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Treating the immune system, treating schizophrenia? -

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Norman Swan: Hello, and welcome to this week's Health Report with me, Norman Swan. Today, a riposte to our story last week on how being overweight might be best to avoid dying prematurely. And speaking of dying, we are going to encourage you to talk about it over dinner tonight.

And what could be a remarkable yet potentially fraught treatment for some young people who in the past have been diagnosed as having schizophrenia. It involves treating the immune system in the belief that the problem is that the immune system is attacking the brain, or at least affecting it. And by doing this a team in Sydney has had some success. In the studio with me are adolescent psychiatrist Dr Liz Scott of St Vincent's Hospital in Sydney, director of the Brain and Mind Institute at the University of Sydney Ian Hickie, immunologist and immunopathologist at New South Wales Health Pathology at Westmead Hospital David Brown, and Cathy McCabe, whose both daughters have been on the treatment program. Welcome to you all.

Liz Scott, where did the idea of this come from?

Elizabeth Scott: Norman, it's been an interesting area of medicine, and it partly came out of seeing a number of cases at St Vincent's Hospital, and in particular the private hospital, that were very perplexing, of cases of early onset of psychosis with young people who had very complex disorders, who didn't respond to the usual treatments, and really went on to develop a very deteriorating course with very severe syndromes resulting in long periods of hospitalisation and a lot of disability.

Norman Swan: So just give me a typical story.

Elizabeth Scott: So, for instance, they would start out with psychotic symptoms…

Norman Swan: That's delusional behaviour.

Elizabeth Scott: Yes, delusions, become very paranoid, often atypical symptoms, so we associate auditory hallucinations, hearing voices, but a lot of these young people had had quite atypical symptoms, they would see things, they would have visual hallucinations or tactile hallucinations. They would often look as though they were quite confused, almost delirious. They would have marked trouble with their sleep, so spend long periods of time sleeping, falling asleep like a narcolepsy type syndrome. Or they would have periods of time where they wouldn't sleep at all.

So a changing clinical picture, complicated by a whole lot of systemic problems, often trouble with their heartrate variability, which would see people collapsing at various times, trouble with their gastrointestinal tract, trouble with…and other trouble related to infections or immune system.

Norman Swan: And this is not a new disorder, it's just that your eyes have been open to it.

Elizabeth Scott: That's right. So we are assuming that we've seen people like this in the past, but just assumed that they've got very severe or treatment resistant psychosis. But because we are much more aware now of the physical health consequences of these types of diseases and disorders in young people, so we are particularly looking at the metabolic effects and other systemic effects, we are looking at blood profiles and looking at the whole history and the whole course of illness, we are much more aware of how complex these syndromes are, they are not just mental health syndromes, they affect the whole body.

Norman Swan: So David Brown, where did the idea that it might be the immune system come from?

David Brown: Well, I've been looking after patients with autoimmune disease for a long time, and they've often had psychiatric symptoms. And over time I wondered whether people with psychiatric symptoms by themselves which were treatment resistant might be due at least in part to autoimmune disease.

Norman Swan: So give me a sense of the autoimmune disease, is this rheumatoid arthritis…?

David Brown: Rheumatoid arthritis, Sjogren's syndrome…

Norman Swan: That's where you've got dry eyes.

David Brown: Lupus, where you have sore joints and skin rashes. And these people often have significant psychiatric disability, and when you treat them they get better. You could always say, well, that's just their disease getting better, but I had a sense that it was more than that. And so that led me on to the question of whether they could present primarily as psychiatric disease. And it seems as though they can.

Norman Swan: Cathy, you've got two daughters undergoing this treatment. We'll get to watch the treatment is in a minute. Tell me their stories.

Cathy McCabe: Elle was very unwell from birth, and it wasn't until she was 16 when she became quite psychotic that someone actually took notice, Dr Scott in fact helped us. And since then…

Norman Swan: When you say psychotic, just describe what was going on.

Cathy McCabe: Well, she wasn't at school anymore, she was at home most of the time. She was terrified that everyone was trying to kill her. She was doing lots of unusual things that we didn't understand. We didn't even know what psychosis was ourselves. So yes, she was very unwell. And it wasn't until she became that bad that somebody took notice and helped us, and we finally have since then…it got a bit worse at times but we've got better…

Norman Swan: On the treatment, and we'll come to the treatment in a minute. And how is she going on the treatment?

