GENERAL MEDICAL COUNCIL
FITNESS TO PRACTISE PANEL (MISCONDUCT)
Monday 2 October 2007
Regents Place, 350 Euston Road, London NW1 3JN
Chairman: Dr Surendra Kumar, MB BS FRCGP
Panel Members: Mrs Sylvia Dean
Ms Wendy Golding
Dr Parimala Moodley
Dr Stephen Webster
Legal Assessor: Mr Nigel Seed QC
WAKEFIELD, Dr Andrew Jeremy
WALKER-SMITH, Professor John Angus
MURCH, Professor Simon Harry
(Transcript of the shorthand notes of T. A. Reed & Co.
Tel No: 01992 465900)
A P P E A R A N C E S
MS SALLY SMITH QC and MR CHRIS MELLOR and MR OWAIN THOMAS of counsel, instructed by Messrs Field Fisher Waterhouse, solicitors, appeared on behalf of the General Medical Council.
MR KIERAN COONAN QC and MR NEIL SHELDON of counsel, instructed by Messrs RadcliffesLeBrasseur, Solicitors, appeared on behalf of Dr Wakefield, who was present.
MR STEPHEN MILLER QC and MS ANDREA LINDSAY-STRUGO of counsel, instructed by Messrs Eastwoods, Solicitors, appeared on behalf of Professor Walker-Smith, who was present.
MR ADRIAN HOPKINS QC and MR RICHARD PARTRIDGE of counsel, instructed by Messrs Berrymans, Solicitors, appeared on behalf of Professor Murch, who was present.
I N D E X
PROFESSOR SIR MICHAEL RUTTER
Cross-examined by MR HOPKINS 1
Cross-examined by MR MILLER 51
THE CHAIRMAN: Good morning to you all. Can I first of all apologise for starting a few minutes late. One of the panellists is not well and in fact now has an appointment to see a doctor for later on this afternoon. I wonder if you would plan today to try to finish around 3.45 so that she can get to the doctor on time. I say that at the beginning so you can plan accordingly how you are going to conduct the business.
Mr Coonan, what is the situation?
MR COONAN: Sir, despite the best efforts, valiant efforts indeed, by the shorthand writing team the email system for the first time in this case failed everybody. None of the respective legal teams (that includes also Dr Wakefield) received their emails of the transcript until about five to nine this morning, even though it was sent off at about 7.20 UK time last night. However, we have been able to talk to Dr Wakefield on the telephone. He will be receiving his transcript this morning US time, and what we have arranged is that I will speak to him finally at about 1 o'clock, which will be (if I get my timing right) about 7.00 a.m. US time and the position will be finalised at that stage, so if you could bear with me until I take final instructions, but in the meantime Mr Hopkins is content to start.
THE CHAIRMAN: Thank you for giving that information. Mr Hopkins?
PROFESSOR SIR MICHAEL RUTTER,
Cross-examined by MR HOPKNS
MR HOPKINS: Good morning Professor Rutter.
A Good morning.
Q As you know, I ask questions on behalf of Professor Murch.
Q Can I just give you a headline overview of the topics for us ---
MS SMITH: I wonder if I could ask Mr Hopkins to get much closer to his microphone. Because he is furthest away from us it is hard to hear him.
MR HOPKINS: I apologise for that, and please feel free to jump to your feet!
(To the witness) I was saying, professor, that there are various headline topics for us to consider during the course of this morning, and just to tell you what they are: I want to start by looking at the 172-96 project, and the division of responsibility envisaged between the different specialities, to move on to the appropriateness of the investigations within that protocol, then to move on to ‘The Lancet 12’ and the role we can glean that Dr Harvey played in it and the implications of his role; moving on from that to the topic of mitochondrial cytopathy and the implications of that for investigations; Professor Gillberg and his protocol of investigations and then bowel pathology and autism, so those are the broad headlines although there will be some detail in-between.
A Thank you, that is very helpful.
Q Let us start with the 172-96 project, and I think it would be helpful if you took out bundle FTP1 at page 200.
THE CHAIRMAN: Mr Hopkins, I think some of the Panel members are also having difficulty hearing you. Would it be possible that something could be put under the microphone to raise it up and bring the microphone a little closer to you. (Same done) Thank you very much.
MR HOPKINS: (To the witness) Looking at page 200, we see, do we not, that this project envisaged a role for four departments at the Royal Free, the Paediatric Gastroenterology Department where Professor Walker-Smith and Dr Murch (as he then was) worked, the Academic Department where Dr Wakefield worked and then the collaborating department, the Department of Neurology where Dr Harvey worked and the Department of Child Health and Child Psychiatry where Dr Berelowitz worked.
A Yes, indeed.
Q We see under Section 1 identification of the responsible consultants, Professor Walker-Smith, Dr Murch and Dr Wakefield. I think you would accept that the meaning of “responsible consultant” is not defined within this document?
A No, it is not.
Q Would it also be right to say that from the documentation that you have seen there was no guidance issued or circulated with this proforma document from Dr Pegg’s committee as to what it meant?
A I think that is right, so one would have to rely on what was the usual interpretation of the phrase, which is all that I have been able to do.
Q Is it a phrase that you had come across before?
A Oh yes.
Q Would it be right to say that “responsible consultant” would be taken to mean that in some way that consultant was going to play a part in the project that the document was about?
A Yes. It would ordinarily mean, listed like this, one would assume that all three were, but as you quite rightly point out it does not specify in what way.
Q The degree of their participation may or may not be defined within the contents of the form itself?
A Yes, indeed.
Q Can we look at what the concept of “responsible consultant” does not mean? It does not mean that an individual named as responsible consultant is responsible for matters outside his control?
A No, it cannot.
Q Or outside his expertise?
A I agree.
Q In other words, it is not a guarantee for the conduct of others who have their own expertise to bring to bear.
A No, I agree.
Q It also does not mean that each of these individuals would be expected to be present at, let us say, the screening assessment for each individual patient?
A No, I think my assumption – but it is an assumption – is that they would share joint responsibility in what was done but that does not necessarily mean that they are physically present, no.
Q And similarly, in deciding what investigations are to be performed for each patient it does not mean that each of them sits down and considers that?
A No, I agree.
Q And similarly, I think it follows, it does not mean that each is present at the investigation itself?
A No, I agree.
Q So we have to build into this, do we not, the very practical day-to-day reality of the way a department or a team would work, there would be a sharing and division of responsibilities from day-to-day?
Q Similarly, we have to build into that the notion of any inter-play between different departments, so in other words the Neurology Department and the expertise they bring to bear in this?
Q Can we see what this document tells us further about the division of responsibility in terms of expertise, and starting with the Department of Child Health, if we move on to page 202, we see set out there a description of disintegrative disorder and the development, there is even a reference to yourself in that list. This area of the project and the definition of “disintegrative disorder” one would take, would one not, to fall within the realm of Dr Berelowitz?
A Yes, although, as I have commented earlier, he has made clear that he is not specifically trained in certainly the instruments that are used in the assessment, but, yes, broadly speaking that is in his area.
Q If we move on to page 214 we see set out a quarter of the way down a reference to the Department of Child Psychiatry, Dr Berelowitz himself, and then about five or six lines below that “Responsibilities:”
“Confirmation and characterisation of features of disintegrative disorder.”
Q So that is setting out the stall, that is what his role was meant to be.
Q If we move on to page 221, we see at the bottom four lines again a reference to the neuropsychiatric studies, with his name alongside that, and again there is mention of “confirmation and characterisation of disintegrative disorder features of …” and then listing what they are?
A Yes, but as we have noted, he is not actually trained in the use of, certainly not the ADI and as far as I know not the CAPA.
Q I understand, and, indeed, that is the evidence he has given, but, nevertheless, when it comes to the labelling of these children in terms of the psychosis that they may have, his role is clearly paramount in that, is it not?
Q Can we look at what this document says next about the Department of Neurology, and if we turn back to page 214, this time halfway down the page at 1.4, a mention of Dr Harvey under the Department of Neurology, described as “Consultant Neurologist & coordinating investigator)” and then a few lines down, “Responsibilities”:
“Full neurological assessment and investigation.”
If we then move on to page 222 we see a further description of that, this time at the top of the page:
“Neurological and neuroradiological studies (Dr P Harvey).
Full clinical examination: MRI, lumbar puncture and CSF antibody profile (measles: rubella), cytokine measurement, EEG with visual, somatosensory and brain stem auditory evoked potentials.”
Just looking at what is recorded in this document, would you agree that it was expected that the Department of Neurology, and Dr Harvey in particular, would be advising on the neurological issues and the investigations to be carried out in respect of these children?
A Yes, the problem though is that on page 214 it talks about a full neurological assessment, which we know from the notes was not undertaken, and that the investigations were decided before Dr Harvey saw the case in almost all instances, so that, yes, you are quite right, I agree, that is the implication of the way that it is put here. It is not actually the way that it happened.
Q I will come on to the evidence that we have about how things happened on the ground for ‘The Lancet 12’ and deal with that, and also deal with the order of the investigation. At the moment I just want to deal with what this document is telling us about this project.
Q I think you appreciate there may well be a world of difference between the project as envisaged and ‘The Lancet 12’ and what in fact was happening before ‘The Lancet 12’?
Q Just looking at this document, I think you accept that the neurological investigations that have been listed on page 222 were expressed to be within the remit and expertise of Dr Harvey and his department?
A Yes, I agree.
Q If we then look to see what the paediatric gastroenterology department set out to do by way of responsibility in this document, can we look please at page 213. We see at the top of the page “Investigators, 1.1, Department of Paediatric Gastroenterology”. It mentions Professor Walker-Smith, Dr Murch, Dr Phillips and Dr Casson. Then we see, five or six lines below that, “Responsibilities”.
“Referral and co-ordination of patient admission for investigation.
Clinical evaluation, procurement of blood, urine and serum samples.
Colonoscopy, and tissue procurement/processing.”
Q Just dealing with the point you made a moment ago, in terms of the evidence of what we have for ‘The Lancet 12’, what was happening on the ground, these functions were being fulfilled as a matter of fact for ‘The Lancet 12’ patients. Is that right?
Q Let us just stand back for a moment and see what it is about this 172-96 project and the investigations that were being identified within it. What was being proposed in this project was that if a child was thought to have disintegrative disorder, then there would be a full clinical work-up that would include the whole list of neurological investigations. Do you agree?
Q And I think you agree that if a child had been appropriately screened for disintegrative disorder, then one would need a thorough investigation to see if they had a progressive neurological disorder and in those circumstances it would be reasonable to carry out, for example, a lumbar puncture?
Q An MRI scan?
Q And EEG, with all the frills that went with it?
A Yes, indeed.
Q I think it follows from that that you accept that this document and the proposals that were within it were all entirely reasonable providing the children had disintegrative disorder?
Q In other words, the investigations envisaged within it would have been clinically justified?
A Yes, provided there had been a proper assessment, as we have discussed.
Q And your view is, if the children were not thought to have disintegrative disorder but were thought to be on the autistic spectrum, then you needed to assess each case individually to see what neurological investigations were required?
A Yes. But even if they had a disintegrative disorder you would still want to do it on an individual basis.
Q Of course.
A It would be reasonable that there would be a general protocol that one would anticipate following; I have no criticism of that. But nevertheless, patients vary and one would want that done if it was part of a clinical study, ordinary clinical care, to look at that on each case.
Q I understand that, and I think what you are saying is, it is perfectly proper to have a protocol. It is almost like a check list?
Q Providing you apply your mind to it when you see each child?
A Yes, indeed.
Q Can I just move on to a separate point. That is to do with disintegrative disorder. I think you accept that disintegrative disorder may arise in children before they are three years old?
A Yes. It does not usually. One should not get too tied up, as it were, with what the official classifications say, but I agree it can occur earlier than that. It does not usually, but it can do.
Q I would like to just have a look at the Hill and Rosenbloom paper with you again, so you need to go to FTP6 this time. For the moment you can put FTP1 away. Would you turn, please, to page 379. This is the Hill and Rosenbloom paper that Ms Smith asked you about – I think it may have been on Thursday of last week. If we turn to page 380 we see, do we not, at the top of that page a table entitled “Characteristics at presentation”. This table reviews each of the nine children the paper is talking about?
Q And their characteristics?
A Yes, indeed.
Q In the left hand column just gives the case number, the next column the sex of the child and then the third column – and it is that column I am interested in – “Age at onset”. Then it sets out what the age of each child was. Then the column beyond that, the duration of the regression. So the age of onset is the start of the regression – is that right?
A I presume so, yes.
Q If we look at the information we have there, we see that there is one child – Child 8, where the age of onset was at 1.2 years?
Q We see that for Child 7 the age of onset was 2 years?
Q There were then four children where the age of onset was at 2.5 years and the remaining three were either at 3 or 3.5 years?
Q So I think it follows, certainly from what is being written in that paper and, indeed, what you have told us, one should not get – as you put it – too hung up about the age?
Q Because disintegrative disorder can start below the age of 3 – indeed, below the age of 2?
A Yes. The paper, of course, does comment that case 8 is different in a whole variety of ways and in terms of my reading the paper, I agree with that. But having said that, it remains that there are a number of cases below the age of three that seem to fit into the overall pattern.
Q Indeed. I think the point you are making is, it is not really the label you attach; it is the clinical condition that you need to consider and to investigate?
Q If, regardless of the age of onset of any regressive signs or symptoms, one suspects a child has disintegrative disorder, then I think you accept that the diagnostic work-up recommended by Professor Gillberg, including MRI, EEG and lumbar puncture, is appropriate, or an appropriate way of dealing with it?
A Yes. But with the caveat that he himself presents; that is to say, it needs to be preceded by a full assessment of the kind that he outlines there, looking at family history, congenital anomalies and so on. But yes, I would agree that if there is a disintegrative disorder in the way the term is usually used, that would be an appropriate way of proceeding.
Q I will come back to the order in which things are done a little later on in our questioning, but I note what you say about that.
Q I think you also agree that it is reasonable, if not important, to repeat medical investigations, even if they were previously negative, if a child’s condition does not improve?
A Yes. One would not necessarily do it just because of not improving, but I certainly accept that in all circumstances one needs to re-think if there are reasons for believing that the earlier investigations might not have been as valid, for one reason or another, than thought at the time.
Q We have seen an example of that in the case of Child 2.
Q Where Dr Surtees, at Great Ormond Street, thought the child had autism, but there were three regressive episodes.
Q Had already had a load of investigations but he decided to recommend a repeat of them?
Q Can I just take you to what you have said, please, in a chapter that you wrote, that we have looked at. It is still in volume FTP6. Would you please look at page 460a to see the start of it. I do not know whether it is behind tab 40 or 41. It is headed “Chapter 33, Autism and Pervasive Developmental Disorders”. I think this was one where the dividers went a little awry.
THE CHAIRMAN: It is tab 41.
MR HOPKINS: Thank you. This is a document that Ms Smith took you too again last week. Page 460a is the start of the chapter?
Q Which you co-wrote with Catherine Lord?
Q Can we go to page 460m, please. If we look at the right-hand column, one third of the way down, we see the title “Disintegrative Disorder”. Then you have a description in the next paragraph about what it is. It is the last four or five lines of that paragraph that I am interested in. You say:
“Even in cases where progressive neurological disorder is eventually identified, initial medical tests are often negative and sometimes diagnoses of hysterical reactions are considered. Thus, it is important to repeat medical investigations if a child’s condition does not improve.”
Presumably you stand by that statement?
Q Thank you. Something that you told us in answer to Ms Smith’s questions dealing with infantile autism, or common autism – whichever word you want to use.
Q You said that regression, which may occur in some cases in infantile autism, is temporary?
A Yes. Usually.
Q Can I ask you then over what timescale you would expect such regression, if it does occur in infantile autism, to recover?
A It is very variable. Over a matter of months as a rule.
Q So that would mean that if there is a regressive episode, let us say with a loss of word and interaction with the environment, you would expect recovery of those lost skills, usually within a matter of months. Is that right?
A The beginning of a recovery, not necessarily complete.
Q Would it be fair to say that one of the features in the cases that we are dealing with in ‘The Lancet 12’, that there was not generally that pattern of recovery of the lost skills?
A Several of them did not have lost skills at all, as far as one could tell, so that the assumption that we are talking about the length of recovery really is not relevant. But more importantly than that, what one sees with the transient regressions with autism is that that concerns predominantly language and language-related skills, whereas in disintegrative disorder there is a much more widespread loss of skills, going well beyond language and language related function. So it is not just a question of duration; it is a question of the overall pattern.
Q I understand that, and I think you are dealing with the severity of the range of symptoms one may have?
A It is not just severity. It is a question of pervasiveness.
Q I understand. I want to deal, though, with the point about infantile autism. Let us just make the assumption that there is a history given, as indeed there is in some of ‘The Lancet 12’ cases, of a loss of language skills?
Q If they have not recovered within a matter of months, that raises some degree of index of suspicion, does it not?
A Some, but not a lot. As I say, it is very variable and the overall pattern would be what you would want to pay most attention to. So certainly there would be an alerting if there was a progressive decline because that would raise the issue of whether there is a progressive neurological disorder that underlies the regression. The mere lack of recovery would not ordinarily lead to this degree of investigation. We are talking about a very common phenomenon, so that all the literature is in agreement in showing that roughly a third of individuals with what you have described as “ordinary autism” do show this pattern of regression. One certainly would not want to be doing invasive investigations in children who had lost language and had not shown the other features of disintegrative disorder.
Q I will come on to that because, as you have already told the Panel, there is a difference of opinion, certainly between you and Professor Gillberg about whether one does the full work-up, even for children on the autistic spectrum generally.
Q All right – we will come to that.
Q And I will give you an opportunity to deal with any differences you may have with him and with me over this.
Q But I just want to stick to this point about ordinary autism. If I understand what you are saying, you are saying that if a child does suffer from ordinary autism, a number of that cohort with have a history of regression, of loss particularly of language skills?
