BRITISH BROADCASTING CORPORATION
RADIO SCIENCE UNIT
CASE NOTES
Programme 3. - Parkinson's Disease
RADIO 4
TUESDAY 13/02/07 2100-2130
PRESENTER:
MARK PORTER
CONTRIBUTORS:
RAY CHAUDHURI
ALISON FORBES
SARAH SALVAGE
TOM ISAACS
LINDSAY ISAACS
TIPU AZIZ
ROGER BARKER
PRODUCER:
GERALDINE FITZGERALD
NOT CHECKED AS BROADCAST
PORTER
Hello. I've come to King's College Hospital at Denmark Hill to meet neurologist Dr Ray Chaudhuri and clinical nurse specialist Alison Forbes. Today's programme's all about Parkinson's Disease, a condition that affects around a 150,000 people across the UK.
It was first described by James Parkinson nearly 200 years ago and ever since medical students have been taught the classic triad of telltale signs - slowness of movement, stiffness and tremor - or the shakes. But we now know that Parkinson's can lead to many other problems; problems that are often missed.
CHAUDHURI
Parkinson's Disease is a neuro-degenerative condition; in other words, [it means that] certain cells in the brain which produce certain types of chemicals die faster than they normally would. There are three main chemicals that are involved: one is called dopamine, which is the main chemical which leads to the classic symptoms of Parkinson's - the stiffness, the tremor; and then there is also serotonin, which can affect mood; and then听there is also noradrenaline, which can affect control of blood pressure. Another key aspect of Parkinson's are symptoms related to these other neurochemicals; such as sleep problems, such as constipation. And I think now the awareness has dawned that we need to look at it in a very holistic manner. So that is a new awareness.
PORTER
So practically what does that holistic approach entail?
CHAUDHURI
Well essentially it means that the physicians or the nurse specialists need to be aware that Parkinson's is much more than just the classical three symptoms.
FORBES
And I'd just like to add in there that as a nurse sometimes patients have raised some of these things and I've been very carefully noting those things down in my notes but it wasn't until we got together as a multidisciplinary team and talked more that we realised how important they were and that together we could produce this tool which would help us to guide our consultation, to ask more people about these things.
PORTER
Now you mentioned the word tool - by tool you mean this questionnaire that we have in front of us. So this is given to patients?
CHAUDHURI
This is given to patients when they are waiting to be seen. This is then handed to the doctor or the nurse who then gets an immediate snapshot view of are there any specific non-motor problems that the patients are also complaining of? By non-motor symptoms of Parkinson's we mean symptoms that are not traditionally associated with the three main symptoms - which is the stiffness, the tremor and the mobility problems - so they can be problems related to the bowels, problems related to mood, problems related to sleep, problems related to sexual function. And you can then focus on that in the consultation because many of these symptoms can be treated, the problem is of course if we didn't know about it we would not attempt treatment of them.
PORTER
Well let's have a look at some of the symptoms you've got here on the questionnaire. I notice that you're asking about the sex life here, what goes wrong in people with Parkinson's?
FORBES
Well I mean in Parkinson's you can see either increased interest in sex or reduced sex drive in particular and sometimes it's a drug related problem or sometimes people just need to be able to talk to you about maybe different positions.
CHAUDHURI
You asked about the non-motor symptoms - how common they are - in fact we have completed a major study in this area, the first one to be done of this sort. And what emerged was that up to 60% of our people with Parkinson's would have a major problem of getting up at night to pass urine. Again something we don't normally concentrate on but if you knew it, it is actually treatable. We found that 30-40% of our patients had problems with sleep disorders and this could be so-called restless legs or sleep being very disturbed by bad violent dreams when people act out violent dreams, often causing a lot of distress to their care giver. Similarly again another problem that emerged was mood related problems - low mood was very common, people feeling generally often slightly depressed perhaps and sexual problems that Alison has just alluded to.
PORTER
Are the non-motor symptoms, like sexual difficulties, like getting up in the night, proportional to the degree of disability you get from the motor symptoms or is it possible for somebody to actually not really have many of the classic symptoms of Parkinson's but be bothered in other ways?