Cathy McCabe: Pretty good, she is doing quite well. She's at uni now, and she is functioning to the best of her ability. She's not quite normal, can't really push herrself too much. But she is quite well compared to what she was, and we are lucky to still have her.

Norman Swan: And your younger daughter developed symptoms too.

Cathy McCabe: Yes, over that adolescent period she had depression, anxiety, she wasn't at school for over six months, had lots of physical symptoms, but she didn't develop a psychosis. But she has improved out of sight since she has had the immune therapy treatment as well.

Norman Swan: So Liz, what happened there? Just take us through how you assess somebody like this and what conclusions you came to?

Elizabeth Scott: So first of all it is about, as David says, recognising that there's something more…

Norman Swan: So what was it about Elle that you thought there was more?

Elizabeth Scott: So I think partly it was her mother's persistence in saying, look, this is not right, but also it is looking for other markers of illness. So we were looking for immune markers, we look at family histories, is there a family history of autoimmunity, which in this case there was, is there a change in the progression, is there a difference in the trajectory of these disorders compared to what we would normally see. So then we start looking for other biological markers of illness or of brain disturbance.

Norman Swan: And what treatment are they on? Is the treatment…do you put your finger in the air and say, well, we will try this, or what?

David Brown: Look, in this particular case, along with all of these symptoms there were some key signs of immunodeficiency and that was frequent skin infections. So in this particular case a diagnosis of immunodeficiency was made, which has a genetic basis, at least in part. And so initially the treatment was directed as you would for somebody with this particular condition, which was intravenous immunoglobulins, and that significantly ameliorated some of the symptoms but not all. And in a subgroup of these patients with immunodeficiency you can also surprisingly get autoimmunity. And so when we had tried the least toxic therapies, we started some immunosuppression.

Norman Swan: Ian Hickie, we are not alone in Australia doing this?

Ian Hickie: No. It turns out in just about every major highly specialised psychiatric service for young people in the world there's a group of people who were traditionally thought to have autoimmune encephalitis, so an inflammation of the brain based on the reaction of the body attacking itself through production of antibodies against oneself, thought to be one in 10,000. The big issues become is this one in 1,000, is this one in 100? In fact of the atypical syndromes might it be as common as one in 10 of the atypical sorts of presentations? The ones that Liz was describing, very acute courses, look almost confused, agitated. And then when you start to investigate with MRI brain scanning, lumbar punctures, EEGs, there is evidence, non-specific evidence of brain change. And then really the clinical decision needing to be made; is something going on?

Worldwide there is a lot of screening for new antibodies. The most important one is anti-NMDA. But also a range of other new antigens or markers that are on the neuron cell surface, the surface of the nerve cells, or the synaptic proteins, the proteins that are part of nerve transmission.

Norman Swan: And we've had a story on the Health Report in the past about anti-NMDA from this bizarre and rare tumour in the ovary in some young women which can then affect brain function and be dramatic when you remove it. So how many people have you treated, Liz, and what sort of results?

Elizabeth Scott: I think we have treated probably around 15 people and I have to say that the results have been remarkable in the majority of cases. These are people who in a sense we have run out of traditional treatments and have had a deteriorating course, and they have almost all got back to work or got back to university or returned to study, and their quality of life has dramatically improved, and the quality of life of their families have dramatically improved.

Norman Swan: But I assume they all have different diagnoses, they don't all have the same autoimmune condition.

Elizabeth Scott: No, so these are not the same disorder, they are mixed disorders, but all have in a sense the same endpoint in effecting the brain causing this kind of disturbance in brain systems.

Norman Swan: Cathy, your kids have gone through an experiment. Did you know it was an experiment?

Cathy McCabe: Yes, but we didn't have any other choice, we were at the end of the road. Elle was very unwell, and we were going to lose her to suicide or something like that if she didn't get some help.

Norman Swan: She was so unwell.

Cathy McCabe: Yes.

Norman Swan: So you'd reached the brick wall at the end of the road.

Cathy McCabe: Yes, and all the girls that we see at St Vincent's, they are amazing, how much they have improved, to see how sick they are, and then see them now, they are at TAFE…they are not like all the other kids, I've got to say, but they are doing really well.

