy is the most common, affecting more than 50 million people worldwide. According to the World Health Organization, the disability due to epilepsy—characterized by recurrent and unprovoked seizures—accounts for 1% of the global burden of disease, comparable to that of breast cancer in women or lung cancer in men.1 In Ontario, it affects approximately 95 000 people, with 6 500 new cases added each year.2 A number of these patients, especially those who suffer from uncontrolled seizures, become physically disabled. Such limitations have a profound impact on their ability to lead an independent, fulfilling life.

Resistance to drug therapy (pharmacoresistance) is one of the major problems in epilepsy treatment today. Although current medications effectively control seizures in 70% of the population, the remaining 30% continue to suffer from seizures despite treatment with one or more antiepileptic drugs.3 The underlying factors that lead to the development of epilepsy (epileptogenesis) are also unclear. Certain brain injuries such as traumatic brain injury and stroke are known to predate epilepsy; however, insights into the mechanisms leading to this chronic epileptic state are scarce.

Epilepsy also has a significant impact on the social and psychological wellbeing of a patient. An Ontario Health Survey found that patients with epilepsy had the lowest quality of life amongst people with self-reported chronic conditions; those included conditions like arthritis, congestive heart failure, and Parkinson’s disease.4 In addition, there is a growing awareness of the psychiatric comorbidities in epilepsy patients. A population-based study revealed that almost one-third of patients with epilepsy had a diagnosis of anxiety or clinical depression—twice the prevalence in the general population.5 But despite the frequency and significance of these comorbid conditions, these patients remain underdiagnosed and undertreated.

Epilepsy Integrated Discovery Project: Bringing Excitement across the Province

A palpable sense of enthusiasm has recently surfaced in Ontario. In 2011, the Ontario Brain Institute (OBI) created the Epilepsy Integrated Discovery Project (EpLink) to refocus attention on the deficits in epilepsy care. The large number of collaborators for the EpLink project—more than 25 researchers and clinicians working at nine different university and hospital sites across Ontario—demonstrates the commitment of the scientific community to come together and identify strategies that will improve the lives of patients with epilepsy.

Also contributing to this sense of enthusiasm is the alliance of the EpLink researchers with non-profit organizations and pharmaceutical companies. The non-profit advisors help keep research relevant to the real world and ensure that research aims coincide with patient needs, whereas the industry partners are crucial to get novel drugs developed and accelerate their transition from bench to bedside. Headed by Dr. McIntyre Burnham, Director of the University of Toronto Epilepsy Research Program, and Dr. Jorge Burneo of Western University, the EpLink program heralds a new era of scientific collaboration.

The key words in this initiative are integrated discovery. Epilepsy is a complex neurological disease that requires a multi-front approach: one that spans multiple laboratories and clinical disciplines; involves collecting different types of data, ranging from imaging and behavioural to genetics and molecular; and applies findings in one epilepsy syndrome to another. The amalgam of patient-focused and basic science research is key in implementing a new platform that allows researchers, non-profit advisors, and industry partners to work together and achieve a common end.

Thus, projects are inter-related not by a single protocol but by a single goal—the desire to achieve seizure control for patients whose seizures are currently uncontrolled. To accomplish this, the OBI and EpLink committee have identified seven core research categories: 1) pre-clinical/clinical drug therapy; 2) diet therapy; 3) seizure prediction and stimulation; 4) cognition, mood and quality of life; 5) epidemiology and diagnosis; 6) seizure surgery; and 7) genetics and epigenetics.

More information about OBI and EpLink, and about their projects, can be found at their websites www.braininstitute.ca and www.eplink.ca.

Projects Involving Improved Therapies

Currently there are four main modalities to treat epilepsy and EpLink investigators are conducting research in all these fields. Drug therapy is almost always the first therapy to be offered; however, there is an overwhelming need to develop new drugs for the patients who are unresponsive to the present ones. Dr. McIntyre Burnham’s group, in collaboration with Dr. John Andrews, CEO of Ketogen Inc., is working on a drug based on the ketogenic diet. Their hope is to evolve the ketogenic diet in a pill. Another research group led by Dr. Michael Poulter in London is looking to test the anticonvulsant properties of a novel compound derived from a plant grown in the Himalayan Mountains.