Q And of that number, you would expect there to be recovery in those skills to commence within a matter of a few months?
A Usually, yes.
Q And if one does not get that history it is a factor, is it not, to take into account as to whether something else may be going on?
A Yes, it is a factor to take into account. I would emphasise that clinical decisions of this kind are made not on an item, but on an overall picture.
Q I would not disagree with that but it is a factor that would be pointing more towards, “Is there a need for further investigations of the type we are concerned with”?
A It would be one element to consider.
Q Can I then turn to the issue now of whether the neurological investigations, particularly of MRI, EEG and LP – those three – were appropriate for ‘The Lancet 12’. I wanted to deal with this in a general way because they are general points I want to explore with you.
A All right.
Q Just to understand your general points about this, I think you are making the point that paediatric gastroenterologists, whilst they may have some background training or experience of developmental disorders, lacked the expertise to determine whether or not these investigations were appropriate for children thought to suffer form autism?
A More specifically I was questioning whether they had the expertise of being able to differentiate between the ordinary regressions that are very common indeed in autism, and the meaning of disintegrative disorder as a condition that raises, as you quite rightly point out, the need for much more intensive investigations.
Q In other words, were they in a position on their own to decide whether these, more intensive, investigations were justified?
Q The second points I think you make is that it is inappropriate to carry out these investigations routinely on ordinary autism cases?
Q Unless one can find a specific clinical reason to do so?
Q And you give Child 2 as an example of there being specific reasons to do so?
A Yes, indeed.
Q So that is your position?
A It is.
Q Let us just look at the question of lumbar punctures.
Q There is something that you said in your report. It may be helpful if you turn up your report, please, at page 38. Would you go to line 3, I think you said this:
“If the issue were simply one as to whether lumbar puncture should be routinely undertaken for children with an autistic spectrum disorder, I would consider that that was an undesirable practice but, on its own, I would not regard it as necessarily unacceptable.”
A That is correct.
Q Why would you not regard it as necessary unacceptable?
MS SMITH: (Inaudible)
MR HOPKINS: I am giving him an opportunity to deal with that point and, indeed, Professor, before you answer it please read to yourself the rest of that passage if you need to refresh what you have said.
MS SMITH: I would like the Panel to have the rest of the passage read.
MR HOPKINS: If I am taking an unfair point I will be corrected either by Professor Rutter or Ms Smith can come back in re-examination.
A Okay. Let me deal with this in two bits then. What I said then, which I would hold by, is that because clinical opinions necessarily are judgmental there is variation in what people do, so that although I think the evidence is really pretty clear-cut that it is not a desirable practice – and I can say more about that if you wish – nevertheless I would not regard that as in itself unacceptable. I think it is undesirable. I think it is poor judgment but on the other hand there are differences of opinion and, therefore, I think you have to accept the reality of those. The problem here is that, as I go on to say, what makes it unacceptable here is that it was planned by gastroenterologists rather than by either neurologists or psychiatrists. What I perhaps should have said is that it is actually not the discipline so much that in one of the days – I have forgotten which one now – I was asked about developmental paediatricians and I agreed that they might well be appropriate. So it is a question of an understanding of what the issues are, rather than the discipline as such.
Q I understand. Indeed, I was going to take you on to your concern. As I understood your concern, it was that the lumbar puncture had been planned by gastroenterologists rather than by neurologists, for example.
A Well, my concern was rather broader than that. My concerns are that in the majority of cases it was not planned in a considered way; it was simply a protocol that was being followed and it was that which led me to, amongst other things, consider that this really was a research study and not a clinical study.
Q I want to explore with you the role of the protocol and the input into it, because I think that is relevant to the opinion which you were expressing. Let me just go back to the observation which you have made about lumbar puncture on its own not being acceptable, because I think you have just told us that you accept there may be a range of opinion about that.
Q I want to ask you a little more about that. Clearly, from your standpoint you would not recommend a lumbar puncture in classic autism cases, but are you acknowledging that there are practitioners who would recommend one?
A As far as I know, there were none in 1996 and there are none now in the UK. I am aware that there are clinics in other countries where this is done – Gillberg you gave as an example and I accept that is an example – but all I can say is that either in terms of what I know of the practice of individuals working in this field – and I will include developmental paediatricians, paediatric neurologists, psychiatrists – or in terms of their own papers, so that I am not relying just on the ones I happen to know, I am not aware of anybody in this country who would have advocated the use of lumbar puncture in the cases of autism.
Q It follows from what you have said – and we will explore the breadth of it – Professor Gillberg is not alone in the international community as being an expert in this field who advocates the use of lumbar puncture.
A No, he is not alone, but he is fairly isolated in that. It is true you can find, and doubtless you have found, that there are others who advocate that, but the point that I would come to is that, as I think would be required of any responsible clinician, you need to go by the evidence and not by the authority. The evidence from Gillberg or any of the other people who use this approach is absolutely consistent in its negativity. That is to say that the yield of lumbar puncture as reported – and I accept that there are not large, systematic serious reporting on findings – are negative, with the exception of progressive encephalopathy of particular kinds. So Gillberg’s own findings actually run counter to the advice that he gives.
Q I will explore with you the advice he gives in some detail; he gives it in more than one place, as I am sure you are aware.
Q And the extent to which we can glean that is followed or indeed independently carried out by other experts in this field as well and look at the rationale behind it. Let us bring ourselves back to ‘The Lancet 12’ and the issues that this Panel may have to wrestle with. I think you would accept that the role of Dr Harvey and what advice he was or was not giving in these cases is an important matter.
A It is an important matter, but it is an ancillary matter, in the sense that the usual convention within hospital practice is that the clinician who has overall charge of clinical care is responsible for the decision making. Of course, using the input of relevant colleagues, that is normal practice too, but the overall responsibility is usually taken by whoever’s care they came under.
Q I am not going to dispute that with you, but one has to recognise within that observation, does one not, that where matters are particularly within the expertise of another department and you seek their advice, unless you think there is something manifestly wrong with it, it would be quite reasonable to follow that advice?
Q I think you have tacitly accepted that position when you came to review the cases of Child 1 and Child 5, because we know from those, as has been explored with you already – I will not go over the detail – Dr Harvey did see both these children prior to lumbar punctures being carried out on them and, as I understand your evidence, you do not therefore criticise the paediatric gastroenterology department in allowing those investigations to be carried out.
A No, that is correct.
Q Indeed, when you were asked questions about this by Ms Smith, if I understand the essence of what you were saying, she said this to you:
“As I understand what you are saying, you are saying that given that the neurologist saw him, you do not criticise the investigations undertaken, but you cannot personally quite understand why Dr Harvey thought it was appropriate. Is that fair?”
And you replied, “Exactly.”
Q I want to therefore look at the rationale for the view or the opinion you have expressed in the cases of Child 1 and Child 5. It is clear on the evidence available that advice was being obtained from a neurologist who, as you have already accepted, would have the appropriate expertise to advise on the neurological investigations such as lumbar puncture or MRI or EEG.
A Well, yes, except that Dr Harvey’s experience is not primarily in this area. He is an adult neurologist, as I understand, and the sort of assessment done is not of a kind that one would ordinarily see as acceptable. So the reason I took the view was that I do not think it was good practice, I do not think it was a good assessment, it certainly was not thorough, but given the reality of differences of opinion, it seemed to me one had to accept that, even though it seemed to me not competently done.
Q I understand you have reservations about how Dr Harvey was performing his task, but I think the essence of it is that you would not criticise those for following the advice that he gave, having performed that task.
A No, that is correct.
Q Can I just see the logical implication of that, taking it one stage further. If Dr Harvey had in fact advised on a protocol of investigations for children considered to be suffering from autism in general, again, one would not criticise the gastroenterology department for relying on that advice, would one?
A But that is purely hypothetical, because as far as I know that point has never arisen.
Q It is a question of fact for the Panel as to what advice was or was not given and there may be further evidence on that. I am putting to you a proposition.
A Can I just make clear, you are putting a hypothetical proposition? As far as I know, on any of the papers that I have seen, the input was in relation to disintegrative disorder; it was not in relation to autism.
Q I understand the point you are making, but let us just deal with the question I asked. If he had advised that this battery of investigations for children considered to be on the autistic spectrum were appropriate, you would not criticise the gastroenterologists for following that?
A I would not criticise the gastroenterologists, no.
Q Can we consider, please, what information there is in The Lancet about the neurological investigations? For that, we will need to go to FTP2. Professor, the article starts at page 783, but if we turn to page 787, we see in the left-hand column, towards the bottom, there is a section entitled “Contributors”.
Q We see there is a reference to Dr Wakefield being the senior scientific investigator, Dr Murch and Dr Thomson doing the colonoscopies and, if we go a few lines below that, Dr Berelowitz did the psychiatric assessment and then this about Dr Harvey, “Dr Harvey did the neurological assessment.” Just dealing with what this at face value is saying, that would mean, would it not, that whatever neurological assessments were being carried out on the children reported in this paper were carried out by him?
A One might think so, although we know from the record that that actually was not the case.
Q Only from the records which we have.
Q If we look at what is written in a later Lancet publication – for this we need to go to FTP3, page 1212 – you will see at the bottom of this page that this was The Lancet in 2004 and the right-hand column contains a statement by Dr Murch. I just want to pick up what is being said and then ask for your comments on it. If we go to the last three lines:
“The consultant paediatricians responsible for the children’s care decided on the investigations, although advice was taken from colleagues at other centres. We determined that these investigations were required clinically, not only to characterise gut inflammation but also to exclude primary neurological diseases. We had in particular taken advice for the neurological investigations, since some of the referrals appeared to have suffered an encephalitic illness, and specifically the inclusion of lumbar puncture was suggested to us as important for assay of cerebrospinal fluid lactate, to exclude mitochondrial cytopathies that can cause both neurological regression and bowel disease. Several of these cases had not been investigated to exclude a primary cause of their regression and we thought it important to ensure that we were not missing underlying metabolic or genetic abnormality.”
Then it goes on to deal with proposed investigations. If what is recorded there is what in fact happened on the ground for these ‘Lancet 12’, you would not criticise the paediatric gastroenterologists, would you, for following any such advice they received either from a neurologist or from the paediatrician with expertise in mitochondrial cytopathies?
Q Can we then consider the potential relevance of metabolic disease or mitochondrial cytopathy? Just dealing with metabolic disease in general, if one has a history of regression in a child, whether they are autistic or not, it may be that that regression is due to a degenerative process such as a metabolic disease.
Q Or mitochondrial cytopathy.
Q Just so we understand what a mitochondrial cytopathy is, I am going to use layman’s terms, so please bear with me, Professor. The mitochondria, is it right that they are energy producing structures found in every cell?
Q Effectively, using a term which I would understand, the body’s power plants in the cell.
A Sort of, yes. They are in the cytoplasm, not in the nucleus.
Q If the mitochondria malfunction, it is then that you have what is called a mitochondrial cytopathy.
Q There can be different types of mitochondrial cytopathy which can affect different parts of the body. Is that right?
Q Often the mitochondrial cytopathies affect parts of the body which use the most energy. Is that right? You are nodding your head.
A Sorry. Yes. The disorders which have been shown to be associated with mitochondrial disease are neurological disorders for the most part, although they involve other bodily tissues as well.
Q It can affect the brain.
A Yes, indeed.
Q It can affect other organs.
Q And has been associated with gastrointestinal disorders.
A That is possibly the case, but I am not familiar with that.
Q Or indeed with developmental delays.
Q The symptoms of mitochondrial cytopathy can vary considerably from relatively minor to quite severe.
Q Can we consider, please, some literature on this? For that, you are going to need a new bundle, which I am going to call Professor Murch’s literature bundle. (Same distributed and marked as D5) Could you go, please, to divider 10 in that bundle, page 58, Professor? This is a paper by Michael Chez and others entitled “Elevation of Tumor Necrosis Factor-Alpha in Cerebrospinal Fluid of Autistic Children”. If we look at the next page just to see where this appeared, at the bottom of the page we see that Paediatric Neurology was the publication and I think we get the date on the very first page; we see “© 2007”. So it is fairly recent.
Q Just dealing with the authors, on page 58, the bottom left-hand column in small print, we can see that they are based in the USA at the Department of Neurology, Rosalind Franklin University, the Chicago Medical School and the Sutter Neuroscience Institute in Sacramento and the Department of Educational Psychology at Illinois State University. Is that right?
Q If we just look at the abstract to see what this paper is about. I will read it out, if you will bear with me:
“Recent reports implicated elevated cytokines in the central nervous system in a small number of patients studied with autism have reported clinical regression. These studies have not focused on tumor necrosis factor-alpha as a possible marker for inflammatory damage. A series of 10 children with autism had clinical evaluation of their serum and spinal fluid for inflammatory changes and possible metabolic disease as part of their neurological evaluation. Elevation of cerebrospinal fluid levels of tumor necrosis factor-alpha was significantly higher … than concurrent serum levels … in all of the patients studied.”
Then if we just drop down a few lines:
“This observation may offer a unique insight into central nervous system inflammatory mechanisms that may contribute to the onset of autism and may serve as a potential clinical marker.”
Then it recommends more controlled study. If we just turn the page – we are in the section which is still part of the introduction – the middle paragraph on the left-hand side:
“With concern for a possible immune process, along with the need to exclude other possible degenerative conditions, for the present study the parent of children meeting criteria of having a history of clinical loss of developmental skills in language as part of their autistic condition after 15 months of age were offered the option of electively having a lumbar puncture performed while the child underwent sedation for a neuroimaging procedure, such as cranial magnetic resonance imaging, as part of their diagnostic work-up. To see if there is a difference in this particular marker of inflammation in patients with regressive autism, levels of the cytokine TNF-α were obtained simultaneously in the serum and cerebrospinal fluid.”
So it is clear from that passage, is it not, that the lumbar puncture was being offered electively to investigate a possible immune process and to exclude other possible degenerative conditions?
Q If we look under “Patients and Methods” just to see what was happening there, in the left-hand column:
“Ten male pediatric patients meeting [the criteria] for autism with a history of regression in language and eye contact between 15 and 24 months of age were given the option of having a lumbar puncture performed under a general anaesthetic while undergoing such sedation for neuroimaging studies such as a diagnostic scheduled magnetic resonance imaging study of their brain. All families gave written and verbal consent for the procedures.”
If we go to the right-hand column, the second paragraph down:
“The current procedure was elective and was done to exclude a degenerative process. The patients had routine clinical cerebrospinal fluid studies performed including cell count for red and white blood cells, total protein and glucose levels.”
The reason the lumbar puncture was being performed, the stated reason why it was performed in these cases, was to exclude a degenerative condition and possibly an immune process at work.
A Yes, but I think there are several comments I need to make. First of all, this is a paper in 2007, so that this had not been put forward at the time of the Royal Free study. Secondly, this was done with no control group, so one has no idea whether these findings are meaningful or not. I would place very little scientific credence on it. It was done by a group which as far as I know have not a particularly strong scientific record. So yes, it is a paper, unreplicated, some nine years – no, 11 years – after the Royal Free investigation. So yes, I note that it is there. I am unimpressed, I have to say, by the paper.
Q One of your reasons for being unimpressed is because there is no control there.
Q So what you are saying is you cannot necessarily rely on the conclusions they reach. It is not the reason I am bring this paper to your attention. What I am suggesting to you is that if there is concern that there may be a degenerative condition possibly involved in the immune process, that the use of lumbar puncture investigation sampling with the CSF is a very valid investigation to carry out.
A No, I disagree. Again, I would come to the point I have made repeatedly: I need to have evidence that it works and we talked on one of the days of the yield of investigations and the evidence of the yield of the CSF investigations is notoriously low when considered in relation to these sort of circumstances. I accept, of course, as I have to, that it was done by this group. I do not accept that it was good clinical practise.
Q It is a similar way of investigating to what was happening to the ‘The Lancet 12’ is it not?
Q Let us have a look at another paper, the next divider in the bundle, the Debray paper, the title of it is “Long-term Outcome and Clinical Spectrum of 73 Pediatric Patients With Mitochondrial Diseases.” We see at the bottom of page 64, that it was published in the journal entitled “Pediatrics” published in April 2007, this year. Looking at the authors, going back to page 63, just under the title, we see that they are based at Montreal University, the McGill University, Montreal and Toronto University: those would be respected institutions, would they not?
Q I will read a few passages from the abstract so we get our bearings again for this paper:
“OBJECTIVES: We sought to determine the clinical spectrum, survival, and long-term functional outcome of a cohort of pediatric patients with mitochondrial diseases and identify prognostic factors.
METHODS: Medical charts were reviewed for 72 children diagnosed between 1985 and 2005 …”
Then under “RESULTS”:
“Patients fell into 7 phenotypic categories: neonatal-onset lactic acidosis (10%), Leigh syndrome (18%), non-specific encephalopathy (32%), mitochondrial (encephalo)myopathy (19%), intermittent neurologic (5%), visceral (11%) and Leber hereditary optic neuropathy (5%).”
It then deals with the age of onset and then says:
“Neurologic symptoms were the most common (90%). Visceral involvement was observed in 29% of the patients.”
If we go to page 64, at the top of the left-hand column:
“Mitochondrial diseases represent a vast group of inherited disorders of energy metabolism that encompass a wide range of symptoms and presentations, severity, and outcome. Together, they form one of the most prevalent groups of inherited metabolic diseases”.
Do you agree with that account given there?
Q If we then go to the right-hand column on this page, under the section “Clinical Data and Phenotypic Classification” and if one goes down seven or eight lines we see there is a reference to “visceral involvement (cardiomyopathy, liver disease, renal dysfunction, etc.)”. We then see:
“Neurologic crises were defined as acute or subacute neurologic deterioration with loss of previously acquired skills and appearance of new neurological symptoms and included episodes of Leigh disease and stroke-like episodes.”
