THE path-breaking discovery of the first epilepsy gene in 1995 by Professor Samuel F. Berkovic, laureate professor and director, Epilepsy Research Centre, University of Melbourne, Austin Health, Australia, changed the way the neurological condition is understood and managed. Since then, Berkovic and his colleagues have been involved in the discovery of numerous other epilepsy genes.
Prof. Berkovic was in Chennai on February 26 to deliver the 37th T.S. Srinivasan Endowment Oration, 2017, an annual programme jointly organised by the National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, and Neurokrish, the Neurosciences India Group founded by Dr Enappadam S. Krishnamoorthy. In his lecture titled “Tracking the Brainstorm: How Genetics and Imaging are Transforming Epilepsy Care”, Berkovic explained the neurobiological nature of epilepsy and how technological advances—genetics and brain imaging—have been crucial in understanding epilepsies and abnormal and normal brain functions and brain network disorders.
A clinical neurologist and clinical researcher, Berkovic won the Epilepsy Research Recognition Award of the American Epilepsy Society in 1995 “for work that holds important promise for the improved understanding, diagnosis and treatment of childhood-onset epilepsy” and his contributions to the genetics of epilepsy, “especially the identification of the first specific molecular defect in an idiopathic epilepsy”.
Berkovic has won many honours and awards since then, the most notable being the Zulch Prize of the Max Planck Society in 2005, the Companion of the Order of Australia for eminent service in biomedical research in the field of epilepsy genetics and election to the Royal Society (London).
Excerpts from an interview he gave Frontline after the oration:
Professor Berkovic, you discovered the first epilepsy gene in 1995 and since then you have been involved in the discovery of many more epilepsy genes. Tell us about the genetics of epilepsy.
When we began this work, we expected that the number of genes in epilepsy might be relatively limited and that we would have the ability to manipulate the consequences of those genes so that we could quickly develop new treatments for epilepsy. But nature is a lot more complicated than we ever think. The number of genes involved in epilepsy that we and other groups have discovered has grown enormously. We are now starting to think in terms of what we call gene networks. Here, the proteins that the genes encode work together in particular pathways. Changes in different genes in the same network might result in similar consequences to the patient. A reason that we think this is likely is because there are the specific patterns of clinical features that we see in patients, what we call phenotypes. Whilst there are many other epilepsies I mentioned in my lecture, they are not infinite and we can group patients together who have similar phenotype. Yet patients who look the same can have different genetic causes, so we hypothesise, and we know that is true in some cases, that defects in genes working in the same pathways or networks can have the same downstream consequences. We have been looking to target downstream consequences to improve treatment, but that still has not been achieved except in some very specific instances.
How has imaging technology helped in detecting epilepsy? How easy is it to detect epilepsy now?
Well, it advances literally every year but with hardware and software improving we are able to do different things almost every year. What we routinely measure is the structure of the brain. In people with structural abnormalities of the brain, we could not detect them at all 30 years ago. Now with magnetic resonance imaging [MRI], we are detecting abnormalities in the brain structure in more and more patients as each cycle of improvement in the technology occurs. Just to be clear, epilepsy is a condition where seizures occur; we do not detect epilepsy we detect the cause of epilepsy. That is what we are looking at, the structural abnormalities that underlie the condition.
There are possibly several causes for epilepsy. How are they detected?
Well, if we had a patient and we do an MRI and we find a particular pattern in the MRI, a lesion in a particular area, we know from all the studies that have gone before that other patients had the same thing and so one can then infer, but that is important.
There are various types of epilepsies and various symptoms.
The symptoms of epilepsy vary from severe convulsions to very minor, where people merely switch off like a daydream. So it is up to the doctor to make the diagnosis and up to the patient’s family to detect any change in behaviour and the doctor does the appropriate tests. The changes in epilepsy are paroxysmal: they start and they stop typically over seconds or minutes. It does not cause a persistent change in behaviour over days or weeks. Epilepsy can, however, be associated with behavioural changes like depression and anxiety, which are often secondary and related to the psycho-social consequences of the disease. There is a relationship between epilepsy and psychiatric disease, but it is not a direct causal one. The treatment varies a lot from country to country and is influenced by resources, by culture, by sociological factors. In this country it is extremely good in some of the large cities and is a big problem in the rural areas.