Patients who are resistant to pharmacological or non-pharmacological therapies usually become candidates for seizure surgery. Primary to surgery is always locating the precise focus—the area in the brain where the seizure activity originates. A number of EpLink investigators, both in London and Toronto, are gradually improving our ability to locate the seizure focus, to increase the efficacy and outcomes of seizure surgery. For instance, in London, Dr. Jorge Burneo is using a 7-Tesla magnetic resonance imaging (MRI) scanner to locate biochemical indicators of seizure foci, and in Toronto, Drs. Hiroshi Otsubo and Douglas Cheyne are using a combination of MRI with magnetoencephalography to localize abnormal activity found in the seizure focus.

Following these integrated diagnostic methods, other research is being done to improve surgical techniques and promote better outcomes. In London, Drs. Terry Peters and Ali Khan are creating a new brain atlas for use in image-guided seizure surgery, with focus on the temporal lobe. Drs. Mary Pat McAndrews and Mary Lou Smith in Toronto are investigating surgical outcomes across multiple domains (cognition, behavioural, quality of life) with the long-term goal of identifying ways to train the brain for resilience.

The newest research trend is to stimulate the brain directly through permanently implanted microelectrodes. Many EpLink groups are working on this, including Drs. Taufik Valiante and Peter Carlen at Toronto General Hospital, and Dr. Jose-Luis Perez-Velazquez at Sick Kids Hospital. With the help of biomedical engineers Drs. Roman Genov and Berj Bardakian, EpLink investigators are working on a tiny, wireless implantable chip, which can recognize the onset of seizure activity and stimulate the brain just when it starts to terminate the seizure.

Projects Addressing Epidemiology, Genetics, and Comorbidities

There is very little information concerning the natural history of epileptogenesis and pharmacoresistance. An important issue to consider is whether pharmacoresistance is an inevitable consequence of the condition (of which certain patients have a genetic predisposition to intractability) or whether it evolves. Epidemiological studies are important to identify this window of opportunity and determine the appropriate therapy. Dr. Jorge Burneo’s team in London are conducting a prospective cohort study to determine how often brain injury leads to epilepsy, and to identify what types are most likely to do so. At the Hospital for Sick Children, Dr. Miguel Cortez and his team are conducting the first Ontario electroencephalogram screening for children “at risk” for infantile spasms, while Dr. Elizabeth Donner, in collaboration with forensic scientist Dr. Michael Pollanen, is attempting to identify the clinical, genetic, and situational factors that lead to sudden unexpected death in epilepsy (SUDEP).

Advances in our understanding at the genetic and epigenetic level can also increase our chances of finding successful treatments and a possible cure. Dr. Berge Minaissan, head of the EpLink Genetics Program, will sequence the entire genome of over 300 epilepsy patients to locate the multiple genes that, in combination, may cause epilepsy or pharmacoresistance in epilepsy. At Toronto Western Hospital, Dr. Danielle Andrade and colleagues have set out to study the genetics of temporal lobe epilepsy—the most common and drug-resistant form of epilepsy in adults. Ongoing studies at the Hospital for Sick Children led by Drs. Carter Snead and Miguel Cortez are exploring prenatal and postnatal factors such as diet and environmental enrichment that might cause epigenetic changes in an animal model of West’s syndrome, ultimately preventing its development.

The EpLink Cognition and Quality of Life group are addressing many of the comorbidities that add to the burden of epilepsy. At the Hospital for Sick Children, Drs. Elizabeth Kerr and Elysa Widjaja are determining whether a computer-based training program can improve working memory in children with epilepsy—a study that has implications for curtailing academic underachievement in children with epilepsy. Drs. Brian Scott and Carter Snead are examining depression-like symptoms in experimental epilepsy models in order to test anti-depression treatments that may benefit patients with epilepsy. Finally, Dr. Kathryn Hum is investigating whether a group cognitive-behavioural program is effective in improving depressive symptoms in adult patients with epilepsy.

EpLink Workshop, February 28 2015: A Year in Review

It was great to celebrate progress in epilepsy research over the weekend of February 28, 2015. The origins of EpLink, progress in the past year, and what is likely to occur in the coming years were discussed. Despite the problems that were faced in the first two years in terms of money flow and start-up, EpLink has remained a successful program. As the program moves into year three, the outcomes of the workshop offered a clear plan for moving forward.

