Genetic testing for epilepsy in low-resource regions

In lower- and middle-income countries, raising awareness of genetic etiologies in epilepsy and genetic testing options may ultimately shift national priorities toward making genetic testing part of the standard of care. Dr. Parthvi Ravat spoke with Dr. Jo Wilmshurst and Dr. Alina Esterhuizen about initiatives to increase awareness of genetics and genetic testing in epilepsy, including a decision tree model for epilepsy care in resource-restricted settings that has been implemented in Africa.

Publication mentioned in the episode:

Precision medicine for developmental and epileptic encephalopathies in Africa—strategies for a resource-limited setting 

Sharp Waves episodes are meant for informational purposes only, and not as clinical or medical advice.

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Transcript

[00:00:08] Dr. Parthvi Ravat: Hello, everyone, and welcome to this episode. I’m Parthvi and this is one episode in the series on genetic epilepsies. We have two very interesting guests with us today. Professor Jo Wilmshurst from South Africa is the head of pediatric neurology services at the Red Cross War Memorial Hospital, University of Cape Town. She is also the chair of ILAE Africa and coordinates a training program, the African Pediatric Fellowship Program, which trains clinicians from across Africa at her center with necessary skills in pediatrics to be able to develop and grow pediatric services in their own home centers. 

With her, we also have a molecular geneticist with us today, Dr. Alina Esterhuizen. She works as a molecular geneticist at the National Laboratory of Health Services of South Africa, UCT, where she helps with the Molecular Diagnostic Service and most importantly, translates local research into diagnostic practice. She is a member of the Genetics Commission for ILAE and also supervises and coordinates internship training for medical biological scientists in genetics at UCT.

Welcome both of you to the show today.

Let's get started with this. Can we shed some light on why considering genetic factors is crucial when diagnosing and treating epilepsy, especially in low-resource settings? 

[00:01:33] Dr. Jo Wilmshurst: I'd like to answer that question. I think it's a critical area for us to open up and consider that the perception in low-resource settings is that the burden of disease is driven by communicable and acquired causes.

And certainly the burden is very high because of that, but it would be extremely naive to assume that genetic causes do not exist there. And indeed, through the work that we've been doing, we're increasingly unraveling that the proportion of genetic diseases equates to anywhere else in the world.

For us, this has then got critical implications for the care that we are offering for our patients. And what has been regarded as state of the art, perceptions that would be regarded as high level and possibly even research driven interventions, are now widely accepted as standard of care and the right of any patient with epilepsy anywhere in the world.

I think one of the key examples in our settings where there's a significant shift potentially in the care of patients is early recognition of diseases such as Dravet syndrome. We have many, many patients that present with recurrent febrile seizures and that immediately fits in with our perception of infection-driven causes. And people don't think any further. 

That has been a critical starting point really for us, where we know that there is high-level evidence of targeted and precise medicines that can be used and should be started early. And this has really been a great opportunity for us to use a disease such as Dravet syndrome as an entry point to try and raise awareness of genetics within low-resource settings.

[00:03:21] Dr. Parthvi Ravat: So in what type of epilepsy specifically do you emphasize genetic testing in these resource-limited areas? 

[00:03:28] Dr. Jo Wilmshurst: I mean, ideally, we would want coverage, broad coverage across everything, but we don't have that luxury. So at the moment, the drive of a lot of the work we've been doing has been related to where there's going to be the most maximum impact from having a definitive diagnosis.

And in our setting, that's typically the children that have the developmental and epileptic encephalopathies, because those are the children where again, there's this assumption that surely there must have been some early birth insult or surely they've had some infection that's caused it. Whereas actually, when you start unraveling and unpacking, you realize this family is carrying a child who has a genetic epilepsy.

And Just to get the diagnostic closure for families who often carry huge guilt burdens is critical, but also to have that precision diagnosis to give them accurate counselling and advice about what the prognostic implications are just makes such a difference for the care. I think in the future we're hoping and we're tentatively exploring some of the other epilepsies such as the focal cortical dysplasias and the IGEs, but at the moment really our target group has been the DEE, certainly within our research work that we've been doing.

[00:04:42] Dr. Parthvi Ravat: Right. So can you briefly introduce us to the concept you've talked about in the paper which you both are coauthors on, about THINK genetics and what inspired you, what gaps you noticed that inspired the development of this decision tree model for epilepsy care in resource-restricted settings.

