Irish Institute of Clinical Neuroscience 14th Annual Neurology Update Meeting

Seizures are not a monolithic event’

The traditional thinking around epileptic seizures needs to be refined, an eminent US epileptologist told the recent IICN Annual Neurology Update Meeting in Dublin.

Prof Sydney Cash, Associate Professor of Neurology at Harvard Medical School and Attending Epileptologist at Massachusetts General Hospital, US, delivered the John Kirker Memorial Lecture 2016. His lecture, ‘New perspectives on seizures incorporating networks, single neurons and both slow and fast activity’, was very well received by his Irish colleagues.

The current thinking, he said, is to tend to regard seizures as caused by or representing some imbalance in excitation or inhibition or runaway excitation.

“We usually think of them and categorise them both as a teaching method and a therapeutic approach as either focal or generalised in this dichotomous fashion, and we also tend to think of them as hypersynchronous, representing some sort of unusual situation where all the neurons are firing at the same time.”

This thinking may not be completely accurate and could partly explain why epileptic therapeutics are “in some way stuck”, Prof Cash said. He added that while most patients do well, a high proportion of 30 per cent are refractory to medications.

“The surgical approaches can be quite useful and curative in some cases, but are often not. The percentages are not that great.”

Furthermore, patients who undergo surgery may achieve seizure control but relapse later on.

“By certain points of view, we’re not doing as well for our patients as we should be and I’d like to argue that perhaps our thinking on what the seizure is, is not entirely accurate.”

He argued that seizures are more of a network phenomenon than a focal event and involve large networks of brain activity. By challenging the dichotomy of focal versus non-focal, it is hoped that this might lead to novel ways of looking at where the seizures come from and how they can be controlled.

Prof Cash is conducting research into how seizures start, what the dynamics are as the seizure begins as it propagates through the cortex and as it terminates. He is also investigating what cell assemblies are involved as well as what the different neurons are doing during the entire process.

“We get data from our patients who are undergoing intracranial investigation for intractable focal epilepsy.”

This information comes from clinical electrodes, including ECoG grids and the Utah array for micro-electrode recordings. This approach allows clinicians to get local field potentials from a very small scale, as well as action potentials from individual neurons.

“That is giving us single neuron activity that we can correlate with the larger-scale activity recorded with the clinical grid.”

Grey matter

A laminar microelectrode array, which spans the grey matter of most of the cortex in patients, is also used to sample local field potentials in single-unit activity at different depths of the cortex.

Already there is a lot of evidence arguing that seizures “are not as focal as we like to think”, said Prof Cash. Research coming out of Montreal, for example, shows that there are various changes in frequency information outside a seizure onset zone before the seizure begins.

“We looked at patients who had stereotactic depth electrodes implemented bilaterally and who were later found to have mesial temporal lobe epilepsy. They had seizures that were exquisitely focal on their onset.”

Examining data from these patients from throughout the cortex, Prof Cash and his team consistently found that, as expected, when inside the focus, a lot of the electrodes show a change.

However, they found that 10 per cent or so of the electrodes outside the focus in the ipsilateral temporal, ipsilateral frontal or even contralateral frontal, show some change in activity right at the seizure onset.

Prof Cash and his team consistently found that, as expected, when inside the focus, a lot of the electrodes show a change

“This suggests that right at the beginning of the seizure, at the earliest point in time that we can detect the seizure, there are changes in activity occurring quite far away from where we think the focus would be.”

Interestingly, this kind of activity can predict what will happen as the seizure progresses, he added, even in cases thought of as highly focal.

“The degree to which there was activity outside the seizure focus was predictive at least to some extent as to whether or not the seizures would generalise,” he said.

Firing patterns

 “Even if you’re outside the seizure onset zone, many seconds before the seizure there is a change in multi-unit activity, so that the neurons in that region are changing their firing patterns in a way that predicts that a seizure is going to happen.”

While it is unknown whether this is causative or enabling, there is a correlation between this activity and the fact that there is going to be a seizure.

This information can be very useful in the creation theoretical modelling approaches. Hour-long recordings of data were taken from patients with intractable epilepsy and that data was used to create connectivity maps.