CHAUDHURI
Some non-motor symptoms can actually occur before the motor diagnosis of Parkinson's is made. An example would be loss of sense of smell, for instance, that can happen 4 to 5, even up to 10, years before the typical signs of Parkinson's emerge. Similarly the sleep disorder that I talked about - REM behaviour disorder when people act out violent dreams at night in deep sleep - has also been associated as a pre-clinical marker. So that again can occur way before the motor diagnosis of Parkinson's can occur.
PORTER
And I suppose that the problem is the way we've been treating Parkinson's traditionally - focussing in on the dopamine problem, these motor symptoms, the stiffness etc., isn't doing - isn't helping any of the others at all?
CHAUDHURI
I think that's correct because many of these symptoms are generated from degeneration of the cells which are addressing the serotonin pathway, noradrenaline pathway etc. Some dopamine treatment or treatment of replacement of dopamine in the brain can actually help these problems as well, for instance all the sleep problems can be addressed but you're absolutely right - we do need to think about this more because these need separate and specific and focussed treatment. Only when we add these in to the traditional, conventional, treatment then you can achieve a very modern sort of holistic care.
PORTER
Neurologist Dr Ray Chaudhuri, and specialist nurse Alison Forbes, talking to me at their busy clinic in Denmark Hill. And we have a link to their screening questionnaire on our website at bbc.co.uk/radio4.
My guest today is Dr Sarah Salvage who is a member of the Degenerative Diseases Research Group at King's College, London.
Sarah, who gets Parkinson's and why?
SALVAGE
Well in general it's a disease of people over the age of 50 and rarely occurs before that, although you do get some incidents of young onset Parkinson's Disease.
PORTER
Do we know why people get it?
SALVAGE
In most cases we don't know why and this is called idiopathic Parkinson's Disease.
PORTER
Medical speak for we haven't got a clue really.
SALVAGE
Exactly. But in about 5% of cases there are what we call familial cases of Parkinson's Disease where we've actually found genes which are associated with the symptoms of the disease.
PORTER
And we think those genes predispose to Parkinson's and other factors are influencing it or ...?
SALVAGE
With these particular genes they seem to be directly linked to the disease process itself. In idiopathic Parkinson's Disease, where we don't actually know the cause of the disease itself, we think it's likely that there is some genetic predisposition, so there's some genetic background for the disease, but that's probably also linked to some environmental exposure to a toxin or chemical.
PORTER
So nature loads the gun and the environment pulls the trigger.
SALVAGE
Exactly.
PORTER
We heard Ray Chaudhuri there talking about what goes wrong in Parkinson's Disease, what can we do about it?
SALVAGE
Well we know in Parkinson's Disease we've lost dopamine in the brain and the main treatment for Parkinson's Disease is an attempt to replace this lost dopamine and we can do this in two ways: we can either give a drug that mimics the action of dopamine and these are called dopamine agonists or we can give a drug which converts into dopamine in the brain and actually replaces the lost dopamine and this drug is called levodopa.
PORTER
Levodopa's probably the treatment that most people would have heard of, is it simply just a matter of giving it and it seeps through to the brain and fixes the problem?
SALVAGE
No, levodopa has to be converted into dopamine and this of course can happen all over the body, not just in the brain. So we give levodopa with drugs which will stop this breakdown and allow the levodopa to go straight to the area in the brain where it can be converted into dopamine.
PORTER
So hopefully only the part of the brain that needs the dopamine gets it, the rest of the body doesn't. Because what would levodopa do to the rest of the body if it's allowed ...?
SALVAGE
Well it can certainly affect your heart, your blood pressure and cause symptoms in your gut and on your bladder and in the kidneys, so there's lots of things that can go on with levodopa.
PORTER
We heard there how important it is to consider this as a condition that affects more than the motor symptoms but they're the main target aren't they for our therapy. How effective is levodopa type treatment?
SALVAGE
Initially levodopa is very effective, it's what we describe as our gold standard treatment for Parkinson's Disease. But within five years about 40% of patients experience movement disorders which are uncontrollable, we call these dyskinesia. And in fact by 10 years most patients experience these in some way. In addition to this the effect of the drug can be quite unpredictable, so on one occasion a drug can - or you take a dose of levodopa and it can last three to four hours, on another occasion it may not work at all or it may suddenly switch off at a completely unpredictable time.