[00:05:00] Dr. Alina Esterhuizen: So perhaps I can talk about this. It stems from the research study that we did and some aspects that we noted. So, of course, genetic testing is expensive. It is expensive in South Africa. It's expensive everywhere else. And considering our limited resources, we've got to be cautious how we test and whom we test.

It is imperative that it is done appropriately and the patients who are most likely to benefit from the test and have informative results that will impact on treatment are tested. That in fact is wholly dependent on good phenotyping. 

So even before we start to talk about access to genetic testing, there is a level of skill required to properly diagnose seizures and discern and recognize a possible genetic etiology that is perhaps not easily and commonly available in the African setting, for example.

We thought that we could try and devise some sort of a helping guide for a clinician at patient entry in Africa to note a patient's presentation and think of genetics as an underlying cause. You know, be able to discern that from various acquired causes of epilepsy, infectious diseases, et cetera. This guide, which is by no means perfect, and it's very much a work in progress, is intended to help a doctor in Africa or perhaps even a nursing sister, whoever happens to be seeing these patients, to think about genetics and refer appropriately for consultation and of course genetic testing if available.

[00:06:39] Dr. Parthvi Ravat: Could you walk us through the structure of the decision tree model and the measurable outcomes of using it in Africa? 

[00:06:46] Dr. Alina Esterhuizen: So if you look at the model, as I mentioned earlier, it's about trying to help someone look at a patient and decide what to do next.

And so basically, “If you see this, you do that,” but in a very sort of simplistic way. So, if you see a neonatal patient or an infant with refractory seizures and then you also have certain additional components like autism spectrum, movement disorders, dysmorphic features, et cetera, you would refer for a specialist consultation and then the additional investigation, such as the EEG, et cetera, would be taking place as a matter of course, if possible. Then as part of the specialist consultation there would be a decision in terms of genetic tests, whom to test and what to test with, because, of course, copy-number variants in addition to single nucleotide changes are also an aspect that's implicated in seizure disorders.

And this is assuming that whole genome and whole exome sequencing, which is the recommended way to go according to international guidelines, is either not accessible or not easily or just too unaffordable, which is the case in South Africa. Whole genome sequencing in a clinical setting routinely is just not possible, not in the state healthcare system.

So we've got to think about how we test and who we test, what that sort of a reflex testing process would be. Chromosomal microarray for those with dysmorphism and prior intellectual delay. If negative, move on to panel testing. Otherwise, if no dysmorphism and no prior intellectual disability, then, for example, for a patient that looks like they might have Dravet syndrome, then panel testing first. Then depending on the outcome, you would then take it further and make decisions for parental analysis if you want to establish de novo occurrence. Multidisciplinary team consultation is very important, right? We've known, we've learned from our study that it is really, really important.

Correlate genotype and phenotype. The one often informs the other, because variant interpretation is tricky in African patients. We've got under representation of African data in the variation databases. And then periodic data re-analysis with uninformative findings and all the aspects that are done in the high-income setting. 

And then obviously those patients who have a positive finding would then be tested and managed appropriately. The idea is that this is done early. The whole point behind devising this is that people are recognized and directed appropriately early in the disease. Because a lot of our patients undergo this diagnostic odyssey. And of course, the whole point of doing genetic testing is to be able to find the cause early, but in the African setting, that gap between the initial seizure and the actual diagnostic closure is way too long. So we want to be able to shorten that. 

[00:09:57] Dr. Parthvi Ravat: So the decision tree genetics model, as we read, has been successfully adapted in Africa. How reproducible do you think it is in other low- and middle-income countries? 

[00:10:06] Dr. Jo Wilmshurst: I'm hoping it's very adaptable. We'll have to wait to see how much it's taken up. There's certainly been a lot of interest in it. 

I mean, I think the key message is exactly as Alina was highlighting. It's raising awareness. It's getting people away from that stage of the unknowing, to actually that light bulb moment of realizing, hang on a minute, this patient is not like something I can box into a standard category. There's something more going on here and I must think genetics, and get them actually putting those pieces together and questioning and re-questioning what they have.

And the wonderful science of how the analysis is done for different caregivers may be completely irrelevant. You just want them to start at that beginning point of recognizing that there might be a genetic ideology and then stepwise moving down, but the stages are really important for acceptance within low-income settings.

So if you have agreement at national or even regional levels that this is an appropriate investment and approach for genetic epilepsies, then you can move forward for greater advocacy, lobbying, to standardize access to care and start making it more available for patients. So we'll have to see.

