GENERAL MEDICAL COUNCIL
FITNESS TO PRACTISE PANEL (MISCONDUCT)
Thursday 27 September 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
CASE OF:
WAKEFIELD, Dr Andrew Jeremy
WALKER-SMITH, Professor John Angus
MURCH, Professor Simon Harry
(DAY THIRTY-FIVE)
(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
Page No
PROFESSOR SIR MICHAEL RUTTER, affirmed
Examined by MS SMITH 2
THE CHAIRMAN: Good morning, everyone after this break, and welcome back to the hearing. Ms Smith, I think you were going to introduce your new witness, or is there any other business to be conducted before that?
MS SMITH: Sir, yes, Mr Coonan wanted to address you.
MR COONAN: Sir, I do have something to say very shortly. Dr Wakefield is not present this morning, and I have to tell you that he will not be present for the remainder of this session. The explanation, insofar as one is necessary, is simple. As you may know, Dr Wakefield and his family live in Texas in the United States of America, and his place of employment is also in Texas. As a result of the substantial increase in the time required to complete this case, and the number of extra sessions that have been identified, he has been put into a very difficult position in terms of undertaking his employment obligations in Texas. In the normal course of event, of course, a person in his position would be able to be present for every part of the hearing. However, quite simply, he cannot leave his post in the USA for a further three weeks now and then have to contemplate a further 14 weeks’ leave of absence from his employment next year. This has resulted in a balance having to be struck to enable him to meet his employment obligations, but he recognises that it is of course vital that he has the opportunity to give evidence to the Panel next year. The consequence is that his legal team will continue to represent him, with full instructions, during this session. The transcript will be emailed to him every day and contact will be maintained by email and telephone on a daily basis as necessary. His absence should not therefore be viewed adversely by the Panel or indeed by anybody else.
Dr Wakefield has asked me on his behalf to convey his respectful regrets to the Panel. He is content that the proceedings should continue in his absence for this session.
Sir, I hope that provides an adequate explanation for his absence.
THE CHAIRMAN: I think that is a very clear exposition of the position. Thank you for explaining, and I think you are quite right: Dr Wakefield as a defendant is entitled to attend every part of the hearing, but obviously because of his situation if he has decided against it, and he is content for the hearing to go ahead in his absence, then I personally do not see any objection to it, but I will ask the Legal Assessor what he thinks.
THE LEGAL ASSESSOR: The rules allow you to proceed in the absence of the practitioner. You have to be satisfied that it is in the interests of justice. Mr Coonan seems to be suggesting to you that it is in the interests of justice that you should proceed, in which case my advice is that you should proceed, and no adverse inference should be drawn against Dr Wakefield for not being here.
THE CHAIRMAN: Thank you. Ms Smith, do you have any comment or observation on this submission?
MS SMITH: I have no comment, sir.
THE CHAIRMAN: I am just going to look towards the Panel members to see whether they would wish to discuss that in camera, or are happy to go on. (Indicated affirmatively.) I think I have had a nod of approval from all the Panel members, and therefore we will proceed with the hearing. Thank you again, Mr Coonan. Ms Smith?
MS SMITH: Sir, in that case I will call Professor Sir Michael Rutter.
PROFESSOR SIR MICHAEL RUTTER, affirmed
Examined by MS SMITH
(Following introductions by the Chairman)
Q Professor Rutter, could I ask you to begin your evidence by giving us your full name and address, please, and your medical qualifications.
A Michael Llewellyn Rutter. My address is XXX. My medical qualifications are rather various. I have an MD, Fellow of the Royal College of Physicians, Fellow the Royal College of Psychiatrists, Fellow of the Royal College of Paediatrics and Child Health, and various academic ones.
Q You are appearing in this case as an expert and you have provided expert reports, which have been disclosed of course to the defence. So that we are all clear, Professor Rutter, the Panel do not have your expert reports. We do. You are very welcome to have your report open in front of you, and indeed it would be helpful if you did so, so that I can tell you whereabouts I am looking in that report when I am asking you questions.
A Right.
Q I am going to start off first of all with your experience and qualifications, and how they render you able to give expert evidence in this case. You have produced a copy of your CV. You have a number of bundles on either side of you, and you should have one which is numbered FTP7.
A Yes.
Q In there at page 71 you should find your CV.
A Yes.
MS SMITH: Sir, can I just say at this juncture that purely through inadvertence Professor Rutter’s CV does not include all his publications, so I am going to hand to you the rest of it, to go on to the back of what you have. What you have I think stops at page 77, and I am handing in all the publications, which go from a numbering of 77A to 77NNN. Perhaps I could ask everybody if they would be kind enough to pop those in their files at the appropriate point. (Documents handed)
THE CHAIRMAN: This is 77A to 77NNN.
MS SMITH: If I could run through the basic position with you. You qualified in medicine from the University of Birmingham in 1955, is that correct?
A That is correct.
Q You then had training posts in neurology and paediatrics and general medicine?
A That is correct.
Q With membership of the Royal College of Physicians in 1958?
A That is correct.
Q You qualified in psychiatry in 1961?
A That is correct.
Q Did you then subsequently train in child development and specialise in child psychology?
A Yes, I did.
Q Since 1956 you have been a consultant in child and adolescent psychiatry at the Bethlem Royal and Maudsley Hospitals.
A That is right.
Q You mentioned your academic posts. Do you also have what was a University Chair and is now a personal Chair as a Professor of Developmental Psychopathology at that hospital?
A That is right. Initially I had a Chair in child psychiatry and when I retired from that Chair in 1998, I had a personal Chair in developmental psychopathology which is a what I still hold.
Q I want to ask you a bit about your research in clinical experience in various different aspects which are different to this case. As far as autism is concerned, have you undertaken extensive research into autism and autism spectrum disorders?
A Yes I have, really beginning back in about 1960/1961, particularly during the 1960s and quite intensively ever since.
Q As far as those research papers on autism are concerned, you say from the early 1960s, was that the beginning of papers on research into autism as opposed to clinical case studies of autism?
A Yes, there had been some studies before then, but that really was the beginning, yes.
Q Have you also been involved with the development, with colleagues of course, of the standardised methods now for assessing children with autism?
A Yes I have, particularly the autism diagnostic interview and the autism diagnostic observation schedule, both of which have come to be the standard instruments as applied to the diagnosis of autism spectrum disorders.
Q You say they are standard instruments, you mean outside your own hospital they are used generally?
A Yes, worldwide.
Q I think in addition you undertook what was one of the first systematic epidemiological studies examining the interconnection between neurological disorders and psychopathology in children.
A I did the Isle of Wight Study, or at least there were several Isle of Wight studies so that led to a book in 1970 and it continued after that in a number of ancillary studies.
Q I am not going to take you to all your books and monographs and scientific papers, except to say so the Panel know if they wish to look at them, that the books and monographs are at between 1966 and 2007 and they are at pages 77a to 77y of your CV. The main scientific papers from 1958 to 2006 are from page 72 to 77aaa. If we were to look at those, would we see a vast number of references to the papers involving studies into autism?
A You would indeed.
Q You say in your report that your standing in research scientist is reflected in your election as a Fellow of the Royal Society?
A That is correct.
Q Was that in 1987?
A It was.
Q I do not want to invite you to blow your own trumpet, but in case there are members of the Panel who are not familiar with that, is that a very distinguished organisation which elects scientists across the entire spectrum of science, not just medicine?
A That is correct and has done so since the time of King Charles.
Q I think now they make about forty elections a year?
A That is correct.
Q Across the entire field of science, all the sciences?
A Yes.
Q Are you the only psychiatric member?
A I am.
Q Since its inception in the time of Charles I, how many psychiatrists have managed to achieve that accolade?
A One, who is now deceased. Before that Freud was elected as a foreign member.
Q As well as your particular and great interest in the science of autism, do you also have some expertise generally in relation to the design of research?
A Yes, I have had a major role in that for a very long time and have written quite a bit on methologic issues.
Q You are aware, of course, that this case is about work on a possible connection between behavioural disorders and bowel disease so it expands to specialisms. I think it is right that you would certainly not hold yourself out to be an expert in gastroenterology in the true sense of the word. Would you regard yourself as having some expertise in co concurrence in the patterns of symptomology, in other words two diseases being looked at to see how they relate to each other?
A Yes, that has been a main clinical concern because it has to be when dealing with chronic disorders of this kind, but it has also been a research concern so that I have both been interested in, and have written on, the issues involved in looking at the co occurrence of different patterns of psychopathology and somatic disorder of one kind or another.
Q I think you have published on that issue relating particularly to psychiatry in a comorbidity setting.
A I have, yes.
Q In addition to that, are you currently involved, particularly, with issues relating to research design in your capacity in the Academy of Medical Sciences?
A Yes, so that I have recently chaired a working party of a report which is entitled “Identifying the Environmental Causes Of Disease – How do we know what to believe and when to act”, which is very much concerned with the important issue of looking at environmental causes of multifactorial disorders, that is to say disorders involving a complicated mixture of genetic and environmental factors which would be the case with autism.
Q That is your general interest in autism and in research design. As far as medical ethics are concerned, are you a member of your own hospital ethics committee?
A I am and have been for quite a long time.
Q Can you tell us roughly how long?
A Two decades or so. I hoped at the time I was preparing my report to give an actual date but, unfortunately, the records have not been kept going back that far, but it is certainly two decades or more.
Q That is at the Maudsley Hospital?
A Yes.
Q In 2001, did you chair the Royal College of Psychiatrists’ working party on the Guidelines for Ethics Committees in relation to psychiatric research?
A Yes, I did.
Q The report, which again is produced in your documents, is that a report of which you were largely involved in writing?
A Yes, I wrote most of that. It was concerned not just with psychiatry but with the interface with neurology and neurosurgery as well, so it was primarily based, as it would be of course, with the Royal College of Psychiatrists on the psychiatric aspects but recognising that the ethical issues often involved an interface with other disciplines.
Q I think also you were a member, again in 2001, of the BMA working party on children and consent to treatment?
A Yes, I was.
Q And the psychiatric aspects of that particular issue?
A Yes.
Q In the context of your own research, this is probably rather an obvious question, but as well as sitting on an ethics committee, have you experience relating to the actual applications to committees in relation to your research papers?
A Yes indeed, numerous applications.
Q You refer to your retirement from your university post, but are you still actively involved in clinical research?
A Yes, I am and in clinical work. My clinical work now is largely in relation to research, that is to say clinical needs that have arisen out of research, but, yes, I remain involved in that and in clinical research.
Q You talk about clinical work, ie seeing patients, when you talk about clinical research, what do you understand that to mean?
A Systematic studies and various kinds which range from observational studies to more experimental studies, so that an example of observational studies would be a follow up that we have been doing of children who were reared for their first few years in Romanian orphanages and who were subsequently adopted into UK families, in which a longitudinal study, which has now gone up to the age of 15, looks at the interplay between earlier experiences and later experiences as they relate to the outcome. More laboratory based studies would be the molecular genetic study of autism, in which I am one of the collaborators, but also was involved in setting it up many years ago.
Q Lastly I want to turn to a small matter in relation to the personal circumstances of your involvement in this case. You allude in your report to the fact that you have actually, personally, assessed two of the children who formed some of the twelve who were in The Lancet paper?
A That is correct.
Q You should have in front of you a laminated sheet with an anonymisation chart on it. Are the two children Child 2 and Child 5, do you remember?
A That is correct.
Q Roughly when was that, in relation to the matters which we are concerned with in 1996?
A This is in relation to what was to be litigation in relation to MMR. In fact it never came to court. My role in that was as an expert witness to deal with both general issues on the science and the specific ones in relation to a group of children chosen by both sides as representative, so I wrote a draft report. As I say, that never came to anything. That was concerned with different issues in that it was concerned with the science rather than the ethics and it did not involve the ethics at all.
Q You say you were acting as an expert, was that on behalf of the vaccine manufacturers who were being sued?
A It was, yes.
Q When you were asked to consider giving expert evidence in front of the General Medical Council in this case, did you refresh your memory at all as to what you thought in relation to these two children when you saw them in the context of that investigation?
A No, in fact I quite deliberately did not do that. I asked my PA to check that I was correct in my memory that I had seen two of them, but I did not ask what I said and I have not looked at the records, so I have only a rather very vague memory as to what I thought at the time. The issues then of course were in relation to a period well after that which is relevant to this case.
Q Just one other matter, because I am going to be asking you to comment on documents at various points, I have already alluded that this case involves two specialisms because there is the gastroenterology side of it as well. You are aware that we have another expert who is being called after you and you are aware of his identity. Have you had any contact with him, read his report in this case or had any views about the views he has expressed when he looked at these papers?
A I have had no contact and I am completely unaware of what his views are.
Q Turning on to more substantive matters. I am going to take you in a moment to the ethics committee applications in relation to this case, but before I do so, just so we are all clear, you saw originally the statements of the main witnesses in the case and you have seen the transcripts as they have been sent to you during the hearing?
A That is correct.
Q You have seen all the main documentation. I am sure you do not keep it all in your mind, but you have been sent it.
A Yes, I have.
Q I shall be referring to you to those documents to refresh your mind and the Panel’s as to some of the background matters. I want to refer to some basic principles and terminology, not necessarily specific to this case but obviously underpinning it. The first of those is the use of the terms “autism” and “disintegrative disorder” and the clinical investigations which are appropriate for those. Then I am going to go on and ask you about the distinction between clinical and research medicine, again in general terms, and then guidelines for doctors wanting to do research as opposed to clinical medicine. We will then look at the ethics committee application and I am going to ask you for some broad overall comments. Then I will take you to the individual children, and then I will take you back to the broad overall comments because once we have looked at the children we can fill in what will, inevitably, be some generalisations to begin with. First of all, autism and disintegrative disorder, as at the time with which we are concerned which you know is around about 1996 to 1998, and I am in paragraph 58 of your report if you would like to turn it up so that you know what I am asking you about, are there distinctions in your view as to the different variants of developmental regression?
A Yes. Developmental regression is a term that is used in rather varied ways so that one of the interesting things about autism is that in about a quarter/third of cases there is a transient period of regression involving the loss of previously acquired skills, which are usually of a temporary variety. That has been known for a very long time. In recent times there has been more of a focus on whether that is distinctive of autism as against other disorders involving language development. There are now a number of studies currently under editorial review which indicate that it is indeed probably highly distinctive of autism as distinct from development more generally.
The regression varies from very minor losses of skills that were only half acquired and some of that will probably be just ups and downs, errors, as it were, of measurement, if you like.
There is good evidence from a variety of sources that there is also a true failure to use skills that had previously been present but which usually recover. There are also cases, which is where it as it were goes to disintegrative disorders, where there is a much more widespread loss, usually at a somewhat later age, and where it can occasionally be progressive. The importance in relation to autism from a clinical point of view, as well as from a scientific point of view of course, is to sort out, as it were, these different varieties because they are likely to have a rather different meaning.
If I can pause for a moment on the temporary loss of skills, there is a great temptation to think that that must mean something happened at that time which led to the loss. It is important that the research is clear in a range of different developmental arenas that that does not have to be the case. So that for example, children who are born with very severe deafness have a normal production of sound up to the age of about 6 months, and thereafter they develop the guttural sounds that we all associate with severe deafness. Now, it is not because anything happened at that point. It is that the way the development of the brain functions, different systems come on-line, come into operation, at that time. At about the same age, there is the well documented phenomenon that babies all over the world can make the same phonological discriminations up to the age of about six months. After that age, it is dependent on the language in which they are being reared.
There are experimental studies in animals showing lesions that artificially induced – damage to the brain – can have no effect at the time but later, as the relevant brain systems come into operation, it is found. So although it is tempting to assume that there ought to be an environmental factor at that time, there are so many examples where that is not the case, that that clearly does not follow. That does not mean of course that there cannot be an environmental factor in some circumstances, and research currently, including that which I am involved with, is trying to sort out whether that is the case as an additional factor.
With the disintegrative disorders, if I can move to that because the issue of the distinction from autism is a critical one, there are two utterly separate issues that one needs to keep in mind. The one is the issue of the implications for investigation so that if you are dealing with a disorder with a lasting decline in functions, it could represent a progressive neurological disorder; a set of investigations is required of a quite different kind because there are neurological conditions that can provide that and, as it were, the psychiatric phenomena with it, whereas in the more ordinary forms of regression the implications for investigation would be quite different.
The second issue, though, is whether, regardless of that, there is a genetic liability that extends across the two. At the time of 1996 the prevailing view was that these were really likely to be completely separate conditions genetically as well as with implications for investigation. In the research that has been done since then, questions have been raised as to whether that is so or not. I think one would just have to say the jury is out on that. We do not know.
Q I am going to take you in a moment to just two or three pieces of the large amount of literature that you have produced, which are contemporaneous with the period with which we are concerned, because obviously nobody had a crystal ball as to the views that were going to be expressed in the future. Can I just ask you briefly. You have made the distinction between disintegrative disorder which may come on later in life. Are there sub-divisions within disintegrative disorder itself?
A Yes, indeed. The one which is clinically most important is the distinction between Rett's syndrome and other varieties in that that is known to have a particular genetic mutation that is responsible fore the great majority of cases – it may turn out all – but certainly the great majority, and where the prognosis is quite different from autism. It is a very terrible disease without, at the moment, a treatment that other than ameliorates the details of it. That comes on at a much earlier point. So that is dealing with a change that occurs, usually around 6 to 12 months of age, rather than later.
There are then also cases in which there is an association with an identifiable neurological disorder, mostly occurring later, and where there are documented cases in the literature where this has been found.
Q I want to just take you, Professor Rutter, to a document you will be familiar with, which is your own chapter in a textbook of the time, which is the chapter that in fact, as you know, these doctors relied on when they made the ethics committee application. It has been pointed out that you do not have a file of Professor Rutter’s literature. We will now hand it out to you. Sir, can I say in relation to this that it includes a very large number of documents obviously because for every proposition that an expert makes, they give you a footnote and a reference for it. I am only going to be taking Professor to a very few, which are the contemporaneous ones, but obviously the defence may ask him about other documents, otherwise you would not worry with them.
