Monday, February 6, 2012

Day 41 GMC Fitness to Practice hearing for Andrew Wakefield

GENERAL MEDICAL COUNCIL

FITNESS TO PRACTISE PANEL (MISCONDUCT)



Tuesday 9 October 2007

Regents Place, 350 Euston Road, London NW1 3JN



Chairman: Dr Surendra Kumar, MB BS FRCGP


Panel Members: Mrs Sylvia Dean
Ms Wendy Golding
Dr Parimala Moodley
Dr Stephen Webster


Legal Assessor: Mr Nigel Seed QC




CASE OF:

WAKEFIELD, Dr Andrew Jeremy
WALKER-SMITH, Professor John Angus
MURCH, Professor Simon Harry



(DAY FORTY-ONE)










(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 IAN WESTERBY BOOTH, continued

Examined by MS SMITH, continued 1


THE CHAIRMAN: Good morning, Professor Booth.

THE WITNESS: Good morning, sir.

THE CHAIRMAN: And good morning all of you. Ms Smith, you were in the middle of your examination in chief.

IAN WESTERBY BOOTH, Continued
Examined by MS SMITH, Continued

Q Professor Booth, I would like to turn now to the second child in order of referral, who is Child 1. I am going to be referring to the GP and the Royal Free records. I am going to deal with the referral and then the admissions, and then ask you about the clinical indications for the gastrointestinal investigations that were undertaken. I am going to intersperse it rather going through it as did Child 2, who has the most complex history. Could we go first of all to the GP records for the start of the referral process, please. Page 125. This is a handwritten an undated letter to the GP from Child 1’s mother, just saying:

“Dear Dr Haughton,

I would like you to refer my son [Child 1] to the below address immediately.”

Then it says:

“a severe metabolic disorder…”.

THE CHAIRMAN: I am sorry. I know that it is page 125, but you have not said it. I am just making sure that everybody has this. It is page 125 in the GP records.

MS SMITH: Thank you.

“I would like you to refer my son [Child 1] to the below address immediately a severe metabolic disorder needs tests done.”

And then giving Professor Walker-Smith’s address at the Royal Free Hospital. Would you put those records away and turn to the Royal Free records. We get the letter from the child’s actual GP, Dr Barrow, referring to Professor Walker-Smith at page 56, please. The first page just gives the general details. Then, if we turn on to the second page under “Reason for referral”:

“I understand that [Mr and Mrs 1] have contacted you regarding their youngest son … who has been diagnosed as autistic.

[Child 1] initially developed normally, reaching the normal milestones until he was about 15 months old. He then regressed and has now been diagnosed as autistic. His elder brother … is also autistic.

[Mr and Mrs 1]’s most recent concern is that the MMR vaccination given to their son may be responsible for the autism.

We do not have very much correspondence regarding [Child 1] but I have photocopied any relevant information that is available.”

That information is after the letter between pages 58 and 62. Page 58 is a letter from a consultant psychiatrist, Dr Hauck. He says that when he met Mrs 1, the conversation ranged widely.

“It gradually emerged that [Mrs 1] is much exercised by [Child 1]’s eating; he is a choosey and slow eater and she feels he is not adequately nourished. He suffers from loose stools on most days, she tells me. From the Autistic Society she has received information about the benefits for some children of a casein-free and gluten-free diet. She feels she would like to try a diet…”

Dr Hauck advised a period of observation and recording of the symptoms. There are also accompanying the letter at pages 59-60 a notification to the education authority about the child’s developmental problems. At 61-62, there is a letter from the education authority setting out the delays that 1 has suffered from. That is the information that was sent to the Royal Free. Turning back to the letter from the GP, which is at page 56, or 57 for the information, Professor Booth, do you have any comments generally on that letter, given that it is a referral to a gastroenterology department?
A Although some of the other records indicate that this child had gastrointestinal symptoms, there is no mention in the referral letter of any GI symptoms.

Q But there is information given in relation, of course, to his developmental problems and his autism. As a paediatric gastroenterologist, would that referral letter with no mention of gastrointestinal symptoms, but details as to the behavioural history, be usual?
A No.

Q If it were to come to you like that, as a gastroenterologist, what would your response to it be?
A I think I would probably write, or possibly even telephone the GP, to say, “Are you sure you have addressed this to the correct person? Should it not go to one of my colleagues elsewhere in the hospital?”

Q Would you expect to see concerns about the vaccination circumstances of the child?
A I think if it was a child where the primary reason for referral was with worrying gastrointestinal symptoms, you would expect that to be in the letter. If, in addition, there were parental concerns it might well be added in subsequently, lower down in the letter for a useful bit of background information, yes.

Q If we turn on to page 55, we will see how Professor Walker-Smith responded to that letter. It is a letter of 23 May 1996 to Dr Barrow, from Professor Walker-Smith:

“Many thanks for your letter. I would be delighted to see [Child 1] and I have arranged for an outpatient appointment to be sent.”