It then says:
“Available biochemical data (blood gases, lactate, and pyruvate concentrations in blood and CSF and plasma amino acids) were averaged for each patient.”
I think it follows from that, that certain for some of these patients if not all, they had undergone CSF sampling, presumably by lumbar puncture, would that be fair?
A I presume so, yes.
Q If we go on to page 67, and if we look in the left-hand column at the second paragraph down it says:
“Twenty-one patients (29%) had visceral involvement …”
And then it breaks that down further between the heart, the liver, the kidney and the gastrointestinal tract, and there were six patients, and they are constituting 8 per cent.
A few lines below that:
“In most of these patients 15 (… 21) [more than] one organ was involved.”
Then if you go a couple of lines below that:
“In 8 patients 911%, Table 1), visceral disease was the predominant clinical manifestation.”
If we go to the right-hand side of the page, under the section “Metabolic Status”, about eight or nine lines up from the bottom of that paragraph:
“The CSF lactate level was raised in 37 (88%) of 42 patients. Four patients with normal plasma lactate levels had increased CSF lactate levels. Conversely, 2 patients with intermittent elevations of plasma lactate levels were found to have normal CSF lactate levels.”
Just looking at the information there, would it be fair to draw this deduction from what they are saying, that blood tests did not reveal all cases of metabolic disease?
A Yes, that is probably correct.
Q Indeed, if we go to page 71, the right-hand column, the last three lines read:
“CSF lactate measurement is less variable and is essential in some patients having ‘cerebral’ lactic acidosis, as illustrated by the 4 patients with normal lactic acid in blood who had clearly increased CSF lactate levels.”
So it would appear from that, would it not, that they are advocating CSF sampling, in addition to blood level sampling because blood is not going to pick up all cases of mitochondrial disease?
A Yes, they are but what you have to remember is that they are dealing here with a group of individuals with complex multi-faceted disorders, most of which involve neurological impairment of a fairly obvious kind, so that generalising that to other samples is hazardous and I do not know whether you are going to take me to page 82 ---
Q Please go there if you wish to.
A --- so that this is the one example of a claim that autism is associated with a mitochondrial DNA mutation, but what is striking about this is, putting aside now the diagnosis of autism is pretty scantily described, but the CSF lactate was normal.
Q Yes, I am not suggesting that necessarily the investigation is going to throw up an abnormality but it may, and the point in taking you to this paper is that if one is concerned that a mitochondrial disorder is a possibility, what clearly these investigators of the clinical conditions were recommending was the sampling of CSF.
A But you are taking it out of context, with respect. They are dealing here with CSF in relation to a group of disorders such as we see here, where the situation is utterly different, so generalising it beyond that is actually not warranted.
Q Can I take you to what they say on page 70, and I will deal with the graph paper in due course. In the right-hand column, under the section “Discussion” it says this:
“Nearly any pediatric specialist may be confronted with the initial presentation of MD” – and that stands for mitochondrial disease – “to which the mnemonic ‘any age, any symptom, any organ’ has been applied. Patients of this study, identified in a community-based tertiary care pediatric center, illustrate the need for a high level of suspicion for [mitochondrial disease] in patients with unexplained organ dysfunction.”
You would not disagree with that proposition would you?
A No. If, with the emphasis on “unexplained organ dysfunction” so that the cases of mitochondrial disease are, as I was indicating earlier, varied, certainly – the point that you were making – but also mainly involve pretty overt neurological disorders; not as the only phenomenon but of the way they usually present. One has also got to say that mitochondrial disorders, although they have been known for some time, an ill-understood group of disorders still.
Q I would not disagree with that, and, indeed, that would go some way, I suggest, to supporting the need to investigate for that because it is a disorder that is not fully understood and not easily recognised.
A As long as it is in an appropriate group.
Q What I think this paper is demonstrating, do you not agree, is that mitochondrial disorders do not have a uniform presentation, that mnemonic that we just looked at makes that point very clearly, and you have accepted that, and what we do know from it is that there can be multi-organ involvement, for example involving the bowel and involving the brain.
A Yes, but one could equally say that any patient you see you ought to do an assessment for mitochondrial disease because it is so varied in how they present, but I do not suppose for a moment that is what they meant to suggest, and certainly is not what the mitochondrial experts in this country would recommend.
Q What I am putting to you is this: if the Royal Free paediatric gastroenterologists received advice that for children with a history of regression, they should be seeking to exclude mitochondrial disorder and the proper way of doing that was to do a lumbar puncture: that was advice they were reasonably entitled to rely on, is it not?
A Yes, we are switching to the gastroenterology expertise, and what I have said before, and I would say again, is that of course gastroenterologists, like anybody else, will need to be responsive to the advice they are given, so I am responding now though as to whether that advice is well-based because in my view, as applied to the sort of cases in The Lancet it is not well based.
Q I understand. I think therefore your criticism goes to the quality of the advice they received (if they received it) but you would not criticise them acting on that advice if they received it?
A No, that is correct.
MR HOPKINS: Sir, I note the time, and I am moving on to a separate topic which involves looking at different literature.
THE CHAIRMAN: Yes, I think it will be better that we take a mid-morning break at this point. It is 10.55 and we will resume at 11.15. Professor Rutter, you are still under oath and in the middle of giving your evidence, please do not discuss the case with anybody.
MR HOPKINS: Professor Rutter, before we depart from the Debray paper, can we go back to page 66 because we have been discussing what presentations there may be in cases of mitochondrial cytopathy, and we see there is a description in this paper of those they were dealing with, so page 66, left-hand column, halfway down, “Clinical Presentation”:
“The first manifestations of the disease were recorded at a median age of 7 months …”
Then it gives the range of 0-16 years.
“… and encompassed a wide range of symptoms including …”
Then it lists what some of them were:
“… non-specific psychomotor delay (38%), metabolic acidosis (14%), failure to thrive (10%), acute or subacute regression (9%), visceral involvement …”
And then a break down of viscera:
“… and various combinations of focal neurologic symptoms (22%) including seizures, ataxia …”
If we go to the right-hand column, second paragraph down:
“Over follow-up, 66 patients (90%) presented clinical signs of cerebral involvement. Developmental delay was common ..[79%] .. in all subgroups except LHON, but it was less frequent in myopatic category … than in other subgroups with the exclusion of LHON.”
MS SMITH: Could I ask Mr Hopkins to speak up, we are having difficulty here.
MR HOPKINS: I am so close to the witness, I do not want to shout at Professor Rutter.
THE CHAIRMAN: I think that is right.
MS SMITH: Mr Hopkins is at a very funny angle.
THE CHAIRMAN: Actually I think some of us on this side of the room are also finding it difficult.
MR HOPKINS: Would it help if I had two microphones, rather like the system Ms Smith has.
THE CHAIRMAN: That may be helpful. (Same done)
MR HOPKINS: (To the witness) I was going to ask what LHON meant, do you know?
A It is an eye disease, Leber’s … I do not know what it exactly stands for, it is optic atrophy.
Q There is nothing more on that paper I wish to ask you about. I now want to move to the separate topic about the advice that Professor Gillberg has given over the years, and if we can first of all consider him. He is now a professor I think, is that right?
A He is.
Q Of child and adolescent psychiatry.
Q He is based now in Sweden, at the Gothenburg University, Institute for Health of Women and Children, in the Department of Child & Adolescent Psychiatry.
A Yes, he has several jobs but that is one of them.
Q He has been regarded internationally as an expert in the field of autism for over 33 years, is that right?
A He has written widely. Let me just explain why I hesitate: to come back to the point I was making earlier, one needs to go by evidence rather than authority. He would certainly claim to be an authority. Let me give two examples, however, to illustrate why I have reservations about that. For example, in the 1960s he had several papers involved with urinary peptide abnormalities in relation to autism, and we did actually a collaborative study in which this was done blind, and the findings could not be replicated. He is even better known for his claim that at least a quarter of individuals with autism had the fragile X anomaly; it is now clear that the figure is way below that, most experts put it at about 2 per cent, so that – and I could give other examples – so that over the years he has an unenviably high reputation for findings that could not be replicated, hence my query of authority.
Q I understand that there may be differences of opinion that you have.
A Well, these are ---
Q Let me finish the question: differences of opinion that you have about the advice that he has given or the reports that he claims for his studies, and you have given two clear examples where you are effectively pointing out that he has been wrong and has over-pitched things, but I want to deal with his general status and reputation: in the mid 1990s he would have been regarded, would he not, as an expert and a competent expert in the field of autism?
A By some people, yes.
Q Indeed, he was invited, was he not, to give the Emmanuel Miller Memorial lecture in 1991 on autism and autistic-like conditions.
Q And that is a rather prestigious lecture to be invited to give, is it not?
A Yes, it is.
Q Indeed, you are been given the same accolade some years after that?
A Yes, and before.
Q Just dealing in general terms then because then I want to look at what he has advocated, and so you understand the point and where I am heading, it is not to test the validity of his views but to see what it is that has been advised and the extent to which his advice may have been followed on or acted on independently by other practitioners: do you understand the point?
A Yes, yes, I do.
Q I think just in general terms you accept that Professor Gillberg has been an advocate of the full diagnostic work-up of autistic children across the spectrum?
Q And he has advocated lumbar punctures and CSF examination of autistic children across the spectrum?
Q And he has also advocated other neuropsychiatric investigations, including MRI and EEGs?
Q You have already been taken by Ms Smith to one of his papers in FTP5, but I would like to revisit that, please, so would you go to divider 20, page 244, and we see the start of this paper entitled, “Medical Work-Up in Children with Autism and Asperger Syndrome”. Parts of this have been read to you already by Ms Smith.
A Yes, indeed.
Q Forgive me if I go over some of the things again because not all was read out to you.
Q Dealing with the abstract first, which was read to you, it reads:
“There is a very conspicuous lack of literature in the field of autism work-up. Guidelines for clinicians planning to work up their patients with autism are virtually nonexistent.”
Let me pause there, would that have been true in 1990?
A Yes I think it probably was.
“This paper reviews some of the very considerable evidence that exists which implies the need for specific medical/psychological work-up in autism. Detailed clinical guidelines for work-up are provided on the basis of this review. It is concluded that all young children with autism need a comprehensive medical/laboratory examination. The work-up essentials in cases diagnosed as suffering from Asperger syndrome are also discussed.”
So, the exercise that this paper purports to do is to look at what evidence was then available in 1990 and draw inferences from that as to how children thought to be on the autistic spectrum should then be investigated, would that be fair?
A That would be correct.
Q If we go, please, to page 245 we then see, do we not, Table 1 at the top of the page entitled “Associated neurobiological background factors in autism and autism spectrum disorders”. This table purports to be a list, does it not, of medical conditions known or thought to be associated with autism?
Q This paper also then goes on to consider the incidence of such conditions. Is that right?
Q If we turn to page 246 and if we go to the left hand column, about half way down, entitled “How often Are Specific Medical Conditions Associated with Autism?” it says this:
“The likelihood that one of the conditions shown in table 1 will show up in an exhaustive clinical and laboratory examination is strong indeed. In a recent study by Steffenburg, 37% of a population-based series of strictly defined autism cases, fulfilling both DSM-III-R and Rutter (except 1 case out of 35 examined) criteria for autistic disorder/infantile autism, were diagnosed as having at least one of the medical conditions listed in table 1 after intensive neurobiological investigations …”.
Then, if we go a few lines down:
“Another important finding in the Steffenburg study was that at least half of this proportion would not have been disclosed had not the medical investigation been exhaustive.”
I know you take issue because you told us already, and you are in print taking issue with this figure of 37%, and I full understand your reasons behind that. I just want to see what this paper is, or the information it would convey to the reader of it. What it is suggesting is that there is a high order of association of medical conditions that may be found on a full diagnostic work-up in children suffering from autism.
A You introduced the paper, quite rightly, as “It purports to do that” – yes.
Q And then it also purports to set out how those conditions should be investigated. Is that right?
Q And if we go to page 251, please, and if we look at the right hand column one third of the of the way down we have in bold type “The Essentials in any Neuropsychiatric Work-Up of a Young Patient Who Suffers form Autism or Autistic-Like Conditions”. It says:
“Table 2 outlines the essentials of a basic medical/psychiatric work-up of any young child who suffers from autism or another severe autistic-like condition.”
If we go towards the bottom of this column, the next paragraph:
“It will be clear that the investigation suggested is much more comprehensive than what is currently usual clinical practice in the field of autism.”
If we look at table 2, then, to see what is being recommended, please go back to page 250. Table 2 is at the top of the page: “Neuropsychiatric assessment in autism”. “Assessment”. Then
Detailed structured assessment …”
The point you make is, that is what needs to be done first. Then:
“General physical examination
Age-appropriate neurodevelopmental/neurological examination
And then, towards the bottom of that table it says:
And we have to go to another table for that. Can we turn, please to page 252. We then see table 3, which is entitled “Relevant laboratory analyses in all medium/low functioning and certain high-functioning cases with autism and autistic-like conditions”. We see there the whole list of the investigations. Ms Smith quite properly drew your attention to the MRI scan and the CSF protein. I think that should be “CSF” rather than “CFS”, should it not?
Q It is a typo?
A Yes, it is.
Q And EEG. Then the footnote about the CSF protein:
“Lumbar puncture for CSF analysis is a safe and relatively non-traumatic procedure.”
I think you agree with that proposition?
“In the Scandinavian countries, it is always considered in the work-up of young children with severe developmental disorders.”
I do not think you disagree with the practice that has been described there, would you, as happening, as a matter of fact?
A In his laboratory.
A The description “Scandinavian countries” – it is actually more varied in Scandinavia, but that is his practice, certainly.
Q We will come on to look at what other Scandinavian countries may do, because there is another paper that deals with that.
Q And it goes on to make the point about extra tests being done on the CSF and the observation that the lumbar puncture is there to exclude progressive encephalitis and encephalopathy. If we go back to see the comment that is made, again please page 251, by Gillberg on these. I started reading out the passage towards the bottom of page 251. I need to read it in its entirety.
“It will be clear that the investigation suggested is much more comprehensive than what is currently usual clinical practice in the field of autism. However, the evidence concerning the association, even of so called classical autism cases, with a wide variety of specific medical conditions, many of which require genetic counselling and a tiny minority of which are amenable to treatment, is now such that it must be considered clinically unacceptable not to perform a work-up of this kind.”
The advice, therefore, that is being given by Professor Gillberg at this point is in pretty strong terms, is it not?
A Yes, it is, but I must come back to table 2. He is placing equal emphasis on a detailed structured assessment in respect of autism, the review of optimality, the review of postnatal events, a review of previous medical illness, growth patterns, detailed psychiatric history, the general physical examination should included measurement of head circumference, minor congenital anomalies and so on. So that what one is forced to conclude is that the recommendations in terms of the thoroughness of assessment were undertaken in none of the cases in the paper.
Q The point I am getting at, Professor, as I think you appreciate, the practitioners here are being criticised for carrying out a range of neurological investigations, and what I am exploring with you, regardless of whether there were other things they might have done or should have done, is whether or not those investigations were appropriate or otherwise. What I am putting to you is that here is an expert in the field who in 1990 is saying not only these are the investigations he would do, but he is describing them as being essential, and it being clinically unacceptable not to perform them.
A Yes, but again, you have to look at the evidence. So the example he gives in relation to CSF – so we need to turn to table 3 – is progressive encephalopathy and he is quite right; that is what the CSF will tell you. But that stands out as being the one specific, and it is one which, of course, ordinarily would be clinically indicated as well as being picked up by the CSF. Table 1, to come back to that, which says, “Associated background factors”; these are not actually medical conditions – mental retardation, epilepsy, adolescent onset deterioration and so on. It is a real mixed bag of phenomena. I do not disagree with the phenomena, but what I am emphasising is that the evidence for doing lumbar puncture in the absence of a proper clinical work-up is inconsistent with what he is suggesting.
Q That is not right, is it, because he is effectively saying that you should do other things in the clinical work-up, in the clinical assessment, and I accept the list that you have read out. He is not saying that these laboratory investigations are dependent on that clinical assessment, because what he is clearly saying is, these laboratory investigations should be carried out in all cases where the child is thought to be on the autistic spectrum.
A Which I have to come back to: the evidence does not support that. His own evidence does not support that.
Q I fully appreciate that there is a difference – a professional difference of opinion – between you and Prof Gillberg and you have debated that in the literature, as we will come to see, and as Ms Smith has shown you. My task is not to sort out who is right or wrong between the two of you, but to try and see if there is a range of reasonable practice. What I am suggesting to you is that there was a range of reasonable practice, because here is someone who would be regarded as an expert in the field, advocating the very investigations that were carried out at the Royal Free.
A That is true except, of course, that in the application to the ethics committee, which we have already looked at, there is no mention made of this advice. So the advice is entirely in terms of the chapter that I co-authored with Catherine Lord.
Q Forgive me, Professor Rutter, that is a different point. I am looking at the range of reasonable practice. Can we go on to see how this point is developed by Professor Gillberg.
Q You will have opportunities to deal with it as we go through it.
Q Before I leave this, I do need to go on to page 253, on the left hand column, dealing with lumbar puncture. It was read out by Ms Smith, but in fairness I think I should read it again. It is about a third of the way down, a sentence beginning with:
“With respect to cerebrospinal fluid (CSF) examinations, current practice tends to vary considerably. In the Scandinavian countries, a lumbar puncture with CSF protein electrophoresis is considered one of the basic procedures in the work-up of severe developmental disorders without a clear cause. In some European countries, and in the US, lumbar punctures appear to be surrounded with much more apprehension, and the general attitude seems to be very conservative. Several authors have documented that clear progressive encephalopathies were first suspected on the basis of results obtained at CSF analysis. It is therefore my contention that a CSF protein electrophoresis should be part of the work-up in autism in early childhood.”
A That is what he says but it is very striking that there are no references given to the several authors, so it is a paper with 55 references; not one of those supports that claim.