(FTP6 marked and circulated)
Please turn in FTP6 to 460a. Professor Rutter? I think it is right that this is a chapter from a textbook which is called Child and Adolescent Psychiatry.
A That is correct.
Q This chapter which was used by the defendants in this case was from the 1994 edition.
A That is correct.
Q Is the textbook still in fact being produced? There have been many editions since.
A Yes, there have been several and there is a fifth edition that is probably due out next spring.
Q You were one of the co-authors of the chapter on “Autism and Pervasive Developmental Disorders”?
A Yes.
Q Were there contributors to the other chapters by other people?
A Yes.
Q Is it regarded as one of the sort of bibles of child psychiatry?
A I suppose so. It is certainly probably one of the best-selling books around the world on child psychiatry.
Q I want just to have a look at this chapter. We have already looked at the particular part that was relied upon which relates to disintegrative disorder. I want to see what the format of the chapter is and go to just a very few parts in it because of course the chapter is on autism, and then deals with various differential diagnoses.
A Yes.
Q We see that it says in the first column:
“The story of autism represents a prototype of the interplay between clinical and scientific progress in the field of child psychiatry in the 20th century. Questions of classification, the nature of brain-behaviour relationships, implications of psychological theory for treatment and the pragmatics of helping individuals and families cope with a debilitating life-long disorder all lie in the short history of the syndrome of autism. Autism is not only a unique disorder, but a window into the linkages among neurobiology, human behaviour and effective treatment in child psychiatry.”
Then it sets out the history of it right back from the first descriptions which were not recognised in the early 19th century but it says “now sound hauntingly familiar”, and then ultimately to what I think was really acknowledged as a first definitive description of it in a clinical context, which was from a man called Kanner in 1943?
A That is correct.
Q We see that he described a particular series of indications in the middle of the page, including “delayed echolalia” – that is repeating what someone says to you?
A Yes.
Q And
“…pronoun reversal, failure to use speech to communicate, an anxious desire to preserve sameness, repetitious behaviours, failure to anticipate being lifted, a general lack of awareness of other people’s existence or feelings and a lack of ability to play imaginatively with other children. Kanner was particularly impressed by the existence of these behaviours in children who functioned at a retarded level in many respects but who gave the impression of normal intelligence, and seemed to have an inborn inability to relate to people and situations.”
So that was his first description. We see at the bottom of the page:
“At about the same time” another doctor, Dr Asperger, “independently described a group of children who were similar in many ways to Kanner’s first 11 patients.”
That of course is the Asperger’s syndrome which we have heard referred to in this case?
A That is correct.
Q In the second column we see how things developed:
“In the 1960s and early 1970s, studies on both sides of the Atlantic confirmed that children with behaviours similar to those described by Kanner could reliably be discriminated from children with mental handicaps or with other psychiatric disorders”.
There is a reference to one of your first epidemiological papers in relation to that issue
A Yes.
Q If we go on to page 460c, we see that there is reference to the two frameworks of criteria, in the right-hand column under “Diagnosis”, which you may or may not be asked about, what it says is:
“The systems both identify three areas of deficit required for a diagnosis of autism: communication, social development and restricted and repetitive behaviours and interests.”
Then, going down the next four sentences:
“Even with its indefinite borders, autism probably remains one of the most reliably diagnosed psychiatric disorders in children…..Currently, autism is classified as a pervasive developmental disorder, a term that is intended to cover children and adults who have severe lifelong difficulties in social and communicative skills beyond those accounted for by general delay….. This term has recently come under some criticism, but no appropriate alternative has yet been suggested.”
Then the clinical characteristics of autism are described. I am not going to go to those except to say the headings, which say that they are social deficits, communication problems and restricted and repetitive interests and behaviours.. Could I ask you to turn on to page 460j where we see the course of autism.
“Age of onset and early regressions
Most autistic children are identified by their parents as showing some abnormalities or delays in the second year of life, and many parents suspect problems long before this.”
Then going on down to the middle of that column:
“The abnormalities identified by parents of autistic children when they are still toddlers are often not specific to autism (such as language delay and difficulties in settling, eating and sleeping) and so it is not surprising that they are not recognized by parents earlier.”
Then skipping a couple of lines:
“About one-quarter to one-third of parents of autistic children report a loss of speech in the first years of life…. often accompanied by changes in social behaviour. These regressions usually consist of the loss of most or all of the child’s few communicative meaningful words. One study found that most children who lost words had been using them for less than 6 months… Few children regained speech within a year, though many did so eventually. Some studies have shown worse prognoses for children who experience early language regressions… and others no differences.. but none have suggested it is a positive sign.”
We will look at a couple of the other papers. That deals with the issue that you described to us in general terms; i.e. a regression to autism which may recover itself. Is that correct?
A That is correct.
Q It involves the loss of abilities which apparently had been acquired?
A That is correct.
Q If we go to the other column,
“Assessment and intervention
Assessment of children or adults referred because of concerns about possible autism is a multifaceted, multidisciplinary process. Information about the child’s history, current behaviour and cognitive skills is necessary and best obtained from a combination of parental and teacher report, observation and standardised assessment. Though the diagnosis of autism may often seem apparent simply from observation, there are many cases, particularly of young children or adolescents, where it is not clear whether such a diagnosis is appropriate, and other cases where such a decision would have been wrong because of a lack of pertinent information. The process of diagnosis is one of eliminating alternative explanations for the child’s behaviour….”
It goes on:
“This process can be carried out in several hours for most children, if good information from other sources is organised beforehand and if experienced clinicians work together to build on each other’s knowledge.”
Then we go on to a title on page 640l, Professor Rutter, which says:
“Differential diagnosis of autism and other pervasive developmental disorders.”
I want to ask you, Professor Rutter, and I should have said this to you at the outset, remembering there are lay members on the panel as well as medical members, can you just explain to us what “differential diagnosis” actually means?
A Sorting out whether the appropriate diagnosis is this or that or some other thing; in other words, the differences among diagnostic possibilities.
Q If we look at those, and turn to page 460m, in the middle of the left-hand column:
“Differential diagnosis consists of discriminating autism from other psychiatric and developmental conditions that lead to abnormalities in language, play and social development. Often it is helpful to begin chronologically and to consider if there was ever a period of normal development. If there was a period of clearly normal development extending beyond 2 years, the possibilities of elective mutism, disintegrative disorder and schizophrenia in children must be considered.”
A That is correct.
Q Then we see set out a number of diagnoses. You will be pleased to hear that I am certainly not going to go through all of them: elective mutism, in other words children who simply choose not to speak; Rett’s syndrome, which you have already talked about; disintegrative disorder, and then going on to the next page we see schizophrenia, some language disorders and severe psychosocial deprivation and an abnormality known as Wing’s triad and Asperger’s syndrome. The only one I want to look at is that relating to disintegrative disorder. We see, as we know, that –
“Disintegrative disorder (or Heller’s disease) occurs when normally developing children suddenly or over a period of several months show marked behaviour changes and developmental regression after age 2, often in association with some loss of coordination and bowel or bladder function.”
It quotes two papers.
“Behavioural changes include social withdrawal, reduced response to sounds, complete loss of communication, unusual sensory behaviours and development of simple rituals and hand and finger stereotypes, much like those of autistic children. However, disintegrative disorder differs from autism in the loss of motor and self-help skills and usually, too, in the lack of more complex stereotyped behavioural patterns (although simple motor stereotypes may occur). This rare disorder can sometimes be linked to measles, encephalitis, cerebral lipoidoses, leukodystrophies or other neurological conditions but in most case no clear cause is ever identified. 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.
Two different courses are typical of children with regressions occurring after the first few years. Most common are regressions that extend over several months and then plateau, resulting in a developmental and behavioural pattern that looks much like autism with severe mental handicap.”
Then there is a reference to a paper which we will go to.
“In some cases, deterioration continues, with increased motor dysfunction, development of seizures and localised neurological signs.
Another disorder that overlaps in symptomatology but that does not have quite so poor a prognosis is Landau-Kleffner syndrome of acquired aphasia with epilepsy. ….children with this disorder lose receptive and expressive language usually over a period of months, typically in conjunction with the development of seizures or transient EEG abnormalities…. Some social withdrawal and unusual behaviours may occur, but usually relatively normal social relationships are maintained with parents and others known to the child. Nonverbal cognitive functioning remains intact. In most cases, the outlook for these children is better than for children with disintegrative psychoses or autism, and sometimes language is eventually regained.”
It seems a rather superfluous questions to ask you, Professor Rutter, since you were one of the authors of that chapter, but did that, as far as you were concerned, sum up the distinctions between disintegrative disorder and autism?
A Yes, it did.
Q You have said that since that time there has been more of a blurring of the boundaries. Those are my words, not yours, but I cannot remember exactly what yours were?
A Nevertheless, that is correct, yes.
Q At that time, the view that you are expressing there that disintegrative disorder and as a sub-classification the Landau-Kleffner disorder was separate and distinct from autism. Are you able to help pus as to whether that was a generally held view?
A Yes, it was. I would have thought that was typical of more or less everybody at that time, so that was not an idiosyncratic view but was simply reflecting not only the view of other clinicians and researchers but also the way things were expressed in the official classifications that were being used at that time.
Q That is the next thing I was going on to ask you. You refer to those and I have referred to them just as the two main systems of classification, I think that is correct, by which psychiatric disorders are diagnosed.
A Yes.
Q Was disintegrative disorder a separate category from autism in those classifications?
A Yes, it was.
Q You have told us and we have seen there a number of children - before I go on to that, I now want to look at the three references that are in that chapter in relation to disintegrative disorder, so in other words, as I say, pinning it to the time when that chapter was written, or informed it. In fact they are all considerably earlier. One is at page 434. This was a paper very much earlier, in 1977, which you quote in your chapter, which is a paper by Dr John Corbett, which was published in the Psychiatric Society’s journal. I am going to take you to extracts from that, so we can see how the science behind your definition of disintegrative disorder in your chapter had evolved. We see in the first paragraph:
“THE TERM ‘Disintegrative Psychosis of Childhood’ was used in 1969 by a World Health Organisation Seminar on Classifications …”
Then it quotes your own involvement.
“This diagnostic category has since been included in the multi-axial classification scheme (for child psychiatric disorders) which utilises the Ninth revision of the I.C.D. The glossary” –
again quoting you –
“… which is at present being evaluated” –
again quoting you –
“… suggests that the category … should include ‘disorders in which normal or near normal development for the first few years is followed by a loss of social skills and of speech, together with a severe disorder of emotions, behaviour and relationships. Usually this loss of speech and social competence takes place over a period of a few months and is accompanied by the emergence of overactivity and of stereotypes. In most cases there is intellectual impairment, but this is not a necessary part of the disorder. The condition may follow overt brain disease – such as measles encephalitis – but it may also occur in the absence of any known organic brain disease of damage’.”
If we go on to page 440, at the bottom of the page it sets out the points which arouse suspicion of a neuro-degenerative disorder associated with disintegrative psychosis. I will briefly summarise them: a prolonged emotional disorder in childhood out of proportion to the psycho-social stresses in the child’s environment; the failure of response of the emotional disorder to psychotherapy or other treatments; bizarre and unusual symptomatology including meaningless rituals and mannerisms; disturbance in relationships, with coldness or difficulty in establishing a relationship; a fall-off in educational or social performance; the appearance of focal neurological signs or abnormalities in the EEG.
The conclusion in the summary is reached:
“The diagnostic category of Progressive Disintegrative Psychosis is appropriate to describe the clinical psychiatric picture in these children. Because of the rarity of such conditions further collaboration between child psychiatrists, paediatric neurologists and neuropathologists is needed to delineate further the psychiatric syndromes associated with the neurodegenerative disorders.”
That is a paper in 1977, Professor Rutter. It uses the term ‘disintegrative psychosis’. Is that synonymous with what became known in the classifications as disintegrative disorder?
A Yes, it is. ‘Psychosis’ was used much more generally at that time, but it means exactly the same thing in the way it was used then as disintegrative disorder would now be used.
Q If we come on to the next one, which is in 1986, that is at page 379. This, as it says in its title, was a follow-up paper. These two authors had identified disintegrative psychosis in a group of children, and then they followed them up some years later, looking at the picture which you subsequently describe in your chapter about regression, and then ultimately a plateauing.
A Yes.
Q It is a paper, I mention in passing, I think, because we will be reverting to his role in this case, which in fact Dr Rosenbloom played a part.
A Yes, indeed.
Q He is a paediatric neurologist at the Alderhay Hospital?
A That is correct.
Q Do you know of him – I do not mean personally – as a paediatric neurologist who has an interest in this particular area?
A Very much so, yes. He has a good reputation in that area.
Q In the left-hand column:
“Rutter et al … proposed the classification for childhood psychosis which is now generally accepted. Using age at onset as a major criterion he distinguished: infantile – onset in the first 30 months” –
which he calls infantile autism; and then, as you have already described –
“disintegrative – onset after the age of three, where normal or near normal development previously existed followed by a disintegration involving severe disorder of emotions, behaviour and relationships …”.
He says:
“Children with disintegrative psychosis demonstrate remarkable consistency in their clinical features. Characteristically, after a variable period of normal development, they regress over several months and lose previously acquired cognitive behavioural and, in particular, linguistic skills. The resulting picture is of overactive children with poor attention span, isolation, obsessional behaviour, limited but variable comprehension and minimal expressive language. Despite good motor abilities such children are functionally severely mentally handicapped.”
They then refer to the original assessment in their own unit, in 1978. This was the follow-up of nine of the ten individuals who had been identified as having disintegrative psychosis when they were between 11 and 16.
We see on the next page, 380, “Course”:
“Since the onset of regression, the follow-up period has been in excess of 11 years for all subjects. With one exception they present a uniform picture as regards overactivity, behaviour and level of functioning, and the course over the past five years has been similar in most children …”.
Going on to page 382, “Discussion”:
“We have used the diagnostic term disintegrative psychosis of childhood to describe a pattern of regression occurring in preschool children who formerly had normal development, including normal language … and in whom subacute concurrent disintegration of emotions, behaviour and relationships occurred in the absence of any discernible underlying organic pathology.
The separation of this condition from infantile autism is, in part, one of definition and semantics. Once fully established, disintegrative psychosis has features indistinguishable from infantile autism of severe degree, in that there are major permanent disabilities of learning, relationships and behaviour. Eight of the nine individuals in this study show a remarkably consistent and homogeneous clinical picture. Unlike the vast majority of children with early infantile autism they undoubtedly showed a period of early normal development, including the acquisition of normal language and normal social relationships. Thereafter, in the absence of any overt encephalopathic illness, and often in association with reported emotional stress, they showed a subacute loss of abilities with a period of regression over three to 12 months. They have subsequently remained severely handicapped and it is clear they have an adverse developmental prognosis and will remain wholly dependent individuals. When counselling the families we describe their children as having an acquired form of autism with an adverse developmental prognosis and unidentified aetiology. In this way some distinction can be drawn between the presentation of this disorder and the more characteristic evolution of infantile autism in which it is common for abnormal features to be seen from earliest infancy and in which the developmental outlook may be better.”
Then turning on to 383, “Conclusion”:
“The remarkable consistency of the clinical features at presentation and follow-up in eight of … [these] children suggest that we are dealing with a homogeneous group within the spectrum of childhood psychosis for which an organic basis has not been established. The children were investigated by methods shown to be effective in the diagnosis of degenerative brain disorders and none has shown continuing regression when reviewed 11 to 16½ years later. Thus their clinical course has effectively been static for the past five to 10 years.
The outcome for developmental progress since diagnosis has been consistently poor. Overactivity and behavioural disturbance, which were the most distressing aspects of the disorder during the early school years, are partially amenable to treatment programmes based on behaviour modification.”
So that is the paper that you quote in your chapter, Professor Rutter. Does that bear out the received knowledge at that time, that if a child is identified as having disintegrative disorder or psychosis, whichever you call it, as opposed to the commoner form of autism, that it may in fact, having regressed, then plateau, or it may get worse?
A Yes, that is very much the experience of everybody at that time, so that I along with umpteen others had clinically investigated a number of children who had shown this pattern, and my experience is very much like Hill and Rosenbloom’s – that is to say vigorous, thorough investigations almost always produced no abnormalities that could be found. Hence the experience in John Corbett’s paper is an unusual one, but it is the conjunction of these two that led to the kind of clinical practice that most people have followed – that is to say it is important to recognise that in the great majority of cases there is not any progressive neurological disorder, but occasionally there is. That means that the investigations need to be done to check that that is not the case. But it is very unusual for that to be found.
Q Going on to the last paper I want to refer to in this context, which indeed underlines the rarity of the condition, it is at page 413. It is the paper by Volkmar and Cohen in 1987, so again some ten years before the period with which we are concerned. Reading the abstract at the top:
“Ten cases of disintegrative disorder were identified within a larger sample of 165 individuals who met the behavioural criteria for autism. These cases were compared to autistic individuals whose disorder had been recognized by age 2 and to those whose disorder had been recognised after age 2. Consistent with previous reports, children with disintegrative disorder had a period of normal development preceding the onset of a profound developmental regression from which they made, at best, only a limited recovery. Both clinical features at the time of regression and various outcome measures support the validity of the diagnostic concept, particularly when such cases are compared to ‘late onset’ autistic ones.”.
So is that making the distinctions that you have in fact made in your descriptions to us?
A Yes, it is indeed.
Q Going on to the discussion, which is at page 418, using the international code which defines what they are looking for, we see:
“… cases of disintegrative disorder were relatively uncommon in this sample; the 10 cases identified represent 6% of the larger sample of autistic individuals. Features of clinical presentation and course were consistent with previous reports …” –
And it then quotes the two papers that I have taken you to.