Then, an outpatient consultation did indeed take place and the records of that are on page 13. Doing the best we can on the gastrointestinal symptoms, Professor Booth, it reports undigested food in the stools.
A That is right, yes.

Q No control – this is at the bottom of the first page. Then it says:

“Has had blood occasionally in stools.”

Can I ask you first of all, where would those symptoms have come from, would you imagine? Who would have provided them in an outpatient’s appointment if they were not in the GP letter?
A The mother – the mother and father.

Q There is subsequently at that outpatient appointment a request for blood tests to be done. We can see that on the next page, on page 14. Then Professor Walker-Smith writes to the general practitioner indicating what his views are after that appointment. That is on page 54, please, dated 21 June 1996.

“Dear Dr Barrow

Many thanks for referring [Child 1] with autism. It is difficult to associate a clear historical link with the MMR and the answer to autism although [Mrs 1] does believe that [Child 1] had an illness 7-10 days after MMR when he was pale,? fever, ? delirious, but wasn’t actually seen by a doctor. Between the age of 1 year and 18 months his development slowed and then deteriorated.”

He notes the fact he has a five-year old brother who has been diagnosed as part of the autistic continuum. Then he goes on:

“As part of Dr Wakefield’s and mine interest in the relationship between immunisation and chronic inflammatory bowel disease, I have arranged for routine blood tests to be done for screening for C-reactive protein, etc. The diarrhoea which [Child 1] currently has does have the features of toddler’s diarrhoea. His mother is concerned by the diarrhoea. Loperamide in a dose of 2mgs twice a day could be tried therapeutically. She was concerned that this could have an adverse effect on his neurological development.”

Then he says he is not aware of such a complication, and it is an option to be kept available if the diarrhoea causes concern.

“My plan would be to see him again in 3 months time and then if [Mrs 1] feels that it is appropriate we could consider performing endoscopy and further assessments neurologically and psychologically of his autism to explore the possible link between measles immunisation, bowel inflammation and autism.”

Can I ask you first of all, Professor Booth, is “toddler’s diarrhoea” a recognised condition?
A Yes. It is very well recognised.

Q Can you tell the Panel briefly what it is
A As the name implies, it normally manifests in children between the age of 12 or 18 months. It often gets better by the time they go to school. Characteristically, they have a variable number of stools every day, sometimes as many as four or five. Typically the stools contain undigested vegetable material, so peas and carrots come through unchanged. It is associated with rapid transit through the gut normally, so parents will report when they have something that is readily visible in the stool to it, like sweet corn, it comes through in a few hours quite often. Then, occasionally, they often switch to an opposite problem whereby their bowel actions so slow, and they may go for a few days and have constipation. Then it switches back to diarrhoea once again.

Q Is toddler’s diarrhoea a common condition?
A Yes. It is probably the commonest cause of loose stools in pre-school children.

Q What is the usual clinical approach to it?
A The main things it to make sure that the diarrhoea is not being caused by some other disorder like, for example, coeliac disease, or there are various problems with mal-absorbing nutrients that can produce similar symptoms. So there are often reasons for doing some other screening tests but essentially it is a clinical diagnosis in that there is no test that you can do that says, “This child has toddler’s diarrhoea.” It is made on the basis of typical symptoms. If you feel appropriate carrying out some screening tests to make sure they are negative.

Q Is that course the course it would appear was in Professor Walker-Smith’s mind when he ordered some screening tests?
A Yes. Absolutely, yes.

Q What comment do you have on his observing the fact, if in three months’ time Mrs 1 felt it was appropriate they would consider endoscopy and then neurological and psychiatric assessment?
A I think, having made a diagnosis of toddler diarrhoea, it would not be my practice to then ask the parents in three months’ time if they wanted a colonoscopy.

Q You referred when I was asking you questions generally about the risks of parents losing objectivity. I should underline this is not a criticism in any way of Mrs 1 or, indeed any other parents who is anxious for investigation, but would this be an incidence where that would be a consideration?
A Yes, I think it would. I think they may well need steering away from invasive investigations if, as Professor Walker-Smith clearly thought at this stage, there was no serious pathology in this patient.

Q Are you surprised to see that as an indication of why he might think about colonoscopy?
A Yes. It would be a very unusual indication against a background of toddler diarrhoea.

Q All in all, the terms of that letter, Professor Booth, with its reference to Dr Wakefield’s and Professor Walker-Smith’s interest in the relationship between immunisation and inflammatory bowel disease, what is your feeling as to the flavour of that letter as to whether it is research or clinical?
A The arrival at the diagnosis and the performance of some fairly straightforward screening tests, the suggestion that Loperamide might be useful would all be consistent with normal clinical practice. I do not think there is anything there to suggest that this would be research activity. When it then goes on to talk about endoscopy and further assessments it is starting to have the flavour or research, that would not normally be something that you would consider doing in a clinical setting in a patient in whom you thought the diagnosis was toddler diarrhoea.