Q I will come on to consider with you the other authors, maybe, because I think you actually identified them in one of your papers. Can we then consider another paper by Gillberg. I am afraid for this we will need to go back to the bundle of Professor Murch’s literature.
A Which I have here.
Q Could you turn, please, to divider 12, page 75. Here we have extracts from a book, of which Professor Gillberg was co-author with a Dr Mary Coleman. I think it is probably a book you are familiar with.
A It is.
Q The book itself was called The Biology of the Autistic Syndromes. Just dealing with Dr Mary Coleman, is it right that she was based at the time she wrote this at the Georgetown University School of Medicine in the USA?
A Yes, she was.
Q She is a paediatric neurologist?
Q And, again, respected internationally as an expert in paediatric neurology?
Q The first edition of this book came out in 1985, but the extracts that we have here came out in 1992. They would have been current at the time that this Panel is concerned with. Is that fair?
Q Again, this textbook would have been regarded as a respectable publication?
Q And therefore regarded as setting out a reasonable medical opinion in the field at this time?
Q If we then look at what is being recommended within this chapter, so starting at page 75, I am afraid many of the points that we have looked at are repeated, but forgive me for that.
A That is all right.
Q The second paragraph down, beginning first of all if you go to the next sentence, it says:
“The work-up should progress through the full assessment until a diagnosis is established and detailed information about the child’s level of cognitive functioning, seeing and hearing is available for the educators who will be working with the child.”
It then goes on to say this:
“The likelihood that a medical diagnosis can be made for a child with autism is no longer remote. In a recent study by Steffenburg (1991) 37 per cent of a population-based series of carefully defined autism cases…”
And then it refers to the criteria again –
“… were diagnosed after intensive neurobiological investigation as having at least one of the medical conditions described in this book.”
Then it goes on to say:
“One important finding of the Steffenburg study was that in at least half of these cases the diagnosis would not have been made had the medical investigation not been exhaustive.”
Then, if we go towards the bottom of the page, it is dealing with the figures of the 37 per cent. It says:
“These figures could be taken to mean that at least 35 per cent of all autism cases are causally related to an underlying known medical condition, 5 to 10 per cent are clearly related to other hereditary factors … 50 per cent have unspecified major signs of brain dysfunction which could be brought about by medical conditions (hitherto undiscovered), hereditary factors or a combination of the two, and only 5 per cent have no strong or clear-cut clue as to the underlying aetiology.”
This is effectively a repeat of the viewpoint that he was expressing in that 1990 paper that we have already looked at. Is that right?
A Yes, it is.
Q If we go on to page 77, please, we see in the penultimate paragraph he deals with CSF examinations. He says:
“With respect to CSF examinations, current practice tends to vary considerably. In the Scandinavian countries, a lumbar puncture with CSF protein-electrophoresis is considered one of the basic procedures in the work-up of severe developmental disorders without a clear cause; some other countries have a more conservative attitude. We recommend this procedure as part of the work-up.”
Q So this is not now just Professor Gillberg who is recommending it. Clearly his co-author is lending her name to it as well.
A It would seem so.
Q If we look at the check list that is set out in this chapter, if we go on, please, to page… Before I reach page 79, let us look at page 78, please, where we see towards the bottom of the page:
“We would now recommend magnetic resonance imaging (MRI) in preference to CT scanning as recommended in the first edition of this book. Because there is no radiation with MRI, more areas of the cranium can be scanned, increasing the likelihood of detecting any abnormality. In fact, there are a number of new studies showing that the MRI may be highly relevant to diagnosis.”
Then can we go on to page 79. We there find, do we not, what is described at Table 25.1 as the “Neuropsychiatric assessment checklist for autism”. We see effectively a re-run of the same points that were being made in the 1990 Gillberg paper. Would that be fair?
A Yes, more or less.
Q Over the page, at page 80, we see that it sets out half-way down the page the laboratory examinations that they recommend, and it is a mix of numbers and bullet points. We go one third to three-quarters of the way down the page. There we see there is a mention of the CSF protein electrophoresis to rule out progressive encephalopathy and then at 4, “Other essential laboratory tests”. Amongst that list is the EEG and the MRI. Again, in this textbook, much the same opinion being expressed this time by two authors on the degree of work-up for all children on the autistic spectrum?
Q You are nodding your head?
Q This opinion was expressed in other papers as well, was it not, current to the 1990s? If we look at a 1993 paper at divider 1 of this bundle, please. The title is “Glial Fibrillary Acidic Protein in the Cerebrospinal Fluid of Children with Autism and Other Neuropsychiatric Disorders”. We see that this featured in Biology, Psychiatry in 1993 and the first author is Ahlsen. Do you know of Ahlsen or any of the other authors apart from Professor Gillberg?
A Gillberg is the person I know best.
Q We see towards the bottom of the page it says that they come from the Department of Child Neuropsychiatry and Neurobiology at Gothenburg University. If we just look at the abstract to see what was happening in this paper:
“The CSF of 47 children and adolescents with autism was analysed for the contents of two astroglial proteins, the glial fibrillary acidic protein (GFA) and S 100.”
In the introduction, on the left-hand side, we see:
The etiology of infantile autism (childhood autism, autistic disorder) is multiple. Specific medical syndromes …. And genetic factors … have been clearly documented to be associated with autism in some cases.”
If one looks at the Material and Methods, going over to page 2, the left-hand column, under the heading “Infantile Autism/Autistic Disorder”:
“This group comprised 47 cases … ”
It gives the age range –
“Consecutive cases meeting DSM-III (APA 1980) criteria for infantile autism and DSM-III-R (APA 1987) criteria for autistic disorder, examined at the Child Neuropsychiatry Centre in Gothenburg (which is a statewide diagnostic center, where children and adolescents with various kinds of neuropsychiatric disorders are referred for diagnosis and work-up) were assigned for study. All children under age 30 months at initial evaluation … were re-evaluated after age 36 months and a definite diagnosis of autism, CSF-sampling is part of the standard laboratory work-up performed at the center in this group of patients.”
Then it goes on to deal with the consent being obtained from parents. So another clear statement that CSF sampling is one of their routine clinical investigations.
A Yes. I accept that is what they do.
Q If we could then go on to page 7, they say more about that:
“The IA group … ”
I think that is an abbreviation for the infantile autism group –
“ … is likely to be representative as it consisted of consecutive referral cases with strictly defined autism referred to a statewide diagnostic center with no specific referral restriction. The CSF study was included in the routine work-up and few families declined participation. CSF analyses are always considered in severe neurodevelopmental/neuropsychiatric disorders in childhood and has been included in the work-up of children with autism in our center for more than 10 years.”
So the description of their practice is that it is not simply what they were doing in 1993, but dated back to 1983.
Q If we move on, please, to the next paper in divider 2 ---
A I must just comment. What is said here is the results could implicate gliosis. This of course is much more satisfactorily investigated through neuropathology and we know that none of the neuropathological studies have shown gliosis. So from a scientific point of view, I would not rate this at all highly.
Q Again, Professor, I am not seeking to rely upon the scientific point being made; I am just considering the evidence about the way they approached the work-up of patients and what they say about that.
A Yes, but in that case one has to come back to the recommendation, for example, the Wood’s light, must be used as part of the clinical assessment because that is necessary in order to identify tuberous sclerosis, which is a much commoner associate with autism than progressive encephalopathy and so what is being done, if I may put it that way, is that there has been a taking out of his recommendations some things and a rejection of others. So to include CSF because rarely it picks up something, but to exclude common investigations like Wood’s light for tuberous sclerosis, seems unusual, to put it mildly.
Q Professor, I fully understand your view. You are critical of Professor Gillberg’s approach, but the point of my exercise is to see what he is telling the rest of the world about his approach and what he is advising the rest of the world to do and then to explore with you the extent to which he is alone or with others. Would it be right that MRI would help pick up tuberous sclerosis?
A Yes, it would.
Q So that would be another reason to underpin the carrying out of MRI?
A Yes, and if you look at the investigations in the two cases where there had been an extensive assessment by paediatric neurologists, in one case Lewis Rosenbloom and in the other case Sheila Wallis, in both cases MRI was included; CSF was not. The point I am making is that I accept that that is what he aw arguing. What I do to accept is two other things. The first is that there is evidence to support these views, because there is not. Secondly, those in this country who were experts, such as Dr Rosenbloom and Dr Wallis, but the same would apply to umpteen others, did not follow that because they looked at the evidence.
Q Whatever their reasons were for doing it their own way, what I am exploring with you is whether there was a range of practice. I think you appreciate there is a world of difference between an expert or someone qualified in a field saying, “I would not do it this way” and acknowledging that there were others who would probably be regarded as respectable saying, “I would.”
A Outside the UK.
Q Whether it is outside the UK or not, autistic children are the same the world over, are they not?
A Yes, but clinical practice is not.
Q Let us look at divider 2, please. This time, we jump ahead to 1995 and we are in a text called Clinical child neuropsychiatry, Professor Gillberg again, in the Cambridge University Press. Just to make a point of bearing, on the left there is a reference again to the 1991 Steffenburg study and the approximation of one in three having an associated medical condition. If we go to the right-hand column, in the middle paragraph, he says:
“In summary, autism is best conceptualised as a behavioural disorder, not quite so specific as previously believed, with multiple aetiologies.”
Then a few lines down:
“It sometimes occurs in conjunction with other disorders and handicaps, and there should no longer be a need to discuss whether a child has, e.g. ‘autism or a hearing deficit’ in a case where it is clear that both diagnoses apply.”
This again is dealing with the issue of: are there other diagnosable medical conditions that may be associated with someone suffering from autism?
Q Then we see lower down this page he comes back to his advice on the medical work-up in autism. It says:
“A medical work-up is required in all cases of autism (and in many instances of autistic-like conditions). Tables 6.4 and 6.5 list the essentials in any work-up of a child under age 10 years who receives a diagnosis of autism for the first time. In older children, those with normal IQ, and in children for which a clear aetiology is at once suspected, the work-up should perhaps be differently tailored.”
If we just see what those tables are – I think again it is familiar territory – page 13, table 6.4, we have the neuropsychiatric assessment in autism, which is very similar to what we have seen in the 1990 publication. Is that right?
A It is right.
Q We see at point 5 of that table there is a reference to the laboratory examinations and, if we go on to page 14, we see that table, which again contains the same sort of list of investigations as we have looked at before, including examination of the CSF, EEGs and MRIs. Is that right?
A It is right. It is moreorless the same table as we have seen.
Q Again, the language which is being used here is one of these being essential, rather than discretionary. That is the tone of the advice which is being given.
A It is.
Q Can I just consider with you, if we have in mind what is in table 6.5 on page 14 – I just want to move to the issue of protocols. I think you have accepted already that it is common practice in medicine to devise a protocol for the clinical investigation of patients who may be suffering or appear to be suffering from similar conditions.
Q Your point about ‘The Lancet 12’ as I understand it is that they had a variety of presentations, and you have given various examples, one of which, for example, was a range in IQ level.
Q So the point you make is that those investigations need to be tailored according to the presentation.
A Yes, indeed.
Q Can I just look at the other side of that and see what the advantage is of a protocol first of all? I do not think you would disagree with these advantage points. First of all, a protocol allows for systematic assessment.
Q In effect, it is an aide memoire, a checklist, so that instead of just someone relying on their own clinical experience or practice, it actually reminds them: do this or think this. Would that be fair?
A Yes, if it is used in that way.
Q Also a protocol helps in teaching and giving guidance to junior doctors who might not be able to identify the relevant investigations from their own experience to date.
A But again, I must emphasise, if it is used as a reminder, that is fine. If it is used as a way of avoiding thinking about the clinical issues, then that is definitely not fine.
Q I fully understand that and I would not suggest otherwise. Can we just see an example of a protocol which was used in the Child 2 case? For that, we will need the Royal Free records for Child 2. If you would turn, please, to page 351, we see Child 2’s name is written in manuscript at the top of the page, but clearly on this document most of the investigations being listed are set out in type, so I think we can assume this is a kind of pro forma protocol.
Q It is entitled “Investigations for Possible Degenerative Disorders of the CNS” and we see it is broken down into various sections. The first section deals with blood. Three-quarters of the way down, there is a section on cerebrospinal fluid and, if we go over the page, there is a section on neurophysiology, under which the EEG and the VER are present. Then Radiology, under which we see MRI. Then Biopsy towards the bottom of the page. Looking at the list which is typed here, we see that it includes, relevant to Child 2, blood tests, CSF analysis, the EEG and the Visually Evoked Responses and the MRI.
Q I think it follows from what you have just agreed with me, having a list like this, a list of investigations like this, would be common practice.
Q Having such a list of investigations does not imply that these are research investigations, but is consistent with a clinical line of inquiry.
A Yes. If used as a checklist, yes.
Q It is the way a protocol is used which is the important thing, is it not?
A It is indeed.
Q If we just look back at page 14 of the literature bundle, table 6.5 and the list of investigations under the heading “Analysis”. In effect, Professor Gillberg has a protocol of laboratory investigations for all children on the autistic spectrum.
Q Regardless of where the child was on that autistic spectrum, his advice and his reported practice was to go down this checklist and carry each of them out.
A That is correct.
Q In other words, he was not tailoring these investigations dependent on the clinical assessment of the individual child he had seen.
A That I think does not follow, in the sense that he is arguing that you do need a detailed assessment of the kind we have gone through before. I would certainly suppose that as an experienced clinician, he was guided by what he found. It would really seem quite absurd to recommend a proper assessment if you are going to ignore it. So no, I do not accept that.
Q We have seen – I have taken you to many passages – he has been advising that this list of laboratory tests was to be done in all cases. He was not saying, “Do the assessment and then consider this list”; he was saying, “Do the assessment and carry out this list of investigations”, was he not?
Q Can we consider then a situation in general terms for ‘The Lancet 12’? There will be one or two exceptions to it, but I just want to deal with the general presentation of the evidence we have. Usually, the child arrived at the Royal Free with a background GP referral letter setting out background information.
Q Usually there was an outpatient assessment by Professor Walker-Smith.
A Yes. I do not remember the proportion but often that would be the case.
Q I think there are one or two cases where that did not happen. Given Professor Walker-Smith’s experience and, indeed, the training he would have, you would expect him, would you not, to be able to recognise the existence of a developmental disorder?
A I am not quite sure what you mean by “a developmental disorder.”
Q If someone was suffering from an autistic-like disorder you would expect him to be able to recognise that from his assessment, would you not?
A Well yes but my query would be of a somewhat different kind, that is to say whether he had the experience and knowledge to realise that there is a difference between disintegrative disorder where there is a significant possibility of a progressive encephalopathy and the rest of the rang of autistic phenomena, and that I would question.
Q I am not suggesting that he had the expertise, and it is going to be a matter for him to say what his expertise is.
A Quite so.
Q To give the pinpoint diagnostic label of where on the autistic spectrum a child was. The point I am making to you is really more simple and basic than that; you would expect him to recognise if a child was likely to be somewhere on the autistic spectrum disorder?
A Possibly, I do not know.
Q Again dealing with generalities: usually when the children were admitted, ‘The Lancet 12’ children were admitted to the Royal Free, there is a further episode of history-taking and physical examination by a registrar, who the Panel has heard form, Dr Casson.
Q What I suggest to you is this, with that type of background information, with that sort of outpatient assessment and with that sort of history-taking/examination again on admission, if the Royal Free clinicians obtained the history of a regressive episode from which there was no significant recovery, and a history of multi-system involvement, in other words the brain and the bowel, it was reasonable for them to investigate those children, according to a protocol, that was looking for potentially diagnosable medical causes that might be amenable to treatment or facility their treatment?
A No, I do not agree with that.
Q In effect, I suggest that what they were doing was working – I am not saying they were specifically relying on Gillberg – in a way which would fit with the application of the Gillberg-type protocol to a child who was presenting as being in the autistic spectrum?
A Well, you could argue that I suppose, but only if one accepts that it ignores the fact that experts within the UK did not accept that advice; did not follow that advice; and as far as I know there are no publications that indicate support for that advice from within the UK. Secondly, you have to accept that the differentiations in terms of the different kinds of regression are meaningless, and I think there is nobody who is expert in the field who would accept that, so that the statement to Dr Pegg in 1996 (I have forgotten exactly what the date was there) that the children had a hopeless prognosis is completely out of keeping with the evidence from numerous follow-up studies all over the world.
Q With respect, professor, that is not the point I am putting to you. the point I am putting to you is that if a child is presenting, and there is sufficient information to put them somewhere on the autistic spectrum, that following a protocol of investigations of the type the Royal Free did, it is entirely consistent with the advice that was being given by Professor Gillberg?
A No, because it ignored the inclusion of, for example, looking, using Wood’s light for tuberous sclerosis, just to pick one example, so that Gillberg does indeed, I accept, argue (I think wrongly but does argue) for the routine use of lumbar puncture, but he also argues for the routine use of clinical assessment which is designed to pick up many of the medical conditions that have been found to be associated with autism, that is what he has not done.
Q Can we go back to page 14 of the bundle, and table 6.5, it is a point I thought we had dealt with, the third bullet point down, where it says “CAT-scan/MRI-scan” and if we go to the right we see mention of tuberous sclerosis, so he is advocating, is he not, the carrying out of an MRI with a view to ruling in or ruling out that condition?
A Yes, but tuberous – yes, but you cannot do that. That is to say, tuberous sclerosis may show itself in terms of very mild skin abnormalities with nothing in the way of tubers that would be picked up by a scan, so I accept the scan is a reasonable thing to be doing and do not accept that to ignore the skin lesions is reasonable.
Q No-one is suggesting skin lesions were being ignored. I think you have accepted, and we have seen, that when these children came into hospital a fairly detailed history was being taken by Dr Casson, and a clinical examination was then conducted by him, either by way of a general type of examination one would do for clerking in any patient, or more specific if anything was flagged up on the history.