“These cases exhibited a period of marked developmental regression after a considerable period of apparently normal development. Often this regression was associated with some psychological or, less commonly, medical event, and the children made only minimal subsequent recovery. … medical evaluations failed to determine a specific aetiology …
As noted by Hill and Rosenbloom …, this condition once established is behaviourally indistinguishable from severe autism. The issue of whether such cases merit a separate diagnostic category must then depend on whether aspects of clinical presentation or course are sufficiently distinctive to establish the need for such a category …”.
And it quotes a paper by you.
“Despite behaviourally exhibiting features of autism, the cases in this series differed from more typically autistic children in both clinical presentation of their disorder and its course; these differences were particularly marked when such cases were compared to ‘late onset’ autistic ones. This difference provides support for providing a separate diagnostic category for disintegrative disorder.”
You told us that indeed there was at that time a separate diagnostic category.
A Yes.
Q The reason I am taking you to these papers, Professor Rutter, is that unfortunately, because of your role from a very early stage, so many of the papers emanate from you, but I wanted us to look at some which did not emanate from you, so that I could ask you whether, insofar as you are able to say, of course, this was a view which was not your simply your view, that there should be a separate diagnostic category for disintegrative disorder?
A That is correct. These papers, as you say, span both sides of the Atlantic, involve authors that also span psychiatry and paediatric neurology, and the view being expressed here is, I think, quite characteristic of what was generally held to be the view at that time.
Q Thank you. Just one last paper of the many you have produced, and that is about this question of regression, and I am still in fact at paragraph 58 of your report. You said in your own chapter that we read out to begin with that a quarter to a third of children with autistic spectrum disorder have a period of apparent regression.
A Yes.
Q That is what is referred to here in the papers that we have been looking at – a period of apparent regression, which does not necessarily mean that they have disintegrative disorder.
A Yes, indeed. It is rather different it its course and manifestations.
Q If I can just look at one paper which backs up those figures, it is at page 314. This is a paper from a doctor called Hiroshi Kurita; it is in 1985, and I am going to look at the first two paragraphs.
“A certain proportion of children with infantile autism seem to show a peculiar pattern of early speech development, that is, some children with infantile autism lose totally their meaningful words before the age of 30 months. Furthermore, these children do not necessarily appear to exhibit more serious developmental problems before they lose their vocabulary.”
Then going on to the next paragraph:
“Every clinician participating in the treatment and study of infantile autism is familiar with this phenomenon. Nevertheless, there have been few reports on this kind of phenomenon in infantile autism.
Lotter … reported in his epidemiological study that, among 32 autistic children, 10 … had an onset including a developmental setback that included speech loss. … he did not investigate it himself … Instead, he studied more general ‘loss of some ability’ …”.
So this was a paper that was going particularly to speech loss. But whether one is taking about speech loss or loss of other skills in conjunction with or instead of speech loss, does the same apply? Would you agree with the proposition that every clinician participating in the study of infantile autism comes across that phenomenon?
A Oh, yes, very much so. It is part and parcel of everybody’s clinical experience; it is well established. It is not well understood, as to what exactly the mechanisms are, but that it exists, and it exists in roughly this proportion in children, or thereabouts, is well established, and people are well familiar with the fact that ordinarily this is something from which the children recover, which is really very different from disintegrative disorder, where the usual pattern is that they do not recover.
Q Sorry, the usual pattern is ---? I did not hear you.
A Is that they do not recover.
Q They do not, if it is disintegrative disorder?
A No.
Q So in summary, Professor Rutter, before I turn on to the issue of what clinical investigations are appropriate for these disorders – and I am asking this question generally, although I will be returning to it in relation to the individual children – if a doctor is embarking on the study of children who have a behavioural disorder, would you expect a differentiation between autism and disintegrative disorder to be made?
A Yes, I certainly would.
Q At the time that we are considering, would the research into the literature indicate a clear difference at that time?
A Yes, it would.
MS SMITH: Sir, I see it is ten to eleven, and I am going to turn on to a separate topic. I do not know whether you would like me to do that?
THE CHAIRMAN: I think it appropriate to have a short break now. It is ten to eleven, and we will now adjourn and resume at ten past eleven.
(To the witness) Can I remind you, Professor Sir Michael Rutter, that you are under oath and in the middle of giving evidence, so please make sure that you do not discuss this case with anyone during the interval. I am sure someone will look after you for a cup of tea or coffee.
A Thank you.
THE CHAIRMAN: We will now resume until ten past eleven.
(The Panel adjourned for a short time)
MS SMITH: I want to turn on to a related issue, Professor Rutter, which you have already touched on, which is the nature of the clinical investigations which are appropriate to the two disorders that we have been discussing, and the first I want to deal with is autism as opposed to disintegrative disorder. I am now talking – and I think it is important that we all understand this – in the context not of research but of what you do in the clinical assessment of a patient with that condition of autism. With regard to autism, whether or not it is the kind that involves an element of regression, would that affect the nature of the clinical investigations that you undertake?
A You mean whether the presence of regression would change things?
Q No. I mean, if you – you collectively, in your experience – looking at a child, think that you are investigating a case of autism, albeit one with a regressive element to it, does that regressive element affect what investigations you do, if you think you are looking at a case of classical autism, albeit autism with a degree of regression?
A No, because it is so common, and because as far as one knows it has no particular implications for either aetiology or prognosis. What is crucial in the clinical investigation of autism is an awareness that a proportion of children do have a diagnosable medical condition, and there is debate as to exactly what that proportion is, but it would be something in the order of 10 per cent or more. So it is very important in both what is done in relation to the history and the examination of the child and investigations, to follow that through in a systematic form, so that a detailed history, detailed family history, developmental history, would be crucial in order to assess whether there is anything unusual in this particular child that is different from other children. Then on the basis of having done a thorough clinical assessment, and a thorough clinical examination, there would be the question as to what investigation should be done routinely.
The general consensus now is much the same in the UK as it was in 1996; that is to say, in relation to the examination one would want to be systematic in looking at congenital anomalies of various kinds. It would be particularly important to examine carefully for the possibility of tuberous sclerosis, which is a neurological disorder, an inherited neurological disorder, where the rate of autism, although occurring in a minority, is significantly raised above the general population. That would involve using what is called Wood’s light, which is an ultraviolet light, which is helpful in picking up whether the skin lesions have the distinctive features that you associate with tuberous sclerosis. Following through on tuberous sclerosis you would want to probably do a straight X-ray. You would not routinely do a brain scan, but depending on whether there were clinical indications, for example in relation to tuberous sclerosis, you might want to do that. You would certainly want to assess chromosome anomalies, in that a substantial minority of individuals with autism do have a chromosomal abnormality. Curiously, with a few minor exceptions, it does not follow a particular form, and the reason why there is a generally raised rate of chromosomal abnormality is a bit unclear still – but important to assess that. It would be important to use DNA methods in order to pick up the fragile X anomaly in that that has important implications for the family, and some implications for the individual. So there are a range of things that would be done. In the ‘80s there would be a tendency to also have extensive metabolic investigations, as reflected in clinical studies of the urine. Most people have now stopped doing that because it proved in all hands so extraordinarily non productive. It is very rare to find anything of diagnostic significance unless there was a clinical lead.
The golden rule, always, is to have a clinical assessment that is sufficiently thorough that there are leads as to where you need to do something different with this child than what you would do routinely. So it is quite a long drawn out business and it is often multidisciplinary in what is required because of the complexity of patterns.
Q You have been through a range of investigations and explained how they may or may not be appropriate in the individual case of autism. When investigating an autistic child in the mid 1990s, would a clinician who is experienced in the investigations of autism carry out a lumbar puncture?
A I know of no paediatric neurologist or child psychiatrist in the UK who would have done so at that time.
Q Before I go any further on that, can I ask you, in fact, is that a position that has changed between now and then and now?
A It is the same.
Q If I asked you the question as of yesterday rather than 1996, would you have given the same answer?
A Same answer.
Q Leaving aside just for a moment, and I will return to it, whether or not it is an accepted investigation, can you tell us, is it in your view, when it is being carried out on children with autism or an autistic disorder of some sort, a decision to be taken lightly whether or not that child should undergo a lumbar puncture?
A No. A lumbar puncture is an invasive investigation, in a minor way it is true, but what is critically important in relation to individuals with autism is that their limited understanding means that their cooperation in the undergoing of lumbar puncture cannot be relied upon, so almost always it would have to be done either with heavy sedation or with a general anaesthetic. That adds a different dimension, so that doing it on a child who is fully cooperative is one thing, doing it on a child where they have to be sedated in order to make it possible is another. Obviously, if there is a relevant important clinical indication, then you would do so, but you would hesitate and check in your own mind, is there really an indication in this child that it is necessary to do that.
Q You have said that you know of no psychiatrist or paediatrician in the UK, then or now, who would do a lumbar puncture on an autistic child. I think you have been asked whether you could find any support in the world literature for the use of lumbar puncture in autism. You were immediately aware of a clinician who has indeed advocated the use of lumbar puncture in autism. Is that correct?
A That is right.
Q That is who?
A That is Christopher Gillberg in Sweden.
Q I am going to take you to one paper in relation to him. The defence may ask you about many, many others. Has he written a great deal on this subject?
A He has.
Q You are going to need your only missing FTP bundle which is bundle 5. (Bundle distributed) Will you turn to page 244. This is a paper by Dr Gillberg from the Department of Paediatrics, Child and Adolescent Psychiatry, University of Göteborg in Sweden in 1990. That is six years before the period with which we are concerned, so we can see what he had to say about it. The abstract of the paper at the top:
“There is a very conspicuous lack of literature in the field of autism work up. Guidelines for clinicians planning to work up their patients...”
“Work up” means investigate, clinically, does it?
A Yes.
Q
“Guidelines for clinicians planning to work up their patients with autism are virtually non existent. 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.”
If I could take you on, to page 252 to the table there:
“Relevant laboratory analyses in all medium/low functioning and certain high functioning cases with autism and autistic like conditions.”
We see amongst the investigations a chromosomal test, an MRI scan and then we see CSF protein, EEG and various other tests. By CSF protein we get a little footnote:
“Lumbar puncture for CSF analysis is a safe and relatively non traumatic procedure. In the Scandinavian countries, it is always considered in the work up of young children with severe developmental disorders. If there is a nearby laboratory doing CSF amino acids (phenylalanine in particular), CSF monoamines and CSF endorphins, these tests should be considered since the child has to have a lumbar puncture anyway (to exclude progressive encephalitis/encephalopathy).”
Going on to page 253 in the left hand column.
A Sorry, I am not with you. It is page what?
Q Page 253, the next page in the paper we were looking at, halfway down the left hand column:
“With respect to cerebrospinal fluid (CSF) examinations, current practices 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.”
As I say, that was a paper in 1990 but I think you would accept that Dr Gillberg has written a number of other chapters in books and papers advocating the use of lumbar puncture?
A Yes, that is a consistent stance he has taken.
Q First, since 1990 when he was writing this paper, have his own subsequent published findings reflected that advocated practice?
A As far as I know he still advocates doing so, but what is quite striking in the published reports is the absence of any evidence that it is actually useful so that the paragraph you read out says:
“Several authors have documented that clear progressive encephalopathies were first suspected...”
etc – no reference given there. In his own papers what he reports is in terms of progressive encephalopathies where there is then a substantial and general deterioration of a kind that one would associate with disintegrative disorders rather than autism. He has generalised that to indicate that it could occur in relation to autism but there is a striking lack of evidence either from his own research or from the research that he quotes that that actually is useful. It clearly is useful if you have got a disorder with a late onset general deterioration. That is not a controversial issue and the practice in the UK would be in keeping with that in Scandinavia. Incidentally, I do not know that his practice is typical of the whole of Scandinavia, but it is typically true of him and his colleagues.
Q It has been pointed out to me, I should not have ground to a halt without reading the rest of that column on the page of 253. Perhaps I will go back to that:
“In high functioning cases, some of which are now often referred to as Asperger syndrome, all the examinations have to be considered, because of the relatively high risk that even in such cases underlying medical conditions/brain damage are common. However, if there is a clear family history of autism or Asperger syndrome in such cases, the clinical analysis might well lead up to a less extensive work up, even though the threshold for further neurobiological investigations should be low.”
So he seems to be applying some gloss to his general view. Has it ever become an accepted practice for the work up of autism in the UK, the view he advocates?
A No, not that I am aware of.
Q I think in fact, although I will take you to one last paper dealing with this, which is you but it is not just you, it is you with colleagues, at page 256 in bundle 5. It is a paper with you and two others, including Dr Le Couteur, about whom we heard from Dr Berelowitz. Is she a paediatric neurologist or a psychiatrist?
A A psychiatrist.
Q In the UK?
A In the UK, yes, currently in Newcastle.
Q If we could just turn to page 257, two thirds of the way down the top paragraphs.
“Second, Gillberg has urged that the supposed strong association with known medical conditions means that extensive investigations including a lumbar puncture and a CAT scan (undertaken under general anaesthetic when necessary, as will often be the case) should be undertaken as a routine.”
And you quote another paper putting forward similar arguments.
“There is a general agreement that a systematic medical history and physical examination should be mandatory and that certain investigations, such as chromosome study, should be undertaken in all cases. However, most reviewers have not considered that lumbar puncture or brain imaging as part of the range of essential investigation to be undertaken in the absence of specific indications. This second issue, of course, needs to be influenced by the diagnostic yield of those tests in the patient groups referred to psychiatric clinics, as well as by the strength of the association between autism and known medical conditions.
Because both the theoretical and practical implications are substantial and important, it is necessary to consider the evidence carefully and critically.”
I will come on to what you say in a moment, but the point you make there of the diagnostic yield, is that the point that you just made, namely that it may have been what Dr Gillberg was advocating, but it does not filter into his scientific papers that it has actually got him information?
A No, that is right. By diagnostic yield, what I mean is, what proportion of the investigations throw up a finding that is of diagnostic importance? So that there are quite a few studies which have looked at this in relation to the urinary studies that I mentioned earlier and have shown that the yield is extraordinarily low, which is the reason why people on the whole have given up doing that unless there is a particular clinical indication. That always has to be added. There are not, I think, the same number of investigations that have been applied to lumbar punctures but, in so far as the evidence is there, what it shows is that it is has not given rise to useful diagnostic findings other than in the cases where you have a late onset progressive disorder and there it can be diagnostic and is important.
Q We will come on to that. If I can conclude the two aspects I wanted to read. Page 264, the bottom of the page:
“Gillberg has contended that lumbar punctures should be undertaken routinely on the grounds that CSF protein electrophoresis is needed to diagnose progressive encephalopathy; and that other CSF abnormalities, although without diagnostic value, help parents appreciate that autism is due to some form of brain dysfunction. It seems very dubious whether it is necessary to perform a lumbar puncture in the absence of any clinical indications of deterioration and certainly this appears to be an unjustifiable way of making autism more ‘acceptable’ to parents.”
A That is my was my view then and still is.
Q On the last page, page 265, I think you make again the point you have just made:
“Third, there is good justification for a careful and thorough medical assessment of individuals presenting with autism and this is especially so when they are also severely/profoundly mentally retarded and/or epileptic. However, a good case has not been made for the routine use of lumbar puncture, EEG, brain imaging, or metabolic studies except when there are specific clinical indications for their use.”
A Yes, indeed.
Q This is a paper by you, or a paper by you with colleagues, but as far as you are aware, has that view been the one that is followed, certainly in this country?
A Yes, that is pretty much a standard view. This is not an idiosyncratic view; that is to say, throughout the world, there is agreement that a thorough medical examination, a thorough clinical assessment, is crucial. That is not controversial, and where the laboratory investigations, as it were, need to follow that and where, if there are clinical leads, then you follow appropriately in relation to the individual child. But, in the absence of that, then there is a limit in terms of the sort of investigations that appear justifiable, and the notion that you should do investigations to help parents realise that it is an organic disorder, really, is not a view that I have ever heard anybody in the UK express.
Q I underline we have been talking about work ups, clinical investigations, for autism?
A Yes.
Q If a clinician wants to do a lumbar puncture on autistic children, not with some degenerative aspect but autistic children, for research purposes, then what steps step does he have to take?
A Then he would need to go, with an appropriate application to an ethics committee, research ethics committee that is.
Q They would have to consider whether or not approval good be given for that?
A Yes, indeed.
Q I think you have answered this in passing, Professor Rutter, but I want to underline it. If you are faced with a child in whom you suspect true disintegrative disorder as opposed to autism with a regressive element to it, then would you regard it as reasonable to include lumbar puncture in your clinical investigations?
A Yes, I would
Q Again, broadly speaking – and we will look at the specifics when we look at the cases – who would you expect to be the decision-maker with regard to the nature of the clinical investigations that should be undertaken on a child who presents with developmental delay and whom this kind of decision has to be made about?
A It would be essential that it be done by somebody who has detailed clinical experience with this sort of problem in relation to problems of autism. I put it deliberately in that way in that whether that translates in a paediatric neurologist or a child psychiatrist would depend, and a paediatric neurologist whose clinical practice does not involve conditions of this kind would not be an appropriate person any more than a child psychiatrist whose clinical practice did not involve problems of this kind. It needs to be somebody with expertise in this area with all the kinds of issues in relation to regression, in relation to the range of symptoms, in relation to the range of medical conditions that might be involved: that is the sort of person who needs to be doing it..
Q You have specifically referred to a paediatric neurologist and a psychiatrist and you have made the point that the actual nature of the qualification is not the important thing but the experience. Would the same apply to a developmental paediatrician? Might he be somebody?
A Certainly. So that there are developmental paediatricians who have a lot of experience in this area and who are very knowledgeable, at least as much so as a paediatric neurologist or child psychiatrist.
Q Would you ever regard it as a satisfactory state of affairs for someone who does not, whatever their exact specialism may be, have that sort of knowledge of the appropriate work-up in autism to be making individual decisions about whether a child should or should not undergo invasive investigation?
A No, I think it is part of good medical practice generally that one practises in relation to the areas where you have expertise, and one of the good things about medicine is that there is no loss of face in consulting with colleagues who do have that expertise when you yourself do not have it.
