How cysticercosis leads to epileptic seizures

One cause of the seizure condition epilepsy is the disease known as cysticercosis. This is the result of ingesting the eggs of the pork tapeworm, Taenia solium. These eggs hatch into larvae that migrate throughout the body forming tissue cysts, which often crop up in the brain, where they are known to trigger fits, although we weren’t sure exactly why. But now, thanks to Hayley Tomes and Anja de Lange, from the University of Cape Town, we have a clearer picture as to what might be going on. These cysts, it turns out, appear to be charged with the excitatory nerve transmitters glutamate and aspartate. And minced up and squirted onto brain cells, a “milk-shake”, as they dub it, of the cyst material triggers a frenzy of discharge activity. This would explain the link to epilepsy and also why, in patients with the problem, the fits seem to kick in after the cysts die off and presumably release their toxic cargo. Anja first…

Anja - So this parasite is called Taenia solium and it's basically a tapeworm, the kind of tapeworms you would think about living in your gut. The condition that we looked at is caused by the larval form of the tapeworm, so it's this like little fluid filled bubble basically with a little tapeworm head tucked inside the bubble and you get this crazy brain condition where these larvae develop in the brain and they cause these lesions and a lot of people who have these larvae in their brain end up having seizures. It's quite a common thing in certain parts of the world where you still have kind of free roaming pig farming.

Chris - These are pig tapeworms then and they get into the brain what? Because they're in the wrong host. If they find themselves in us they go wandering and instead of staying in the intestine they find themselves in the brain.

Anja - Yeah, we are the hosts for the adult tapeworm and they live in our guts. While those worms are living in our intestines they actually release a whole bunch of little eggs through our feces into the environment and then in areas where the hygiene isn't great, control in the environment isn't great, those little eggs end up getting into our food and we then end up eating these eggs. But you wouldn't see them, they're like very, very microscopically tiny.
But when we eat those little eggs they actually burrow through our stomach into our bloodstream and they circulate through our bodies and they kind of just go and sit in different tissues. But they seem to really like our brains and the crazy thing about these tapeworms is that they actually live there for an extended period like months or years quite happily and only when they kind of finally give up or the body's immune system finally attacks them or sees that there are some intruders, that's actually the stage at which the seizure onset happens.

Chris - So Hayley, do you get seizures because you have a physical entity sitting in your brain that shouldn't be there or is there something else going on where there's actually something more than a physical entity, it's maybe a chemical conversation between the larval form of the worm and the brain?

Hayley - That is the question because you can get seizures from traumatic brain injuries, from scar tissue, like you said, a sort of entity in the brain but you could be another reason and that's what we really wanted to find out. How do these tapeworms get into the brain, sit there silently for sometimes years, five, ten years in some cases and then suddenly seizures happen? That's what we set out to investigate.

Chris - How? What did you actually do to explore that?

Hayley - We did some electrophysiology, so looking at one neuron and sticking an electrode in that neuron while it's alive and recording how excited that neuron is, what is it saying, how is it communicating.

Chris - Specifically, are you talking about listening to a nerve cell that's right next door to one of these parasites so you can see if there's any influence of the parasite being there?

Hayley - We're actually specifically looking at the dead version of the larval parasite because that seems to be when the seizures develop, when it goes wrong. So I would have the worst day in the lab where I would make the tapeworm milkshake from all the larvae and essentially make this tapeworm juice which we would then spritz onto the cell body of the one cell that we were recording from in each instance and then we would watch the effect that that dead tapeworm would have on a single living neuron.

Chris - What effect does it have?

Hayley - Well, they get very, very excited. The first time I saw it in the lab was quite a moment, no idea what was going to happen, no one had ever looked with this technique at this kind of a thing and to just see that neuron spike, sort of fire off action potentials, communicate through electricity was quite remarkable.

Chris - Therefore, there's something in the milkshake, as you put it, when you grind up these larvae and you just put that onto the cells. I love the use of the word spritzing, it makes it sound much nicer than I'm sure it really is. But when it goes onto the cells, there's obviously something in there that's tickling the neurons. Do you know what is doing that?

Hayley - Yes, absolutely. And that was the finding. We knew that they were excited, now the hunt was on for what molecule in that tapeworm milkshake is having the effect.
And we did a bunch of experiments to determine that and we discovered that it is something called glutamate. Glutamate is an amino acid, but it is basically what our brains use for any excitatory signaling. If the tapeworm was releasing more glutamate or had glutamate in it, it was very likely then to be as excitable as we were seeing. So it all made sense when we got the answer of glutamate.

Chris - And Anja, why is the dead larva rammed full of glutamate?

Anja - It seems likely that it's kind of a byproduct of some metabolic process that they use. It could also be something that they're specifically producing in bigger amounts because we do actually see in some other brain pathologies, like brain cancers, those cancer cells produce a lot of glutamate because that kind of gets those neurons around them really excited. And when neurons get way too excited, they actually die off. And in cancer, it's kind of hypothesized that this is how the cancer cells make more room in the brain for them to grow into, which is something we suggested could also be true for the tapeworm larvae.

Chris - That is an interesting hypothesis. So you're saying that almost like the larva excites nerve cells to death to make space, but why would it do it when it's dead? And also, if it's dead, why does the epilepsy persist?
Is it because you've done damage to the brain by then?

Anja - Yeah, so they don't actually cause these seizures while they're alive, but we show in our paper that they do actually also release glutamate and aspartate while they're alive. So you would kind of expect seizures to be happening throughout the infection, but it only really happens when these larvae die. We think that it's because if you think about the size of these larvae, which can kind of be up to a couple of centimeters large, just the sheer volume of fluid that's inside that larvae and the amount of glutamate that must be in there is probably enough to push the brain over the edge. It's also true that you get a lot of inflammation when these larvae die. And we know that when there's inflammation in the brain, the brain gets less good at handling too much glutamate. We think that possibly that combination of already the brain not being too happy with having excess glutamate around and then together with just the sheer amount of glutamate that's probably coming out of that larvae upon death, I think that's why the seizures happen when the tapeworm dies. About 30% of people who have these tapeworm larvae in their brain and get seizures kind of continue to have seizures for quite a period of time. We think that that might be because our brains make scar tissue and then every couple of months or so, it goes back to that scar tissue and it tries to remodel it and kind of make it a little bit better. And each time that happens, there might be another exposure of some of the tapeworm elements and another kind of immune attack. But it's also possible that some of the people just have something that makes them a little bit more at risk of having seizures. And then once you kind of kick start that process, it kind of sustains itself.