Q If we go on, on the same day, 21 June, we have a letter from Professor Walker-Smith to Dr Wakefield. That is on page 53:

“Dear Andy

I saw this interesting child with autism which began some weeks following MMR although there was 7-10 days after the MMR at the age of 1 a brief illness during which he was pale, possibly had fever and his mother said he may have been delirious. [Mrs 1] was keen that you would have a look at a document that she got concerning homeopathic remedies and I am passing this on to you.”

The next thing is, we have the results of the blood tests that have been undertaken on 19 June, and those are at page 97. It is in the column which is dated 25 June. Can you just run your eye down those, Professor Booth, and tell us what, if anything, those blood tests revealed?
A HB stands for haemoglobin, that is at the top there, and it is 10.8 which is fractionally low at this age group – you would accept 11 as the lower limit of normal, but it is only just outside the normal range. The white count is normal; the platelets are normal; the CRP, C-reactive protein, it is three, that is normal, so apart – and the albumin is normal as well – so the inflammatory indices, apart from a fractionally low haemoglobin, are fine.

Q We know Professor Walker-Smith had indicated in a letter he had sent that he was going to see the child again in three months time, but in fact he was admitted to the Royal Free Hospital without more ado under Professor Walker-Smith’s care on 21 July 1996, so that is a month later: is there anything in that intervening period – we have gone to the blood tests, there does not appear to have been any other contact – which would have suggested the sudden need, rather than a review in three months, for an admission for colonoscopy?
A I am not aware of anything in the medical record, no.

Q If we can now turn to that outpatient admission, the admission clerking note is at page 9 of the Royal Free records. We see at the top of the page “Referred for work-up of ? relationship between autism/measles/IBD” and then “complaining of classic autism, diagnosed a year ago, diarrhoea, concern over ‘deterioration’ of eyesight” I think that is. Then there is a description of apparent behavioural regression and we see that that is referred to in the next paragraph down. Under that, in brackets “(recently associated with measles because of bowel symptoms”. Turning over the page, “Gastrointestinal tract [GIT]” at the top of the page, “Diarrhoea – started at 18 months” I think it is then “watery: no blood: no mucous: undigested food” then I think it says underneath that “no blood ? occasional mucous” is that right?
A That is right, yes.

Q “Not offensive: occasionally pale.” I am being prompted from my left, would you wait a moment? (Pause) I am sorry, just going back, “since then undigested food. Now [7 times] a day: no bowel control: no blood: occasional mucous: not offensive: occasionally pale” is that correct?
A Yes.

Q And “small appetite: occasional vomiting”, so that was the clerking note. There is a further clinical note on page 11. We see at the top of the page: “elective admission for colonoscopy”. What does “elective” usually denote?
A It just means that the procedure was arranged in advance of the patient coming into hospital so the opposite of elective would be emergency. An emergency admission would be unplanned, whereas an elective is planned.

Q If we go down to the middle of the page we see “chronic diarrhoea from 18 months up to 7-8 times a day, loose stools: ? no bleeding” and then “poor appetite generally: no previous investigations for diarrhoea”. If we go on to the next page, at the bottom of page 12 we see the plan “admit for elective colonoscopy” and then “consent: bowel preparation: bloods tomorrow” and we have a consent form for the colonoscopy and biopsy and that is at page 88 of these records. Is that the standard consent form for a clinical investigation?
A Yes, it would be, yes.

Q It is accompanied by a consent form for extra biopsies to be taken for research purposes.
A Yes.

Q In 1996 was it relatively standard to make a request of parents, where a biopsy was being carried out, for material for extra biopsies?
A Yes.

Q Then we have an attempt at the colonoscopy undertaken by Professor Murch, and the report on that is at page 100. I use the word “attempt” because we will see that Professor Murch says the finds were:

“Severe faecal loading: histology not taken … Procedure abandoned due to gross faecal loading. Repeat later after clear out”.

When it refers to “clear out”, Professor Booth, you have already told us that that a standard part of the procedure would be to have a clear out of the bowel before it was undertaken.
A Yes.

Q Is this suggesting that that should be repeated?
A Yes.

Q As far as that attempted colonoscopy is concerned, on the symptoms that we have been discussing, is it your view, given Professor Walker-Smith’s conclusions of toddler’s diarrhoea and the normal blood tests, apart from the very small abnormality you have mentioned, and the presentation at admission, in view of all those matters do you regard this colonoscopy as one which was clinically indicated for this child?
A Not on the basis of the information that was available from the outpatient clinic and from the inpatient clerking, no.