Q Just one short matter, Professor Rutter, in relation to this issue of behavioural disorder: with regard to behavioural disorders, autism perhaps particularly but behaviour disorders generally, is it common for there to be an association with gastro-intestinal – perhaps that is the wrong word – or with bowel problems?
A Yes, quite common, so that any child psychiatrist, or for that matter paediatric neurologist with experience of autism, will have come across this many times.
Q If you are seeing a child who has a bowel problem who is also behaviourally disturbed, do you have to make some sort of assessment as to whether the bowel problem is associated with the behaviour or whether they need referral to someone who will look at their guts?
A Certainly, so that it should be part of ordinary clinical experience and practice to be familiar with the kind of things that one need to be alert to. For example, there is well documented association with pica – that is to say eating substances of an inappropriate kind – and that can be associated with bowel problems. There is also a well recognised association with incontinence and their inability to control bowel motions and this is very common. There is also an association with behavioural features that lead to a reluctance to use the lavatory in the ordinary way and this can lead to constipation, leading to partial blockage and an overflow incontinence, that is to say a seepage past the blockage. So that it would be usual, as it were, to be well knowledgeable about those sorts of features. Sometimes it is quite straightforward in recognising that this is the sort of problem and that it would be dealt with in the usual way, but you would always have to be concerned: is there something unusual about this? If there possibly is, then you would of course consult with an appropriate expert as to what his or her view was as to what should be done.
Q If a doctor is going to embark on research in this area of children with behavioural problems and with apparently some sort of associated bowel problems, would that be an important matter to assess the interrelationship between the two?
A Yes.
Q I want to go on now to a separate subject, because again I am filling in the background on various factual issues before I take you to the specifics of the case, and that is the basic distinction between clinical medicine and research. If it helps you, I am at paragraph 78 in your report. As I say, having said that, I am not concerned with the specifics of this case. I just want to ask you some questions generally about it. I wanted just to look at two definitions that we have, which I think you will concur with because they are indeed quoted in the recent guidelines with which you were involved in 2001, but these are contemporaneous to the time. They are in your FTP4, please, at page 23, which is the start of the document. This is the Royal College of Physicians, 1990, assistance on research involving patient. I just want to look at the definition section at page 29. We see the basic proposition:
“What constitutes research in patients?”
That is a question.
“When an activity is undertaken solely with the intention of benefiting an individual patient, and where there is a reasonable chance of success, the activity may be considered to be part of ‘medical practice’. The progressive modification of methods of investigation and treatment in the light of experience is a normal feature of medical practice and is not to be considered as research.
In contrast, where an activity involving a patient is undertaken with the prime purpose of testing a hypothesis and permitting conclusions to be drawn in the hope of contributing to general knowledge, this is ‘research’. The fact that some benefit, expected or unexpected, may result from the activity does not alter its status as research.
The distinction between ‘medical practice’ and ‘research’ is often less clear than is suggested above because both are practised simultaneously. A doctor who makes careful records of the outcome of treatment, the effectiveness of a diagnostic investigation or the use of some resource in the course of his ordinary work may be considered to be engaging in quality control – now often referred to as ‘medical audit’ – rather than in research. In general, however, where an effort is made to formalise the acquisition of information gained in the course of medical practice this may be considered to be at least a component of research. A retrospective review of case records is usually to be regarded as research, particularly where this is undertaken systematically according to a formal protocol or when an individual other than the person who constructed the records undertakes the analysis. Any activity which affects the patient in any way which is additional to ordinary medical practice is to be regarded as research.”
Then underneath that it goes into the possibilities of innovative treatment, which is particular to an individual patient.
“Sometimes special circumstances of an individual patient’s illness lead a clinician to step outside what is accepted as normal medical practice.”
Then:
“In innovative treatment, the sole motive for the action is to choose the best possible course of action for the individual patient even though it be unconventional. It remains innovative treatment rather than research even if, as a byproduct, useful information is gained. Responsibility for employing innovative treatment remains that of the clinician who remains subject to the usual constraints which direct ordinary medical practice.
Where a clinician contemplates a marked digression from normal medical practice in an individual case, with the prime purpose of acquisition of information for application in future patients, the activity clearly becomes research and must be subject to ….. scrutiny by Research Ethics Committees…..
Innovative treatment may quite rapidly become part of medical practice without being the subject of formal research, for example where a speculative new procedure is thought to be successful in a previously hopeless situation. Usually, however, when a doctor finds that a major innovation is being called into regular use and the procedure is not yet incorporated into medical practice generally, it will be expected that the innovation should become the subject of formal research without delay so that its true worth can be established.”
That is one definition. The only other one I want to go to which is in very similar terms is at page 89.
“The definition of research continues to present difficulties, particularly with regard to the distinction between medical practice and medical research. The distinction derives from the intent. In medical practice the sole intention is to benefit the individual patient consulting the clinician, not to gain knowledge of general benefit, though such knowledge may incidentally emerge from the clinical experienced gained. In medical research the primary intention is to advance knowledge so that patients in general may benefit; the individual patient may or may not benefit directly.”
Then it too goes into a definition of innovative treatment. It is worth noting the footnote at the bottom.
“In this context, an ‘experiment’ is a procedure adopted on the change of its succeeding. ‘Research’ is a systematic investigation to establish facts or principles and generalisable knowledge.”
In the heading “Research”, it states:
“Any investigation in humans designed to develop or contribute to generalisable knowledge raises ethical issues, although these may be small. Because such studies may involve subordination of at least the immediate interest of the individual participant to the objective of the advancement of knowledge, they should be subject to ethical review.”
That applies to non-medical as well as to medical research. So those were the views of the College that were expressed at the time, Professor Rutter. When we turn to look at the individual cases, we are likely to be using, as indeed we have been using so far throughout this case, the phrase ‘clinically indicated’.
A Yes.
Q What do you actually mean when you use the phrase as a doctor, that something is clinically indicated?
A As these Royal College of Physicians reports both bring out, in terms of ordinary clinical practice, of course the good clinician is wanting to improve things and in so doing will be looking for ways of doing so. So it is part of ordinary practice to be trying things out to see whether they are going to be helpful in this patient. As the documents bring out, there is a clear distinction between what you are doing because you think that it is going to help this patient as distinct from what is important to be doing because it may give generalisable findings that can be applied to other patients. Obviously there is al link between the two. Clinical indication would be in terms of this patient and the specifics as well as the things that this patient has in common with others, that you are trying something out, that you think it is going to benefit them, not going to bring further knowledge. If, inadvertently or otherwise, it brings general knowledge, fine, but that is not why you are doing it.
Q As you know, this case is to some degree at least concerned with asking about whether these doctors were involved in clinical or research practice. The guidelines say that sometimes the actual specific definition is difficult to make. In normal practice as a doctor seeing patients, normal clinical practice, is it actually difficult, in your experience, to differentiate between the two?
A Not really. I have been involved as it were across the spectrum on this. To give a specific example in relation to autism, in the early days – looking back now to the early 1960s – one of the things we were doing was trying out behavioural treatments to see whether it made a difference. That was clearly on the basis of what we thought might be helpful to the individual. In the event, it turned out that it seemed as if it was being helpful to the individual, and we then moved into research mode and did a comparative study to try and test out the extent to which that was the case. So the former was clinical; the latter was research. Although the two blend in some senses, it is usually pretty clear which you are doing at any one point in time, and indeed it is important that you come to some decision on that because what is required in terms of permissions is different in the two cases. So that in terms of clinical need, if you are doing something very exotic, it would be prudent to consult with colleagues as to whether they think that is a sensible and appropriate thing to be doing, but it is consulting with colleagues in relation to clinical need, not in terms of research, whereas if one is looking at whether this is something that could give rise to a general principle, then that goes the research ethics route.
Q If you are, in the normal course of your clinical practice, seeing patients and doing clinically-indicated investigations of them, and generally administering medicine in a clinical sense, do you have any need to consult a research ethics committee at all?
A No. As I say, if it seems unusual, a good clinician would always consult with colleagues; but that is a different matter. It is a question of sharing decision-making on this, it is not a research ethics issue.
Q Just so we are all clear, it so happens that the doctors from whom we have been hearing as witnesses, and indeed the doctors involved, are all doctors who are engaged in doing research, but are there many hospital doctors who in fact never do any research at all, but simply do ordinary clinical medicine?
A Yes.
Q Again generally rather than specific to this case, which I will come on to at a later stage, was it in the mid-1990s sometimes the case that specimens which were obtained from patients for clinical reasons in the course of ordinary clinical investigation s were then used for research purposes?
A Yes.
Q And that was a common occurrence, is that correct?
A Sorry?
Q That was quite a common thing to happen?
A Yes; and would require research ethics permission to proceed. I do not know whether it would be helpful to expand a little bit on the area, as it were, of moving from clinical need to clinical research? Would it be helpful to say a bit more about that?
Q Yes, please, if you think the Panel would find it helpful.
A If one starts, as we have discussed up to now, in terms of what you do with individual cases, and of innovation, that is clearly clinical and I think that is completely non-controversial. One may do this with several patients, and a point would come then when you have a group of three or four or whatever the number may be, where you have proceeded on the basis of clinical need but where you are becoming aware that there may be a more general issue that requires research.
I think there has been some discussion about distinctions between clinical cases and clinical series. I must say that is not quite the way I would put it, so both of those in my mind fall clearly in the clinical.
Then there is the question of a series in which you are asking permission to make use of samples that may be obtained in the course of what you are doing. If that is being done on the basis of it varying from patient to patient, that you may be getting a sample of this or that, in some cases, what you are asking then is the permission to obtain further blood sample or whatever it may be, for research purposes. That then falls into something that does fall into research ethics, but we are now on the basis of individual variation that would not in that case be a protocol.
You then move one step nearer the research, in which there is a protocol, in which you are saying “Yes, this is something that is being done on a clinical need basis, but because this is a relatively homogeneous group it is reasonable to suppose that one will want to do the same investigations on all cases”. That would be OK clinically, if you have a well-defined, well-demarcated clinical condition where that would be generally accepted as appropriate.; You would still need permission to use the samples for research, but it could be justified as being required on the individual case.
The situation changes, however, if you have a protocol that is being applied regardless, in a group that is clinical heterogeneous ---
Q In other words, just to stop you on that, just so everyone is clear – I am not insulting anybody – when you say ‘heterogeneous’ you mean they do not have a completely similar condition?
A They are varied in their manifestations. That I think most people would see as clearly in the research arena, that it may be well justified from the point of view of research but it is something in which not only the samples you would need permission for from the research ethics, but the whole protocol, as it were, needs to be looked at from a research perspective.
That may not involve a control group at that point; one is simply applying it in a standard fashion. The next stage beyond that would be with a control group. That would always fall into the research category and would go to a research ethics committee in the normal way.
Q A control group – in other words, comparators. A normal group of people to compare whatever it is you are looking at, against?
A Yes.
Q That is very helpful. Can I ask you this: you have given us a sort of thumbnail sketch, as I invited you to, of how doctors view research in clinical medicine. Would you expect any senior doctor who is involved in research to be aware of and able to explain those distinctions?
A I would certainly hope so.
Q If what you are doing is research or you believe it to be research, is ethics committee approval always required?
A Yes.
Q I am going to look very briefly at the guidelines again – very briefly – because we have not done so since the case was opened, or not those that I am going to look at. I want to ask you this, Professor Rutter. As far as these guidelines are concerned, they are there to assist ethics committees, but are they rules in any way?
A No, that is not how the system works. They are, as you quite rightly say, guidelines, and they provide a way of approaching the issues, and they are reasonably helpful in that connection. But each individual ethics committee has to decide on the evidence on any application that comes its way, what is required. There is not a rule. That also means, incidentally, that you cannot go from one ethics committee to another – that is to say, you submit to one ethics committee, and if you do not like the answer you get, you cannot say “Well, hold on, I don’t like that. I’ll go to some other committee that will give me a more favourable opinion”. That is not the way the system works. Each ethics committee has not only the power but the responsibility of deciding in each application what is required, and that is the way it worked then and it is still the way it works now, although it has become more bureaucratic.
Q Would you look at your FTP bundle 4 please, page 89. I want to go on now to where I stopped before, because this is the same place we looked at when we were looking at the distinction between clinical medicine and research. I now want to see what it says about research, because we have to bear in mind, do we not, that these guidelines are presupposing that research is what you are doing.
A Certainly.
Q If we go, as I say, to where we stopped before, which is “Classes of research”:
“3.4 There are two major classes of research:
i that which involves making observations without any direct interference with the subject (non-intrusive or non-invasive), such as research involving the use of … medical records …
ii that which involves interference with the subject (psychological intrusion, including intrusion on privacy, or physical invasion). Such interference, psychological or physical, raises ethical issues which may be sometimes large or very small; both should be subject to ethical review.”
A Yes.
Q So although in this case we are, as you know, going to be taking about invasive physical tests, that is why if you want, for instance, to do a psychiatric interview for research reasons rather than clinical reasons, you have to go to an ethics committee?
A You do indeed.
Q Because you are invading another kind of privacy.
A Yes.
Q Not bodily, but psychological.
A Yes.
Q We see:
“3.5 Research may also be classed as: (a) which may benefit the individual participant (therapeutic research) and (b) research that will not or is unlikely to benefit the individual participant (non-therapeutic research). Whilst Ethics Committees will be concerned with both, they will naturally give particularly close attention to non-therapeutic research.”
A Yes.
Q That is because ---
A That is because there the assumption is that there will be no benefits for the individual, whereas with therapeutic research there may or may not be, and so it is viewed slightly differently. In the footnote on the page you are reading they deal with randomised control trials, as to whether that comes into therapeutic research or not, and they conclude – as I think everybody else would – yes, they do.
Q Yes.
A And that the randomised control trials are justified, because you do not know whether something is going to work, or for that matter whether it is going to have unacceptable side effects. So it is therapeutic. I am not sure that nowadays people would see that as requiring less ethical scrutiny. Times I think have changed on that, because we are more aware than we used to be of the problems of side effects as well as benefits. But the distinction at the time was certainly like that, and the issue in relation to non-therapeutic research is the same now as it was then; that is to say there are no expected benefits for the individual and therefore one has to look at it, whether it is justified scientifically and ethically.
Q Yes. I want to go straight on to one we have not referred to before, which picks up that very point about therapeutic and non-therapeutic research, which is the Medical Research Council, “The Ethical Conduct of Research on Children”, dated December 1991 and reprinted in August 1993. Would you go to page 161, please.
“3.3.1 The primary intention of all medical research is to acquire knowledge that will be of benefit to humanity as a whole – to all who are or may become ill. Therapeutic research is directly concerned with treatment and thus offers the possibility of immediate benefit to participants. Direct benefits to participants in non-therapeutic is either unlikely or long delayed.”
Then would you go on to 167, please.
“THE ETHICAL CASE FOR INCLUDING CHILDREN IN RESEARCH
6.1 General
6.1.1 There is … a broad consensus, with which we concur, that a principled case can be made on ethical grounds for research on children. There are a number of situations in which knowledge that is badly needed for the sake of children suffering from various conditions can only be acquired by research on children.”
Then it goes on that:
“ … there is agreement on the need for strict safeguards ...”
And the middle one of those:
“all projects must be approved by the appropriate LREC(s).”
A Yes, indeed.
Q Local research ethics committee. Going on to page 171, please:
“7.2.10 In one sense all research carries an element of risk: babies have been dropped when being bathed, children have slipped and fallen when stepping on the scales, the taking of a blood sample has led to injury. Although there has been no authoritative legal decision involving research, and … no unanimity among lawyers as to the strict legal position, there is a respectable body of opinion which takes the view that there is no obstacle to the consent by a parent to a procedure which carries no greater risk for the child than the risks that reasonable parents commonly expose their children to in everyday life. This is, we think, the same idea sometimes expressed by saying that non-therapeutic research involving children must not involve greater than ‘minimal’ or ‘negligible risk’. We cannot visualise any circumstances where non-therapeutic research which placed a child unable to consent on his or her own behalf to greater risk than that described at paragraph 6.3.3. above would be ethically justifiable.”
The last one I wanted to go to is in the British Paediatric Association guidelines, which we already heard something of from Professor Howell, which is at page 184, please.
“Children are unique as a research group for many reasons. They are the only people, in British law, on whose behalf other individuals may consent to medical procedures. Many children are vulnerable, easily bewildered and frightened, and unable to express their needs or defend their interests. Potentially with many decades ahead of them, they are likely to experience, in their development and education, the most lasting benefits or harms from research.”
Then going on to page 188 we seek the risks:
“Minimal (the least possible) risk describes procedures such as questioning, observing and measuring children, provided … [it] is carried out in a sensitive way, … Procedures with minimal risk include collecting a single urine sample (but not by aspiration) or using blood from a sample that has been taken as part of treatment.”
Does that mean clinical treatment?
A I presume so, yes.
Q
“Low risk describes procedures that cause brief pain or tenderness, and small bruises or scars. Many children fear needles and for them low rather than minimal risks are often incurred by injections and venepuncture.” –
the taking of blood. Then:
“High risk procedures such as lung or liver biopsy, arterial puncture, and cardiac catheterisation are not justified for research purposes alone. They should be carried out only when research is combined with diagnosis or treatment intended to benefit the child concerned.
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. Higher risks in research and novel treatments are accepted when children are enduring very harmful disease. Illness and anxiety alone may put pressure on families to assent to heroic experimental procedures. In cases of severe or chronic disease, therefore, the harms to the child of the condition, of the medical treatment, and of the stress through taking part in research need to be assessed, so that all avoidable distress may be relieved.”
We have heard from Professor Howell, whose evidence I think you have read, that taking blood in some circumstances is regarded as minimal and in some as of low risk. I want to ask you this, Professor Rutter, from your experience of sitting on an ethics committee: how would you categorise the risk, using broadly those classifications, of colonoscopy and lumbar puncture?
