Advances in epilepsy surgery in TSC

From an interview with Dr Simon Harvey, paediatric neurologist and director of the Children’s Epilepsy Program at Royal Children’s Hospital, Melbourne. This article was first published in the October 2016 issue of Reach Out, TSA’s twice-yearly magazine.

What is epilepsy surgery and what role does it play in the treatment of epilepsy for a person with tuberous sclerosis (TSC)?

Epilepsy surgery is treating a person with uncontrolled, drug resistant seizures that have a focal basis by removing the source of the seizures. The source is typically a lesion (such as a tumour or malformation) that we can see on an MRI. Commonly surgery is done in someone who is having focal seizures, but it is also possible for a person having generalised seizures where we know there is a focal basis for the generalised seizures.

People with TSC have multiple cortical tubers in their brain. We know that it is the tubers that sit on the outside of the brain, in the cerebral cortex, that give rise to seizures, not the other brain abnormalities seen in TSC (such as nodules, SEGAs or white matter changes). Because there are multiple tubers, and potentially multiple sources for seizures, epilepsy surgery can be more complex in a person with TSC.

What types of seizures can be treated with epilepsy surgery? Is it only focal seizures?

In people with TSC, all seizures have a focal basis, even spasms or a tonic seizure that may not look focal on an EEG.

We know that abnormal networks form in the brain. These abnormal networks induce multi-focal generalised epileptic patterns and setup and sustain these types of seizures. This can all be due to a single abnormal area – in the case of TSC this could all be due to one tuber.

It is rare that we can show for a child having spasms that there is a single part of the brain that is the focus for a seizure, from which the seizure then becomes generalised. Rather, what we think is happening, is that the rest of the normal brain is reacting in an abnormal way to a focal seizure process, giving rise to the seemingly generalised seizures. We find that after we remove the focus that the spasms and the tonic seizures continue for a while and then they start to calm down.

Read our information page on epilepsy and TSC for more information, including explanations of different seizure types.

This sounds like a different way of thinking about seizures than we’ve had previously. Many people with TSC have been told that they had multiple foci for their seizures so surgery was not an option.

The mistake that some neurologists make is that they see all these epileptic discharges on EEG coming from all these different locations in the brain and presume that all the tubers are giving rise to the seizures and discharges, and therefore nothing can be done. Alternatively, they see tonic seizures or spasms with no clues to focality on EEG and similarly believe nothing can be done. Our approach is that you don’t have to prove that the seizures are starting in one area and spreading to become spasms, because that’s not the case.

So how do you identify the part of the brain that is responsible for seizures? What tools do you use to figure out that puzzle?

Doing epilepsy surgery in TSC is one of the most challenging areas in epilepsy surgery and this is because of the challenges of localisation: working out what part of the brain is giving rise to the seizures. There can be lots of tubers, the EEG can show generalised seizures and it’s hard!

There are some very invasive tests we can do, such as two stage surgery with intracranial EEG monitoring. This involves opening up the brain and putting electrodes over tubers and other regions, sometimes on both sides of the brain. We then record seizures. That is something we used to do a lot, and many TSC families in Australia will have gone through this at our centre. It is still common in some centres overseas. We don’t do this as much now as we’ve learnt a lot from the TSC children we did this monitoring on and now don’t think that it is necessary in the majority of children.

There’s a form of positron emission tomography (PET) scan being used in one centre overseas. This uses an agent called AMT that lights up tubers that are giving rise to the seizures. That centre uses this test in combination with the intracranial EEG. This type of PET scan is not really available outside of that centre.

We used to do single-photon emission computed tomography (SPECT) scans. However these often gave us misleading information as it would light up lots of areas in the brain where the seizure had spread to, and not the onset region. We no longer use SPECT scans for children with TSC

What we often do is go back to basic principles. For example, on the MRI scan there are tubers that look different to the others. They might be bigger, more calcified and have a different appearance to other tubers. This includes having a bullseye, or an abnormal centre to them. We often see several tubers looking like that, but that narrows it down a little bit. We do look at the EEG recordings but this is problematic, because seizures propagate, or spread from one tuber to other parts of the brain. In fact we think that even when you first see changes in the child and on the scalp EEG this is well after the seizure has started. What we hope is that the seizure spreads locally. Sometimes the very earliest EEGs or even videos of the very first seizures the child had can provide useful information.

It sounds a lot like your full title should be ‘forensic epileptologists’. I picture you sorting through all these different clues.

It is like that! It is building a case for a tuber or group of tubers being the source of seizures, based on different tests and pieces of information and using this to come up with a plan for surgery.

Can you tell me about the research your team has been doing in this area and how it has changed the way you approach epilepsy surgery for your TSC patients?

We’ve had two publications in this area. Both go against the grain of what others are doing around the world. Other centres will put electrodes in the brain and interpret the epileptiform activity recorded as meaning seizures are coming from all these different parts of the brain. They will then take out these parts of the brain, including tubers and in some cases normal brain. I think this is crazy because kids with TSC need all their normal brain. There are some children with TSC with large numbers of tubers and the last thing I want to do is take out bits of normal brain.

Our first paper showed that seizures come from tubers, not from normal parts of the brain[1]. Abnormalities on EEG that we record in the normal parts of the brain are either the seizure spreading or the normal brain reacting to the seizures coming from the tubers.

The second paper builds on the first. When we put electrodes deep into the tubers, not only did we show that seizures start in tubers, but we showed that it is actually just the centre of the tuber that is giving rise to the seizure[2].