Q Just so we are clear, why in particular do you say that?
A The investigation of colonoscopy would be primarily carried out because you thought the patient might have inflammatory bowel disease, but I agree with Professor Walker-Smith’s review of this patient that there was not anything to suggest inflammatory bowel disease. Toddler diarrhoea was a reasonable clinical diagnosis.

Q This is a procedure that was carried out by Professor Murch, and I have asked you generally the duties of the person who is actually carrying out the colonoscopy, and I asked you in respect of the first child we looked at, so I am not going to repeat it for every one, but for every case where a colonoscopy is being carried out by someone other than the person who orders it, does that person have the responsibilities that you have already identified to be satisfied that it is clinically indicated?
A Yes, they need to be satisfied, although the opinion about whether to do an endoscopy is always easier for the person that has seen the patient in the clinic and examined them. If you have not had that opportunity in the time available to come to a decision is more limited but I think you still need to be satisfied that it is indicated.

Q What I am really asking you is, in circumstances where somebody else has ordered it – in this instance Professor Walker-Smith – is the person who carries out the procedure entitled simply to say, if they come to the conclusion that they do not think it is clinically indicated, are they entitled as a clinician to say, “Well Professor Walker-Smith wants it done so I won’t question that”?
A Yes, that does happen, I guess. I cannot think of an instance. It is quite difficult I would imagine to challenge the clinical view of a more senior colleague sometimes, but I think you still have responsibility to satisfy yourself that it is clinically indicated.

Q Is it clinically acceptable practice in your view not to make an independent judgment?
A No, I think you have a responsibility to make your own decision.

Q We have looked at the inflammatory indices in this child prior to the admission and you have told us that they were not such as to change the management in any way, can we just look at the results of the blood tests which were undertaken following admission, and accepting that these would not have been available until after the colonoscopy but just to see what they show, they are at pages 120 and 124. The full blood counts are at page 124. Are there any abnormalities that you can see?
A The haemoglobin is now in the normal range. The platelets are normal; white count is okay, the ESR is okay, and on page 120 the C-reactive protein looks as if it is up a fraction. It looks as if that might be seven with an upper limit of normal of five, so slightly high.

Q Do they add at all to a clinically significant degree to the blood tests that were apparent prior to admission?
A No, I do not think it would change your clinical decisions.

Q The one on page 120, I think you were referring to the October C-reactive protein and in fact we are in July.
A I beg your pardon, sorry.

Q Can you help us as to what the July one indicates?
A Yes, that is normal.

Q Is that a normal result?
A Yes. There is a comment on page 124 in relation to the white count. Although the total white count is normal there is a neutrophilia that they have had a look at on the blood film examination which would be consistent perhaps with some intercurrent infection.

Q Those results, as I say, were post the colonoscopy, albeit during that admission, and if we can now continue with that admission, page 64, this is the EEG report, so we know the child had an EEG on 23 July, and on page 66 an MRI of the head on 24 July. If we revert to the clinical records at page 17, remembering that the first colonoscopy had not been successful, we see 25 July, the plan was that he should undergo a further colonoscopy and small bowel biopsy, and we have again got a consent form on page 42 in relation to that further procedure. On page 93, a further clinical consent form which you told us was in a standard form.
A Yes.

Q The second attempt of colonoscopy is shown on page 99, again carried out by Professor Murch, and we see that the findings were normal: the histology report was to follow:

“Some evidence of scope trauma in the descending colon. Terminal ileum obscured by food debris and not entered. No obvious pathology.”

So, again, that indicates that Professor Murch was unable to get right round to the terminal ileum, is that correct?
A Yes, because there was a lot of food there.

Q In the descending colon the only indication of any abnormality was trauma, which was probably caused by the colonoscope itself.
A That is correct, yes.

Q I think this is probably self-evident from the answers you have given in relation to the first attempt at the colonoscopy but bearing in mind the reasons for the failure of that first attempted colonoscopy, do you think that this second attempt was clinically indicated?
A I think if you find that the patient is rock solid with constipation it makes it very, very unlikely indeed that they have got substantial inflammatory bowel disease.

Q And you are saying that the first attempt of colonoscopy which failed, it failed because of the faeces ---
A The patient was rock solid, yes.

Q --- indication.
A Yes.

Q “Rock solid” is your phrase, that is why I was asking you to explain this.
A Severely constipated.

Q That would be the conclusion you would reach for not being able to colonoscope a child would it?
A Yes.

Q Returning to the history, he was discharged on 26 July. The histology report on the biopsy after the colonoscopy is at page 103 and the comments are at page 104:

“Colonic serial biopsies with focal active chronic inflammation in the caecum.”

The last thing is, on page 52, which is a letter from Dr Casson who was the registrar at the time in the department, to Dr Wakefield of 8 August 1996:

“When would you like us to review this pat again and are there any other procedures we should be performing?”

If this were an ordinary clinical admission, would you expect to see a letter in those terms?
A No.