A Lumbar puncture would clearly fit into high risk as defined here, so it would have to be justified, as they have put here, only in relation to children whose condition is such where it is very important to do this. The guidelines I think are appropriate, and they are appropriate today as they were then, but I would emphasise that this has to be considered in relation to the circumstances of the child and of what is being done. So it does not neatly fit into a sort of tick-box approach, and that in unusual circumstances it could be justified, whereas he certainly would not have to justify in other circumstances. In other words, judgment has to come in at some point, but it is important the overall guidelines be followed.
Q These guidelines apply to children across the board and we are concerned with children with a very particular, and it would appear, severe disorder?
A Yes.
Q The observations in relation to the care of assessing whether investigations should be undertaken, whether they are clinical or research, does the nature of the disorder that the children have, in the broadest terms, whatever exactly it is, play a part in the ethical decision making?
A Yes, it does.
Q With that basic background, I want to turn to a more specific nature of the documentation that you have to consider to the ethics committee application which was made in respect of this particular piece of work. It is in bundle 1, page 200. First, overall, this application to the Royal Free Ethics Committee in 1996 you have had experience, I am sure, of hundreds of such applications in twenty years on an ethics committee and you have also had experience, I assume, of filling in a large number of such applications?
A Yes.
Q In broad terms, does this follow a fairly standard presentation for committee applications at that time, both the application form and the way it is filled in?
A Yes, I would have thought it does.
Q We can see the date of it which is on page 200. It has been signed off on 6 August 1996. At page 233, I should say “signed off” and we have heard evidence, which we are not in a position to argue with, that that is the signature of Professor Pounder who is the Head of Department. At the back, at page 233, the signature of the investigator is given, that is Dr Wakefield’s signature. If we go back to 200, we see the doctors under “Responsible Consultants” are Professor Walker Smith, Dr Murch and Dr Wakefield. What is your understanding of what a responsible consultant putting in an application of this sort, what does it mean, what does it denote?
A I think, ordinarily, the consultants who are responsible for the decision making, so that this would apply to the decision making of investigations on clinical need, if that is what it is about, or on ethics, if that is what it is about. Either way they are the key people who are concerned with the issues involved with anything that goes on in relation to the application.
Q It may be a rather obvious question, but would you expect a doctor who is named as a “Responsible Consultant” on an application of this kind to give accurate information in relation to it?
A Certainly.
Q What about any conditions which the committee may lay down, whose responsibility is it to ensure that those conditions are complied with?
A They would be the responsible consultants, I presume.
Q Would you necessarily expect an ethics committee to have any kind of policing or overseeing to make sure, or would they assume that the conditions had been complied with?
A They would assume unless there was evidence to the contrary.
Q What about making sure overall that the patients who were included in this study in respect of which the application was made, qualified for that study, the inclusion criteria. Who ensures that that happens?
A Well, ordinarily, that would be made clear in the protocol, so that, in this particular case, page 201 indicates the kind of assessments that are going to be done, so that, for example, it talks about a structured assessment for disintegrative disorder which refers back to the title of the project, which first refers to disintegrative disorder and so on throughout. The expectation is that what is said here is what happens. It would not be practical for an ethics committee to police it, but they would expect – that would be so in the 1990s just as it is today – that if there is any variation from that, that they are alerted to that variation so that, for example, in the ethics committee on which I have sat for umpteen years, it is quite common to have a supplementary application made in which permission is requested to vary something in relation to what is being done. That would apply either to research in, sort of, all the elements as it were or in terms of the use of tissues for research on a sample that has been collected for clinical need, so the onus is on the responsible consultants to make sure that happens in an appropriately prompt and detailed way.
Q That is in relation to the inclusion criteria of the patients. You said there was an expectation that what it says is what is done. Does that apply equally to whether the children in fact, or the patients, are treated in accordance with what approval has been given as specified?
A Yes.
Q There are three responsible consultants here. You told us in broad terms what the title denotes. What would be your expectation with regard to communication between them?
A Well, one would expect that they would have sorted out how that is going to happen. Again, this would be something that the team would have to deal with in their own way. The ethics committee really could not deal with that, but the assumption would have to be that, in whatever way it is done, that there is proper communication among the key players on all things that matter.
Q Can I ask you, Professor, is there anything unusual about a collaboration between clinicians and an Academic Department of Medicine?
A No, that would be quite common.
Q Have you been involved in research projects which have involved clinicians and academic departments of medicine?
A Oh, yes.
Q I should preface this by saying that I am conscious that generalisations are very dangerous, and I am going to ask you. I am asking you for some generalisations, but I am then going to go to every individual patient and look at them and then we will go back and I will ask you to re-look at those generalisations when we have looked at the individual patients. First, broadly, when you looked at the case records, what was your impression as to the respective roles of Professor Walker Smith, Professor Murch and Dr Wakefield, did you find it easy to understand?
A To the contrary, I found it impossible. Having gone through the records detail, I was left really quite uncertain as to who was taking what decisions in what way.
Q I think you are aware, I can take you too it if you want me to, you are aware of the terms of Dr Wakefield’s job description within the Academic Department of Medicine and his role as a researcher in that department.
A Yes.
Q Was it your overall impression that he was not involved in the clinical management of these children?
A No, it seemed that he was, but it was very difficult to sort out precisely what was happening. I mean that was one of the difficulties, going through the notes. The nature of his appointment is a highly unusual one, or was a highly unusual one. I cannot say I can recall an example of a clinician having a clinical appointment that did not allow them to undertake clinical work, so it was a very peculiar situation. I have no idea why that was done or indeed what the Royal Free Hospital expected to happen. So that the situation that the three responsible consultants had to deal with was a complicated one for that reason alone. Obviously, it would be desirable for that to be spelt out more clearly than was the case, but it is easier, I imagine, to see that with the benefit of hindsight than it was at the time.
Q If the expectation was that Dr Wakefield would not have an involvement with the clinical management of these patients, looking at the records was it your impression that he fulfilled that expectation or not?
A There are various places in which he seemed that he was involved, but, as I say, from the records I found it quite impossible to come to a firm conclusion on that.
Q As to whether you are an academic or a clinician in a research project, as is set out in the ethics committee application, does that affect your responsibilities as a responsible consultant? You told us what your expectation of being a responsible consultant means, generally, in terms of communication between you, the responsibility for the overall accuracy of the application and that kind of matter. Would you draw any distinction?
A No, not really. If you are involved in a project like this, whether you are, put it in employment terms, whether you are employed by the university or the National Health Service is really neither here nor there, but you have the same responsibilities in terms of whatever is proposed.
Q We have looked at, and we know the title by now, “A New Paediatric Syndrome: Enteritis and Disintegrative Disorder Following Measles/Rubella Vaccination”, and we see the objective:
“We will test the hypothesis that in genetically susceptible children, measles vaccination is associated with persistent enteric (and possibly CNS) infection, enteritis and malabsorption of vitamin B12. In the rapidly myelinating brain, which is particularly susceptible to vitamin B12 deficiency, the latter predisposes to encephalopathy.”
The words, “We will test the hypothesis”, is that the kind of terminology you would ever expect in relation to clinical medicine?
A No, what is somewhat ambiguous about this application is that it deals, as it were, in hypothesis terms but does not clearly separate off that this is referring only to the use of specimens obtained on the basis of clinical need. It is an unusual application in that respect, so that this comes back to the point I was making about a standard protocol that is being applied generally is much more usual in research application than it is on a clinical need application. That is sort of ambiguous in the application we have here.
Q We go on to that because we see that the next heading is “Design of the Study”. There are set out a series of investigations:
“Children referred either by their GP, or via the vitamin B12 unit ... who manifest disintegrative disorder and symptoms and signs of intestinal disease will be admitted to Malcolm ward for a period of one week, under the care of Professor J Walker Smith. With fully informed parental consent, children will undergo the following investigations in an attempt to characterise the intestinal and cerebral pathologies that potentially underly this condition.”
They are then set out. The first is a structured assessment for disintegrative disorder. What does a structured assessment mean?
A “Structured” would ordinarily mean that it is systematic and it is structured in the sense that there is this way of making the assessment for this purpose and there is this way for that purpose. It is divided up, as it were, in a standard way.
Q Did you in fact see anywhere in the records of any of the children at whom you looked, any results or any evidence that such a structured assessment had been undertaken?
A No, I looked for it and could find it.
Q As a plan, would you say it is something that should have been done?
A Oh, yes. If you are looking at an unusual disorder like this it would seem mandatory to have some systematic assessment of what it is you are investigating.
Q Then we see the rest of the investigations that they were proposing to do. We will look at those when we look at the individual children – colonoscopy, barium meal and follow through, MRI, EEG, evoked potentials, lumbar puncture and blood testing for measles and rubella and various other blood tests and vitamin B12 studies. Can you tell us what evoked potential involve?
A It is looking at the brain’s response to particular stimuli, usually either auditory or visual stimuli.
Q How do you carry it out?
A Well it is a kind of EEG test which is done in relation to specific stimuli provided. What you are interested in looking at is, if you like, the response of the brain to the stimuli and you are looking at a particular pattern so that it is something that is of considerable use in getting an understanding of brain functioning in relation to a range of different conditions.
Q On page 202, we see the introduction:
“There are indications of the emergence of a new syndrome...”
and setting out what it is and saying that it had been linked anecdotally but consistently with either measles or measles/rubella vaccination.
Under the heading “Disintegrative Disorder (Heller’s disease)” we see it is in fact verbatim from the chapter that we have already read under the section on differential diagnoses?
A Yes.
Q On page 204, this is going into the science behind the project under cobalamin, that is B12, deficiency and disintegrative disorder:
“A recent, as yet, unreported pilot study of cobalamin metabolism in children with disintegrative disorder and/or attention deficit/hyperactive disorder (AD/HD) has shown that many had abnormally increased MMA excretion and other signs of impaired cobalamin function (Linnell J personal communication).”
Is that a research you are aware of?
A No, in fact I did a bit of research to see whether publication has come on that and I have not been able to locate one.
Q On page 205 we have the two hypotheses set out for disintegrative disorder and on page 208 the selection criteria, we get:
“The presence of disintegrative disorder:
Symptoms and Signs of intestinal dysfunction and parental request for investigation to be undertaken.”
On page 209, elaborating on the selection criteria:
“All subjects will be under the age of 16, and all will manifest disintegrative symptoms and signs to differing extents. They will be accompanied at all times by a parent, and will have a designated nurse(s) in attendance throughout the week. Invasive procedures and MRI will be carried out under either standard sedation or general anaesthesia (ileocolonoscopy and biopsy and the lumbar puncture will be performed on the same morning), as indicated. Parents will be aware that they can withdraw their child from the study at any stage.”
What would be your observations as to that paragraph in relation to this issue of research or clinical medicine? Would you expect, in normal circumstances, admission for a week, with a designated nurse in attendance and the procedures to be carried out during that week in a set order?
A No, you would not. This is where it comes back that if you were dealing with a highly circumscribed group where it is clear what needs to be done, you might do it like that, but that would be very unusual and would need some justification.
Q I am going on down the page. We see details were asked as to whether there were any controls and the answer was “Nil”. The funding:
“How are the substances for this study being provided and how is the study being funded?”
The answer was:
“Clinical research at the Royal Free Hospital (ECR).”
We have been told that is extra contractual referral, that method.
A Yes.
Q Going on to paragraph 11:
“PROCEDURES AND SAMPLES TO BE TAKEN FROM SUBJECTS
(Venepunctures, arterial blood, urine, tissue, biopsy, etc state type, frequency and amount).
1) Two venepunctures of 10 20 ml each.
2) Ileocolonic tissue biopsies 10 per patient.
3) One 24 hour urine collection.
4) Cerebrospinal fluid 3 ml.
Would the procedure(s) or sample(s) be taken especially for this investigation or as part of normal patient care?”
The answer is:
“Yes: in view of the symptoms and signs manifested by these patients, all of the procedures and the majority of samples are clinically indicated. Additional intestinal biopsies (5 per patient) will be taken for viral analysis. DNA for genotyping will use blood cells isolated from the routine blood sample, and will not require an additional sample.”
So there is specific information given as to that. How would you read the words “all of the procedures are clinically indicated”, what would you read as “procedures” meaning?
A I think everything above.
Q This is an obvious question but the reason I am asking it will become apparent later. Is there any way, other than by lumbar puncture, that cerebrospinal fluid can be obtained?
A Not really. You can obtain it from a cisternal puncture, which is in the neck, and in the days in which imaging was being done through injecting dyes and the like – it is not done nowadays – you of course can get a sample that way, but that is a much more unpleasant and somewhat more risky procedure, so that nobody does that nowadays.
Q If you saw a reference to the obtaining of cerebrospinal fluid in normal circumstances ---
A You would assume it is from a lumbar puncture.
Q If these children had indeed on your definition been suffering from disintegrative disorder or the indications were of disintegrative disorder, from what you told us previously before the coffee break, you would not argue with a lumbar puncture being clinically indicated in those circumstance?
A No, because of the concerns over a possible progressive neurological disorder.
Q Attached to this document there was an appendix which sets out all the virology tests that were envisaged; that is Appendix 1. At page 212 there is a copy of the proposed clinical and scientific study. We see that sets out in considerably more detail the same envisaged investigations. If we look at the responsibilities as they are set out there on page 213, we see Professor Walker-Smith and Dr Murch and their responsibilities as:
“Referral and co-ordination of patient admission for investigation. Clinical evaluation, procurement of blood, urine and serum samples. Colonoscopy, and tissue procurement/processing.”
Then we go on to 214, “Dr Mark Berelowitz (Consultant Psychiatrist & co-ordinating investigator)” and his responsibilities were, “Confirmation and characterisation of features of disintegrative disorder.” Dr Peter Harvey, who is a consultant neurologist in the Department of Neurology and co-ordinating investigator: his responsibly was for “Full neurological assessment and investigation.” Is that correct?
A Yes.
Q As far as Dr Berelowitz’s role, which was the confirmation and characterisation of the disorder, does that accord with the responsibilities that Dr Berelowitz told about in his evidence: i.e. that he played not part in the decision making in relation to lumbar puncture?
A Yes. What it does not do of course is focus on disintegrative disorder using a structured assessment in a way that the protocol indicates somebody would be doing. It does not actually specify whether that is Dr Berelowitz or not.
Q Absolutely, but that is what you would have expected as part of the disorder?
A Yes, indeed.
Q We heard from Dr Berelowitz that in fact it was not he who made any decision in relation to lumbar puncture?
A Yes.
Q What I was asking you was whether his setting out of responsibilities, in other words the “confirmation and characterisation” would accord with that. You would not expect him to be making decisions about lumbar punctures in that context?
A No.
Q If we go on to 223 of the scientific protocol, under “Practice issues” it states:
“Firstly, and significantly, this is a demanding protocol both for the children, and for those clinicians carrying out invasive procedures in particular. Due consideration should be given to this when planning ….. However, it is essential that we characterise as comprehensively as possible the pathogenesis of this condition – control of any underlying intestinal immunopathology may open up new therapeutic avenues for the treatment of affected children. Our ability to confirm or exclude a role of measles or measles/rubella vaccine also has major implications for public health.”
It then refers to the co-ordination of the referrals and a plan of investigation is shown, which I will go to. That identification of the demanding nature of the protocol and the essentialness of characterising as comprehensively as possible the pathogenesis of the condition, albeit with reference to the possibility of opening up new therapeutic avenues for treatment, Professor Rutter: how would you categorise that with reference to the guidelines we have looked at as to whether that is a therapeutic or non-therapeutic aim?
A It is a bit ambiguous I suppose, but both there and the starting point that we covered earlier on deal with it as a hypothesis and that if you are dealing with a hypothesis that ordinarily means research because you are testing out something from which you are hoping to draw general conclusions. It may benefit the individual as well, and the guidelines make clear that that will often be the case, but it reads like a research procedure with a research aim.
Q Turning to 226, we have the appendix which is attaching all the virology that was anticipated to be done on the samples that were obtained. Then at 231, the timetable. I am not going to go through that in its entirety save to say that we see that it would appear the neurological aspects, using that in a broad sense (in other words the MRI, lumbar puncture, EEG) that were seen by Dr Harvey and Dr Berelowitz were to be arranged by Dr Wakefield and that the paediatric gastroenterology were dealing with the gastrointestinal aspects. There is a set timetable. Then at 232 there is the handout to the parents. I am certainly not going to read the whole of that but I would like to ask you about the second paragraph.
“We would like to carry out a series of tests which, we believe, will help us to establish the features of this possible disease. Our aim is to characterise the problem, so that, for the future, we may be able to treat affected children and improve their wellbeing.”
A That is research language.
Q That is research language.
A May I comment on just one aspect on page 231 because what I found surprising was that the decisions were based on clinical need supposedly – that was what was put forward – but the assessment on the neuro-psychiatric side actually followed the investigations not preceded them. That would be all back to front in terms of any clinical approach.
Q Thank you. I will indeed be asking you about that in detail. I was really establishing the documentary background first. You said that is research language. I would like to take you on to 234, which was the consent form which was envisaged for the parents. It expressly refers to the fact:
“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.”
Is that a standard phrase?
A It is in research because the expectation is that the consent is, as it were, provisional and that if the person changes their mind, they have the right to do that and, moreover, they have the right to do so without giving a reason and without it affecting treatment. What is unusual is to see that in a clinical needs consent form.
Q Because obviously if they withdrew, they would be affecting their treatment inevitably?
A Yes.
Q You have anticipated the question that I was about to ask you, Professor Rutter, but I will ask you it again. I was going to ask you with reference to the timetable what you would expect in terms both of the timing of these investigations, which I think you have now answered – you are saying it was curious to see it this way round. Can you tell us exactly why you say that?
A Well, let us come back to the area where Professor Gillberg and I are at one: that is to say, you need to have a proper, though assessment before you decide what to do. We differ only with respect to the value of lumbar puncture. So that what he is arguing and what I have argued is that because autism can be associated with a range of different medical conditions, you need to have a proper assessment and you need to tailor your investigations according to what comes out of this clinical assessment. It follows therefore that you have to have your clinical assessment before you decide what to do.