A I am unaware that he used Wood’s light.
Q Can we go on to consider Gillberg’s passage on page 15, please, in the right-hand column, under the section “Atypical autism/autistic-like conditions, and it is about a third of the way down where he says this:
“Some children do not show overt evidence of autism until after age 3 years. These can now be classified as suffering from ‘autistic disorder’ according to the DSM-III-R, but doubt remains whether they represent the same type of condition as autism with early onset or not. In some of these instances, a case can be made for diagnosing childhood disintegrative disorder or Heller dementia.”
Do you agree with that?
A Well yes in the sense that an onset after age three years would raise the issue as to whether there is a disintegrative disorder but, of course, that needs to be diagnosed in terms of the clinical manifestations.
Q Moving on to page 16, left-hand column, the second paragraph down:
“Whatever the label, children with childhood disintegrative disorder … are often clinically indistinguishable from those with autism once the regression period is over after 2-20 months.”
Do you agree with that?
A I do agree with that.
Q It follows does it not that carry out a lumbar puncture and CSF sampling is potentially useful in the investigation to rule in or rule out a disintegrative disorder?
A No. It is useful to rule out a progressive encephalopathy. Progressive encephalopathy and a disintegrative disorder are very far from synonymous and the case which have been investigated with a clinical defined disintegrative disorder have only very rarely been shown to have a progressive encephalopathy.
Q So you have identified that lumbar puncture being useful to rule out a progressive encephalopathy?
Q You also accept that once the period of regression is over the clinical presentation for disintegrative disorder may be very much like ordinary autism?
A Yes, I agree with that.
Q It follows therefore, does it not, if one does not carry out the battery of investigations recommended by Professor Gillberg one might well miss the underlying disorder in some children?
A I know of no examples that document that though.
Q It is not the documentation, I am thinking of the logic: it must be right.
A I do not agree, sorry.
Q What is illogical about the proposition I have just put to you?
A Well because it is assuming that the yield is sufficiently high to indicate that if you do not do something you will miss something, but empirically what you have to decide is what is the evidence that cases are picked up by this investigation when there are no indications on the full clinical assessment, and that is what I am querying. I do not think there is evidence for that.
Q Can we just see how you have put this view forward, because I accept you have been consistently putting forward your critique of Professor Gillberg, as you have told us, and you gave the Emmanuel Miller Memorial Lecture in 1998.
Q I think in that you were reviewing the interplay between research and clinical work in the field of autism.
Q Can we have a look at that paper because I think there may be things in there helpful to the Panel. It is FTP5, divider 12, and at page 79 we see the title of the lecture you were giving, “Autism: Two-way Interplay between Research and Clinical Work.” If we just look at the abstract you say:
“The two-way interplay between research and clinical practice in relation to autism is reviewed with respect to: (1) diagnosis and syndrome delineation; (2) the nature of the disorder; (3) intervention studies; and (4) aetiology, as manifest during four time periods; (a) the 1950s and 1960s; (b) the 1970s into the mid 1980s; (c) the late 1980s and early 1990s; and (d) the late 1990s. It is concluded that clinical practice has changed out of all recognition during the last 50 years and that research findings have been crucial in bringing about that change. It has not however been a one-way traffic. Many key advances were prompted by astute clinical observations and some extravagant research claims were given a more balanced perspective through the light of clinical experience. Crucial research and clinical tasks remain but the means to meet them are there if the opportunities are taken and attention is paid to the lessons of the past.”
What is clearly set out in that summary, or the abstract, is that you count an overview of , if I can put it this way, the ethos of the times, the way autism was regarded by way of definition, and the right way of investigating it?
Q Would that be fair?
A That would be fair.
Q If one looks at what you were saying about the 1970s and the 1980s, can we turn on please to page 84, and just so we have got our bearings if we go back to page 83 just to see the title of this section, it is “Phase 2: The 1970s into the mid 1980s: Diagnosis and syndrome delineation.”
On page 84, in the left-hand column you are dealing with aetiology, and in the middle paragraph you say:
“The second phase of research saw many studies investigating different possible medical causes of autism” – then you cite Coleman, Coleman & Gillberg and Golden – “Several different strands with lessons for research and for clinical practice may be delineated. First, there were many reports that autism was associated with some medical condition. Almost all of these were based on single case reports or very small samples. The inferences to be drawn from these case reports were problematic for several reasons, as came to be recognised later. The findings were important, nevertheless, in highlighting the possibility that autism could arise on the basis of diagnosable medical conditions. These reaffirmed the need for a careful medical evaluation of all cases of autism.”
A Yes, indeed.
Q And presumably you stand by what you wrote there?
A I do.
Q There is then a section which starts at page 86, dealing with what was happening in the late 1980s and the early 1990s. I would like to go to page 88 and to pick it up there. It is in the left column, the second paragraph down, beginning “The quantitative genetic findings, and if we go to the next sentence:
“Over the same time period, there was a veritable flood of reports, mostly of isolated cases, of associations between autism and either some diagnosable medical condition or some somatic abnormality such as a chromosome anomaly (see Gillberg & Colman in 1992). It has proved extremely difficult to know how to interpret these findings. They could represent nothing more interesting than coincidence. Thus very few of the associations have been replicated. On the other hand, it is possible that some of the associations do reflect a valid connection and the challenge is to know which is which. It might have been hoped that the associations would give rise to a pattern that would provide clues on the nature of the underlying neural processes. Unfortunately, that has not proved to be the case either. Thus, when last reviewed, there were reports that autism was associated with anomalies in all but three chromosomes (Gillberg, in press). Similarly, autism has been associated with a mixed bag of metabolic abnormalities and with a range of infections in the prenatal period, and occasionally postnatally (Gillberg & Coleman).”
Just dealing with that passage, a couple of points arise: you make reference to there being a “flood” (to use your word) of reports of associations between autism and a diagnosable condition. Therefore, presumably in this era, raising the issue as to whether or not one should be looking for a diagnosable condition underlying autism?
A Oh yes indeed, that is a point I made quite explicitly in several different papers.
Q You also say I think that autism has been associated with a mixed bag of metabolic abnormalities.
Q Can we then see what you say about the incidence of diagnosable medical conditions because I think it was in this lecture (as, no doubt, elsewhere) that you start taking Gillberg a bit to task, if I can put it that way.
Q If we go to the right-hand column, four or five lines down, you say this:
“Finally, the claim that 37% of cases of autism were associated with a diagnosable medical condition (Gillberg, 1992) seems likely to have been a substantial overestimate. Rutter et al … in 1994, putting together the evidence from several studies, concluded that the rate was probably of the order of 10%.”
So the point you are making there, as I understand it is that there is a disagreement about the level of incidence of potentially diagnosable underlying medical conditions?
A Yes, although there is agreement that a significant minority of cases are associated with a medical condition. That is not in dispute.
Q To put it in a nutshell, what Professor Gillberg had been suggesting was it was around one in three and what you are saying here is, “No, it is about one in 10”?
Q Even if it is one in 10, as you were suggesting in 1998, that is still a significant number of autistic patients where it is thought there might be an underlying diagnosable medical condition.
A Yes, indeed, so that I too have recommended a thorough medical assessment on exactly those grounds.
Q This reported incidence of an underlying medical condition, whether it is what Professor Gillberg was suggesting, around one in three or whether what you were suggesting, one in 10, in fact had an impact on the way doctors approached the clinical work of the children, did it not?
A Oh yes, it did.
Q If we go two-thirds of the way down page 88, in the right-hand column, you say:
“A further clinical implication drawn by some researchers was that a wide range of medical investigations, including lumbar puncture, EEG, brain imaging and metabolic studies, should be undertaken as a routine.”
There you quote not simply Professor Gillberg or Gillberg and Coleman but also Elia et al and Frederico et al.
Q Most clinicians have resisted this invasive approach to medical investigation. I just pause there. Would you look at the phrase, “most clinicians”. It is clear from what you are saying that whilst it may be the majority have done this, you recognise that there are a number of practitioners who have gone down this route of intensive investigation?
A Outside the UK.
Q Whether it is outside the UK or not, you recognise that that has been happening?
Q And not in some far-flung third world countries?
A No, but one needs to look at mainline centres, and I would not claim that it is not done in any but it would be unusual.
Q Let us look at Elia et al. Where were they based?
A I do not remember, I am afraid.
Q And Federico et al?
A I do not remember.
THE CHAIRMAN: I am sorry?
MR HOPKINS: I am sorry, I was asking where Elia et al and Federico at al were based. Professor Rutter’s reply was, he does not remember. You go on to say in this paragraph:
“The key question is how often the investigations lead to a diagnosis that cannot be obtained more straightforwardly through clinical history and examination.”
Q Which effectively is the point you are making to this Panel?
A It is indeed.
“The answer is that it is rare for the tests to reveal undiagnosed medical conditions; many of the supposedly abnormal laboratory findings have no unambiguous clinical implications; and the clinical value seems so slight as not to justify the distress inevitably caused to young children if such investigations are routinely undertaken.”
So clearly setting out your stall then, in 1998?
Q But what I suggest is that by the very review you have carried out, you have identified that there was an ethos, certainly for some practitioners in this field in the mid-nineties, of carrying out an intensive work-up of children on the autistic spectrum?
A Yes, indeed. In this review, as elsewhere, I have deliberately tried to take an even-handed view, an even-handed presentation so yes, I emphasise that there is not just one person; there are several, which is the case. It still comes back to the point that within the UK and, indeed, in most other major centres around the world, the view that I am expressing here would be followed by most, but I emphasised, as I should do in the paper, that is not all.
Q We have seen your referencing to some who took the Gillberg line.
Q So Elia and Federico.
Q Can we also look at what other papers may suggest others were doing, going down a similar line.
Q It is a 1999 paper. Again, we need to go back to Professor Murch’s literature bundle, the blue bundle, please. Could we turn to divider 4. We see a paper entitled, “Levels of cerebrospinal fluid nerve-growth factor differ in infantile autism and Rett syndrome”. It is a paper in Developmental Medicine & Child Neurology in 1999. The authors were Rikonen in the Department of Child Neurology at the Children’s Hospital, University of Kuopio in Finland, and Vanhala at the Hospital for Children and Adolescents, University of Helsinki, again in Finland. Let us look at the method that they are describing in this paper, so we are on the right-hand column, two-thirds of the way down the page:
“Fourteen children with primary autism and 121 children with classical RS”
- I think that is Rett syndrome?
A Rett syndrome, yes.
“… were included in this study … The study included all 11 patients with RS and seven patients with autism, admitted during 1997 to the Hospital for Children and Adolescents at the University of Helsinki, and seven patients with autism who were admitted to the Children’s Hospital, University of Kuopio, during the same period. The clinical picture and CSF NGF concentrations of the patients with RS have previously been reported.”
If we drop down to the bottom of this column, five lines up:
“These children underwent extensive studies which included physical examination (especially for neurocutaneous disorders), neuroimaging, chromosomal analysis, EEG (for subclinical seizures)…”
I pause there. “Subclinical seizures” mean what, so that we know that?
A Actually it does not mean anything very much. Technically what it means is that there is some manifestation which falls short of an identifiable seizure. It is not actually a term most paediatric neurologists would accept.
Q Could it be taken to mean that children suffer from epilepsy but there may be no clinical sign of that, and only this type of investigation and an EEG will reveal it?
A Presumably that is what is purported, yes.
Q It goes on to describe the tests:
“… tests of blood and urine for metabolic disorders, CSF examination (to rule out encephalitis and progressive encephalopathies), plus careful evaluation of the visual and auditory systems.”
It then deals with the mean age. Dealing with the CSF sampling a few lines down on page 20P:
“The CSF samples were drawn as part of the clinical investigations because 11 to 37% of specific disorders have been reported to be associated with autism.”
Then it quotes Gillberg and Coleman in 1996. I think that was probably a paper that was in reply to your critique of the 1 in 3 cases that Professor Gillberg had mentioned?
Q In any event, what they are doing is to say that there has been a reported range of medical disorders and it is a range between 11 and 37 per cent, and that is the reason why we are doing this CSF sampling.
A I suppose so, but from the scientific point of view it is, of course, nonsensical. So that what they find is a normal level of NGF in individuals with autism, but an abnormal range in Rett syndrome. But, of course, Rett syndrome is differentiable in umpteen other ways. For example, if one had looked at the head circumference, what one would find in Rett syndrome is that the heads are pretty uniformly smaller than normal, whereas in autism that is not the case and, indeed, there is a substantial proportion where it is raised. The course of the disorder is entirely different. The change in Rett syndrome, although it can occur later, is usually in the second half of the first year of life, i.e. between six and twelve months, and there are all sorts of other changes. So in order to differentiate Rett syndrome and autism, to rely on a normal CSF in autism seems an extraordinary way of going about things.
Q We understand that you criticise these practitioners for the way they were approaching it?
Q I am interested to see what the practice was, what they were doing.
Q And they go on to describe what they were doing, and giving their rationale, because they say, six lines down that an important non-genetic cause of autism is prenatal infection.
“Neurodegenerative disorders may also be initially misdiagnosed as autism. Full medical investigation, including lumbar puncture, was thought to be important for an understanding of the basic nature of autistic conditions, both in research and clinical practice.”
So what I am suggesting to you is that this is again another example of practitioners using a battery of investigations because of what they perceive to be either a 1 in 10, or a 1 in 3, chance of picking up a diagnosable medical condition. Do you accept that?
A That is what they claim.
Q Can we also, please, consider a paper that you referred to when we first started this session. It is at divider 13 in the same bundle, please. It is page 82. This is a paper by William Graf et al, entitled “Autism Associated with the Mitochondrial DNA G8363A Transfer RNA Mutation”. It appears, as you will see on the next page, in the Journal of Child Neurology, and it was in 2000 that this was published. Can I just deal with the authors, please. They are described on page 82 towards the bottom left-hand corner as being at the Departments of Pediatrics and Neurology at the University of Washington, the Molecular Cardiology Institute in New Jersey, the Departments of Pediatrics, Neurosciences and Medicine at the University of California in San Diego. In terms of institutions, those would be regarded as respectable institutions?
Q I turn to the parts of the abstract so we can see what it is that is being summarised about this paper, so one-third of the way down page 82.
“We report a family with a heterogeneous group of neurologic disorders associated with the mitochondrial DNA G8363A transfer ribonucleic acid (RNA) mutation. The phenotype of one child in the family was consistent with autism. During his second year of life, he lost previously acquired language skills and developed marked hyperactivity with toe-walking, abnormal reciprocal social interaction, stereotyped mannerisms, restricted interests, self-injurious behaviour, and seizures. Brain magnetic resonance imaging (MRI) and repeated serum lactate studies were normal. His older sister developed sign of Leigh syndrome with progressive ataxia, myoclonus, seizures, and cognitive regression. Her laboratory studies revealed increased MRI T2 –weighted signal … elevated lactate in serum and cerebrospinal fluid…”
And there was also muscle histochemistry carried out in respect of her. I am pausing here, because I do not want to read out more than I need to. Let us look at the case report, so the right-hand column on page 82, two-thirds of the way down. It says “Case Reports”. Then “The proband”, and then there is a reference to Table 1. Can you just tell us what the proband is, please?
A Basically the subject, the patient.
Q It then gives a description of the patient from birth and in the perinatal period. A few lines down:
“There were no growth or health problems in infancy. The patient sat by 6 months, walked by 14 months, and was reported to have about a dozen speech sounds by 11 months. He never developed more than 10 to 20 single words or two-word phrases. By the end of his second year of life, he had lost speech and play skills. At age 2 years, he was formally evaluated and was found to meet the essential diagnostic criteria of autism. By the time of a subsequent evaluation at 3.5 years, he still had complete absence of functional receptive and expressive language and marked hyperactivity, as well as a lack of emotional control with prolonged episodes of screaming and self-injurious behavior. He was never toilet trained. His parents described paroxysmal episodes of dissociative, nonconvulsive behaviors that suggested partial complex seizures.”
There is then a description of physical appearance and neuromuscular function and gait and balance sensation, etc. being normal. Then the next paragraph below it on page 83:
“Normal clinical laboratory evaluations included chest radiography, electrocardiography (ECG), echocardiography, brain magnetic resonance imaging (MRI), nerve conduction studies, and electromyography. A detailed but normal metabolic evaluation included cerebrospinal fluid lactate, cerebrospinal fluid pyruvate, serum glucose and fructose after loading and fasting, multiple serial plasma lactate and pyruvate measurements….”.
There was also an awake EEG. Then if we go to the next paragraph down:
“At the time of a formal neuropsychological assessment at age 4.3 years, the patient met the diagnostic criteria for autism based on the Autism Diagnosis Interview, a parent interview-based examination. From additional direct observation and testing, he also met the criteria for autism of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the Childhood Autism Rating Scale.”
And it gives the score, obviously confirming the diagnosis. The point I wish to ask you about in this case is not so much the outcome of their investigations but the type of investigations they were doing, because the clinical presentation of the proband, the young child, who eventually was diagnosed or confirmed to have autism, was not that dissimilar to many of these cases that were being looked at in ‘The Lancet 12’, was it?
A No, except it is part of a family with all these other disorders.
Q Then, if we look at the type of work-up this child was getting, as being reported in 2000, again it is very similar, is it not, to the sort of investigations that were going on at the Royal Free, including CSF, EEG and MRI?
Q And so what I suggest is, this is yet another example of a practice, I accept this time in America, showing that there was (and indeed probably still is) a range of approaches to children who are on the autistic spectrum. Because of the reported incidence of underlying medical conditions, whether it is 1 in 10 or 1 in 3, there are respectable practitioners who would use the type of investigations that were being used at the Royal Free?
A Yes. I come back to the point I made earlier. In fact, the CSF was normal. This is in the context of a family where we have known cases with a mitochondrial mutation. So yes, this is their practice, I accept, but it actually, in terms of what the yield is, that is to say, what the diagnostic value of the CSF, it is evidence in this case – it is only one case, of course – is that it was not informative.
