Epigraph Vol. 25 Issue 2, Spring 2023

Neurocysticercosis and epileptogenesis: Dr. Hector Garcia

Reported, edited and produced by Nancy Volkers, ILAE communications officer

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Podcast Transcript

[00:00:21] Hector Garcia: Hi, I am Hector Garcia. I am the head of the Center for Global Health of the University of Peru. I'm the head of the cysticercosis unit at the National Institute of Neurological Sciences in Lima, Peru. And we're going to talk about neurocysticercosis, which is an important cause of epilepsy and other neurological morbidity worldwide.

And I just want to disclaim that whatever I'm going to talk about is not personal work. We have a pretty large network of research in Peru that we call the Cysticercosis Working Group in Peru.

[00:01:00] ILAE: So I've read that neurocysticercosis is one of the most common causes of epilepsy worldwide. Is that the case, and can you explain either way, whether it is or is not?

[00:01:15] Hector Garcia: First, we have to differentiate epilepsy in children and epilepsy in adults, right?

When you take epilepsy in children, those are usually epilepsies from genetic origin or hypoxia during delivery. Those comprise most of the epilepsy in children. And then you have another bunch which are temporal sclerosis from febrile seizures, et cetera, et cetera. But in general, it's stuff that comes from the earliest stages of age.

But when you talk about people after age 15, age 20, they develop a new epilepsy. There's something happening. So you have a crash, you have a tumor, you have an infection, you have something. And if you take that group of epilepsies, cysticercosis is by far the most frequent cause in the world.

Cysticercosis is present in most countries, including Muslim countries which are not pure Muslim, like India. India's a perfect example. India has a Muslim population, but they have lots of cysticercosis because they have a couple of non-Muslim populations and in Africa, many countries which are mixed with a majority of Muslims, they still have cysticercosis.

So the few meta-analyses that exist, they say that in countries where cysticercosis is present, which is a vast majority of the world, 29% of the epilepsies are attributable to cysticercosis. It's a lot. And it comes from several different studies from different groups. It's very consistent, about 30%.

So yes, the answer is yes. If you look at the causes of epilepsy and adults in the world, cysticercosis will be by far the largest cause of epilepsy acquired after the teenage years. Cysticercosis infection, infection seems to be extremely frequent. If you go to a community where there is transmission, lots of people will have been exposed to cysticercosis. So when we check antibodies specific to cysticercosis, it's not uncommon to find 10, 15, 20% of the village having antibodies to cysticercosis and you try to take into account that another bunch of people will have had antibodies and become seronegative after the exposure was passed.

I go to a community, I do a survey with Western Blot, which is the best antibody test, and I find 10 or 15% of people with seropositive blood, but then I do CT scan in people in this community, and I find another 10 to 15% of people with calcifications and they don't overlap. So there's a proportion, very large proportion of people with calcification who are already seronegative.

So my unsupported guess is that endemic populations, probably half of the population gets exposed to cysticercosis at some point. Some of them will get infected, will develop a cyst in a muscle, in the liver or in the lung or wherever, and the immunity will kill it.

So exposure and infection are going to be very common, but a proportion of them will have the cyst in the brain, and then a proportion of them will have symptoms from the cyst in the brain, and then a proportion of those, we have symptoms severe enough to make them go to a doctor. That's what we see in the hospitals.

It's the tip of the tip of the iceberg, and still it's a lot of people.

[00:05:23] ILAE: Do you have a best guess as to, you know, of the people who become infected, how many of them have seizures as a symptom?

[00:05:33] Hector Garcia: Not, not really. My best educated guess it will be less than 10%, but again, there are too many people infected. There are way too many. So eventually that comes out to be a significant proportion of people, with seizures attributable to cysticercosis not because it happens all the time because it's so frequent that the small proportion of them makes a lot of people. And you are skipping one part. There are epilepsies that the patient will not notice, right?

How many people will see lights? Or just have a numbness in their right hand and forget it after a few minutes. And so there's a bunch of oligosymptomatic disease that will be extremely difficult to quantify. One of your questions was what kind of symptoms you can get and, when I was a very young, good-looking young physician, I wanted to be a neurologist. And I went to my neurology professor and said, “Doc, I want to be a neurologist. What should I do?” And he told me, “You should do your thesis work in cysticercosis because you will learn neurology.” The parasite goes everywhere in the brain and will give you symptoms from everywhere in the brain.

And basically that's correct. You may have one cyst in your occipital lobe. You may have 300 cysts everywhere. You may have one cyst in your frontal lobe, or you may have one cyst in the brainstem, and you will see different disease coming from the different locations of the parasites. And it gets more complicated, because it may be small or maybe larger, or maybe inflamed or not inflamed. And maybe living or dying or dead and calcified. So it's a very complex matrix that will give you basically almost any neurological symptom.