So we have shown firstly that only some tubers are epileptogenic (responsible for starting seizures) and secondly only the centre of the tuber seems to be epileptogenic. And the centre of the tuber is where we see this bullseye appearance on the MRI scan.

And that’s matching what you’ve seen in your practice of noticing that bullseye feature on the MRI scans.

Yes. What it looks similar to is focal cortical dysplasia that we see in some people with focal epilepsy that don’t have TSC. When we look at those lesions under the microscope we can see a lot of similarities between dysplasias and tubers. We are also starting to understand that these are similar at a genetic level and that some dysplasias are also due to abnormalities in the mTOR pathway. So what we think is that perhaps in TSC we have these small focal cortical dysplasias sitting in the middle of these much more noticeable tubers.

What this has allowed us to do is just to remove the centre of the tuber and not the whole tuber. This reduces the risks that our surgery will have negative impacts on the other parts of the brain. It’s almost like leaving this donut shape behind and this acts as a buffer for the rest of the brain. We’ve done this in a very small number of children but we will start to do this more.

Given your focus on only removing the tuber itself, or even only removing the centre of the tuber, do you see lower rates of negative impacts of surgery compared to other centres doing this type of surgery on TSC patients?

We don’t have deficits, I can’t think of any of our TSC kids where we’ve had complications like that from epilepsy surgeries. What we are trying to do in TSC is stop seizures, or at least the worst types of seizures and try to stop them early to achieve developmental gains.

Another thing we have observed is the children we’re seeing now who have been “pre-treated” early with vigabatrin are much better developmentally. We think this is because we’ve stopped them from developing spasms. They still tend to develop focal seizures, but they are much easier to localise and treat surgically, as they have spread less within the brain.

So the rest of the brain is a bit more resistant to joining in the seizures when they start?

Exactly. They don’t get these multi-focal and generalised seizures and abnormal EEG patterns. So we’re just treating their focal seizures and preserving their normal development. The early diagnosis and monitoring is just so important. Any child diagnosed with TSC prenatally or neonatally has to be seeing a neurologist who is going to actively manage this. I am not waiting for clinical trial results to come out; this is obvious to me and should be discussed with parents.

These are impressive accomplishments. What is coming next?

We have a grant application with the National Health and Medical Research Council (NHMRC) to extend on this work. We will look more closely at both the structure and the genetics of this tissue from the centre of the tuber.

We’ll also try to publish our small series of children in whom we have only taken out the centre of the tubers. We’re also contributing to book chapters and trying to spread the word about what we’ve discovered.

We do need to publish our results of surgery in TSC and report longer term outcomes. We want to show the results of our approach ie. just doing tuberectomies (not taking out normal brain tissue), operating multiple times when we find there are multiple foci, and not doing two stage surgeries.

One of the challenges we have is whether mTOR inhibitor medicines might be distracting. I think there is a role for these medicines after we have fixed up the infant’s seizures with vigabatrin and surgery.  mTOR inhibitors may control some of the mild seizures, and help with cognition and other aspects of TSC. I don’t think mTOR inhibitors are the panacea for these early- life seizures, such as spasms, that affect development adversely. I think what we are learning is that it’s a combination of vigabatrin, steroids and surgery that are needed in infancy to maximise seizure control and developmental potential.

I’d like to bring us back to the people that are going through this difficult process of considering epilepsy surgery. Given your experience with working with these families and making difficult decisions about epilepsy treatment options, what advice would you give them?

What I normally do is emphasise the effects of seizures and EEG abnormalities on the developing brain. This is based on the links between seizures and what we see on the EEG with the development of autism and learning difficulties. I go through the process involved with the actual surgery, which understandably can be a little bit horrifying. We try to reassure parents of children with TSC that epilepsy surgery is something we do frequently, once or twice a week, every week, and that we’ve operated on more than 60 children with TSC. Surgery in our hands is very safe, because we do a lot. I know that for any family going through this for the first time it is a scary process but a lot of them say later it wasn’t as bad as they imagined it would be.

The real big thing I get families prepared for is disappointment. They’re always worried about the risks of the surgery. What I am worried about is that the child is still going to be having the same seizures after the surgery or develop new seizures. However, families are often knocking down the doors when new seizures start, wanting their child to have surgery again. I think that’s because they’ve been through it once, seen that it wasn’t that bad, and seen the benefits in their child’s development.

You’ve talked about surgery in babies and younger children. What options are there for an older child or even an adult with uncontrolled epilepsy?

They should get advice from a centre that does epilepsy surgery. This centre should have contacts with a paediatric centre which does TSC epilepsy surgery. The worry in adults is that seizures have been going on for so long and these abnormal epileptic networks have been “cemented”. So even if we take out the tuber that was the original cause of the seizures, the seizures may continue. I think there may be some cases where we could make an adult seizure free, but the chances of this would be lower.

Dr Harvey’s TSC epilepsy surgery research has been supported by:

• Brimbank ToRCH, an auxiliary of the Royal Children’s Hospital Foundation;
• The Romios’ Family in honour of Kristian Romios;
• The many families who have entrusted their children to the surgical team.

References

1. Mohamed, A.R., et al., Intrinsic epileptogenicity of cortical tubers revealed by intracranial EEG monitoring. Neurology, 2012. 79(23): p. 2249-57.
2. Kannan, L., et al., Centre of epileptogenic tubers generate and propagate seizures in tuberous sclerosis. Brain, 2016.