Q Yes. In the particular circumstances of this, we have looked at the inclusion criteria, which were very specifically for children with disintegrative disorder.
A Yes.
Q The psychiatric and neurological assessment which you are saying should have taken place at the outset, would that also have determined, one hopes, the nature of the condition that they had?
A Yes.
Q So that if you are embarking, if this was indeed research as you say it was, on research in relation to gastrointestinal symptoms which may involve invasive investigations for that and if you are doing them on children with disintegrative disorder, as this ethics committee application says they were, then is the order in which you do those investigations important in relation to what the child is actually subjected to?
A Yes. If it is on a clinical needs basis, you would assume that an assessment has been done to sort out first of all: does the child’s disorder meet the inclusion criteria, but, also beyond that: is there anything particular about this child which means that we should vary what we do; either do more or do less or do it differently according to what comes up. That is sort of standard so that you have a thorough assessment and you then proceed on the basis of what that thorough assessment shows.
THE CHAIRMAN: We will adjourn for lunch now. Professor Rutter, I remind you yet again that you are still under oath and in the middle of giving your evidence. Therefore, please do not discuss the case.
(The luncheon adjournment)
MS SMITH: Professor Rutter, I have asked you about the ethics committee application, and that is all I am going to ask you about it for now. We will revert to it when we have looked at the children. I do just want to go on and have a look at the correspondence which followed on from that application. Would you go to bundle FTP1 at page 265A. That is a letter on green paper, because it has been submitted by Professor Walker-Smith, and it was missing from the ethics committee application, but I think you have had an opportunity to look at that letter?
A Yes.
Q It is a letter to which Professor Walker-Smith then responded, which was in the bundle and you have seen.
A Yes.
Q It is a letter from Dr Pegg, simply saying that the submission was to be discussed at the next meeting, and inviting comments. The comments were:
“2. It is a very intensive regime involving some unpleasant investigations – Lord Penrose, 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).”
He then quoted the guidelines, that:
“’It would be unethical to submit … [children] to more than minimal risk when the procedure offers no benefit to them, or only a slight or very uncertain one.’
Your submission indicates that all these tests would be carried out (apart from 5 extra biopsies and some extra blood) in the normal care of the child[ren]. I would therefore like you to:
a) Confirm that the child would undergo this regimen even if it was not in a trial
b) Indicate what benefit the child will receive from having been investigated in this way. Will the benefit be more than ‘slight or uncertain’.”
He encloses the guidelines. Then, if I may, I will take you on to the letter I want to ask you about, which is Professor Walker-Smith’s response to that, which is at page 291. Professor Walker-Smith said, going to paragraph 2:
“Clearly this is an intensive regime with procedures that cold be regarded as ‘high’ risk although they are particularly used for the investigation of children with chronic inflammatory bowel disease. These children suffer from a disease with a ‘hopeless prognosis’ in relation to their cerebral disintegrative disorder. They have often not had the level of investigation which we would regard as adequate for a child presenting with such a devastating condition. In relation to their gastrointestinal symptoms which will be present in all the children we investigate, these have often been under-investigated. 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:
a) Establishing a diagnosis and excluding metabolic and other causes
b) Commencing on a therapeutic regime
The whole study is parent/patient driven as every case referred has been initiated by the GP by the parents of the child.
I can confirm that children would have these investigations even if there were no trial. I must make clear that we would not be investigating children without gastrointestinal symptoms.”
He then deals with a query in relation to consent. We see that letter was copied to the two other investigators, Dr Wakefield and Dr Murch.
Can I ask you this: from the overall look that you have had at these children, was it correct to describe the disorders that they suffered from as cerebral disintegrative disorder with a hopeless prognosis?
A No.
Q If we can just cut it down into the two components of that, Professor Rutter, the reference to them having cerebral disintegrative disorder, again generally speaking, would you regard that as being an appropriate description of what these children were suffering from?
A With the possible exception of Child 2, no. Child 2 had a very unusual pattern, and although the pattern actually is not quite like you would ordinarily expect with a disintegrative disorder, it nevertheless had sufficient features in common that I would see that as within that general arena. The others not.
Q We will look at Child 2 – in fact that is the first child, as we know, and we will look at his individual case in a moment. As far as all these children are concerned, they ranged in age we know from one who was nine, who was by far the oldest, but most of them were young, toddlers. Would describing them as a “hopeless prognosis” be something that you would have agreed with?
A No. The cases clinically as far as I could tell would fit for the most part, autism spectrum disorders, but, as I say, with the exception of Child 2, not the disintegrative disorder. Consequently the prognosis would be quite varied. To say that they had a hopeless prognosis is completely out of keeping with the evidence from other studies, in which such children have been followed forward in time. That is to say some of them do relatively well, some intermediate, and some indeed do do very badly. But as a group, to describe them as having a hopeless prognosis, is clearly wrong.
Q I will revert after we have looked at the children to the observation that they had not had the level of investigation that was appropriate. But as far as Professor Walker-Smith’s indication that the children would have had the investigations even if there had been no trial, what did you understand that to mean?
A I presume what was meant was that this is the sort of approach that would ordinarily be followed with children with this particular kind of pattern. The difficulty I have here is that it is not clear what this group is; that is to say, from the point of view of both the gastrointestinal symptoms – they were quite varied – and the neuro-psychiatric condition was also quite varied. So I find it difficult to consider quite why one could have a standard protocol that fitted a group like that, whereas, as came out earlier when you were questioning me, if this had been a group with a disintegrative disorder of the kind ordinarily conceptualised in that way, I would view it differently.
Q Differently? In what regard differently?
A It might well be appropriate to have a protocol of that kind.
Q That is confining yourself to the neurological aspects, the psychiatric aspects?
A Yes. I cannot comment on the gastrointestinal.
Q I am trying occasionally to orientate you in your report, because I am all over the place, I know. I am now at paragraph 62, and I wanted to ask you: in the light of what you have just said, if that information was given to the ethics committee by Professor Walker-Smith, as we know it was, would you expect an ethics committee to consider further the nature of these investigations themselves, if they were given the assurance that they would have been performed anyway?
A No, I think that, as with any other ethics committee, you have to go ahead on the assumption that the facts that are presented to you are as correct and as honestly portrayed as they can be, and as such I think one would not follow through in any further way. Appropriate questions were posed, but an answer was given that I think the ethics committee would have to accept.
Q Yes, of course they would accept what a senior clinician in their own hospital told them; but the question I was really asking you was, the information that he gave, i.e. that the children would have the tests anyway, once the ethics committee have that information, are they going to be subsequently concerned in any consideration of those tests – if they are told that they are clinically indicated, in effect?
A If they are truly clinically indicated, on the basis of what is required for an individual child after a full and thorough assessment has been made, no, they would not enquire further than that. The query would be simply in terms of being assured that it had followed a thorough assessment.
Q Yes. As far as your overall look at the cases, Professor Rutter, do you regard the information that Professor Walker-Smith gave to the ethics committee in their letter as being satisfactory?
A Not really, because of the statement about the hopeless prognosis. I am not sure what that could have been based on, but in terms of the cases, and the fact that they did not follow, with that one possible exception, a pattern of a disintegrative disorder, then that is a misleading statement. Whether he was aware of that or not, of course I cannot say.
Q Overall, having studied these individual cases, what was your overall view as to whether the neurological investigations were conducted for clinical or research reasons?
A By investigations you mean the testing, or the assessment as a whole?
Q I mean both, but you can deal with them separately if it is easier for you to do so.
A The thing that stands out with respect to the clinical assessment is how un-thorough it was. It does not fit in with what is described in the protocol, but nor would it fit in with what was recommended, either in my own writing or for that matter Professor Gillberg’s writings. So that is curiously back to front, deciding on the investigations before you have looked at the children on a case-by-case basis. In terms of the investigations I come back, if these had been children with a disintegrative disorder then I would accept that that was a reasonable way of proceeding. But on the basis of a much more heterogeneous group of autism spectrum disorders, I think that raises questions.
Q Whose responsibility would you regard it as being to answer accurately and clearly any clarifications that were sought by the ethics committee?
A I think the three responsible consultants, presumably they will have thought it out amongst themselves who was going to be their key spokesman, and that could be any of them, so that there would not be any necessary expectation that it would be the most senior person or the most junior, or whatever. That is to say it was presented as coming from a trio of responsible consultants with other advisors as well, of course, and you would ordinarily expect it to be left up to the team who would be the spokesperson. But obviously you would expect that the other members would be consulted as appropriate, and that they would be fully kept in the loop as to correspondence and queries and concerns.
Q Had this committee been told that these were investigations being carried out for research purposes – in other words, they would not be carried out were it not for the study for which an application had been made for approval? If they had been told that, how should they have reacted? Before you answer that, can I preface it by saying I am not asking you what they should have concluded, because obviously no-one knows that, and that is up to the individual committee, but what would they have been considering if they had been told that these were research investigations?
Q They would be concerned on the scientific rationale, of course, and on the issue as to whether this degree of risk or invasiveness was justified. In other words, they would be looking at the protocol as a whole and coming to a decision one way or the other as to whether or not that was justified.
Q The information that was given them when they queried, what in your view would have been the result of giving that investigation, as far as what they then considered? If I can put it another way, would you have been expecting them in those circumstances to do an assessment of risk and benefit and matters of that kind, if they had been told ---
A No, if they had been told that this was individual clinical need then I think they would just have to accept that that was not for them to question.
Q We heard from Dr Pegg, Professor Rutter – and I know you have seen the transcript of his evidence – that clinicians and researchers frequently consult him as chairman of the ethics committee if they have any concerns or queries as to what is required of them. Does that accord with your experience in your hospital, that the chairman is approached – is accessible if people want to enquire as to what they need ethical approval for?
A Yes. That would often be the case, and would have been more so in 1996 than it is now, so the thing has become more bureaucratic. But yes, there certainly would be an expectation that if researchers have a query as to how they should proceed, it is perfectly proper to approach the chairperson of the committee to get feedback.
Q Thank you. Can we turn, please, to file FTP3, page 940. This is a letter you comment on in paragraph 59 of your report. It is a letter from Professor Walker-Smith of 15 July 1998, so considerably later. We see that the clinical designation has now changed to autism – “Autism and Non-Specific Colitis and Lymphoid Nodular Hyperplasia”. The letter says:
“Further to our original study, we are now continuing to see such children by clinical need and performing ileo-colonoscopy and limited blood tests in order to decide whether to give such children Mesalazine. As Dr Wakefield is carefully analysing our results and some of the biopsies taken are being used for research (we already have research permission for taking extra biopsies in children who we colonoscope) I would like formally to request Ethical Committee approval for our clinical research analysis of these children who we are continuing to see by clinical need.”
You know the context of this letter was when enquiries were raised as to the ethical status of this study by Professor Howell and then by Professor Zuckerman. There is no reference in that letter to the change in title. Was that a significant change in your view in the context of a letter which indicates that children are being seen by clinical need, as were those in the original application – the fact that we are now talking about children with autism, rather than children with disintegrative disorder?
A Yes, that was certainly quite a major change, particularly so in the light of opinions in 1996, so that the onus is very much on the researchers to highlight changes. It is not up to ethics committee to try and spot when there have been changes, and in relation to this particular ethics committee, of course they did not have people on the committee with expertise in the area of autism so that, doubly so, is it necessary to highlight the change? As I have argued before, in terms of what is needed, clinically, if you are dealing with a disintegrative disorder that might involve a progressive neurological disorder, what is necessary and acceptable is quite different from looking at a mixed bag of children with autism spectrum disorders.
Q If I can revert back to the actual application in the ultimate conditions which had been imposed by the ethics committee and then we will begin on the children. They are in bundle 1, page 358. The letter is addressed to Professor Walker Smith from Dr Pegg of 7 January 1997. Just taking you to the relevant parts, he said:
“As you may be aware this application was discussed at length at two committee meetings and the approval is conditional on the following:
1) Only patients enrolled after the date of the December meeting will be considered in the trial.
2) The Schilling test was to be removed from the protocol.
3) The consent form to be modified so that the possible complications of lumbar puncture are explained.”
They then they refer to the need for annual reports. Then:
“The Ethics Committee must also be informed of, and approve, any proposed amendment to your initial application which has bearing on the treatment or investigation of patients or volunteers.
A copy of the patient consent form and information sheet must be lodged in the clinical notes.”
The reply to that is at page 362. This is a letter to Dr Pegg from Professor Walker Smith and Dr Wakefield is copied into it, dated 9 January 1997 thanking Dr Pegg for his letter:
“I accept its contents and we will modify our protocol as you recommend and give an annual report of the progress of the study.
We will place a copy of the patient consent form and the information sheet in the clinical notes.”
The conditions that were imposed by the ethics committee when they gave permission for this study, who would you expect to be aware of them?
A The three responsible consultants. I note that Professor Walker Smith’s letter is copied only to Dr Wakefield and not Dr Murch, as he then was, but I would assume that there would have been communication, there certainly should have been.
Q As far as the letter from Professor Walker Smith simply saying that he accepted the contents and would modify the protocol as recommended and ensure that the patient consent form and the information sheet were included, he does not specify the way in which the protocol was to be modified. What would be your view as to the responsibility of the two others who are named as responsible consultants in those circumstances?
A They would need to be consulted on that.
Q Would you be happy with them going ahead with the protocol if they were not aware of the modifications put on it by the ethics committee?
A No, because if you are identified as a responsible consultant you have to have the information available in order to be responsible.
Q As far as the undertaking to include a copy of the consent form and patient information form for parents, if for some reason, which I will not try and speculate about, but if for some reason the responsible consultants had concluded those documents were not needed or they were needed in a different form, who would you expect them to indicate that to?
A I do not know. A specific request had been made, which is fairly routine, that information sheets and consent forms ordinarily are included in the hospital notes. I cannot imagine why there would be a good reason for not doing that. Obviously, even in a well functioning system, there is the odd thing that goes missing but I do not know who you would consult on that.
Q Sorry, I think you may have misunderstood me. I do not mean consultation as to whether they should be included in the clinical notes or not, I meant if, for some reason, they were not regarded as being documents that were any longer appropriate so that consent was not going to be taken in that form, would you expect any further communication from the ethics committee in relation to it?
A They would need to know in that a specification was made and therefore if a considered decision was taken to depart from that, that would ordinarily go back to the ethics committee.
MS SMITH: Just after getting those general comments from you, I am going to turn to the individual children and then we will come back to these when you have told us what your views are on those children one by one. I am going through them in the order in which they were referred to the Royal Free. You have an anonymisation chart so you know which child is which. I am beginning with Child 2. So you know, Professor Rutter, Child 2 is at page 5 of your own report if you would like to have that open in front of you.
THE CHAIRMAN: Will we need the Royal Free bundle?
MS SMITH: You will, sir. I was planning to tell Professor Rutter where they are in his own report so he has a moment while you are looking for them to refresh his own memory. You will indeed need the Royal Free Hospital records for Child 2. I think that is all you will need, I think it is all in the Royal Free. I am going to follow the format of your report, in other words to go to the referral circumstances to the Royal Free Hospital and the tests that were carried out, and then revert to the behavioural background prior to that and then ask you your views in relation to those matters.
If we can first look at the referral. This is a little boy who was referred to Professor Walker Smith first of all when he was at St Bartholomew’s Hospital in 1995. We can see the letter for that at page 197. I should have said that, as I know has been indicated to you, we are going to refer to these children by number, but if you slip the press do understand the issue.
A I will try and remember.
Q This is a letter from Dr Wozencroft, who is a child psychiatrist, to Professor Walker Smith:
“I write to ask you to see [Child 2] and to express an opinion upon him. I know that his parents have contacted you and your colleague, Andrew Wakefield. The family Doctor, Dr Cartmel, also wants the benefit of your opinion.
[Child 2] is a boy who has been seen by a great many doctors over the years. I have become involved only recently. My tasks are to take an overview of the situation; to follow [Child 2’s] development and to discuss it with the parents and to help the family find their way to any source of medical help which might be available.
At present, [Child 2’s] condition in Child Psychiatric terms falls within the diagnostic category of Autistic Spectrum Disorder. Plainly, such a disorder can arise through more than one mechanism. [Mr and Mrs 2] feel that there is a strong physical component to [Child 2’s] difficulties. I must say that I agree with them. At the moment, [Child 2’s] physical, medical and emotional states are all deteriorating. In the past, just such a deterioration has been nipped in the bud by B12 injections. I think it entirely legitimate for [Mr and Mrs 2] to be seeking your expertise.
For my part I am not familiar with the research evidence which connects immunisation with the difficulties like [Child 2’s]. Naturally I am trying to educate myself in that area. [Child 2’s] condition, however, is going downhill again and his parents, his GP and I would be grateful for an urgent opinion from you.”
The reply to that is at page 196 from Professor Walker Smith thanking him for the referral in August 1995, still from St Bartholomew’s:
“I am left some what confused as to what the evidence of B12 deficiency is. On examination there is no evidence of Crohn’s disease which concerned the mother, in view of the possible association between measles and Crohn’s disease. Apparently there has been a gastrointestinal problem in the past and I am writing to the various professionals to try and find out what has been done in the past and I plan to see [Child 2] again in 2 months time.
One of my former research fellows, Dr Mark Beattie, as you know has come to Peterborough as a consultant paediatrician. Mother is saying that she has not had a consultant paediatrician concerned with the overall management of [Child 2] and I think it might be very helpful in due course for Mark Beattie to see [him].
However I plan to see him myself again in 2 months time when I have more information available and I have done some routine blood tests.”
Professor Walker Smith also writes to Dr Cavanagh at page 193. To summarise, he says he is puzzled by the child, interested in the diagnosis of B12 malabsorption. He asks Dr Cavanagh, the paediatric neurologist, to outline for him his assessment of the child. He says:
“The child was referred to me via Andy Wakefield of the Royal Free because of mum’s perception of the child’s illness really began with MMR and in view of the possible link of measles with Crohn’s disease.