So when I give the lecture on cysticercosis, I always say you can have basically everything, but in order to simplify things, we can think of cysticercosis as two major boxes: a box where the parasite is embedded in the brain parenchyma, which is called parenchymal cysticercosis. And then the problem is irritation, inflammation, and seizures. And then another box where the parasite is not in the brain parenchyma. And then the problem is it grows and infiltrates and causes mass effects and blocks CSF circulation. Then the problem is not seizures, it's headache, intracranial hypertension, and hydrocephalus, and this type of extra-parenchymal cysticercosis had a mortality of 30% to 50% as late as in the 1980s. It was really bad. Now we manage it much better, and mortality has significantly decreased, but we still lose people to extra-parenchymal cysticercosis even these days.

[00:08:50] ILAE: It's improved, so what's brought that about?

[00:08:54] Hector Garcia: Well, I will say that initially the availability of anti-parasitic agents and then, improvement in surgical techniques. And you have to understand that for cysticercosis, up until 1979, there was no drug to kill the parasite. Zero. People used to give steroids, antiepileptic drugs. Shunts, surgery to extract large lesions. Necropsy. That was it. There was no other thing to do. And then, somebody in Mexico, who was actually a veterinarian, found out that praziquantel killed parasites in the pig. So he went to his friend, a neurosurgeon, and told him, “I have a drug that kills the parasites in the pig.”

And the neurosurgeon said, “We have a kid in the hospital. Let's give him praziquantel.” So they did, to show you how research has changed in 40 years. They gave the kid praziquantel, the kid improved. They had a CT scan at that time. They showed the lesions shrank and they published a paper that says we have a drug that kills cysticercosis.

Everybody began to use the drug and some people died. Because when you treat the parasite with a drug, you attack the parasite, and then the parasite, which is in homeostasis with the immune system, will release antigens and cause an acute inflammation and that could kill you or cause a status epilepticus or intracranial hypertension.

And then the Brazilian group very quickly says, this is inflammation. Let's give them steroids. And that kind of modulated it, but still, it ignited controversy that I will say is still not dead. Some people will not use antiparasitic drugs in cysticercosis even now. But I will say the conclusion of the wealth of data now is that in general, patients will do much better if you kill the parasite with anti-parasitic drugs than if you don't.

[00:11:19] ILAE: So I'm thinking about the epilepsy aspect of it. So people who have acquired epilepsy from cysticercosis, it sounds like it could be anywhere, right? It could cause any type of seizures.

[00:11:32] Hector Garcia: Absolutely, and it'll show up as generalized seizures, but we all think those are focal seizures that generalize too fast because the biology of the parasite doesn't really suggest that it may cause generalized seizures.

I saw a patient who had anomic epilepsy. Anomic epilepsy. So he forgot the name of a thing and then he had a headache. That was his epilepsy.

[00:12:06] ILAE: So there is no, there's no type of seizure that you can say, oh, that's neurocysticercosis related.

[00:12:13] Hector Garcia: Definitely not. But if you have somebody who comes from Latin America or Africa and has just developed epilepsy after age 15, 20, you are highly suspicious.

[00:12:26] ILAE: So what, what do you do in those cases? Does anti-seizure medication work, or…

[00:12:33] Hector Garcia: Yeah, they in general, they respond very well to antiseizure medication. But that's not curing anything. Right? Right. We're just managing the symptom.

What do you do if you don't have a CT scanner? And my answer is always, I don't use antiparasitic drugs, because I don't know how many cysts this guy has and whether he has a cyst in the brainstem or a large cyst that will herniate him if I just trigger inflammation with praziquantel. So curing guidelines say you should use neuroimaging to diagnose neurocysticercosis.

[00:13:16] ILAE: And then once you do that and you know how many cysts there are, where they are, that would guide your treatment, whether you used anti-parasitic drugs.

[00:13:26] Hector Garcia: Yes. Just to give you an idea, if you do your CT scan or your MRI and find out that your patient has five calcified parasites, then you don't need to use anti-parasitic drugs anymore.

Or you find one small cyst, you are very comfortable with antiparasitic drugs, but then your next patient has 300 cysts and you are very, very worried how to get in with anti-parasitics. So it’s tailored to the patient. But what we do expect is that if all the cysts have died after antiparasitic treatment, the likelihood of no seizure relapses will be much higher.

[00:14:13] ILAE: Is there any age epidemiology for neurocysticercosis?

[00:14:17] Hector Garcia: Yes. Children behave very different than adults. If you have a five-year-old with cysticercosis, he was probably infected in the last year or past two years, while if you or I get infected with cysticercosis and show up in a hospital, we may have been infected 10 years or 15 years before, and finding the infected tapeworm will be extremely difficult. With children, you find the tapeworm mostly in people living around the children, and that's one important difference because you have to look for it and try to avoid further infections.

The second thing is, for a reason we don't understand yet, children most times present with a single degenerating cyst, a much more benign presentation and it's usually one small cyst, which is dying, and the prognosis is very good. It may resolve even without antiparasitic drugs, and likelihood of calcification is 20% to 30%. Likelihood of seizure relapses is 20% to 30%. So it's pretty good. And the interesting part is that's what you see in children in all the world, and it's very similar to what you see in travelers and it's very similar to what you see in India.