Norman Swan: Yes, it's not a cure, but it is helping a lot. And where you nervous about it, given that it was an experiment and you were going into the unknown?

Cathy McCabe: No, we were desperate to try anything.

Norman Swan: Ian Hickie, there are huge ethical issues here, are there not? This is not a randomised trial, you are just stabbing in the dark.

Ian Hickie: There are huge issues, and there are huge issues with a number of things. So this is a typical thing that happens in clinical medicine. Something that is thought to be very rare, as you say, the teratoma type example, something that is thought to be one in 100,000 type cases, you make an individual clinical decision, but it's never going to become a clinical trial because it's so rare. You make the clinical decision to save the person's life at the time.

As you move to thinking, hmm, maybe this isn't so rare, you get in this situation. So now what we proposed across a range of people in these areas, major centres across immunology, psychiatry, is what protocols do we need to have in place for testing, for decision-making, and then for the discussion…

Norman Swan: Because we could be open to the cowboys now, you've opened the door.

Ian Hickie: Exactly. So if I suddenly say not one in 10,000 but one in 10, you can imagine the difference we are into, then we are into really controversial areas. So the other issue for us here is adequate…see, practitioners can sit around and go, okay, we all agree about a protocol, but the issue that fusses me most is actually involvement of parents and young people themselves in the progressive decision-making. This is not a one-off decision to be in a clinical trial, it's not a one-off decision to have some specific tests, it's a process of weighing up at each point along the way what might be the relative benefit of actually taking this course versus conventional therapy versus what are the significant risks, short and long term, of changing a person's immune profile.

Norman Swan: Liz Scott, it has been known for a while that there's something funny about the immune system in general with people with schizophrenia, and mothers who have…well, rather than reverse it, when you look at people with schizophrenia and then look at their mothers, they are more likely to have an infection in the antenatal period. Could this apply more broadly to people with schizophrenia, or is it just in this specific group?

Elizabeth Scott: I think, as Ian says, that it is likely that what we see are the very rare and severe cases, but there are probably a group of people underneath that who have subthreshold disorders. So this is probably much broader than we think, and it gives us the opportunity for real prevention and new interventions. So I think it is a great opportunity but we have to approach it extremely carefully.

Norman Swan: David, do we know the right tests, do we know the right treatment? These treatments seem very toxic.

David Brown: Sure. So, look, these patients fall into three broad categories. One is that you can make a diagnosis of an immune disease, the other category is that there is clear evidence of inflammation there which makes it easier to explain why you want to do…what the options are and what the side-effects could be. The third issue is where there is really no evidence of any immune perturbation, and that's much more difficult to justify, and at this point in time I think…

Norman Swan: So have you treated anybody that you thought was this condition but you couldn't find any immune abnormalities?

David Brown: No, I haven't, because I think that it's difficult to justify.

Norman Swan: Because the treatment could kill…unlikely, but it could kill the person.

David Brown: Correct, it could kill them, and I think that really we have to approach this methodically and scientifically and have trials to work out what the best tests are and to work out…

Norman Swan: But all your researchers are doing different things around the world. Are you getting together on this?

David Brown: Yes…

Ian Hickie: Norman, that's the big goal. The big goal is not for everyone to do something funny in their own individual centre, and that's the danger at the moment, and a lot of controversy amongst professionals about what is the right person to treat or not. And there is an issue whether some of the standard presentations that actually we would not have thought of as classically having an immune problem actually do have an immune problem. As the tests have become more sophisticated, guess what, we find more evidence from brain scanning and better antibody screening of actually more young people who didn't have atypical disorders who have indicators of this type of problem. Unless we get it together nationally and internationally, we won't know what we are doing.

Norman Swan: It could be too wide a spread with too toxic a treatment. Thank you all very much indeed, that is fascinating, we will catch up. And particularly thank you Cathy for coming in to tell the story of Elle and Pamela. And the results of this will be further discussed on Friday at the Meeting for Minds conference in Fremantle.

And you're listening to Liz Scott, who is an adolescent psychiatrist and runs the youth mental health services at St Vincent's private hospital in Sydney, Ian Hickie who is the director of the Brain and Mind Institute at the University of Sydney, David Brown who is from New South Wales Health Pathology and director of Immunopathology at Westmead Hospital, and Cathy McCabe.

You're listening to the Health Report here on RN with me, Norman Swan.