PORTER
And these are what people talk about with the on/off episodes that can occur at any time through ...
SALVAGE
Yes, the on/off can occur at any time and also we have wearing off where the time the drug will act for will shorten. And this again is unpredictable.
PORTER
Problems all too familiar to 38-year-old Tom Isaacs. Although Parkinson's, as we said, is typically a disease of the over 50s it can strike much earlier - 1 in 20 cases occur in people under the age of 40. Tom, founder of the Cure Parkinson's Trust, first noticed something was awry when he was in his mid 20s. And it was particularly noticeable after a few drinks with the boys.
TOM ISAACS
There was actually one night where I'd had a skinful and actually couldn't move at the end of the evening, which was strange, I just thought - put it down to being a little bit drunk. Looking back on it, it was obviously the first signs of Parkinson's. It's funny, you don't really know what symptoms you've got because it's just something you've always lived with. I have something called celiac disease, which I've had since birth, which is obviously a problem with the gut and I suspect that that is related to my Parkinson's, although there's no clinical proof of that. I've always noticed that my Parkinson symptoms are far worse when I've got some sort of gut problem - if I'm constipated or if I've got diarrhoea - then the knock on effect of my symptoms is very marked.
LINDSAY ISAACS
I met Tom at a party five Christmases ago and his symptoms at that point were quite minimal, he was probably more controlled with the drugs at that point and the disease has progressed since then.
TOM ISAACS
I was just showing off at the party.
LINDSAY ISAACS
Yeah, I got sucked in.
TOM ISAACS
Yeah absolutely. She fell for it.
LINDSAY ISAACS
No, he's quite cute too.
TOM ISAACS
It's very difficult living with someone who hasn't got Parkinson's because you quite often feel like a bit of a burden. Although Lindsay never makes me feel like a burden it makes you angry about the disease, you know you feel okay I can cope with it but why does it have to affect other people's lives as well.
LINDSAY ISAACS
It affects your relationship in lots of different ways because it stops you doing things as spontaneously as you would have with somebody who doesn't have Parkinson's Disease. I mean Tom himself makes the relationship really easy, you need to be able to talk openly about the disease with each other, which most of the time we manage.
TOM ISAACS
That's the key isn't it - communication.
LINDSAY ISAACS
It is and trying to understand what they're going through because you can't - even though you're witnessing it you can't actually feel what they're feeling and sometimes it is very painful when he's shaking, his muscles go into complete spasm and you're left helpless not really knowing what you can do, there is nothing you can really do except watch him and hopefully the drugs will kick in.
TOM ISAACS
I see myself as a sort of Jekyll and Hyde type character where when I'm off I'm not me at all, I'm just someone else who shakes and when I'm on I'm Tom Isaacs. If I can separate those two things and forget about the Mr Hyde when I'm Dr Jekyll and then that makes it easier, and it makes it easier to deal with.
LINDSAY ISAACS
You know the way that I think we deal with it is just taking each day as it comes.
TOM ISAACS
We do but we both have this inherent belief that - that we are going to cure this thing and ...
LINDSAY ISAACS
Yeah, very strong actually.
TOM ISAACS
And that actually that we'll come through this and come out the other side and I will improve eventually.
LINDSAY ISAACS
Yeah. Pills?
TOM ISAACS
No - yeah I actually do need ...
LINDSAY ISAACS
It's like an insulin pen, so it's really handy to take out and about and all he has to do just - and you dial it up to the set thing and pull it back and then he just jabs it in his tummy or his leg or arm. And it's meant to kick in within about 10-20 minutes. And it only lasts an hour maximum type of thing, so it's great for times let's say - because quite often in the evenings Tom's drugs kick out quite early so if you're at a dinner party we kind of have to head home but this is hopefully - he can nip to the toilet and be okay in about 10-20 minutes and be able to carry on for a bit longer which will be great.
TOM ISAACS
Yeah, this new treatment that I've got is it's like a quick remedy really, a quick fix, which can - will hopefully get me out of tricky situations if I get stuck somewhere and be right as rain in sort of a relatively short period which should actually help me enormously.