On examination there is absolutely nothing to suggest the diagnosis of Crohn’s disease. His weight and height are both close to the 50th centile. The gastrointestinal story sounds very much like multiple food allergy/irritable bowel syndrome rather than inflammatory bowel disease or indeed coeliac disease. However, I have done routine blood markers, CRP, endomysial antibodies etc and I plan to review him again at the Royal Free in 2 months time.”
He asks Dr Cavanagh to send his opinion. At page 195, Professor Walker Smith also writes to Professor John Warner, who had been involved in the care of child, he is a paediatrician, asking for an opinion on this child:
“...who is diagnosed as having autistic syndrome and has had evidence in the past of multiple food allergy and of which I understand there has been some history of possible B12 deficiency.”
He indicates that it is a very complicated problem. Dr Cavanagh writes back to Professor Walker Smith on page 184. Most of the letter is about the B12 issues, but it encloses a previous letter when he first saw him. I will turn to that in a moment. The remainder of that letter, on page 185, indicates that this boy was being seen in the neurology outpatient clinic at the Chelsea and Westminster. As I say, it refers to vitamin B12 absorption studies. Enclosed with that letter was a letter from when he had first seen the boy at the Royal Free at page 190. This is a letter way back from 1993 to the GP. It gives a history from birth, questions as to whether he was having some sort of fits, but an EEG did not corroborate the diagnosis of epilepsy:
“Nevertheless his neurological development and behaviour seemed to be proceeding normally for the first year to 18 months of his life (at 18 months he had 25 words for example) and the regression was without obvious explanation.
Twelve months ago he seemed to be wasting away and very miserable and then responded to Vitamin B12 injections.”
Then it says that the present situation is with his gastrointestinal symptoms. It says, “He gets hyperactive with some foods, clumsy in the past, now managed to learn to ride a bicycle and is more dextrous, not potty trained, understanding variable, can become interested and enjoy things”. It says:
“He seemed unduly sensitive to loud noise. A brain stem auditory evoked response in the past has been reported to be normal...He has no words, but does have language in the sense that he can link words said to him with pictures in a book.”
He did not play properly with his toys. Dr Cavanagh gives the opinion that:
“Examination of [Child 2] does not reveal any focal or formal abnormal neurological signs. Clearly, he is hyperactive and has an attention deficit.
The history points strongly to an underlying dietary sensitivity, and I note that he has never been on an oligo anti genic diet. Nor has he ever been on Ritalin.
In discussion with his parents (and Dr Bhatt) they express the preference to explore Vitamin B12 metabolism as a first step and go along with any treatment that might be indicated, but failing help from that they would consider any dietary exploration, and possibly even treatment with Ritalin.
It was agreed that he would be admitted for a Valine Load (Dr Bhatt discussed this in detail with them), and we hoped at the same time that he might be seen by Dr Hariri, our Consultant Audiologist, querying the possibility of a high frequency loss.”
That was the information that was sent to Professor Walker Smith by Dr Cavanagh, as a paediatric neurologist, including his assessment back in 1993. The other information that he had was from Professor Warner, the paediatrician to whom he had also written. That is at page 186. Again, it is encloses correspondence for Professor Walker Smith to read. That previous correspondence is at page 188:
“Thank you for referring [Child 2] who is clearly a very worrying problem. I would have thought that the best label that might be attached is one of Asperger’s syndrome. Whether or not this can ever be established to be associated with any food intolerance remains to be seen.”
This was in 1992. It sets out his birth history:
“He began to have screaming fits from about 6 months of age but first began to have severe temper tantrums and over activity between 16 and 20 months. At that stage he lost all language which he had acquired.”
It then says:
“Diagnostic labels attached from assessments included a specific language problem and receptive...”
The letter has a section missing in the middle, but it then goes on at page 189 – I will try and find the other page:
“I would prefer the assessment was done in collaboration with Dr Rolles and the Autism Assessment Group in the Unit. [Mr and Mrs 2] are happy about this and had already heard of Dr Rolles.
I pointed out that there are many ways in which one might interpret or misinterpret an apparent reaction to food and we would need to consider doing appropriate challenges and also consider whether a small bowel biopsy was required to exclude Coeliac disease.”
He then says at the bottom that he discussed various gastrointestinal symptoms with the parents. That is the correspondence that Professor Walker-Smith carried out in 1995 when this child is referred to him at St Bartholomew’s before the matters with which we are concerned. Broadly speaking, I am not again asking you to comment on the gastrointestinal aspects, the queries to other consultants that he made and the responses that he got. Would you regard that as being consistent with normal clinical care in the patient referred?
A Yes, it is perfectly sensible.
Q When he got it all, Professor Walker-Smith reverted to the GP, and that is at page 178, dated September ’95. He said;
“I have now reviewed [2] and I think inflammatory bowel disease is extremely unlikely and I have had a copy of the letter which Dr Bhatt wrote to you and I do believe that the best way forward is for a Schillings Test. This is a test which is best done by experts—“
He recommends it be done at the Chelsea & Westminster and the involvement of a local paediatrician. He said:
“I have not arranged to see [2] again but I would be happy to do so should the need arise.”
He wrote in very similar terms – all these letters are dated the same date, 13 September 1995 – to Dr Wozencroft, and that is at page 179:
“After reviewing [2]I don’t really believe there is any evidence of chronic inflammatory bowel disease and I think that the next way forward is in fact to do a Schillings Test…….
I have not made an appointment to see [2] again, but I should be happy to do so again in the future and I have left the line of communication open with Mrs [2].”
He writes to Dr Cavanagh, and that is page 180, asking Dr Cavanagh, who we know is a paediatric neurologist connected with the B12 unit, to do the Schilling test. He said:
“I have spoken a number of times on the telephone to Mrs [2] and I don’t really believe [2] has any features of chronic inflammatory bowel disease.”
He says at the bottom:
“I would be very interested to hear what turns up but I have not made an appointment to see the child again.”
That appears to have concluded those views by Professor Walker-Smith, but then 10 months later we have a letter that Professor Walker-Smith writes directly to Mrs [2], and that is at page 165. This is May ’96, so 10 months later.
“Dear Mrs [2],
I think it would be very helpful if I saw [2] again. I have had discussions about [2] with Dr Wakefield. We have a plan for investigation but I think if it were convenient for you, it would be helpful for me to see [2] first in outpatients and discuss and plan what we have in mind. I have arranged an outpatient appointment for 9.30 am on Friday 14 June 1996 which I hope may be convenient for you.”
As far as that letter is concerned, Professor Rutter, is that a method of clinical referring which is usual or unusual, if referral is the right word, the writing to Mrs 2, having apparently decided not to see the child again with a plan for investigation?
A No, that would be somewhat unusual.
Q Obviously you may be asked about the factual circumstances surrounding that letter but, on the face of it, a plan to see the child again in order for him to undergo a particular plan for investigations: would that be consistent, in your view, at least on the face of it, with a clinical plan?
A What is puzzling is that Professor Walker-Smith had earlier on come to reasonably definite conclusions on the nature of the gut problem, and obviously I cannot comment on whether that was correct or not, and of course it is entirely okay for people to change their mind if new evidence comes in but it is not clear that new evidence has come in that would alter Professor Walker-Smith’s opinion on this, or at least I am unaware of it. So that we are now switching, as it were, to a plan of action that was predicated on a protocol that talks about enteritis, which has been ruled out earlier on, and in terms of the disintegrative disorder. As I indicated in my report, Child 2 does not fit the ordinary criteria for a disintegrative disorder but there is no doubt that Child 2 had a very worrying series of regressions – not one but several of them – and that although Child 2 did not fit the criteria, as a clinician, I would have been inclined to approach it in the same sort of way, so that this is a case where it seems to me, following a full assessment, one quite likely would want to go on to investigations of a kind that would pick up the possibility of a progressive neurological disease.
Q Staying with the referral for a moment, can we look at the next step in the story. This child does indeed attend outpatients, and the appointment was for 14 June. In fact, he attended Professor Walker-Smith’s outpatients on 21 June, and after that there is a letter from Professor Walker-Smith to Dr Wakefield, which is at page 162, dated 24 June, so a few days later.
“Dear Andy,
I at last saw [2]. I think he is now the most appropriate child to begin our programme. Can we discuss together the most appropriate date? I think September might suit Mrs [2] best. She has some apprehension about colonoscopy and she was concerned that last time [2] had a general anaesthetic he reacted with a transient fall of blood pressure. In fact we will not be using a general anaesthetic but it is difficult to judge whether he might in any way react to pethidine.”
That is if it was being done under sedation, is it?
A Yes.
Q “I think she would like a copy of the protocol that we are using. I don’t know whether you think it is appropriate for you to send her that or whether I should.”
Are the terms of that letter suggestive to you of a clinical or a research investigation?
A It sounds to me much more like a research proposal in that there is not an indication here that there has been a change of view on the gastrointestinal problem. There may have been that I am unaware of, but that is not the way it is put forward. It is put forward in terms of a trial and that this would be the first child to go into the protocol. The child clearly does not meet the criteria for disintegrative disorder and has not been assessed in that way, so there has been no thorough medical assessment of the kind that is always recommended, and there has not been a structured assessment of a disintegrative disorder. Yes, it sounds as if this is a child where there is a research plan and the child sufficiently nearly fits that it would be reasonable to include. That is the way it comes across.
Q Can I ask you: if it was an ordinary clinical investigation of this child, would you expect discussion with a researcher as to the sending of a protocol to the parent?
A That would be unusual.
Q Would you expect references to the beginning of a programme of investigation?
A Again, that would be unusual.
Q The next thing is a letter to the GP from Professor Walker-Smith, which is at page 130, to the GP, Dr Cartmel:
“I duly saw [2] in the clinic. As you know I first met Mrs [2] via Dr Andy Wakefield who is concerned with measles immunisation and possible Crohn’s disease. I think Crohn’s disease is unlikely. Dr Wakefield has the view that there may be some kind of other inflammation which may be a relevant factor in [2’s] illness and we now have a programme for investigating children who have an association with autism and a possible reaction to immunisation. I am arranging for [2] to come in for investigation at the end of August.”
Again, Professor Rutter, is that letter suggestive to you of a research or a clinical investigation?
A It sounds much more like a research investigation. It talks about a programme for investigating children. As for the link with immunisation, clearly that was a driver for what was being done. That was clear in Mr Wakefield’s way of dealing with things, but that would not be ordinarily seen as a clinical need investigation at that time. That is the kind of thing that if research had shown a meaningful association, it could become so, but that certainly was not the case at that time.
Q I am not asking you to comment on the gastroenterological investigations. It does not matter what the investigations are, but if you have a senior clinician who comes to a view as to whether or not a child has a particular disorder and who then apparently, if we read this letter, has a view about some particular special kind of condition conveyed to him by a researcher, would you expect that to drive the clinical treatment of the child?
A Not really because this is a hypothesis. It is a hypothesis that could reasonably be the subject of research but it would be unusual for that to drive clinical need.
Q If it were driving research need, in inverted commas, in other words a research idea that a clinician wanted to investigate, I think we should be clear there is no harm in that: is that correct?
A No.
Q But then how would you expect it to be carried into practice as far as the investigation of a particular child is concerned?
A This is where one would expect the application to the ethics committee would describe it as a piece of research in the protocol, in the same sort of way as is already in the application, but as it were for this to be viewed in research terms as a whole. That would have been perfectly okay. Whether or not that would have been approved by the ethics committee, I could not say, but there would be nothing unusual, as it were, in making such an application.
Q In fact, a few days earlier than that letter was sent, some five days earlier, there is a letter from Dr Surtees at the Great Ormond Street Hospital, and that is on page 153. It is a letter that was sent, we know, to the Royal Free and addressed to a consultant in paediatric disability and dated August 1996. Dr Surtees was a senior lecturer in paediatric neurology, is that correct?
A Yes.
Q We see he says:
“Thank you for letting me see this eight year old boy who now has the features of a child with classical infantile autism. What is unusual is that there have been three episodes of regression each proceeded by some months of increased activity and misery. Following each episode of regression he has never regained the skills lost. On formal neurological examination there are no focal findings. I am afraid that I do not recognise this as a defined neurometabolic or immunological disorder. However, I do think reinvestigation is necessary if only to make an authoritative decision on what he does have. To this end I would suggest the following investigation.…”
He then lists: MRI of the brain; a repeat EEG; repeated metabolic investigations including, and then he set out the tests that he would be particularly interested in – detailed immunological investigations looking at T and B cell function and auto antibody screen and an immunological consultation; a detailed dietary review; and a gastro intestinal consultation. He says:
“I understand that further investigations are being proposed and it would clearly be economic if the above could be combined with these.”
First of all, his view that these periods of regression are very unusual, and his differentiation between that and what he has described as classical infantile autism, would you agree that they were very unusual?
A Yes, I would.
Q And that they do indeed differentiate him from classical infantile autism?
A Yes, I am sure he is absolutely right in that.
Q Would you further agree that the examinations of the kind that he sets out would be appropriate in this particular child’s case?
A Yes, I do.
Q In fact, do any of those tests that Dr Surtees suggests involve a lumbar puncture?
A No, unless I have misunderstood them, but as far as I can see, not. He is talking about plasma levels, not CSF levels.
Q This child was admitted on two occasions. Just so that we are clear about that, could you go to page 4 so that the panel can see the dates? This is the printout of an admission: from 1 to 6 September 1996 under the care of Professor Walker-Smith and from 10 to 12 November 1996, also Professor Walker-Smith. Can we look at the first admission? What I am going to do with all these children is to do what you do in your report, Professor Rutter, to take you to the discharge summary so that we can see what tests were performed and then go back through those tests seeing the order in which they were done. The discharge summary is at page 145 and it is dated 16 September 1996. This is the letter that was sent after he had been at the Royal Free. It says:
“[2] was admitted to our ward on the 2nd September 1996 for further investigation of several problems. The main problems are of developmental regression from 20 months of age, diarrhoea … and abdominal pain …
Until 20 months of age, mum notes that he had a normal developmental progress. He walked at 1 year … using recognisable words at 13 months … growing well and feeding himself. Mum does recount that at 13 months of age he had had his MMR immunisation and 2 weeks following this had started with head banging behaviour and screaming throughout the night. He subsequently seemed generally sickly. Nevertheless the most major changes appeared to have stemmed from the age of 20 months. At this time he started losing words. He apparently had a vocabulary of approximately 35 words at that time which he subsequently lost. He also became hyperactive. He stopped recognising people and did not … respond normally to them.”
Then he deals with his gastrointestinal symptoms, which I do not need to trouble you with.
At three years of age, a sudden onset of weight loss. No precipitating events for this.
“As it appeared to resolve it became apparent that he had lost several of his skills. Most specifically mum notes his interaction with other children. It is important to note that 3 such episodes of acute exacerbation with subsequent loss of developmental skill have characterised [2]’s illness.”
At four years of age he had the second of these episodes; he developed the odd facial appearance which now manifests itself. There were worries about food intolerance. Reported diagnoses were made, specifically of a specific language disorder and other suggestions of Asperger’s.
“He was seen by Dr Rolles at Southampton and assessed for a possible diagnosis of autism. An EEG at this time apparently showed the possibility of slow waves in the right temporal lobe. He had had this under anaesthesia and … [was unwell].”
Increased diarrhoea, decreased appetite, aberrant B12 metabolism. Then at the third paragraph up from the bottom:
“In summary, his present condition is characterised by odd episodes which occur roughly every 18 months, the last of which was in April of this year.”
As far as his family history, a 15-year-old brother with a slight speech delay and some degree of clumsiness. A sister with some mild dyslexia, and a maternal uncle with schizophrenia. Dr Casson goes on:
“He was extensively investigated. A full panel of blood tests was performed with regard to his developmental regression. He had a colonoscopy, … an MRI … a sleep EEG and evoked responses. A Schilling test was performed.”
It sets out the details of those. The colonoscopy and Schilling test; the MRI, which did not show any structural abnormalities, an EEG which was within normal limits, although with one apparently slightly abnormal result. Evoked responses, which were normal again. Blood tests were done. We have the CSF results, so we know he had a lumbar puncture; urine tests, a barium mean and follow through. Then at the bottom of the page it says:
“With regard to [2]’s neurological problems an opinion of a neurologist and a child psychiatrist have also been sought. I am sure that they will forward further information to you.” –
and indicating that the child would be reviewed in two weeks.
We have a consent form which was signed on the day of admission, and that is at page 340. Could I ask you, Professor Rutter, is that a standard clinical consent form as opposed to a consent form with any research investigations indicated?
A It is a little bit different from what I would be used to.
Q I am sorry – I realise it is because you are looking at the papers, but you are so far away from your microphone that I cannot hear you.
A I am sorry. I was saying it is in a form that is not quite as I would have expected either way, so it is not like a research or a clinical, in the way of forms that I am used to, so it does not help me which way to go.
Q If it were in the research form that you are used to, what would it have included?
A It would be clear what research is being done, so that the information sheet is crucial to the consent form, and nowadays it would be required that the two are together in one document. In 1996 it would have been expected but not required, I think. So the person would need to know what it is that they are agreeing to, why, and it would be made clear that they could withdraw. The waiting list is in this, which would be more in keeping with a research consent form, but there is not an information sheet which sort of links up, as I can see. It certainly is not there in the file.
Q No – thank you. Why I was hesitating there, could you just identify for us where you say the reference to being able to withdraw is.
A At 341.
Q Thank you.
A Where it says ---
Q “Has a legal right to grant or withhold consent prior to examination or treatment”?
A Yes, and that they can withdraw consent at any time. That is a research-type statement rather than a clinical one.
Q Normally speaking, I think you told us, in relation to a research consent form you expect to see that the patient can withdraw and it will not affect their treatment in any way?
A Yes, exactly.
Q You have seen what the investigations which were carried out were. If we go to the actual investigations as they unfold, 257, which is 2 September – so the day after admission – we see a request form for an EEG and EP – that is the evoked potential test that I asked you about, is that correct?
A Yes.