What is the major challenge in epilepsy research?
To discover the causes, develop new treatment and methods for prevention.
Can you tell us about Epi4K and Epi25, the epilepsy genetics project you are involved in?
Epi4K is a project that is now near completion. It is a five-year project. The funding ended for that last year. It was funded by the National Institutes of Health from the United States. It was a $25-million project with investigators mainly from the United States, but also other countries, including Australia; my colleague Ingrid Scheffer and I were involved. The aim was to sequence 4,000 epilepsy patients. Now we are finalising and analysing the results. It led to some major discoveries in more severe epilepsies known as epileptic encephalopathies. We are still in the stage where we are analysing large numbers of some of the common epilepsies. It has been a highly successful project. It has given birth to “Epi25”. Here we are upscaling again to try and sequence 25,000 patients, and we have already done 6,000, from the world over. We are hopeful of including patients from India, but there are some bureaucratic blocks to that which we have to overcome. There is willingness among Indian neurologists to support this. We hope that this massive project will lead to a much better understanding of the causation of epilepsies.
Does epilepsy run in families?
Yes, it may. If you already know that a family member has it, that is the information you need and then one can go and try and detect the genes, which we can do. And then one can use that information for counselling.
Can febrile seizure lead to epilepsy or other neurological conditions?
Most febrile seizures are benign without consequence, but about 7 per cent of children with febrile seizures develop epilepsy later.
What is the global burden of epilepsy?
It affects one in 200 people worldwide. Its burden is particularly high in children and therein affects the whole family.
What is the future of management of epilepsy?
As we know more and more about the disease, we hope we can get to a stage where we can target each particular patient with specific treatment and help them. That is on the horizon. Seventy per cent of epilepsy can be completely controlled. The majority are not suited for surgery.
If epilepsy is not detected can it lead to some other disorders?
It can kill you. People die in seizures. They can injure themselves, they can fall, break limbs, have head injuries. It is very unwise to leave it untreated. In a person with epilepsy, the fits occur sporadically and seemingly unpredictably. The underlying cause might be genetic or a structural abnormality, but then the question is, over time why does the seizure occur say on a Sunday afternoon at 5 p.m. We don’t have the answer to that. We know that factors like sleep deprivation, stress, alcohol, etc., increase the risk. So there are external factors and one manipulates these or advices the person to look after themselves, take tablets regularly, have regular meals. It is particularly important to have regular sleep. And they must be judicious with alcohol. When you do that, you reduce the tendency for the seizure to occur, though you may or may not eliminate epilepsy completely.
How does the disorder respond to treatment and diet?
About 70 per cent of patients are well controlled on currently available treatments. A balanced diet and regular lifestyle are important for good control, especially regular sleep. In some cases, special diets may be beneficial but these are reserved for challenging cases as the diets are quite restrictive.
You said in your lecture that imaging and genetics have actually transformed epilepsy care. How is advanced imaging helping in the diagnosis and management of epilepsy? What is the success rate of medical management and surgical management of epilepsy?
Sure. The way we treat the patient is very, very dependent on what we find in imaging. And, similarly, where there is a genetic change detected, that alters the management in terms of counselling the family, the treatment we use and whether we can refine the treatment more specifically, how we understand the future and the prognosis. So there are big changes.
Are there any drugs for intractable epilepsy?
There are newer drugs introduced every year or so that help a small proportion of otherwise intractable cases.
How is genetics crucial for the management and outcome of epileptic surgery?
This is unclear at the moment.
Are people with autism spectrum disorders prone to epilepsy?
The frequency of epilepsy in people with autism is greater than that of the general population. So the two disorders go together to some extent. More people with autism have epilepsy than the general population and people with epilepsy have autism in general. So there is a bit of overlap. And we know that there are some genes that pose a risk for both of them, but overall they are separate but there is some overlap.
Are there self-help groups for epilepsy patients?
There are. There is an Indian Epilepsy Association. I got to talk to them in Bengaluru. People get a lot of comfort and advice, good advice, by talking to people who have been through the same.
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