Q I understand the point you are making but with respect I suggest it is missing the point. What I am trying to establish with you is whether or not there was a range of respectable opinion about how these children should be worked up. You have given your reasons for why you did it in your way, and one fully understands that, but I am suggesting to you is that there are other responsible practitioners who took a different and more interventionist line back in the mid-nineties?
A Yes. That is the case but nevertheless it is in the context of a much fuller assessment from a neurodevelopmental point of view than any of the cases at the Royal Free. So the point I was making is yes, it is accepting one aspect of what was done, but excluding others.
Q I now want to leave that topic to one side. I think I have exhausted that, and turn to the topic of bowel pathology, which will not take so long. For that, we will need to look at the literature again. Dealing with the bowel pathology, I think it is common ground that gastrointestinal abnormalities – I will call them GI problems for short – are a frequent occurrence in autistic children.
Q If we look at divider 5 of Professor Murch’s literature bundle, we see, do we not, starting at page 24, there is a paper by Horvath and others entitled “Gastrointestinal abnormalities in children with autistic disorder”. This was published in The Journal of Pediatrics in November 1999 and the authors, if we look at the bottom left-hand side of page 24, were at the Department of Pediatrics and Pathology at the University of Maryland School of Medicine in Baltimore.
Q Again, that would be a respected medical school, would it not?
Q If we look at the objectives set out in the box on page 24:
“Objectives: Our aim was to evaluate the structure and function of the upper gastrointestinal tract in a group of patients with autism who had gastrointestinal symptoms.
Study design: Thirty-six children … with autistic disorder underwent upper gastrointestinal endoscopy with biopsies, intestinal and pancreatic enzyme analyses, and bacterial and fungal cultures. The most frequent gastrointestinal complaints were chronic diarrhea, gaseousness, and abdominal discomfort and distension.
Results: Histologic examination in these 36 children revealed grade I or II reflux esophagitis in 25 (69.4%) chronic gastritis in 15, and chronic duodenitis in 24.”
If we just drop down to the conclusions in this box:
“Conclusions: Unrecognised gastrointestinal disorders, especially reflux esophagitis and disaccharide malabsorption, may contribute to the behavioural problems of the non-verbal autistic patients.”
Professor, I fully appreciate that gastrointestinal matters are not within your expertise, but the reason I want to ask you about this is the association of GI problems with autistic children and the point which has been made in that broad context in this paper. That is why I am focusing on it. Having looked at what they were doing, if we go to the right-hand column, three-quarters of the way down, we see:
“Many parents report gastrointestinal symptoms in their autistic child.”
Just pausing there, you would agree with that from your experience, would you?
A I would.
“However, until recently, gastrointestinal symptoms of these children received little attention.”
Would you agree with that?
A I would also agree with that.
“In 1996, D’Eufemia et al reported increased intestinal permeability in 9 of 21 … patients with autistic disorder.”
Were you aware of that?
A Yes, of course. As far as I am aware, that has been replicated, however.
“The report of Wakefield et al …”
And this is obviously going to The Lancet report in 1998 –
“ … represents the first effort to evaluate the gastrointestinal tract in children with autism.”
Would you agree with that statement?
A Yes, I would.
Q If we then go over the page to paragraph 2 on page 25, it then says:
“This report describes several gastrointestinal abnormalities in low-functioning autistic children and underlines the importance of comprehensive gastrointestinal evaluations.”
Then they proceed to set out the nature of the investigations which they carried out. If we go to the bottom of the left-hand column, under “Clinical Investigations”, a few lines down:
“The full upper GI workup included esophageal, gastric, and duodenal biopsies for histology, measurement of the digestive enzymes of the small intestine … and pancreas … and bacterial and fungal cultures.”
If we go to the right-hand column, three-quarters of the way down, they set out that they had obtained ethical approval and consent for the project. Then if we turn on to page 27, please, in the middle column under the section “Discussion”, four or five lines down, they say:
“A plausible reason for the paucity of GI evaluation of these children may be their inability to verbalise and describe their abdominal pain or discomfort and a lack of co-operation in non-invasive studies, such as breath tests.”
Would you agree with that suggestion?
“The upper GI evaluations of children with autistic disorder support the presence of a chronic inflammatory process in the gut, as reported by Wakefield et al.:
Then it goes on a few lines below that:
“In our study chronic inflammation of the esophagus, stomach, and duodenum was the major and most consistent finding.”
If we turn on, please, to page 28, in the left-hand column, a quarter of the way down:
“Children with autistic disorder frequently have loose, extremely foul-smelling stools and gaseousness.”
Let me just pause there. Do you agree with that?
“These symptoms are not associated with growth failure and cannot be explained by the limited diet preference of these children.”
Would you agree with that observation?
A No. I think we just do not know that. We just do not know whether that is true or not. The dietary preferences of children with autism are often extremely marked and unusual and of a kind that can give rise to all sorts of symptoms. So, no, I would question that.
Q Then towards the bottom of that column, the last paragraph:
“In summary, our findings suggest that GI abnormalities may contribute to some of the behavioural problems frequently described in these children.”
Would you agree with that proposition?
A I think it is something certainly well worth looking at. The general proposition, just to return to that for a moment, is that individuals with autism frequently have GI symptoms. That is uncontroversial and clear. It would be of potential value to understand what on earth that means. I agree with that. Therefore the investigation of those in more detail I would certainly support. I obviously cannot comment on the detailed investigations done, because that is outside my area of expertise, but I do agree that looking in more detail would be helpful. The paper focuses on a particular sort of approach and it does not deal with some of the known problems the other way round, that is to say, of the behavioural abnormalities which lead to gut problems such as pica. So it is one-sided, but I entirely support the notion that investigating this more thoroughly would be a useful thing to do.
Q Professor, that is the last of the literature from me. There is one small point and then I have finished. Can we turn back to Child 2, please, and take the Royal Free notes? Could you please turn to pages 340 and 341? Just so you know where I am going, you were asked by Ms Smith to consider the consent form in the Child 2 case for the colonoscopy and other tests carried out. The consent form appears on pages 340 to 341. In answering her questions, you told us that the format which you see on pages 340 and 341 is not something you had used or come across before. I think the gist of what you were saying was that it is neither like a clinical consent form nor a research one, although it contains some features, and I think you relied on page 341, where there is a mention of the right of the patient to refuse treatment, which might be akin to research type statements.
A Yes, indeed.
Q What I want to do is just to explore that with you, because what I am going to suggest – and I fully accept you may not have come across this format before – is that this would represent a standard consent form for use in clinical cases. That is where I am going. If we just look at page 341, we see that this effectively is giving advice to two people. The first part of this is giving advice to doctors. Is that right?
Q It is reminding doctors of the well-known fact that a patient has a legal right to give or withhold consent before they are examined or treated.
Q And that they have a right to withdraw that consent at any time.
Q It is a simple statement of the obvious and a reminder to the doctor that a doctor cannot just do what he or she wants, but the patient has to be the one to say yes or no.
Q The second part of this is addressed to patients. We see that on this form it says “The doctor dentist”, so in other words, it is meant to cover cases where dental treatment is being given as well. It sets out what the doctor/dentist is meant to do, in other words, explain the proposed treatment and alternatives and it says that the patient can ask any questions and seek further information and can refuse treatment.
The latter part under the last bullet point deals with the training of health professionals, telling patients that doctors may be under training and, in the last sentence, that the patient may refuse any involvement in a formal training programme without that adversely affecting their care and treatment. Keeping that page open, could I ask you to go to bundle FTP1, please, page 234? What we see at page 234 of FTP1 is the consent form which was appended to the 172-96 application to the ethics committee. If we look at the wording, we see it is really a different type of form, is it not? It says:
“I have read and understood the aims and nature of this study.”
So it is using the language of study.
“I hereby agree to let my child … ”
Then details are to be inserted –
“ … take part in the study. I understand that I can withdraw my child/ward from the study at any stage without prejudicing his/her management or treatment in any way.”
This is actually drawing a distinction, is it not, between participation in a study for research purposes and saying that if they do not want to continue with it, it will not affect what clinical treatment or management they receive.
A Yes, that is right. What it does not say of course is what they are consenting to.
Q I am not suggesting that is an ideal consent form; I am just looking at the language used. Indeed, the ethics committee said the form needed to be changed. I am not going to the merits of the form; it is just the language which is used. If we go back to Child 2, we were looking at the consent form at pages 340 to 341, if you just turn on to page 346, we now see the consent form – it is actually in bold type – for research biopsies, in other words, the extra biopsies being taken under colonoscopy.
Q It is clearly addressed to the parents of the child, it says the child has been referred for diagnostic colonoscopy, it describes how the biopsies would be taken and it says this:
“It is therefore of great value for laboratory research to have such biopsies available to study how inflammation in the bowel develops and is influenced by treatment. Your permission is asked to agree for two extra biopsies to be taken for these purposes.
Whether or not you agree to this will in no way influence your assessment or treatment.”
Again, the language which is being used in this consent form for research purposes is very much, “This is additional, this is research; it will not affect the clinical management of your child.” Do you agree?
A I do agree.
Q Can we then see what example we have of a consent form used by another hospital? By chance, we have it for Child 3.
A Before we leave that, can I just make two comments? I may have mis-remembered, but surely it is not actually two extra biopsies, but five. Is that not correct?
Q We can check the detail of that.
A The other is that this deals with the colonoscopy; it does not deal with the extra specimens being taken for other purposes.
Q You miss the point of my questioning, Professor.
A I accept the point that this is dealing with the research aspect. All I am saying is that it only partially covers.
Q So your concern is?
A I am making an observation, rather than a concern. The consent form on the research side I think has the number of biopsies wrong, although I am open to correction on that, but it also does not deal with the specimens being taken other than from the biopsies of the gut.
Q Professor, I think you misunderstand the point I am suggesting to you. The Panel has already heard evidence that the consent form we see at page 346 was the standard consent form used for all children undergoing colonoscopy when they came into this department.
Q This has nothing to do with the proposed 172-96 project.
A I accept that.
Q I am not suggesting to you that this child or any other of the children were consented for the 172-96 project. I am not going down that path.
Q What I want to do is to look at Child 3, please, in the local hospital records. You will still need to keep your bundle for Child 2 at pages 340 and 341. If you turn, please, to page 36 and have open as well page 340 from Child 2, looking at the local hospital record for Child 3 at page 36, we see again this is a consent form for a medical or dental investigation, treatment or operation. We can see the hospital is the Alder Hey, it relates to Child 3 and we then see set out a box for doctors or dentists and, if you compare it with page 340 for Child 2, although the format of the typing is different, the content and the information which is being given is, if not identical, very close to it.
A I accept that.
Q The same for the patient/parent/guardian. If you turn to page 37 and compare that with page 341, it is giving the same advice firstly to the doctors and dentists and then secondly to the patient, as we see in the Child 2 case.
A Yes, I accept that.
Q What I am suggesting to you – and I fully accept you may not have come across the format of a consent form like this before – in fact can we take it that this is a standard consent form in clinical instances rather than research?
A Yes, I accept that.
MR HOPKINS: Professor, that is the end of my questioning. Thank you.
THE CHAIRMAN: Thank you very much indeed. It is now 1.05, so we will now adjourn for the lunch break and resume at 2.05. Professor Rutter, you are still under oath, so please do not discuss your evidence with anyone.
THE CHAIRMAN: Mr Coonan?
MR COONAN: Sir, I have no questions, thank you.
THE CHAIRMAN: Mr Miller?
MR MILLER: Sir, just as you came in I was discussing timetabling with Ms Smith. This witness cannot be here on Thursday or Friday but we will comfortably finish him tomorrow. I am aware that one of your number has to go early today. I will not finish my cross-examination by the time we rise at 3.45, but because I want to go through some of the individual cases I think if I may I would like to postpone that until tomorrow morning, because otherwise we will be jumping up and down, going through bundles; not to the same extent as we went through with the professor in chief but it will be easier to do it in that way, so it may be slightly earlier than 3.45 when we come to a convenient point.
THE CHAIRMAN: I am sure that will be a much more sensible way to do it. Thank you. Ms Smith?
MS SMITH: Rather than interrupting Mr Miller’s train of thought now, before you go at the end of the afternoon I was going to indicate to you the implications for the timetable for the rest of the week, and I am in a position to do that, unless you would like to know now.
THE CHAIRMAN: I am happy if you want to address us on that point now or later, I am quite happy.
MS SMITH: All I was going to say was that in view of Mr Coonan’s indication I am somewhat more relaxed in terms of whether we will finish Professor Rutter tomorrow. It seems to me that we certainly will, even building in, of course, the Panel’s questions, which may be some time, and any re-examination I have.
Sir, we have a clear day on Thursday because the timetabling is such that Professor Booth, who is my second expert is coming on Friday morning. It does seem to me that given the density of some of the evidence you have been hearing that is quite a useful day in the middle because it will enable you to look at all Professor Rutter’s evidence in its final form before we go on to Professor Booth, and so, as I say, we will be sitting again on Friday, if you are happy with that, and I will call Professor Booth then.
Professor Rutter I know will be profoundly relieved to hear that we will be finishing with him tomorrow afternoon.
THE CHAIRMAN: Yes, that seems quite satisfactory unless Mr Hopkins, Mr Miller or Mr Coonan have any comments or observations to make about what Ms Smith has said?
MR COONAN: None at all, sir, thank you.
THE CHAIRMAN: Thank you Ms Smith. Hopefully we will finish with Professor Rutter’s cross-examination and the Panel’s questions by the end of tomorrow.
THE WITNESS: Thank you.
THE CHAIRMAN: Thank you. Mr Miller?
Cross-examined by MR MILLER
Q Professor Rutter, we will go much more quickly if you agree with the questions and propositions that I put to you. (LAUGHTER).
A Thank you for that warning.
Q I think you qualified in medicine in 1955.
A I did.
Q And had training posts in neurology and paediatrics and general medicine.
A That is correct.
Q And you then began to specialise in psychiatry?
Q Presumably that was at some time in the late 1950s?
A Yes, it was. I had an early psychiatric and neurology post but basically it was when I came to the Maudsley Hospital in 1958, indeed.
Q You became a consultant in 1966 ---
Q --- at the Bethlem Royal and Maudsley Hospitals.
Q Are they exclusively psychiatric hospitals?
A No, they include both neurology and neurosurgery.
Q So “head” in one form or another?
A Yes, yes, that is true.
Q They deal with adults and children do they?
Q And there are inpatient wards for adults and children are there?
A Yes, there are.
Q And outpatient clinics for adults and children as well?
A Yes. I should just say for the sake of correctness that they also include liaison wards of a general kind, so that Dulwich Hospital was one of the places I worked, for example, which is part of King’s College.
Q So there are satellites outside the main hospital?
Q I think the two hospitals provide also acute care for other hospitals in the region?
A Yes, yes, they do.
Q I want to see if I can understand how your role as a psychiatrist, to use a horrible word, interfaced with other clinicians, first of all in a clinical setting and secondly in a research setting.
Q We have had a bit of insight into that from Dr Berelowitz, but, of course, he is based in a London teaching hospital which also has the function of a district general hospital, so he has everybody on site with him in different specialties.
Q What is your clinical experience, in terms of how you would come across and work with, collaborate with, other specialists?
A Well in a variety of different ways, and it would vary throughout my career, but, for example, for quite a while I was much involved with head injuries and at that time had a lot of liaison work with neurosurgery and was also involved in research that went to other neurosurgical units; also contact with neurology but it was predominantly with neurosurgery. I did work, as I mentioned, at Dulwich Hospital, which was a general hospital, and so I had a fair amount of contact at that time with the range of conditions that come along. I have had involvement with paediatrics in a number of different settings, more research than clinical, because I have not done paediatric liaison work of a kind that one would do in a general service; I had a lot of contact with speech pathology because of my interest in speech and language disorders and as part of that I had a lot of contact with paediatric neurologists and audiologists; at the time I was chairing the Communications Disorder Working Party of what was then called the Spastics Society and we used to go round centres looking at children with a range of problems, all of which involved language in one way or another, but including a broader range.
Q We are still talking about the clinical setting are we?
A Yes, yes.
Q So that is going round a specific disorder in which other specialists who had been dealing with the problems (not necessarily medical) but other specialists, and it would be a collaboration to identify what, if anything, could be done for the people who were there, presumably?
A Yes, indeed.
Q Dr Berelowitz told the Panel that as a consultant child psychiatrist in a teaching hospital which contained those many specialisms he had a particular role in collaboration with the Paediatric Gastroenterology Department, which involved him seeing them as a clinician to deal with problems that may have been caused either before or during their admission to the unit, so he would lend his expertise to that department to see if he could help the children while they were being cared for by the paediatric gastroenterologists.
Q You can well understand, I imagine, that sort of role?
A Yes, indeed.
Q And that would clearly be a clinical role in which he would assume some responsibility for the patients.
Q Did you ever have that function in collaboration with a paediatric gastroenterology department?
Q There is no sting in any of these questions, I can say that, it is just to get the flavour of how different specialisms worked together and what they bring to bear on the issues that have to be considered. Have you been involved in a research setting with a paediatric gastroenterology department?
A Not directly, no.
Q Is yours a university department? When you had the chair of child psychiatry was it a university department?
A Yes, it was.
Q So I think it follows from that that with most university departments there is a research or academic background noise about a lot of the work that is done.
A That would be correct.
Q We have heard about the differences between the various people within the paediatric gastroenterology team but you would see the professor, the senior lecturer and the lecturer as being part of the academic team, as well as providing NHS care?
A Yes, that would be right, although for quite a long time I did a very large amount of clinical work and that involved a very wide range of problems.
Q Whether the NHS gets the benefit, whoever pays for it, whether they get the benefit it, all of the people who have an academic appointment clearly have an honorary appointment within the National Health.