I rattle with pills, I've been through quite a few different regimes. I'm obviously on the el-dopa which is the standard medicine for Parkinson's. I take that, I take something called a COMT inhibitor - an add on - there are lots of add on drugs with the el-dopa which help to prolong its effect. And it's constantly trying to - trying to keep a balance because with the el-dopa you tend to have these very distinct ons and offs and when you're on you have control over your movements and when you're off you're very rigid or shaky. But then you have the other extreme where if you're over on then you have this thing called dyskinesia which is basically when you have too much movement and you feel a bit like an out of control John Travolta on the dance floor - it's pretty unpleasant. And it's very frustrating because although your mind works perfectly normally and you have total control over what's in your head you have no control over what your body is doing. And when people are looking at you like that they tend to think because you can't control your body you can't control your mind and that's the sort of stigma which is unfortunate with Parkinson's.
PORTER
Tom Isaacs and his wife Lindsay.
You are listening to Case Notes, I am Dr Mark Porter and I am discussing Parkinson's disease with my guest Dr Sarah Salvage.
Sarah, what causes those distressing movements - the John Travolta impressions that Tom referred to?
SALVAGE
The dyskinesia that Tom was referring to are caused by an imbalance between two pathways in the brain which actually control the way we are able to move.
PORTER
I mean are they an inevitable price we pay for the treatment of conventional symptoms of the Parkinson's?
SALVAGE
At the moment it seems to be the case. The dyskinesia seem to come on because what we're trying to do with the treatment with Parkinson's Disease is to replace dopamine, which exists in the brain, but the way we're replacing the dopamine isn't what we describe as physiological, we end up with peaks and troughs of dopamine, instead of a nice smooth response.
PORTER
So this is a pure side effect of the therapy that we doctors are giving, not the Parkinson's Disease itself?
SALVAGE
Yes it is, it's a side effect of the therapy and it's something that we're trying to improve with different treatment regimes.
PORTER
And are we making any headway, can they can be controlled, are we controlling them better now than we used to?
SALVAGE
Well we certainly know that if you get rid of the peaks and troughs in the stimulation of the dopamine systems then you get a reduction in the dyskinesia.
PORTER
So practically how might we achieve that?
SALVAGE
There's a number of ways we can achieve that. We can use much longer acting drugs, levodopa itself is a very short acting drug, it has an activity of about four hours and if we can extend the duration of the activity of levodopa then we reduce the risk of having dyskinesia.
PORTER
So we're looking for a sort of steady state?
SALVAGE
Exactly, we're looking for a steady state. And there are a number of drugs we can give with levodopa that actually improve that and I think Tom mentioned one which was called a COMT inhibitor- entacapone.
PORTER
The so-called add ons?
SALVAGE
Exactly, yeah, the add ons, which will increase the length of activity or the duration of activity of the drugs.
PORTER
Tom also referred to his on/offs, you mentioned them earlier and he had an off right in the middle of the interview there. Now we couldn't really see much - because listening to him you can hear him grinding to a halt - he went off to the loo, 15 minutes later was almost back to normal. Fifteen minutes is okay if you're at home but you know it's a long time if you're out on a train or in a shop. The drug that Tom used was what?
SALVAGE
The drug Tom used was a drug called apomorphine. I mentioned earlier on that there are two ways of treating Parkinson's Disease: one with levodopa, where you actually replace the dopamine; and the other one with a dopamine agonist, which mimics the activity of dopamine in the brain. And apomorphine is a dopamine agonist - it's ...
PORTER
So it copies the actions of dopamine.
SALVAGE
It copies the action of dopamine and the advantage of apomorphine is that the action comes on very quickly. And so it's very useful in a situation like Tom had where you need to turn yourself back on very quickly, particularly if you're shopping round in a supermarket or something like that.
PORTER
So is this effectively correcting one of the troughs that you were talking about, it's a temporary boost?
SALVAGE
It's a temporary boost which gets you out of one of the troughs. But it's - unfortunately apomorphine is very short acting and it's just something that will get you going enough in order to try and get you out of the situation or allow you to take your next levodopa dose or dopamine agonist dose.
PORTER
Now he was using that pen type system for administering it, are there other drugs and other ways that you can use little top ups, that patients can adjust their therapy during the day?