We work very closely with many colleagues and networking and certainly I think genetics has been of great interest in other regions. I don't know about other low-income settings. And I think it's very exciting because I think this is our beginning of trying to meet where high-income countries are and kind of joining to start making equitable care for patients.

[00:11:41] Dr. Parthvi Ravat: As you said, one of the challenges in low- and middle-income countries is simplifying complex clinical data into simple decisions and following the algorithm and without losing accuracy. So what other barriers do you think they face, the lower- and middle-income countries?

[00:12:00] Dr. Jo Wilmshurst: They are and have been huge, as we've seen.

So there are different systems that operate everywhere, different health care access points and providers, the awareness. Let's just start with recognizing seizures and epilepsy is significant. Reaching through to the point of doing what would be regarded as a high-level intervention such as genetic tests.

So in many parts of Africa, you can't even get a full blood count or a lumbar puncture done, let alone access to an EEG. So you're already talking about lots of perceptions and then thinking about the challenges that we have with the stigma that's carried by epilepsy. And this is really where it is so crucial for the counseling, because obviously many of the variants will be de novo although we will have some family groups and the need to equip people with effective counseling.

And so there are non-government organizations, but they're often also poorly funded and often very poorly resourced. And they need their own support and education to understand what they can and should be saying to patients. And really it leads us into the fact that counseling goes beyond the actual testing. Obviously counseling is far more, it's actually that grounding and explaining of what the disease is and where a genetic process may be happening. The testing is the latter part and only a portion of it. 

I want to hand over to Alina because I know she's involved in some very exciting work through the Genetics Commission.

[00:13:36] Dr. Alina Esterhuizen: Yes, perhaps I can just mention even though this is relatively preliminary and has not been published or presented anywhere yet. So in broad strokes, the Genetics Commission has put out an international survey looking at accessibility, availability of genetic testing, the ability to interpret results, individuals who actually feel confident in ordering tests and using the results. And worldwide, the discrepancies between the high- and low-income settings are quite stark.

So this is not just hearsay. It's been very clearly demonstrated. We'll be presenting those findings and publishing them soon. So there is very definitely a need to work towards a more equitable access to genetics because in low-income settings, the communicable diseases is not all there is.

And we need to find a way to address those health care concerns quite aggressively, because we have a lot of epilepsy in Africa, for example. 

Relating to genetic counselling that Jo touched on. Genetic counseling training of genetic counselors certainly in South Africa is possible and we have very good international standard courses, training courses and degrees for genetic counselors and people are being trained. The problem is that they're often not employed, the posts are not made available. The authorities don't necessarily bind to the fact that you need genetic counselors to do this work well and to provide the aspects of service that Jo has mentioned.

So that is another thing. It's about awareness and the understanding of genetics, genetic testing, the benefits and the importance of counseling. People train and they go, they leave, they go and get jobs overseas.

[00:15:34] Dr. Parthvi Ravat: How do we tackle those challenges? 

[00:15:37] Dr. Jo Wilmshurst: I can cover that question. I think it's like a million-dollar question. And actually you almost need to work backwards.

Most of the care providers that are at the rock face where a patient, a person with epilepsy will present… we don't have epileptologists. These are people that are incredibly busy that are covering many, many, many different diseases. And actually the beginning is getting them to recognize that it's a seizure and that that seizure meets the criteria for epilepsy. And that starting point is actually lacking. 

So we've been running these courses called the Pediatric Epilepsy Training Courses. These are one-day workshops and they were developed by the British Pediatric Neurology Association. And PET 1, the starting one, is for entry-level pediatric epilepsy, and it takes a clinician, a healthcare practitioner, through the steps of what is a seizure, how to recognize a seizure, and it's done in an extremely adult-learning-effective way.

It's been analyzed and tested, and they've actually looked at the learning outputs, which are phenomenal. Embedded within that are the ideologies. So that starts at that stage of somebody who's had no perceptions and no real understanding. And in fact, the myths and stigma around epilepsies are huge. We still have children that are refused in school, never mind the issues about bewitchment and being possessed, but actually people are concerned that the child's infected. So if a child has a fit in the classroom, they will infect the other children with seizures and then the child is removed by the teacher. And it's this kind of level, of making people aware that there are multiple different causes of epilepsy and de-stigmatizing the problem. 

The course has been so successful that we're now adapting it for adults as well. So it will be a similar one-day course running the same teaching aims, but targeted at the adult epilepsies. And again, the starting point is to target the widest population of people that are the most likely ones to receive people with epilepsy and to start that light-bulb moment. So the concept of genetic epilepsy is embedded in that. The THINK genetics is referred to and available in the conversations that we have with people during the course, and it's the beginning of a conversation that starts, I think, layered on that is where we've talked about genetic counselors and the need to widen genetic counselors that should also be available at the entry level of care.