Q The reasons for the request and the relevant history are given as disintegrative disorder, regression of mild social skills, B12 deficit, and then query abnormal myelination; and it is signed by Dr Wakefield. If those were standard clinical investigations in the clinical investigation of this child, would you expect Dr Wakefield to be requesting the investigations?
A No, because in the terms of his contract he was not allowed to be able to be involved in clinical care.
Q The results of that test are at page 245. It took place on the third, the next day, and we see the patient was alert, very restless, had to be held still throughout, he did eventually fall asleep. He seemed to be mute and very immature. In relation to the EP tests, when he was stimulated the responses are indistinct. Movement potentials are extremely troublesome. The patient disliked the stimulation, and the conclusion was that the record was within normal limits. That was the EEG. Then at 258 we get a particular form of evoked potential, binocular flash, “reproducible responses, of appropriate latency were readily obtained”, and the conclusion again was “A normal study”.
THE CHAIRMAN: Sorry, did you say 258?
MS SMITH: Yes, sir, 258.
THE CHAIRMAN: I have a page which is totally unreadable.
MS SMITH: We will have to get you another copy, sir. Perhaps you can take it from me that it is the result of an EEG ---
THE WITNESS: The bit that is readable on mine is the top bit which is typed. The rest is fairly blurred.
THE CHAIRMAN: Yes.
MS SMITH: We will get another copy, but can you read on it that it says “Conclusion: A normal study”, Professor Rutter?
A Yes.
Q Then the lumbar puncture, if we go to the records at page 9. We see that that took place on 4 September, so three days after admission, “lumbar puncture”, and then:
“CSF for protein electrophoresis
Lactate/pyruvates/glucose” –
And then “measles antibodies”. So that indicates that he had a lumbar puncture on that day, and that it was tested for measles. On page 22 we see the results of that. At the top of the page there are other investigations, and you will see three lines down “CSF measles antibodies: negative”. Then after that, on 9 September, so five days after the lumbar puncture, page 13, this child sees Dr Harvey, who we know was a neurologist who was said to be responsible for that side of matters. We see a note by Dr Harvey which sets out the history of head banging after MMR inoculation, followed by psychosis – I think that is “intellectual decline”, but I may be corrected. He says: “In so far as you can get near him” – I have difficulty in reading the whole of this. “The mother is adamant that when his bowel is empty his” – I think it is a reference to his condition improving. He says not spastic, not ataxia. “I await the CSF studies with interest”, I think that is. Then a PS, “Why not try him on some Ritalin?”.
So, as I say, he was awaiting the CSF studies, and the lumbar puncture has been performed. There was no mention in the discharge summary of a psychiatric assessment, but he was assessed psychiatrically because we have the report at page 143 by Dr Berelowitz. We know that Dr Berelowitz, from that letter, saw Child 2 on the ward on 5 September, so in other words the day after the lumbar puncture but a few days before Dr Harvey. This is a letter addressed to Dr Murch. He says:
“Thank you for asking me to see [2], who I saw on the Ward on the 5th … I saw him at the request of yourself and Andy Wakefield, for the purposes of learning more about possible links between his presentation and measles vaccination and bowel disease, but it was not intended that I should have clinical child psychiatric responsibility for him. I saw him together with his mother.”
Then he sets out his birth history.
“At the age of 13 months … he had 25 words, … gradually lost these words over the next 7 or 8 months. … thought … to be … clumsy at about 15 months.”
Then at 20 months he began to go downhill, and she described the way in which he began to lose the words that he had been able to speak, and lose interest in toys.
“She has become confident that changes in diet affect his behaviour. She said that he has had diarrhoea from 20 months, … unabated …” –
and that he is hyperactive. Then there are gastrointestinal symptoms, in the next paragraph.
“In terms of diagnoses, she said he had been diagnosed as having a specific language disorder when he was under 4. This was clearly wrong. She said that at Harper House they said he was not autistic. He was reviewed by [them] more recently and again she said the diagnosis was not of autism. He is about to see a metabolic specialist. His fragile X is negative and his brain-scan is normal, as is his EEG.”
Then it talks about his siblings, and says:
“[Mrs 2] reiterated that [2] started head-banging about 2 weeks after the MMR and hasn’t looked right since.
I observed [2] while talking to [Mrs 2] and noticed that he had no eye contact and no language. He did not relate to people or objects … He did not behave as though the other people in the room had minds of their own which were of interest to him.
I thought that the history and presentation were very typical of autism or a related disorder. [Mrs 2] explained to me that she had previously had someone tell her that the problem was that she was unable to accept the diagnosis of autism. I explained to her that I was not going to attempt to do the same myself and was merely noting that his presentation looked like autism, whatever it actually turned out to be. I must say I thought the presentation was indeed very typical and I await the next patient with considerable interest.”
So that was Dr Berelowitz’s assessment of the child, as he says in that letter, without having any clinical responsibility for him.
Chronologically, Professor Rutter, you refer to these documents in your report, so it may be that you want to comment on them later, which is why I am including it now.
In October, the month after this child was seen, we know that his certificate for involvement in the MMR litigation was given to him, and that is a document which has to go into everybody’s bundles, sir, if you can be handed copies of that, please. (Document handed) It is page 265D, and it has to go into FTP1, so that it is chronologically in that bundle.
Put that document in FTP1. I want to go through it. It is the legal aid certificate.
THE CHAIRMAN: Ms Smith, can I also request you, I think for the benefit of the Panel members but also for the benefit of the witness, that at some stage near if you can find an appropriate moment.
MS SMITH: I have anticipated that. Perhaps I can just finish the history and then I will have a break. We can see, Professor Rutter, on the second page we see it simply grants legal aid on 18 October 1996:
“To bring a case to be represented in proceedings for damages for personal injuries and loss sustained as a result of vaccination against MMR.”
That was is in the October. On 10 November, the child was admitted for a repeat colonoscopy. The reason for that was – I think there is no argument about it – that he was on enteral feeding and that was a standard procedure. If we then look at the GP records at page 124, it does take a long time to find there are a lot of blank pages -
A This is in which file?
Q In the GP records for Child 2, page 122 is the one that is easily identified and the number is on the bottom of the page. It is a letter. Are you able to find it?
A Yes, I have located it.
MS SMITH: It is a letter to Dr Maule, the doctor for Child 2, from Dawbarns, the solicitors acting for the claimants in the MMR litigation, saying he was acting for the parents of Child 2 and legal aid had been granted to enable them to grant claim for compensation and requesting the medical records. Those are the only records I wanted to refer to in relation to any involvement in the litigation should it be relevant. Sir, I think that perhaps if we stop there because there are a few more documents relating to the child’s behaviour that we will have to go through.
THE CHAIRMAN: It is 3.25 pm. We will adjourn for a short tea break and we will resume at 3.45 pm, but once again, my usual reminder that you are under oath and when you are giving the evidence, please not discuss this case. We will resume at 3.45 pm.
(The Panel adjourned for a short while)
THE CHAIRMAN: Ms Smith.
MS SMITH: Professor Rutter, I want to take you to one other document which you refer to in your report because it is a very extensive assessment which was carried out on this little boy when he was five in 1993. You cited it as the background for the views I am going to ask you about. It is at page 228 of the Royal Free Hospital records. This is the full autism assessment that was done in relation to a suggestion that was made earlier. We see “Assessment of Autism and Related Disorders”. I am not going to read it all. It indicates his first year was normal, he was a sociable baby, at one year he began to change, he became hyperactive, aggressive, demanded constant attention, glazed expression. He was observed to lose some of his words and it sets those at.
“At approximately 20 months he lost all speech apart from ‘juice’. Speech development has been delayed and deviant since then. [Child 2] has stopped responding to his name.”
He developed food allergies. If we go on to 229, we see the medical problems, the gastrointestinal symptoms that he undoubtedly had listed. At 230, references to speech at one year. He lost all speech at two and a half years:
“At three years he began to make consistent sounds and has approximately 20 words. Some stayed, some he lost.”
Under “General Behaviour” he was a happy, cuddly baby with good eye contact. Personality changes were noticed at 13 14 months. Severe temper tantrums at 15 16 months, worse when he was unwell. There was a lengthy family history, including schizophrenia in a maternal uncle. Suggestion of some difficulties in relation to other children. At 233, “Language and Communication”:
“Eye contact stopped at 20 months. Marked improvement during the last 12 months coinciding with the introduction of the diet and after ears syringed.”
If we go on to the end, “Cognitive and Psychological Appraisal” at page 238, a detailed examination as to how the child reacted and his play and symbolic understanding. Test results are at page 240. The “Summary and Recommendations” are at 241. He was assessed – just referring to how old he was at that time four years and seven months:
“Physical examination normal.
Investigations for developmental delay (summarised in the previous section) were also normal.”
His EEG was normal.
“His symbolic understanding, language and communication skills were extremely limited and represent an area of particular weakness. [Child 2’s] poor attention span and lack of interest in the test materials affected his performance adversely in all areas.
Certain features of [Child 2’s] behaviour are similar to those which characterise Wing and Gould’s triad of impairments...”
That is one of the differential diagnoses we touched on in your chapter referring to disintegrative disorder, is that correct?
A Yes.
Q It said:
“...found amongst children who fall within the autistic spectrum of disorders. This trial comprises:
1) impairment in reciprocal social interaction
2) impairment in communication and the development of imaginative play
3) a restricted repertoire of repetitive behaviours.
...
Autistic type features are commonly found amongst children whose development is severely delayed and it is uncertain how much importance should be attached to them. A clearer picture may emerge as [Child 2’s] development is monitored over time, but at present his general developmental delay is the most notable feature from the point of view of his educational needs.”
It then sets out the best environment for him. That was a very full assessment considerably before his referral to the Royal Free Hospital.
I now want to just ask you some general questions, having looked at the background documentation. If it assists you I am at paragraph 14 of your report. No one is asking you to diagnose this child or any of the others on the basis of the papers, but you have told us already that your impression, at least from the records you have seen, is that he did have these very unusual periods of regression. In very broad terms, what would you say, what category would you say, he probably fell into?
A I think that is exceptionally difficult in his case. In terms of the general features as Vanessa Moore’s report brings out, he certainly shows the very characteristic features of an autism spectrum disorder, so I have no doubt that he is within that spectrum. What is unusual are not just one period but three periods of regression. That does not fit easily into any of the recognised clinical syndromes so that I would not know quite what to call him.
Q Do you include in that disintegrative disorder?
A Yes, as I said earlier on today, I was saying that, with the possible exception of Child 2, the children did not show a disintegrative disorder. His problems do not fit the usual picture of a disintegrative disorder, but they raise similar concerns as to whether there is some progressive brain disease which is underlying all of that, so that, although I do not think he fits the usual criteria nevertheless, clinically, I would be inclined to deal with it as if he did in that it is the nearest approach one could get.
Q We will go to the nature of them in a moment but, as far as the undertaking of some pretty extensive investigations in that child, would you regard that as being something that is desirable?
A Yes, I would.
Q If those investigations are being carried out by the Royal Free because they were necessary for those clinical reasons, would you have regarded the assessments that were done as satisfactory?
A At the Royal Free?
Q Yes?
A No. They are in striking contrast. You took us through Vanessa Moore’s report, which is very thorough and multifaceted in what it covers. The assessments at the Royal Free were pretty minimalist by comparison and it is not obvious what additional gain there was from the assessments done there – putting aside the investigations now, but on the assessment side – in that this child had had quite thorough assessments by quite experienced people that did not land up with a clear answer, as regrettably is often the case, and it was striking that the neuropsychiatric assessment, in so far as it was done, does not deal with the family history. I do not know, what significance, if any, that had, but it does stand out. One would expect, in the same way that Gillberg brings out in his account of what you should be doing, this is the kind of thing that one would want to follow through. So the brother with so called Asperger’s, was that indeed what the brother had? The uncle who had schizophrenia, was that indeed schizophrenia? If it was, it is not likely to be related, but given terms are used in quite a loose sort of way if you get them third hand, it is possible, so, no, I am struck that this is not dealt with. Indeed, in Dr Harvey’s assessment, the family history does not get mentioned at all and the focus is very much on Ritalin which is focusing on one particular aspect of this boy’s very complex multifaceted problems.
Q It has to be said, in fairness to Dr Berelowitz, he does expressly say in the report on this child, that he was not assuming any kind of clinical responsibility in doing the report that he did. If the neuropsychiatric assessments, ie by the neurologist and the psychiatrist, had been being done for clinical reasons, would you have regarded it as satisfactory?
A No, I would not because this story is such an unusual one and such a sad one in terms of the progressive decline in these three steps. It would require a much more thorough assessment than one would ordinarily do because it is so puzzling.
Q Having said that, Professor Rutter, I think you do accept that in this case doing a lumbar puncture was reasonable given these very odd periods of regression?
A Yes, I do.
Q Is there any aspect of the undertaking of that lumbar puncture, the decision to undertake it, that you regard as unsatisfactory?
A Only in the sense that the assessment that was associated with it is not of the kind of quality one would ordinarily expect, but the nature of the disorder, I think, did require detailed investigation and I would be entirely accepting that that might reasonably include lumbar punctures as one of the things to be done.
Q We know the chronology of it, if I can remind you, which is that the lumbar puncture took place on 4 September, Dr Berelowitz saw the child on 5 September and Dr Harvey saw him on 9 September?
A Yes.
Q Do you have any observations about that particular aspect of the timetabling?
A Yes. I commented earlier: I think that investigations on an individual case basis need to follow not precede clinical assessment and that it is a universal recommendation that, given this kind of situation, there is a thorough clinical assessment including family history, congenital anomalies, the usual range or things that one would be taking account of, and that one would want to be considering: is there anything about this child’s very unusual history which would point to something you had not thought of that might be needed. I do not know quite what that might be but it is a very unusual case and required particular assessment. To do the assessments afterwards, as I say, seems all back to front.
Q Someone obviously made the decision that the child was to have the lumbar puncture.
A Yes.
Q Who would you regard it as being appropriate to have made that decision?
A I come back to what I said earlier. I think that it needs to be someone who has experience with the various varieties of regression that can take place in autism spectrum disorders and that there is the clinical meaning, as far as one understand it, of these different patterns and the implications for investigation. Ordinarily that would be a child psychiatrist or paediatric neurologist or developmental paediatrician. I would not relate it to a particular discipline. I would simply say I would want it done by somebody who has recent detailed experience, not just of the investigations but of how one approaches a clinical problem of this kind.
Q As far as the records are concerned, do you see any evidence that there was anyone involved in the decision in relation to this child who would have had that expertise?
A Not that I am aware of.
Q I know I am asking you to go over again matters you have already covered to some degree, Professor Rutter, and I am going to be doing that in respect of every single one of these cases. With regard to the whole manner of dealing with this case, do you think that it is more in keeping with a research protocol or with a clinical investigation of the child, the clinical needs of the child?
A It is a very pertinent question but it is one that is very difficult to give a straight answer to. The clinical picture is of a kind in which approaching it as a clinical need would have been appropriate. What is puzzling is the way this was done without paying particular regard, as far as I can tell from the records, to what had been done before because this child had seen quite a few different people. Therefore, sorting out what to do on the basis of clinical need does not seem top of the agenda. Rather, what comes across, as I say as far as I can judge from the records, is much more that this is a child with an usual picture that involved loss of skills and that therefore wanted to be put into what is described as a clinical trial, which was, in terms of protocol, a research protocol.
Q With regard to the research protocol, we know that one of the ethics committee conditions was that children who were admitted prior to 18 December 1996 should not be included in the study that was written up. We know the admissions, as a matter of fact, were in September ’96 and November ’96, so, on the face of it, as a matter of fact, did this child qualify for this study in any event?
A No, because the ethics committee had made no explicit requirement that the permission only applied after ethics approval had been given, and they have the authority to be able to do that. What was done here in terms of the timing clearly runs counter to that requirement.
Q I took you to the research consent forms which were envisaged and the patient information sheet envisaged; i.e. those attached to the ethics committee application. I am happy to remind you if you want to be, but you may feel familiar with them. Could you find those forms in the clinical records that you saw?
A I do not think I did, no.
Q Should they have been there?
A They should have been there. I see that in view of the complexity of the notes for a complex case as something that is desirable, had been required but, given everything else, I would not see that as a serious problem. It is easy for things to get mislaid. Yes, it should have been done. I would not see that as a major problem.
Q The filing in the records you would not see as a major problem?
A Yes.
Q But would you regard as a major issue whether the children who were involved in this were properly informed, or their parents, as to whether it was a research project or not?
A Yes, indeed, that is the important matter and is a requirement.
(Pause while Ms Smith took instructions)
MS SMITH: Thank you, Professor Rutter. That is all I have got to ask you about Child 2.
Sir, I see it is past 4 p.m. I am entirely in the panel’s hands. I can of course go on to another patient, and we have a number to cover. On the other hand, I am aware how similar some of these are and I do not want you to get boggled, if I can use that word. I am not suggesting you are showing any sign of it, I hasten to add, but it is always a danger for all of us. I am in your hands whether you would like to start another one now. I will not finish, that is certainly the case, but I can start.
THE CHAIRMAN: I wonder if there is some other short matter that we can deal with until about 4.30.
MS SMITH: I do not think there is, to be quite frank, sir, because, as you will appreciate, I have dealt in very general terms and it is now very important that you know the details of the individual cases before Professor Rutter gives and overview as to his views, otherwise it sounds as though he is generalising when you do not know the facts.
THE CHAIRMAN: In that case, it would probably be appropriate to break at this time and resume tomorrow morning.
MS SMITH: I should say in some comfort that Child 2 has one of the longest histories as far as the records are concerned and the neuro-psychiatric side of the others I think will take a little less time.
THE CHAIRMAN: Thank you, Ms Smith. In that case, we will now adjourn.
Professor Rutter, you are under oath overnight. I am sure you are quite used to that but please make sure that you do not discuss this case.
A I do understand.
THE CHAIRMAN: Thank you again.
(The Panel adjourned until Friday, 28 September at 9.30 a.m.)
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