SALVAGE
Not to a very great extent. The alternative is to take another dose - to wait till the time you need to take your next treatment but you could be off for some time before that so this apomorphine treatment is very good. But if you know that you are susceptible to periods of off or wearing off then there are ways of administering the drugs so that you do get a longer duration of activity. For example, by the use of pumps and in fact apomorphine can be given using pumps.
PORTER
These are little pumps that deliver just under the skin?
SALVAGE
Yes, yes they are. They're ones ...
PORTER
Constantly.
SALVAGE
... they deliver constantly but in fact you have control over them so you can turn them off. And more recently some of the dopamine agonists have been produced so that you can use them as a patch, and these are like sticking plasters which you put onto your skin and these again will release dopamine right the way through the day.
PORTER
Travels through the skin gently throughout the day.
SALVAGE
Yes.
PORTER
Well surgery is another option for dealing with difficult side effects of the disease. Neurostimulation uses high frequency electrical currents to block nerve impulses causing distressing motor symptoms. It's an expensive and complex procedure performed on just 500 people a year in the UK. And for the best results patients need to come off all their drugs and have wires inserted deep into their brain while they are awake. Professor Tipu Aziz is a consultant neurosurgeon at the Radcliffe Infirmary in Oxford and I asked him how it all works, and why the wires can't be put in under a general anaesthetic.
AZIZ
Because if I'm going to improve their Parkinsonian symptoms I prefer to see the untreated state while they're awake and I'm operating.
PORTER
So you can actually then apply the electric current and see what effect that that has?
AZIZ
Yes and the patient can tell me immediately whether they appreciate the degree of alleviation we've achieved and also whether they're suffering any side effects because you might find that their speech gets a bit slurred as you turn the current up or they may get severe tingling.
PORTER
It might come as a surprise to a lot of listeners that you can actually operate on somebody's brain while they're awake, can you just briefly explain how that works?
AZIZ
Well you see the brain itself although it receives sensation from all the body, in itself has no sensation, it's not responsive to pain at all. And although it's noisy, drilling a hole through the bone isn't painful. And then you hit the membrane that surrounds the brain and that's slightly uncomfortable and once that's penetrated by mere puncture the wire itself can be slid down to target through the substance of the brain, which is very much that of a blancmange.
PORTER
And presumably this is all done under some form of x-ray guidance, so you can see where you are - where the tip is within the brain?
AZIZ
Well the patient, before we start, has his or her head bolted in a frame and the frame provides the three dimensional reference. And when the patient is taken to the x-ray department the CT scanner scans the whole patient's head within this three dimensional reference point and with a computer you can work out the exact reference within that frame that matches the target in the brain and also the entry point on the skull - it's like a GPS system of the head. And once the electrode's in and we're happy with the placement we take the patient down to the scanner again to check where the electrode is and if it's in the right position and the patient's happy we connect it to the pacemaker. And we turn on the stimulator, current is delivered by the wire deep into the brain. And although it's called neurostimulation it is actually -by shooting off at high frequency we're actually switching these cells off because they can't cope with that degree of stimulation.
PORTER
What sort of results do you get?
AZIZ
If we choose our patients rightly 9 out of 10 patients will improve very significantly.
PORTER
Professor Tipu Aziz talking to me earlier.
Deep brain stimulation may help alleviate some of the symptoms of Parkinson's Disease but it has no effect on the underlying problem - deterioration of the nerve cells in the substantia nigra region at the base of the brain.
But there is another established surgical option that might - transplantation - introducing new brain cells into the affected area. Consultant neurologist Roger Barker works at Cambridge University's Centre for Brain Repair.
BARKER
The history of transplantation in Parkinson's goes back about 25, 30 years and initially the first cells that were used were the patient's own cells taken from a gland in the tummy, called the adrenal. They proved not to be very successful because they didn't survive very well. So the most successful work, which was started in the late 1980s, involved taking the cells which are lost in Parkinson's Disease from foetuses which are collected from termination of pregnancies or abortions. So the basic strategy is you take this tissue, you isolate the developing bit of the brain which will give rise to these dopamine cells and it's those cells which you then transplant into the patients with the condition.
PORTER
So the theory being that you're reseeding them with the sort of tissue that's disintegrating or deteriorating in Parkinson's Disease?