Q What does it suggest to you in terms of the involvement that Dr Wakefield was having with these patients?
A It implies that in some way Dr Wakefield was some sort of éminence grise to whom referral needed to be referred for further guidance.

Q We have a discharge summary at page 49. We will run through the matters relevant to gastrointestinal symptoms:

“[Child 1] was admitted for further investigation of his autism and specifically to look into a possible association between his neurological condition and any gastro intestinal disorders. The main problems are a ‘classical’ autism diagnosed 1 year ago, and of diarrhoea.”

Then it sets out his developmental problems:

“His diarrhoea started approximately 18 months ago. He passes 5 watery stools a day which contain no blood or mucous. They do contain some undigested food. He appears to have no control over his bowel motions and frequency is increasing. His appetite has always been poor and there has been no obvious change in this. He has only very occasional episodes of vomiting.”

Then his immunisation history and a parental concern that had bearing on his condition. We see in the middle of the page:

“An initial colonoscope was attempted but had to be abandoned due to gross faecal loading. He was subsequently cleared out and the procedure was repeated 3 days later. On this occasion, the caecum was reached although it was impossible to pass further.”

...

Histological examination of the biopsies taken demonstrated a small degree of focal active and chronic inflammation within the caecum.”

Then the rest of the investigation and a brain scan:

“There is a plan to review [Child 1] in clinic to discuss the implication of a mild degree of inflammation seen in his biopsies. It is also not entirely clear whether his neurological condition in fact represents a neurological deterioration in view of lost milestones, or whether it is a classical autistic picture.”

That was the discharge summary. It is followed on by Professor Walker Smith writing to the GP suggesting a therapeutic trial of anti-inflammatories at page 48. He suggested a therapeutic trial of sulphasalazine or Salazopyrin syrup and asking whether that the GP should prescribe the dose.

“This should have some symptomatic benefit. However his CRP(3) and ESR(10) were normal.

I have not planned to see him again but Dr Wakefield will be assessing the research aspects of this problem and I would be happy to give further advice.”

Arrangements are then made for a second admission on page 47 direct to the child’s mother from Dr Casson in a letter dated 3 October:

“This letter is to confirm that [Child 1] should be admitted to Malcolm Ward on 23 October 1996.

He is due to have a barium meal and follow through on Wednesday. He will have an EEG and evoked potentials at 11am on Thursday. This will be performed under sedation. In association with this, whilst still sedated, he will need a lumbar puncture.”

Where there any reasons on the history so far why this child should have a barium meal and follow through?
A I think the supposition following the biopsies was on the basis of some mild inflammation in the caecum, that he may have inflammatory bowel disease. It would be very unusual indeed to make a diagnosis of inflammatory bowel disease in a patient who was so severely constipated all the way round the colon. If you accept that the thought was that he had inflammatory bowel disease, then it would be reasonable, to do a barium follow through, yes.

Q As far as the other investigations, do they accord with the investigations we looked at in the ethics committee applications?
A Yes, I think they do.

Q He is seen by Dr Harvey on page 19. He makes a limited examination but says the child was not cooperative so it was not possible to do anything else. I will not take you to the documents but he has a consent form for a lumbar puncture under sedation. We know that lumbar puncture was indeed carried out because we have the CSF results. Going back to the history, he is discharged on 25 October, and the clinical notes indicate that the plan, at least, is for another colonoscopy. If you look at page 23, perhaps I could take you to the preliminary report on the barium meal, it says:

“Barium meal and follow through examination was attempted. Because of the behavioural difficulties it was very difficult to perform an adequate study. 50mls of barium were ultimately successfully ingested by the patient, albeit intermittently. The stomach and the proximal small bowel appear normal, without evidence of dilation or stricture. It was not possible to get very early views ... although I suspect that it is normal. Due to the marked faecal loading, passage through the small bowel was delayed. The mucosal folds within the terminal ileum region appear preserved without any suggestion of significant inflammatory bowel disease.”

The conclusion was that there was a normal small bowel. We see at the bottom of the page
A Which page are we on?

Q I am sorry, page 23. We see clinical notes, a long discussion with Mrs 1 and then:

“He needs to have repeat colonoscopy in view of the fact that we have never reached the terminal ileum.”

That was on to be on a date to be arranged as discussed with Dr Murch.

It then says that he needed treatment for his constipation. He never actually had another colonoscopy of this child and you said you do not think he should have had the attempt and the one he did have. If it is the case that these doctors regarded it as clinically necessary for him to have another colonoscopy, would you have expected him to have undergone that procedure?
A If it was felt on the 5 November 1996 to be indicated, yes, you would expect him to have another one.