The issue is that in Africa, we rarely have the luxury of having specialists, certainly at that point of care. As I said, we don't really have epileptologists, so why would we have the luxury of having a highly skilled genetic counselor? But that doesn't mean that we can't do the task sharing. 

Some of the other ways that we've been tackling this is through raising awareness and getting interest. Those courses are often the entry point of then further layering, further communications, removing the barriers of pathway to care, opening up connectivity, and actually making people know who to talk to when there's something that they're not comfortable with, when they recognize that there's something more complex, and just really strengthening our network of care for patients with epilepsy in the region.

[00:19:09] Dr. Alina Esterhuizen: If I could just add onto this with regards to the genetic access and availability of genetic testing. So, the expense is obviously a big problem. It's a barrier because our resources, our budgets are limited. But here is where health economics comes in, you know, from convincing the authorities that genetic testing is, even though it's expensive initially, it is cost effective downstream. There are savings downstream in terms of the health care, you know, the diagnostic odyssey, et cetera, the ongoing MRIs, the various other investigations and the discomfort to the patient. Having a genetic diagnosis makes a difference and it creates money saving down the line, and health economics is something we need to engage with to demonstrate this and to prove it, to convince the authorities to make funding available for testing.

[00:20:02] Dr. Parthvi Ravat: Are there any countries or associations that you are working together with on the THINK Genetics decision tree? 

[00:20:10] Dr. Jo Wilmshurst: For me, the one that seems to be having the most impact is the training program we're running, so the African Pediatric Fellowship Program. We take clinicians from other African countries and we train them in lots of different areas, but obviously my passion is pediatric neurology. Because if you want to make change, it's often inappropriate for us as individuals to go into another country and dictate to them, “Well, you've got to do this, it must work this way.” You kind of need a leader within the country that understands the health structure and can actually do that conversation from the community level through to the Ministry of Health. 

So our job through the program is that we train people up with the clinical skill set and to understand neurological diseases, but especially epilepsy and within this epilepsy genetics. When they go home, they, it's like opening Pandora's box. They're now looking at diseases that they never realized were in front of them. And it's often overwhelming. And in fact, having strategies and having that person in the country to actually then start looking at pathways to care, developing specialist clinics, raising awareness with going out into the community and then talking to the Ministry of Health. It’s exactly as Alina is saying, demonstrating that by doing this, you're actually improving the disease burden and improving the outcomes for patients. Then you can actually start making a shift and a change.

So to me, that's one of the most exciting collaborations. I think that we also always interested in other collaborations with other centers overseas, but certainly from the African experience we feel very strongly that approaches should be done within Africa by Africans and that we must take the responsibility for doing this. And we must make sure that whatever we do is sustainable. 

We are very cautious of overseas centers magnanimously offering to dive in and do something—and then they're gone. It doesn't happen again. We feel that we should actually take responsibility for what we're doing and skill up our own population to be able to be their own advocates.

[00:22:16] Dr. Parthvi Ravat: Right, so respectively for the various LMICs, a lot of our listeners are epilepsy care quality workers or they work with the government. Do you have any advice for them, how they can work better to integrate this into epilepsy care? 

[00:22:30] Dr. Jo Wilmshurst: The Intersectoral Global Action Plan (IGAP) against Epilepsy and other Neurological Disorders, I kind of feel like it was written for Africa and written for low-income settings, because it's just got such fantastic didactic statements that you can use as entry points. To have the WHA actually approving it and now rolling it out is just such an opportunity, and if you think about epilepsy genetics 20 years ago, it wasn't even considered as an entity in Africa. 

And in fact, even internationally, we were chatting earlier about that wonderful graph of the paradigm shift of the data from 1975, the 1970s, where they had that pie diagram of that whole chunk where they had no idea actually what the cause was. And then as epilepsy genetics came in, realizing that the whole chunk was actually probably genetic etiologies. And we've done similar data looking in the African setting and demonstrating that in fact, there's similar outcomes in in our setting as well. So we've kind of got the proof. 

But actually now what we need to be doing is advocating for our patients. And I think IGAP is a really great leveraging opportunity.

And I've already seen some phenomenal projects that have been happening working with our various chapters as well as collaborating with the IBE and various other NGOs to just use this as a voice to make sure that epilepsy is really sort of on the front page for healthcare provision.

END