This can help create an accurate model of the dynamics that underlie the seizure. The model can also be manipulated to remove electrodes, so as to even predict the outcome of surgery. Prof Cash said it was quite accurate at predicting when a patient would have a good outcome, but was less accurate at predicting a bad outcome.

The thinking around how the seizure is propagated should also be revisited, said Prof Cash.

“We tend to think of the seizure as this explosive event. But from a physiological point of view, it tends to take quite a while to spread out from a given place in a cortex.”

The speed can be quite slow and can take 20-to-30 seconds, suggesting that it is not a typical synaptic mechanism, which should be of the order of tens of milliseconds. It is possible that non-neural or non-typical neural mechanisms are at play.

“Ionic concentration, particularly extra cellular potassium, is likely to be playing a role; neurotransmitter build-up in the extra cellular space, particularly glutamate, could be playing a role too.”

The speed and progression of the seizure is also a predictor for likely surgical outcomes.

“Patients who had a really nice progression from one place to another generally did much better than those who had a complicated and changing pathway,” he added.

The seizure too is not a monolithic event — it goes through a number of stages, categorised by early connectivity but a middle lack of connectivity.

“Once the seizure has encompassed a fairly large area of brain, you can still see multiple stages of activity.

“As the seizure starts, there is a slight decrease in the number of components. Things have become slightly more connected but then as it propagates, there is a large increase in the number of components, as if the network is fractured.”

As the seizure comes to an end, the number of components decrease.

“There is evidence that the seizure is a much more heterogeneous event,” Prof Cash said, with neurons behaving in ways that are not expected or uniform.

“We see a correlation here between the loss of the inhibition and the shift from complex activity to something that is much more coalescent and coherent across space and time.”

Network phenomenon

In conclusion, he argued that epilepsy is a network phenomenon and “while the focus dominates, it is not the only player”.

During the early period of the seizure, other areas are being recruited but that tends to be slow and probably involves non-synaptic mechanisms. Investigating these mechanisms could open up a whole range of therapeutic targets, Prof Cash said.

In the termination period, a greater coalescence is observed. A tipping-point is reached where the patient flips in and out of the seizure and ultimately to the postictal stage.

During a questions and answers session after his presentation, Prof Cash was asked about the recurrence of seizures following surgery. He speculated that perhaps networks can be self-regulating and that one can have an epileptic network.

Speaking to the Medical Independent (MI), Prof Cash said he was delighted to speak at the IICN meeting. He added that how other regions of the brain become involved in seizures remains the ‘big unknown’. “What we don’t know is, is highly abnormal activity using the same mechanisms and pathways and techniques that normal communications in the brain are using, and I think the answer is it’s not really clear that that’s the case.”

When asked why some patients have fast progression and others slow, he suggested that it may have to do with initial conditions, such  as coming out of sleep.

“Currently, we are solidifying the data I’ve presented here by getting a larger number of patients, trying to understand better these interactions between really slow activity and fast activity and how they relate to each other.”

He is also looking into examining the non-neural mechanisms but added that this is a “real challenge”.

John Kirker Memorial Lecture

Dr John Kirker was Ireland’s first epilepsy specialist, having left Ireland in the late 1940s and travelled to North America to learn about the use of EEG (electroencephalogram) in the diagnosis of epilepsy.

In the early 1950s, Dr Kirker arrived home and was by default the senior epilepsy specialist in the country. He practiced all over Dublin but was always affiliated with Trinity College Dublin and worked in St James’s Hospital, Dublin, and then Beaumont Hospital, Dublin, where he and Hugh Staunton formed a lasting partnership in developing Ireland’s first epilepsy surgery programme.

Apart from the unrivalled depth of knowledge of his field, Dr Kirker was known for an abundance of kindness that shone through all his interactions with both staff and patients.

Dr Kirker went on to become the President of the RCPI and was a founder member of the Irish Epilepsy Association in 1966, which latterly became Brainwave, before finally becoming Epilepsy Ireland. In 2007, Dr Kirker was presented with a lifetime achievement award for service to epilepsy at the International League Against Epilepsy (ILAE) Annual Meeting in Singapore.

He passed away in 2011.