Q It looks as though there was no division in this department between those who were hands-on and those who wrote the papers, they all seemed to be hands-on.
Q And that is as you expect ---
Q --- and that is the way the combination works of academic and NHS service practice?
A Yes, I agree.
Q I would like to ask you about inflammatory bowel disease again, which is a feature, not a central feature but a feature of this case, and there has been quite a lot of evidence about it, but you have concentrated on the other aspect of the case as identified in the papers. Again, you have not been involved in the investigation of inflammatory bowel disease?
A Not as such although I have quite often been involved in the investigation of bowel problems in autism because that is such a common feature.
Q One of your last answers, I think, to Mr Hopkins was that it is a recognised feature of autism that it can affect the children in strange ways (or strange to us anyway) and they may have very strange selective diets, self-chosen diets, and have their own problems so they do go together.
Q Purely in terms of inflammatory bowel disease ---
A No, that is not an area of my expertise.
Q In your clinical capacity when you were providing NHS clinical care, which I assume you did?
A Yes. I still do to some extent.
Q You might have somebody referred to your hospital under your care.
Q So the printed form might say “Under the care of Professor Rutter” ---
Q --- stamped on the top?
A It might well do I suppose.
Q Presumably you had a team as well who would be working with you? If they were coming in to be seen/investigated/worked up/structured assessment, whatever, there would be a team working with you?
Q Although, as you have said, you would be in overall charge and have overall responsibility for what happened, each of the clinicians involved would have their own personal responsibility as well, would they not?
A They would. My own practice is perhaps a little atypical in that, in that it was exclusively – well, not exclusively – almost exclusively outpatient practice so I would actually see all the cases, which would not apply to all centres I have to say.
Q So that would mean you would be in a position of somebody to whom the patient was referred; there would be an outpatient appointment and you decide what was to be done after that?
Q But your experience, presumably, of inpatient care, which you must have had.
A I had some, yes.
Q But the consultant in overall charge is in overall charge and bears general responsibility, but the doctors, some of them senior working under him, clearly have their own responsibility for the patient in the way that they decide to treat him?
Q I want to go on to a slightly different topic: have you ever before had to go through a group of patients’ case notes and documentation to decide whether or not investigations carried out amount to clinical care or research?
A I do not think I have in relation to that specific question, no.
Q Because that is what you have done in this case, is it not?
A It is indeed.
Q You were provided with case notes and had the good fortune to see all of the case notes from all sources.
A I am not sure that I would describe it as “good fortune”, but, yes.
Q You were better informed than some others in the case, but you did see the case notes and looked at the individual cases from various aspects, not simply psychiatric, and then formed a conclusion as to whether or not in your judgment investigations amounted to clinical care or research.
Q You have explained that to us what your views are and we will come to that in a minute. The expertise that you bring to bear in that exercise is (a) many years of clinical practice in psychiatry, that is the first thing.
Q (b) many years of involvement in research?
Q And (c) many years of membership of a research ethics committee.
A Yes, correct.
Q So you have combined the knowledge that you gained from that and that is the expertise really that you are using, but presumably, professor, you would be fair enough to accept that you can only go on the documents supplied to you and your experience applied to those documents?
A Of course.
Q And that you have had no information about the precise circumstances of each referral in this case, taking that as an example, because I think you have seen the transcript evidence of the GPs and you have not heard any of the background from the parents or why they were going to the Royal Free, and thirdly you have not heard, obviously, from any of these doctors?
Q Distilled down, what you say is that in your opinion, from your experience, it smells like research, basically?
A If you like, yes; an overall judgment, yes.
Q Rather than clinical care?
Q Recognising, obviously, that you have no first-hand knowledge of how gastrointestinal problems may have been investigated in 1996?
A Sure, that is correct.
Q Near the end of your evidence you put forward, I think you numbered it four but I read five reasons why you thought that this was research rather than clinical need, and it may be that I divided up one of them, but the first was heterogeneity of the presenting signs and symptoms which in your judgment required, if this was clinical care, different responses for each child?
Q I think you are concentrating there on the developmental problems, are you not, rather than the gastrointestinal?
Q Secondly, the timing of the investigations, that is the lumbar puncture, the MRI and EEG, before a thorough investigation, neurological and neuropsychiatric had taken place?
Q Thirdly the fact that there was a programme of investigations and you made the point also that there are some references, some references, in the correspondence to “trial”.
Q Fourth, that in some of the referrals there is no mention of gastrointestinal problems. That is the referral letters, even though the referral was being made to a paediatric gastroenterology department?
A That is correct.
Q And fifth, the justification put forward to the ethics committee was that the children to be investigated would have disintegrative disorder when the children in The Lancet paper, you say, clearly did not fall into that category?
Q As far as the fifth one is concerned, I suppose that actually does not point towards a research into disintegrative disorder, because clearly they did not fall in that category. Maybe that is the fifth one – it did not exist. That is just an observation that you made?
A I think that is just an observation, yes.
Q These are your overview features that you rely upon and there were others along the way, individual cases, which we will have a look at (or some of them, anyway, probably tomorrow), but this was your overall conclusion?
Q In that list you would have to accept that clearly in relation to the timing of any investigations that applied to all of the children but in other areas, such as the referrals not having a reference on the face of them to gastrointestinal problems, that is very much the minority in the letters that we have?
A Yes. I think it is.
Q I would like you just to consider something which we have not really touched on, except at the end of each case when you pointed out from the point of view of dates that a child could not be included in 172-96. Can we just look at 172-96 for a moment? That contemplated at the beginning, when it was being put together, a study of 25 patients which involved a number of examinations, investigations and procedures which were said to be clinically indicated in view of the signs and symptoms manifested by the pts?
Q It was envisaged, and it is in the protocol, that these examinations, investigations and procedures would be carried out over a period of six days following admission to the hospital on Sunday?
Q And the timetable for these various examinations, investigations and procedures was set out in the application to the ethics committee?
Q It is page 20 of the original application. FTP1 at page 231.
A Yes, I have it.
Q The timetable, which is included in the protocol, or in the application anyway, has admission on the Sunday with consent and a history and an examination, and we have heard from Dr Casson that not only with these children, but his general practice was to try to get in there on the Sunday in order to do this admission note, to see the children on admission?
Q And for a large number of the ones that we have, anyway in The Lancet paper, he was the junior doctor who clerked the children in. But the history and examination take place on the Sunday. Blood sampling, colonoscopy and upper GI endoscopy, MRI and lumbar puncture were to take place on the Monday, according to the timetable?
Q EEG and evoked responses on the Tuesday, barium meal, follow-through and Dr Berelowitz’s assessment on the Wednesday, and Dr Harvey’s assessment on the Thursday. That was written into the timetable at the outset?
Q Then we have heard from others during the course of the trial that on the Friday there would be a meeting about the cases, and the children would then be discharged. So it follows that certainly as far 172-96 is concerned it was contemplated from the outset that both the psychiatric and the neurological assessments would follow the colonoscopy, lumbar puncture, MRI and a barium meal?
A Yes. That is correct.
Q The application was made – I think we can ignore any other date for the purposes of this exercise – to the ethics committee on 16 September 1996 and approval was given by a letter dated 7 January 1997 which contained a condition, amongst others, which we will look at. We will look at the letter in a moment. There was a condition that only patients enrolled after the date of the December meeting would be considered to be in the trial and, realistically, they did not get that until the Sunday after 7 January because the first communication about that and other conditions was in that letter although, as the letter says, the project was approved. So far, so good?
Q We have the timetable not only of what was envisaged in various investigations, but also of how it got to the approval stage. As far as The Lancet reported children are concerned, the eleven who form part of the charges were all referred between 9 February 1996 and 5 December 1996, so all of them had been referred before approval was given, and all but three of them had been investigated before 7 January 1997, the date of the letter of approval. The substantial majority had already been through the system before approval was given?
A In terms of outpatients. Not in terms of ---
A Oh, I see. Okay.
Q And the ethics committee clearly was aware that a number of these children had already been investigated because Professor Walker-Smith told them of this in his November letter.
Q So whatever the status of the application in terms of whether it was approved or not approved, in November 1996 Professor Walker-Smith was telling Dr Pegg of the experience that they already had in investigating these children. The Trust also knew about the fact that children were being investigated before Dr Pegg’s letter because you may or may not have seen a letter written by the Chief Executive of the Trust, Mr Else, to Dr Wakefield, on 4 September 1996. Do you remember seeing that?
A I do not remember seeing that, but I may have done.
Q Just have a look. It is FTP1 at page 192. This is a letter written by Dr Wakefield, following a discussion, we were told, by Mr Else. It is dated 4 September 1996 so before the application was actually made?
Q And you will see the reason for it in the letter itself. The second sentence of it – it relates to the Special Trustees paying for research assistants.
“I understand that children who would fall within the scope of the project are currently being seen at the Royal Free as part of the normal process for the delivery of health care and that tests, investigations and procedures that are clinically indicated are being undertaken.”
Q So that is something which the Chief Executive had been told, presumably before that meeting. And the application, which he was suggesting needed to be made, also makes the same point, does it not? It asserts on the base of it that – paragraph 11 which we have seen a number of times already – in view of the symptoms and signs manifested by the children all of the procedures, or the majority of the samples, are clinically indicated?
Q So in terms of the paediatric gastroenterology department certainly, and in fact all of those who subsequently became or were involved in seeing these children, the Trust, through Mr Else and the ethics committee, Dr Pegg, were being told that the test procedure and investigations were clinically indicated?
Q You were asked yesterday about what is the position of an ethics committee. Does it have to accept what clinicians tell it about whether things are clinically indicated, and you said, “Well, they cannot go behind what is being said unless they have special expertise”. But it looks as though the ethics committee did not take that statement completely at face value, otherwise that would be a simple rubber stamp for the project. Professor Walker-Smith was asked, effectively, to justify it, was he not?
A He was.
Q Would you look at Dr Pegg’s letter, 15 October 1996. It is the same bundle, 265a. I am not sure this is a letter you ever saw when you considered the papers, because it did not emerge until the hearing had started. You may have seen it since – I do not know. Do you remember seeing this?
A I do not know, but I may have done. I have seen so many papers now.
Q It did not arise. It was not in the bundles when we started.
Q So you may well not have seen it unless it has been passed to you since the hearing began.
Q But this is, in fact, Dr Pegg’s letter. Look at the green one – 265a.
A All right. Okay. No – I have seen this letter.
Q If you look at the green one, it was rather strange because in the original bundle we just had the reply from Professor Walker-Smith, but here is the letter which prompted that reply.
Q What he is saying: he is not on the face of it accepting that merely because a clinician says something is clinically indicated he is obliged to accept it because he is asking about the investigation, in this letter?
Q And he is asking about them by reference first of all to the BPA guidelines?
Q And the BPA guidelines were including with that letter at page 265c, two pages on.
Q And he is doing it quite clearly by reference to that. In sub-paragraph 2, if you just turn back to 265a:
“2. It is a very intensive regime involving some unpleasant investigations – LP, endoscopy, MRI etc. some of which may require a general anaesthetic. I would consider the risk of such procedures to be ‘High’ (BPA guidelines classification). The guidelines state ‘It would be unethical to submit child subjects to more than minimal risk when the procedure offers no benefit to them, or only a slight or very uncertain one’.”
Q That is a clear reference, is it not, to the words of the BPA guidelines?
A Yes, it is.
Q The BPA guidelines have nothing to do with clinical care. They are all to do with research?
Q So he is effectively saying, “This looks for research purposes as if it is high risk and if it is high risk, identify the benefit”. That is what he is saying, is it not?
A Well…. Or he is saying, “I have assumed that there are aspects of this that he is uncertain about and, in particular, he is asking for a firm assurance that there is a clinical need.
Q Is that right? If you look at what he is saying, he has identified lumbar puncture, endoscopy, MRI, some of which may require GA?
Q “I would consider the risk of such procedures high,” and then he refers to research guidelines. Then he quotes from the guidelines which, again, relate to research rather than clinical care.
“It would be unethical to submit child subjects to more than minimal risk when the procedure offers no benefit to them, or only a slight or very uncertain one.”
A Yes. I am referring, if I may, just to come back to (a) and (b), where the (a) is asking for confirmation that all of this would happen even if it was not in a trial, and (b) is asking about benefit.
Q I was going to come to that.
A I am sorry.
Q On this paragraph 2, he has lifted the quotations from the guidelines which apply to research, and said, “Look, this is what happens if you are considering doing these investigations for the purposes of research, you have to identify the benefit.” Then he deals with the next part of it – as you say, (a) and (b). “Please confirm that they would add this anyway,” and then reverts back to the research point?
Q Which is what benefit they would get which again, as I can say for the third time, has nothing to do with clinical care, does it?
A Well, it does, in that if it is clinical care, then the benefit is crucial. Obviously the benefit is not necessarily in relation to a therapeutic step. It could be in relation to diagnosis.
Q If it was purely treated as clinical care, the research ethics committee would not be involved in it.
Q This research ethics committee would not be involved in it because if a patient was referred to this unit, and they were investigating for the purposes of trying to help the child, it would be a matter for their clinical judgment as to what they did. It is only if it becomes something which is research, or involves research, that the ethics committee becomes involved.
Q My simple point is that Dr Pegg, anyway, seems to be policing this to the extent that he is saying “Identify under the BPA guidelines what the benefits would be. Are they ‘slight or uncertain’”, which again are the words drawn from the BPA guidelines on research on children.
A I cannot speak for what was in Dr Pegg’s mind. I had read it slightly differently, and as to whether your interpretation or mine is correct I have no idea. The key thing here is, I think he is asking for reassurance that the child would undergo this regimen if it was not in a trial. That is the sort of question that the ethics committee needs to know about and needs a firm statement. I presume, but I do not know, that this arose because of uncertainties within the ethics committee as to whether this was research or routine clinical care.
Q We have seen a letter. I will not get involved with what happened with the research Committee because we have seen the letter in which one of the members – a lay member, I think – was concerned about the intensity of the regime.
Q But the simple point – and then perhaps we can move on – is that he is not only just asking for an assurance that it would be done anyway, but he is also asking Professor Walker-Smith to identify the benefit, which is (b)?
A Yes. It is (b), yes.
Q And (b) is drawn directly from the BPA guidelines. You had seen before Professor Walker-Smith’s answer, which is at page 291. In (2), he is responding to directly the points that have been put by Dr Pegg, is he not?
Q I am not going to deal with the point about the hopeless prognosis, because he will explain that in his evidence. You will see that it is in quotation marks, “hopeless prognosis”. Just to reassure you, he is not saying that all children have a hopeless prognosis; it is a quotation and again it is a matter of evidence as to what he had in mind when he said it. I am going to ask you about (a) and (b) under paragraph 2, which starts four lines up:
“We have so far investigated 5 such children on a clinical need basis, all in fact have proved to have evidence of chronic bowel inflammation. One child has already had a significant response to enteral feeding. Certainly there is a measurable benefit to the child:”
Then he identifies those first as:
“Establishing a diagnosis and excluding metabolic and other causes”
Which may or may not be part of the gastroenterological work-up, but he is certainly flagging up the exclusion of metabolic and other causes. Then (b):
“Commencing on a therapeutic regime.”
Which again, may or may not be directed at the gastrointestinal side of things, but it is likely to be the latter, is it not?
Q Then the last line:
“This whole study is parent/patient driven as every case referred has been initiated by the GP by the parents of the child.”
That is not terrible attractive English. I was going to say that English is not Professor Walker-Smith’s first language, but I think probably, even as Australian, he would say that it was! I had understood that to mean that the parents are, through the GP, initiating the referral. That is how you have understood it, is it not?
A Yes, it is.
Q The permission for the proposed study is in the same bundle at page 358. The only thing that is clear about it is that the project was approved at the meeting of 18 December. I will come back to that in a moment, because what is unsaid in it is any limitation on the extent of the permission. The first condition which is imposed is that here should be no backdating, effectively, and that anybody who is going to be considered to be in the trial should have been enrolled after the date of the December meeting.
Q Although that condition is not imposed until 7 January, which is when the notification is given. It is not clear from the letter or any other correspondence which you or I have seen, but Dr Pegg told us in evidence that the reason that condition was imposed was because he had been told about other cases already having been investigated. So that is the first condition. No Shilling test. That is a clinical matter, is it not?
A It is really, yes.
Q Thirdly, that the consent form was to reinforce the possible complications of lumbar puncture, which again, if this was accepted as being for clinical need, would not be a matter for the ethics committee, would it, because lumbar punctures are done by doctors without having to go to the ethics committee?
Q The letter of 7 January is silent as to any suggestion that all that was being approved was the collection of cases for report and publication. There is no reference to that on the face of the letter, is there?
Q In your evidence yesterday – and it may be because it was near the end of the day – you said that the ethics committee had some doubts about whether the proposed investigations were clinically indicated because of the repeated requests that they made and that they asked for that assurance not once, but several times. Could you help me about that? When were the repeated requests made to Professor Walker-Smith or anybody involved for an assurance that these were clinically indicated? We have seen one; we have seen the one in the letter from Dr Pegg.
A Yes. I may be in error in terms of there being several. What I was referring to was the fact that there had been several meeting before that and therefore, during those, various questions had been asked. You are correct as far as I can recall in saying that this is the one and only time when there was a specific request for an assurance on clinical need, but of course the issues more generally certainly had come up earlier.
Q We of course are not party to what happened in the ethics committee itself, because none of the practitioners were there. The first notification appears to be the letter from Dr Pegg, which is responded to in Professor Walker-Smith’s letter which we have just seen. It is true that a point was raised later by Professor Howell with Professor Zuckerman, but that was in the middle of 1998, which is some time after The Lancet paper was published and related to the continuing need to investigate children after that.
Q That, as far as we can see from the correspondence, involved communication only between Dr Pegg and Professor Zuckerman as far as that issue is concerned. Do you recall that it was at that time, the first time on paper anyway, Dr Pegg said, “We were only giving approval for the collection of cases and writing up publication”?