In India, most of the cysticercosis cases are in children and teenagers with a single degenerating lesion. So it's very likely to be early exposure to the parasite with a non-immune host. So you have a non-immune host who is exposed to a small challenge of eggs and then overcomes it by natural immunity.

But if it happens to an adult who has been exposed to it a couple of times, you will not get infected unless you have a heavier load of eggs that will overcome your immunity and establish, and then adults will show up with five cysts, three cysts, subarachnoid cysticercosis, much more severe types of cysticercosis that arise from heavier infections overcoming natural immunity.

[00:16:56] ILAE: So let me just clarify. You said an adult could be infected 10 or 15 years before they show any symptoms?

[00:17:05] Hector Garcia: Absolutely, yes.

[00:17:06] ILAE: So there's really no way to track transmission in adults?

[00:17:11] Hector Garcia: No, it's very bad. You will only find a tapeworm in 5% of the patients. Let me give you a piece of information which may be biased but it's only one we have. In the 1930s, India was a British colony, so British military were sent to India on duty for an exact year, and they came back to England and had seizures from cysticercosis. And the British Army put together a research unit that tracked down 454 English military or their relatives coming from India with cysticercosis and seizures. Most of them, seizures. And what you will think at that time is that if you have a parasite coming into your brain, you will get seizures when the parasite gets into your brain. Well they did a histogram of when they had the first seizure, compared to the time they went back to England and were not exposed anymore to the parasite. Surprise, surprise, 70% of them had seizures three to five years after being back in the UK.

So what causes the seizures and cysticercosis is not infection. It's something that happens years after. And then brilliantly they say, is the parasite dying? And then people say, okay, this parasite is dying. We don't have to worry about it. But the trick was you may have 10 parasites and you only need one parasite dying to get your seizures and then if you have nine parasites surviving in your brain, you will have them giving you trouble for the next 20 years.

So this experiment demonstrated that seizures occur years after and are probably triggered by one of the parasites, at least one of the parasites, beginning to degenerate. And that is what traced most of the conflict when praziquantel was available. Because people say, “No, no, these parasites are dying. Why do we want to give them praziquantel if you may trigger more symptoms?”

[00:19:41] ILAE: There's two more questions I'm hoping we can get through, as well as anything else you want to add. One of them is about transmission, which probably could be an hour, in and in of itself talking about interventions that have been attempted to reduce transmission. Can you talk a little bit about where things stand now? Is that a reasonable possibility or is it just something that we're going to have to live with the fact that this is endemic and it's going to stay?

[00:20:14] Hector Garcia: We believe it can be eradicated.

There are drugs to kill the tapeworm, which is the infective agent, and they are very, very safe drugs and simple. And there is a pig vaccine developed in Melbourne that works very well and there are new diagnostics.

So a few years ago we demonstrated in a large area in northern Peru that transmission can be interrupted. We applied a complex program for a year, and at the end of the year there were no traces of transmission in most villages. And one year after, half of the villages where we intervened were still with no transmission, without further intervention. So we have proof of concept that we can interrupt it and it may last, but now it requires to be taken systematically, adapted to local realities, made cheaper, put into programmatic approaches and taken up by governments. It's very likely that we could eliminate transmission, but then we will have to deal with calcified cysticercosis for another 30 or 40 years.

[00:21:27] ILAE: Is there anything you wanted to mention that we haven't discussed? Bearing in mind that this is being produced for an audience of epilepsy professionals, so they're interested in the epilepsy angle of things.

[00:21:43] Hector Garcia: Yeah, considering that this will be mostly listened to in the US and probably Europe, and I will bring up that awareness is key. So if you have a good grasp of endemic areas for cysticercosis in the world, which include Latin America, Africa, Southeast Asia, parts of China, and India. And then you have a patient with those origins showing up with a late onset epilepsy or an intracranial hypertension, you will be much prone to get into the right diagnostic track.

[00:22:24] ILAE: So last question I guess would be, if you were speaking to a junior person, someone who's just starting out and is interested in cysticercosis as it relates to seizures and epilepsy, are there areas of research that you think are particularly exciting and interesting, like where would you suggest they start?

[00:22:45] Hector Garcia: Well, why do you think I'm not retired yet? Cysticercosis we really think may give important clues on epileptogenesis. Particularly now, we have rat and pig models for neurocysticercosis that have been developed in the last decade.

We can kill the parasite with anti-parasitic drugs, and we can look at epileptogenesis in the animal models, and we can also monitor human patients to see what's going on with their epilepsy, of course under appropriate standards of care.

In the last decade, there is also a growing body of epilepsy that shows that hippocampal sclerosis is also associated with cysticercosis and not necessarily in the temporal lobe. So somehow cysticercosis infection may act as an initial precipitating injury and damage the hippocampus, whether it is by antigens and chemical immunological reactions, or whether this is because we are having seizures in a focus that we are not detecting.

We don't really know it yet, but I think cysticercosis will be a spectacular model to study epileptogenesis and brain inflammation.