BARKER
Absolutely. So you try and replace those missing cells by putting in the ones from an aborted foetus.
PORTER
Roger, you say it's been going on for 25 years how advanced is this technology now, are we still in an experimental phase or is this a very real therapy that's being offered?
BARKER
I would still say we're in an experimental phase. The initial studies which were done in the late '80s, early 1990s, clearly demonstrated a proportion of them improved. This led on to bigger studies in America and the outcome of those two trials showed that the cells had an effect in some patients, they also produced side effects in other patients and the overall outcome of the study was rather disappointing in that it didn't appear to have a major benefit to the patient. As a consequence of which people have sort of re-evaluated the field and said is this a sensible way forward, is this the way we should be going in treating Parkinson's Disease and I think there's a perception that actually it is the way forward and it's certainly the way forward we'll have to go if we want to take stem cells into the clinic.
PORTER
From what we know already who do you think might benefit most or who's likely to benefit most from this sort of therapy?
BARKER
I think the data to date would say that the people who have done best with this type of treatment are the younger patients, say patients under the age of 55 or 60, patients who aren't in the very advanced stages of disease, where other complications are starting to arise as a consequence of their disease. If one sort of targets that group of patients I suspect one will get a much more consistent response and show a greater benefit.
PORTER
If you get a good result how good a result can that be - can people come off medication?
BARKER
There are patients who are now 10-15 years post-transplantation who have done extremely well with the transplants, they sill require small amounts of medication but generally speaking 25 years into their illness they're on a very small dose of tablets and have a very good quality of life. So when it works well it works very well.
PORTER
Roger Barker speaking to me earlier from our studio in Cambridge.
Dr Sarah Salvage, there's been a fair bit in the press recently about stem cell transplants and these are the magical embryonic cells that theoretically can be encouraged to develop into any sort of tissue, including in nerve cells. What might they add to this field?
SALVAGE
This is a very exciting area at the moment and it's something I'm always asked about when I go round to branches of the Parkinson's Disease Society and talk about our research. The use of stem cells in Parkinson's Disease is really similar to dopamine replacement therapy but in the case of stem cells we're putting cells into the brain which will actually release dopamine in the area that we want. And this sounds like an ideal situation and ultimately I think it will be. But at the moment we really still need to be sure that we can control how those cells are working in the brain. Firstly we need to make sure that they can stay alive within the brain tissue and secondly, we need to be able to control the connections that they're making - the brain's a little bit like a computer and if you start making the wrong connections you start actually creating more problems.
PORTER
Yes, you can't just drop another chip in can you and expect it to work properly.
SALVAGE
No, no.
PORTER
What other developments are there in the pipeline?
SALVAGE
As far as the treatment of the symptoms of Parkinson's Disease are concerned mainly it's improving the way levodopa and dopamine agonists are used and also trying to treat some of the non-motor symptoms - the symptoms that aren't involved in movement.
PORTER
So this is optimising existing drugs and tailoring therapy to the individual but nothing new on the horizon in that way?
SALVAGE
The most exciting area of course is to try and reduce the progression of disease, slow the disease itself down with what we describe as neuroprotective agents, these are drugs which stop the nerves in the brain from dying.
PORTER
Because we heard earlier that you might have lost 50% or even 80% of the cells in the affected area, so coming up with an agent that protects those and keeps them there could keep you well for years?
SALVAGE
It could keep you well for years. The brain is a fantastic organ, even losing 50 or 80% of the neurones in one area it's able to compensate and still function fairly normally.
PORTER
I feel a but coming on.
SALVAGE
Yes the problem is that there's more than one process involved in these cells dying - lots of things are going on with respect to the death of the cells and if you stop one process pretty much another process takes over and the cells carry on dying. So what we're really looking for now are a number of different treatment regimes which will prevent more than one of the processes of cell death from occurring. And by doing that I think we have a greater chance of finding a drug which actually slows down the progression of the disease and that's really where we are at the moment.
PORTER
Dr Sarah Salvage, I am afraid we must leave it there. Thank you very much.
Just time to tell you about next week's programme when I'll be looking at recent developments in the field of contraception. From the latest period free methods for women to that elusive holy grail of family planning, the male Pill. Are we ever going to see it? Do men want it? And will women ever trust them to take it?
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