The talks in the Drug Therapy session offered many takeaways. Dr. John Andrews of Ketogen Inc. shared the strategies his time used to develop their novel acetone analogues—as prodrugs and/or carriers to ensure that antiepileptic drugs (AEDs) get to the brain without getting degraded or distributed too quickly. This came after discovering that acetone potentiated the effects of AEDs. Likewise, Dr. Malik Slassi of Fluoronv Inc. discussed his group’s orally active anticonvulsants. One of their compounds has demonstrated broad-spectrum activity (which means it can be used in more than one epilepsy disorder) and good tolerability. Further in-vitro work elucidated the mechanism in which their compound acts: inhibition of a novel voltage-gated sodium channel subtype.

In the last talk of the session, Dr. Berge Minassian uncovered how his lab is working toward a cure for Lafora disease, which is arguably the most severe form of epilepsy that exists. His group demonstrated that reducing production of glycogen synthase (GS) by 50%—by removing a protein targeted to glycogen (PTG), an activator of GS—in a mouse model of Lafora disease cured the condition. Future work will employ cutting-edge genetic techniques (CRISPR, antisense oligonucleotides) to target GS and PTG in animal models more selectively. Successful completion of this study may pave the way for future development of gene therapy treatment in humans.

This set the stage for Dr. Rogawski’s keynote talk, who continued to describe similar kinds of translational products that came as a result of basic science research. The view that neurosteroids can be used as anticonvulsants gained some scientific heft in a landmark study published in 1942.6 Many investigators, including Dr. Rogawski, have since addressed the mechanism of action. At the workshop, Dr. Rogawski described results from his research laboratory using animal models of status epilepticus, a potentially fatal seizure that lasts more than five minutes. His group demonstrated that allopregnanolone, a metabolite of progesterone, was effective in treating this condition in animal models. Now they are in the process of developing allopregnanolone for patients who suffer from intractable forms of status epilepticus.

There was a strong focus on holistic care in the Combatting Comorbidities session. Dr. Kathryn Hum’s EpUp study involving distance-delivery of a group cognitive behavioural therapy program is unrivaled in many aspects. As mentioned earlier, depression is a common problem in patients with epilepsy and it often goes unrecognized and untreated. The EpUp study is designed in a way that breaks down the barriers patients may experience such as lack of access to a psychiatrist or neuropsychologist due to costs or transportation. The attractive quality of this approach is that it encourages patients to continue therapy over many weeks and months, improving the chance of lasting gains. Preliminary accounts from patients who participated in the program are promising, and the next cohort is set to begin shortly. Ms. Mary Secco, Director of Strategic Initiatives at the Epilepsy Support Centre in London, ended the session by addressing the socioeconomic impact of epilepsy and introduced the “Clinic to Community” program. This program strives to provide coordinated care for patients with epilepsy, with a focus on education and management for families, general practitioners, nurses, and educational providers (teachers, principals, etc.) in the community.

Conclusion

The OBI funding that is supporting EpLink is the most significant contribution to epilepsy research anywhere in Ontario. Although the next few years will decide whether the patient community will reciprocate the enthusiasm of the epilepsy research community, the real transformation will come in the long-term. Ontario has an excellent reputation in neuroscience research and the hope is that EpLink’s influence will provide the impetus for the development of similar programs across Canada.

References

1. Murray CJL, Lopez AD. Global Comparative Assessment in the Health Sector: Disease Burden, Expenditures and Intervention Packages. World Health Organization. Geneva, Switzerland; 1994.

2. Tellez-Zenteno JF, Pondal-Sordo M, Matijevic S, et al. National and regional prevalence of self-reported epilepsy in Canada. Epilepsia. 2004;45(12):1623-29.

3. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342(5):314-19.

4. Wiebe S, Bellhouse DR, Fallahay C, et al. Burden of epilepsy: the Ontario Health Survey. Can J Neurol Sci. 1999;26(4):263-70.

5. Tellez-Zenteno JF, Patten SB, Jette N, et al. Psychiatric comorbidity in epilepsy: a population based analysis. Epilepsia. 2007;48(12):2336-44.

6. Selye H. The antagonism between anesthetic steroid hormones and pentamethylenetetrazole (Metrazol). J Lab Clin Med. 1942;27:1051-3.