Q Again, clinically, can you see any reason why that conclusion would have been reached, that it was necessary to do another one to try and visualise the internal ileum, from a clinical point of view?
A Not from a clinical point of view. As I said, the fact that this patient was so constipated, it would be very much against significant colitic illness. The fact that he was constipated was also confirmed in the barium meal and follow through result, and the radiologist from the report on the barium meal and follow through gives information about the terminal ileum. Therefore, it is difficult to see why one would need to expose this patient to a third colonoscopy.

Q What did conclusion did you reach, in those circumstances, as to the reasons why they were anxious to visualise the terminal ileum?
A I do not think I could form a view on that. I do not know.

Q Going back to the discharge summary for completeness, that is at page 43. This is the discharge summary for the second admission dated 5 November, the same day. He was readmitted in order to perform the various tests which were not performed – abdominal x ray, faecal loading throughout; barium meal and follow through, appear normal; lumbar puncture; various blood tests; EEG and Visually Evoked Responses, again appear not to show any significant abnormality:

“We will need to arrange a further admission for [Child 1].”

That never actually happened:

“Previously we have not visualised terminal ileum due to marked constipation.”

Advice as to treatment for constipation in the form of liquid paraffin was given.

As far as the follow up is concerned, I am only going to deal with it very briefly, but there were indeed outpatients’ appointments with Professor Walker Smith and a letter subsequently to the GP at page 39. Professor Walker Smith said:

“I reviewed [Child 1] in the outpatients. There has been some improvement with Salazopyrin however, her mother has not really given it very long. She was concerned at one stage that Salazopyrin might have produced a rash. I think it is most unlikely that the rash she demonstrated is anything to do with Salazopyrin. At present he is taking paraffin and Salazopyrin. I recommend continuing this for the moment.

I have made no definite appointment to see him again. I would recommend continuing on this medication as we have found other children who have had this kind of colitis have responded well to this therapeutic approach. [Mrs 1] also raised the question of whether we should investigate the brother. I think it might be appropriate to do this in due course, although his gastro intestinal symptoms do not appear to be very severe.”

That is the plan, that he was indeed prescribed those R by the GP. In fact Professor Walker Smith did see this child again – I will not go to the notes – but in June/December 1997. There is another outpatient appointment clinic on page 26. We see again the Wakefield clinic stamp at the top of that page. You have already dealt with the implications of a consultant having his stamp on a note of this kind in respect of the previous child we looked at, Child 2. Do your same observations apply?
A Yes.

Q There is a continuation of some follow up by the Royal Free. Professor Walker Smith writes to the GP at the Royal Free Hospital records, page 38. On this occasion he says that he has seen the child again at the mother’s request and that she was exploring another treatment prescribed by another doctor in Scotland and that she wanted investigations into the role of aluminium and trace metals:

“This is certainly not in our area of expertise and I have told [Mrs 1] that we are unable to help her further and, accordingly, I have not arranged another outpatient appointment to see him.”

There is then continuing correspondence at least between the Royal Free and the GP. The last thing I want to take you to is page 64 in the GP records. This was a letter which was sent by the local paediatrician, Dr Rolles, in Southampton directly to Dr Wakefield:

“You will know [Mrs 1] and her sons very well...”

I am not going to read out the entire letter, but I will let everybody just read to themselves the second and third paragraphs and the last paragraph on that page. Turning over the page:

“I am sorry to trouble you over this matter but I do feel that if at least I could have a response from you it will help me as I try to support this lady who is very much absorbed trying to unravel, in her own way, the complexity of her children’s problems.”

I underline that I am not asking you this because I am critical of this mother in anyway, but when you see a letter of that kind, does that, to some degree, inform your concerns about parents losing objectivity and not relying on them too much for making decisions in relation to investigations?
A Yes, I think the issues that Dr Rolles refers to in his letter about Mr and Mrs 1 are, unfortunately, far from rare in the case of parents of children with unpleasant diseases which are chronic and which are unexplained. They will often go outside conventional medicine and seek help in other areas, and also, as a result of their concerns, often have a very low threshold for agreeing to tests being carried out on their children.

Q Turning to a couple of general matters on this patient. Overall, Professor Booth, does it seem to you, at least in so far as the gastrointestinal investigations are concerned, that this was a clinical or a research series of investigations?
A I have not been able to determine any clinical reason for the endoscopies on this patient. On that basis one assumes that they must have been carried out for some other purpose, ie research.

Q Turning to the issue of qualifications for the study, there is no evidence of Dr Berelowitz having carried out a behavioural assessment in this case, although, as you will know from the letters we have looked at, Professor Walker Smith mentions that a neurological and psychological assessment of the child’s autism was going to be undertaken. Can you see any evidence in the notes that the diagnosis of disintegrative disorder was confirmed before these invasive investigations were embarked upon?
A No, I cannot.

Q Does that concern you?
A Yes, it does.