A Yes. Whether there had been previous reference to that, I am afraid I do not recall.
Q I have not seen any. If I am wrong, I will be told that I am wrong. That is the history of first of all the timetabling of the application and also the concerns which were raised by the ethics committee and how they were responded to by Professor Walker-Smith. Also there is in that letter another condition, which is that the consent form should be included in the case notes.
Q So in practical terms, it would follow that if anybody was going to be recruited into this trial, it would have to be after 7 January 1997.
Q You have taken the view that the children reported in The Lancet were the product of the study contemplated in 172-96, had you not?
A I have.
Q But that cannot be right, for a number of reasons, Professor. The first and most obvious is that most of The Lancet children had been investigated before ethics committee approval had been given to the knowledge certainly as far as five out of 12 are concerned of the Committee. So investigations had in most cases taken place and that was the end of it by the time that permission was given..
A Yes, but of course it is not just that they had been investigated before, but extra specimens had been taken for research purposes. So the ethics committee was entirely within its responsibilities to say that those cannot be included in the trial, because the question of seeing them for clinical need is one thing, getting extra specimens is entirely another. That had to be an ethics committee responsibility and my understanding – correct me if I am wrong – is that that is what is being referred to and that is where the stipulation about the cases having to have been included only after approval had been obtained.
Q It could not possibly relate to anybody who had been investigated and extra specimens taken, if they had been, before that date, because they were expressly excluded. In other words, the investigations give rise to the extra specimens. Whether they are under an ethics committee approval separate or under the general ethics committee approval for an extra two biopsies which you were shown earlier on, we do not know. The investigations: colonoscopy, MRI, lumbar puncture (if appropriate) EEG, had all taken place before ethics committee approval had been given in nine out of the 12 Lancet cases.
A Yes, but as I say, extra specimens were taken for research and ethics approval had not been given for that.
Q I am talking about the investigations which are the subject matter of a number of the subheads of charge in this case. What is clear from the timetable – and we can go through it identifying them case by case, but I believe that I am right – is that all but three of those in the charges had been investigated before approval, which means they had obviously had a colonoscopy, MRI, EEG, whatever, before that date. Added to that, the process of the investigations, that is, the idea of them coming in to be seen in the paediatric gastroenterology department, had started long before any application was made to the ethics committee, because we have seen in the case of Child 3 that the first contact was in February 1996, which is well before any protocol, any application, has been made, if the application was made in September 1996. Over the period which followed after that, children were being referred and some of them were being investigated, until you get to the stage when, in January, after 7 January 1997, only three of The Lancet children had yet to be investigated. You treated them all as being part of 172-96, even though some of them entered the system in February 1996.
A Yes. I am afraid I am confused by the point you are making. Let me try and explain what I see and then please correct me if that is inconsistent with what you are trying to present. The ethics committee has to have responsibility for approving or disapproving, as the case may be, the taking of extra specimens. That is standard practice. The point that I was making was that these extra specimens were taken before ethics approval was given. That seems to run completely counter not only to what the ethics committee specified, but counter to accepted practice. So the issue of the clinical investigation, i.e. separating that off from the extra specimens, is not really the issue that I was focusing on.
Q I realise it was not the issue that you were focusing on, but I am trying to identify from you how, if an ethics committee gives approval for what we are told by Dr Pegg was the collection of cases and the publication of the data, which was the only ethical issue which he says existed and that is what he wrote in his letter to Professor Zuckerman, if that is given in January 1997, how it can be said that investigations carried out before that application was ever contemplated, or certainly after it was approved, can be said to be part of that study.
A I am afraid I do not share your puzzlement on that. It seems to me reasonably straightforward.
Q What was happening, and it was what was declared to Dr Pegg, was that these children were being seen and investigated within the gastroenterological department with assistance from other clinicians for a period of months before ethics committee approval was obtained. Those investigations were being carried out, as the clinicians explained to the ethics committee, on the basis of clinical need. The evidence will be that is what they were doing and that is in fact what they were telling everybody they were doing at the time, before the ethics committee gave any permission at all.
A But they were also taking extra specimens.
Q Where is the evidence for the extra specimens, apart from the general ongoing research permission that they had to take two extra biopsies? Where is the evidence of the extra biopsies that you rely upon?
A There are clinical reports on those biopsies which appear in the records.
Q Those are clearly biopsies which were used for the diagnosis of the bowel pathology which was reported by the histopathologists at the time and discussed at the weekly meetings.
A It goes beyond that, in that it deals with measles for a start off. So that those were part and parcel of the investigations being done at the time and there is no way in which that could be seen a routine investigation at that time; it is a hypothesis being put forward.
Q We have seen other evidence of measles being looked for in other departments in one particular case. If these children are being investigated and biopsies are being taken which are being reported upon by Dr Davies and discussed at the meeting for the purpose of the clinical care and management of the children, why is that research, merely because another biopsy has been taken at the same time? How can that render the biopsies taken as a result of a colonoscopy undertaken for clinical care research, because it is part of the care of the child?
A I cannot really comment on the colonoscopy, because that is not my area of expertise. My arguing, as I have, and still do, that the overall impression given of this being research rather than clinical care comes from several different items, some of which we have touched on, but let me just go through them again. Firstly, there was a standard protocol being followed for a very heterogeneous group of disorders and, moreover, the decisions on applying this were done before clinical assessments were made in many of the instances.
Q Just so that the Panel have it clear, this is in relation to the developmental disorder?
A Yes, indeed. Secondly, the way in which the cases came we know was stimulated by parents who in some cases were interested in the trial, as distinct from seeking help for a particular aspect, and many of them were involved in litigation. It is difficult to sort out what was in everybody’s minds, but clearly the timing coincided and, moreover, the way it was put coincided and, moreover, the funding from the Legal Aid Board was in relation to the admission of these patients.
Q Let us be very careful. This is the dangerous thing about poring over the documents and coming to conclusions from that. The case which is being advanced is that these children, all of the children, were admitted in the National Health Service to a National Health Service ward and were treated on a National Health Service basis. As far as the funding which concerns Dr Wakefield is concerned, that does not affect the way in which the children were cared for, because they clearly came through by extra contractual referrals, because they came from other parts of the country. Do not just, with a broad paintbrush, say the Legal Aid money was for the investigations, because there is absolutely no evidence that that is the case. The contrary is the case: that the payment for the care and investigations came through the National Health Service for all of these children, with the exception of one American, who is not here.
A Well, with respect, that is true in the sense that it was covered by the NHS, but the Legal Aid Board was providing money for those admissions.
Q That is nothing to do with the Gastroenterology Department, Professor Walker-Smith was ---
A Okay, no I am not commenting as to who is responsible for it.
Q It is important because the correspondence, which we have seen, is between Dr Wakefield and solicitors acting for the children. There is no implication that it involved the other two doctors at all.
A No, I agree with that. I accept that. Can I come back though to the “hopeless prognosis” thing which you point out is in inverted commas, and I accept that, and, of course, I have not heard and will not hear Professor Walker-Smith’s explanation of what that is all about, but what it does indicate here is a clear statement about this being a group of children with a very bad prognosis and that this is put in a way that seems to apply generally to the group. I accept that he may or may not argue that that does not necessarily mean that there was exactly the same for each: I mean, that would be accepted, but it is clearly wrong in terms of the group of children with autistic problems being seen, so that as a statement it is highly misleading and the problem that I face is to know what conclusions to draw from that. The conclusion I have drawn is that although, of course, a gastroenterologist will have experience of lumbar puncture and will be perfectly entitled to order lumbar puncture, that Professor Walker-Smith in saying a statement like this, of a “hopeless prognosis” is making a wrong judgment in that all the evidence and follow-up studies indicate that that is not the case. The only alternative, which I have drawn back from because I saw no reason to go down that route, is that he was seeking to mislead the Ethics Committee, so I think that in terms of clinical need the difficulty is that the decisions were being taken in relation to a clinical phenomenon in which this statement is highly misleading.
Q I cannot debate with you about that. The Panel will hear, and I have said, it is in quotations and it relates specifically to the experience at the time from at least one of the cases, but what you have done, professor, which is, again I am not sure how helpful it is, you concentrate quite naturally, on disintegrative disorder, autism spectrum, as though that really is the fundamental point of investigation in these cases. I am going to come to this in a bit more detail tomorrow, because then you say, “Look, we can’t find disintegrative disorder here, there, it is not worked up properly”, whereas these children were being referred to the gastroenterology department and that is where the principal investigations were taking place, principally in relation to the gut pathology, as you would expect if that is the balance of the referrals. What we will come to later is whether or not anybody ever envisaged that the structured work-ups, structured assessment which you say is necessary, was ever going to be carried out anywhere in the hospital for these patients.
Q Throughout your evidence you say, “Well I look at Patient A, B, C, whatever it is, and I see no evidence of this and I see no evidence of a structured assessment”, it is quite clear from what Dr Berelowitz said right at the outset that that was not his role, he did not see himself in the role of doing that.
A I understand that.
Q So when you are looking for admission for clinical need it is substantially, if not exclusively, in the realms of the gastrointestinal pathology which you would have them to have expertise about.
MR MILLER: Sir, I do not know what your plans are. I know we have a cut-off point. Do you want to have a break now or do you want to break off now?
THE CHAIRMAN: I did say this morning that one of the panellists is not well today and so she has had to make an appointment with her doctor and she is going to see the doctor later this afternoon. Because we are going to have a shorter afternoon we would not want to lose any time. Ms Smith?
MS SMITH: Sorry, could I just rise to say as long as Professor Rutter does not feel he just needs five minutes, because being cross-examined is quite tiring.
THE WITNESS: I am perfectly happy to carry on.
THE CHAIRMAN: That is absolutely right and that is why I gave Professor Rutter the indication the other day that any time he feels under any kind of pressure or tired to give me a signal and I will be quite happy to give him a break.
THE WITNESS: I appreciate Ms Smith’s concern but I am perfectly happy to continue without a break.
MR MILLER: Sir, you were thinking of stopping at 3.45.
THE CHAIRMAN: Yes, between 3.30 and 3.45.
MR MILLER: If I can just go on until 3.30 then we miss out on the tea break but that may be better.
(To the witness) Professor Rutter, I think it is quite important that we grasp this particular nettle: you make the point, looking at all the notes: “Well I can’t see disintegrative disorder anywhere here with the possible exception of one atypical case, despite the fact that somebody who you say is highly experienced in the field, Dr Sheila Wallis, tentatively put it forward in relation to one of the others but you do your review afterwards and say, “No, I don’t see disintegrative disorder here.” It does not look from the papers as though anybody was searching for disintegrative disorder rather than seeing autism spectrum cases, does it?
A With respect, the application was made strictly in terms of the one and there was a change of title later on that was not highlighted.
Q We are going back over the same ground. This is based upon the premise that from the outset we are locked in, well before an application is made, locked into 172-96 and my point is that if that were so, if this indeed was looking for disintegrative disorder in all these cases you would expect, and there being recruited to a trial, you would expect those who would be dealing with that aspect of the study to be looking for children with disintegrative disorder or at least a good steer towards it, would you not?
Q And you would also, if you look at 172-96 be looking not only for those children but also those who had measles and measles/rubella immunisation rather than MMR because there is no reference to MMR in there, and you would be looking for 25 children to get your study complete.
Q If what they were doing was from the outset following 172-96 because those are three aspects, are they not, of 172-96?
Q How easy do you think it would have been to recruit 25 children with true disintegrative disorder?
A Exceedingly difficult.
Q And just to add to that, having had measles and measles/rubella immunisation rather than MMR?
A Exceedingly difficult.
Q Looking at the documents, as you have, it is clear that that is not the position, there is not a motivation to go out and find people with disintegrative disorder, as far as the documents disclose anyway, is there?
Q Looking at the individual cases, you make the point that nowhere in the case notes can you find the patient information sheet or the research consent form.
Q In fact, for none of these children do you have that documentation, do you?
Q Of course, it was a condition imposed by the Ethics Committee on 7 January, so it would have been difficult anyway to put it into the case notes for children who had already been investigated?
Q Because it would involve the consents associated with the trial, and what you have instead, for all of these children I think, are standard consent forms for procedures to be carried out, and Mr Hopkins took you – you are nodding.
A Yes, yes, sorry. I must not nod!
Q I thought you were dropping off, that is all.
A Not at all. (LAUGHTER)
Q But he took you to the consent form for another hospital which looks as though it is for the 1996 model anyway, a standard NHS consent form for procedures to be carried out of whatever type?
A Yes, indeed, I accepted his suggestion that those were as near as anything comparable.
Q So rightly or wrongly, those who were involved in carrying out these tests and commissioning the investigations were asking the parents to fill in a standard form, NHS consent forms for those procedures, not research ones?
Q If we want to look at it in a slightly different way, tomorrow we will look briefly at case No. 2 but you know that in his case he was truly enrolled in a trial of enteral feeding: you have seen that have you not?
A Yes, I think I probably have, yes.
Q As a result of the investigations that were carried out it was decided that he would be a candidate for that and for that reason he had another colonoscopy afterwards to see what the results of that were, and we will see tomorrow the research consent form for that because he was entering a clinical trial.
Q And that is as you would expect?
A Yes, indeed.
Q Looking at it overall, professor, the process appears to have been – and this is not going back over the same ground – that by whatever means word had got out that the Royal Free was investigating children with bowel problems and autism: we see that from a number of different sources, and in some cases parents were approaching the hospital direct, getting in touch with Dr Wakefield or they were approaching their general practitioners direct and asking the general practitioner to refer to Dr Wakefield or to the Royal Free because in many cases the address of Professor Walker-Smith and his unit was being given.
Q That appears to have been the process. When they contacted Dr Wakefield, again derivatively from the GP notes and some of the other letters, we see that he was telling them that they had to get a referral from the GP or from their local paediatrician, a referral not to him but to Professor Walker-Smith, and to his unit.
Q It is clear, is it not, that the parents individually wanted the Royal Free doctors to help them to find out what was wrong with their children?
Q And what might have caused the problems, and in some ways – we have not had all the evidence yet – were also interested to see whether anything could be done about the condition of their children, which would be quite understandable.
Q And again, it is clear from surrounding documentation that the Royal Free doctors were interested to see if there might be a link between the bowel symptoms and the developmental problems?
A Yes. I have already indicated that seems to me to be a perfectly legitimate objective, and I have no problem with it.
Q That may be something which, if you are dealing with a teaching hospital specialist unit, would not be altogether surprising; that they would like to see people to investigate if it would help the people concerned?
Q And also to inform them of whether there was such a link. But what you can also say, and it is a point that you yourself make, is that whereas on the face of it, it looks as though there was an extremely thorough investigation of the gut problems through colonoscopy and histology, that the developmental problems were dealt with in relatively short form by Dr Harvey and Dr Berelowitz?
Q And that was because, as I think Dr Berelowitz made clear in the first letter that he wrote, which we saw yesterday in case 2 ---
Q --- that he was not assuming clinical care for the child and effectively, what he was doing was confirming, if it was possible to do so, the diagnosis that had already been made by others who had been specifically detailed to make that diagnosis?
Q That is the theme, really, of his involvement, not as somebody who either you or Professor Gillberg would say, “If you are going to be the front line diagnoser of the problem, then you have to do a structured assessment to identify if it is possible what sort of problem this child has – as the primary diagnoser.” Clearly what he was doing could not possibly have been that function, could it?
Q And as you said in relation to each of the children, when you went back to the surrounding documentation, a lot of that work had already been done in the case of most of these children. Some cases were done afterwards at the Newcomen Centre, or I think with Professor Le Couteur in relation to one child. In relation to four of the children, the paper itself makes clear that the authors accepted the diagnosis that had already been made before the children were admitted and there was no subsequent confirmatory diagnosis from Dr Berelowitz at all. That is what it says in the paper, does it not?
A I do not remember, but it quite likely did.
Q It was four out of twelve, I think he said.
Q “We accepted the diagnosis that had already been given by others who investigated.” So on that aspect of it, although you may criticise the paucity of investigation, it is clear that the role that Dr Berelowitz had was merely to confirm, as it turned out, something within the autism spectrum as being present in most of these children, but not all of them.
A Yes, indeed.
Q Indeed, it is that which represents that the other side from the gut pathology in the paper that was published. The only two strong points that come out, or parts that come out of the paper, are the proposed link based only on twelve patients between autism spectrum, developmental disorder and the findings in the gut?
A Correct, yes.
Q That is all that comes out of it, does it not?
Q And as far as his brief findings go, you are not persuaded by disintegrative disorder in any of them, although the closest one gets to it is in Child 2?
Q Unusual. You are not persuaded, without more, about an encephalitic episode in one of the children but you do not necessarily dissent from the classification of autism, or autism spectrum/developmental disorder given to the others?
A That is correct.
Q Just before I leave it, you have not seen, or have not been shown, a paper reporting, or anything reporting, 172-96 as a study, have you? In other words, you do not find 25 children with disintegrative disorder following measles or measles-rubella vaccination?
A That is correct.
Q But you do know only from a footnote to The Lancet paper itself that a number of other children were seen and investigated, who appeared on the face of it to have these two conditions which were described in the paper – autism spectrum, or developmental disorder, and the unusual gut pathology described both histologically and colonoscopically?
Q Microscopically. And indeed you know, presumably from having seen Dr Berelowitz’s evidence, that a large number of children were investigated subsequently, who again seemed to have the same sort of combination of signs and symptoms?
MR MILLER: Sir, would that be a convenient point?
THE CHAIRMAN: Thank you. I think that is very helpful. Thank you again, and we will now adjourn. Professor Rutter, my usually warning and reminder again: please do not discuss this case with anyone. We will resume at 9.30 tomorrow morning.
(The Panel adjourned until Wednesday 3 October 2007 at 9.30 a.m.)