Q That is all I have to ask you about Child 2 [sic]. We can put away the records on Child 1 and go on to Child 3. You will need the GP and Royal Free records. This boy, again, if we can look at the referral circumstances to the Royal Free first. The Royal Free Hospital records, page 38. It is a letter dated 19 February 1996 to Professor Walker Smith from Dr Shantha:

“Thank you for asking to see this young boy who developed behavioural problems of autistic nature, severe constipation and learning difficulties after MMR vaccination. The batch incriminated was D1433, incidentally, which was the discontinued batch following adverse reactions.

He has seen Dr Oppenheim at Alder Hey Hospital and Dr Rosenbloome at the same hospital.

He is attending special school. His severe constipation is requiring frequent enemas and oral medication.

The parents are very convinced that the difficulties in his behaviour etc started only after the vaccination.

I am only extremely grateful for you to have taken on [Child 3] for case study.”

Two things, Professor Booth. First, that letter refers, obviously, to gastrointestinal symptoms of severe constipation?
A Yes.

Q I am not taking you to all the GP records, but that is indeed borne at by all the records. Indeed, Dr Shantha herself has told us that constipation was the problem. As far as the start of that letter, Dr Shantha cannot remember the precise circumstances which led her to write it in those terms. Does it seem to you to be an unusual beginning for a referral letter to a tertiary referral centre?
A No, I think that tertiary centres are often referred patients with severe constipation. What would be unusual would be to send a patient with severe constipation several hundred miles to another centre during which time they drive past quite a few other good tertiary centres of gastroenterology.

Q If the request for a referral had been prompted, as in envisaged in the first sentence:

“Thank you for asking to see this young boy”,

would that be unusual?
A Yes, that aspect would be unusual, yes.

Q Continuing with the history, page 57, we see Professor Walker Smith’s reply saying that he would arrange for an outpatient appointment to be sent. At page 9, we have that appointment. The gastrointestinal symptoms are at the bottom of that page:

“He developed constipation from the age of six months. Had some motion with bleeding from about six months.
...

On lactulose & enemas.”

If we turn on to the next page there is a request form for blood tests to be undertaken and the inflammatory markers to be tested. I will revert to the significance or otherwise of those symptoms in a moment, but if you could look at what the blood tests revealed on page 102 – we see them under the column, 3 April 1996. Can you just help us as to whether they reveal any abnormalities?
A The urea is normal, potassium, sodium normal, creatinine 54. It has got a “low” against it but I think perhaps the lower limit of their range is 60, but a low creatinine under these circumstances would not really signify anything, I do not think, with the abnormal C-reactive protein at the bottom.

Q And the C-reactive protein would be a marker of inflammation if that was high?
A Yes.

Q Professor Walker-Smith writes to Dr Shantha at page 39 after that outpatient appointment dated 4 April 1996.

“Many thanks for referring this child. As you say there is a clear history of the child being completely well until the age of 14 months when he had MMR. On the second day after the injection he developed a fever and a rash and since then his mother noticed dramatic change in his behaviour. He has also been investigated in Alder Hey Hospital. Recently his mother had been told by Social Services that it is likely that the MMR might have caused the problem, had been in touch with the organisation JABS who had mentioned the research that Dr Andy Wakefield has done at this hospital into the role of MMR vaccination and Crohn's disease, hence my interest. We have now seen a number of children who have had features of both Crohn's disease and autistic behaviour following MMR. Whether this is causally related I simply don’t know at present. [Mrs 3] is keen that we pursue this avenue. In the first instance I have screen [Child 3] with routine blood tests etc., and we will consider in due course whether it is appropriate to go ahead and perform a colonoscopy. A colonoscopy offers the opportunity to demonstrate if there is any ongoing infection in the gastrointestinal tract which could be in some way cause related to his present problems.

Many thanks for referring this interesting child.”

It appears from that letter that the colonoscopy was to be dependent, at least to some extent, on the blood tests and from what you have told us when you made your general comments at the beginning of this case, is that what you would expect?
A Yes. I think that the first thing to say is, there are a curious set of tests to request in a patient referred with severe, long-standing constipation. Under those circumstances, you may well request some investigation looking at thyroid function, for example. Looking for inflammatory bowel disease would be a most unusual way of approaching a patient with severe, long-standing constipation. So one is just concerned about why this patient was referred, and the referral letter from Dr Shantha ends by saying that Child 3 was taken on for case study, which is an unusual way of making a referral. It is difficult to see either on the basis of the symptoms that this patient had, severe constipation, or on the basis of subsequent tests, why a colonoscopy might be considered.

Q What about the last sentence:

“A colonoscopy offers the opportunity to demonstrate if there is any ongoing infection in the gastrointestinal tract which could be in some way cause related to his present problems.”

Do you understand that to be the behavioural problems or the gastrointestinal problems, or both?
A Possibly both. Generally speaking infection in the colon with a bacterium or some other infectious agent would be a specific contra-indication to carrying out a colonoscopy and infection in the colon is much more readily diagnosed by culturing the stool unless, of course, you are looking for some other sort of latent infection for which you required mucosal biopsies.

Q Would that in itself be unusual for a child referred with severe constipation, as a first investigation?
A Very unusual indeed, yes.

Q On the same day that Professor Walker-Smith writes that letter to Dr Shantha, he writes to Dr Wakefield. That letter is at page 40, the next page.

“There is a clear history of this child having been perfectly well until the age of 14 months and then the second day after the MMR injection there was a change in behaviour which has persisted thereafter and he has been diagnosed of having behavioural problems of autistic nature.

On examination he looks well and fit but clearly has disturbed behaviour. I have the routine bloods etc, and I have told the mother that we would like to consider colonoscopy within the next one or two months and she has agreed. I have not yet booked for a colonoscopy until we have got the full details of the investigative protocol worked out.”

First of all, the reference to the child looking fit and well: does that have any relevance as far as whether it is appropriate to undertake colonoscopy?
A If this patient had substantial inflammatory bowel disease, then you would not expect him to look fit and well.

Q A colonoscopy, as you have told us, would be unusual with symptoms of constipation, but if for some reason Professor Walker-Smith had decided that he was going to undertake a colonoscopy for clinical reasons, would you expect its timing to be dependent on an investigative protocol?
A No, no.

Q And you have told us that blood tests would be an initial step, normally speaking. If they are going to be taken, would you expect the decision as to whether a colonoscopy was appropriate or not to await results of those blood tests?
A Yes. Otherwise there is little point in taking the blood.

Q Absolutely. The indications of the apparent decision of considering colonoscopy in the next one or two months was “an investigative protocol [has been] worked out.” What does that suggest to you as far as clinical or research medicine is concerned?
A The fact that the protocol needs to be worked out first would suggest strongly this was a research investigation. The timing within the next one or two months I do not think is helpful in determining clinical or research either way.

Q No, no. And then, on the same day, we have a letter which Professor Walker-Smith wrote to Dr Rosenbloom, who was the paediatric neurologist at the Alder Hey Hospital. That is at page 53.

“Dear Dr Rosenbloome,

This child was referred to me by his GP because of the work of my colleague Dr Andy Wakefield at this hospital concerning the role of MMR in the genesis of Crohn's disease and more recently possibly in relationship to the association with autistic behaviour. We have seen several children who have had both features of Crohn's disease and autistic behaviour related to MMR vaccination. I have therefore seen the child in the clinic. I would be most grateful if I could have a report of your diagnosis and previous investigations and particularly his views concerning his autistic behaviour.”

Then there is a response to that by Dr Rosenbloom enclosing the child’s notes. I would just like to look at the reply by Professor Walker-Smith to that, which is in the local hospital records, I am afraid, at page 180. Just to orientate you, the letter from Dr Rosenbloom to Professor Walker-Smith is at page 182, and it is saying he is interested in the link between MMR and asking for references that Professor Walker-Smith might have. Then we see page 180:

“I am actually passing on your letter to my colleague Dr Andy Wakefield who is the inspiration of our work linking MMR, autistic behaviour and Crohn's disease and I am asking him to write to you to fill you in on our proposed study.

I am grateful for your help…”

And he acknowledges the records. There is a further outpatient appointment at the Royal Free and after that Professor Walker-Smith wrote to the general practitioner. That is back in the Royal Free records, please, at page 11. We are now at 17 July 1996. We can see the note for the outpatient appointment. It says that he has had constipation since seen last and that is has improved now. He is on lactulose and enemas if he goes for three days without stool. We then see:

“Arrange admission for colonoscopy …”.

And following on from that, a letter to Dr Shantha at page 52 in the same file:

“Initial screening tests for [Child 3] for inflammatory bowel disease were negative. However we are arranging for [Child 3] to be admitted on Sunday the 8th September for colonoscopy followed by a period of investigation in the ward. We will let you know the results of these investigations in due course.”

Then, on the same day a letter to Dr Wakefield at page 49:

“This child with autism has had no evidence of bowel inflammation on routine blood tests, however we are arranging his admission for colonoscopy on Sunday the 8th September, followed by your intensive investigations. I would be very grateful if you could arrange the other aspects of his admission.”

What are your comments regarding that, Professor Booth, that sequence, particularly with regard to whether or not this is a research activity? Can you understand why the plan was made to admit this child for a colonoscopy, clinically?
A I have not been able to detect any clinical reason for this kind of a colonoscopy. This patient had bloods. The grounds here would indicate that this patient was being admitted for research investigations.

MS SMITH: Sir, I see it is 11 o’clock. I was hoping to finish this child before the break, but I do not want to overload you with information. I think it will take a little longer than perhaps you would wish to go all at one stint.

THE CHAIRMAN: You do not think it is likely we will finish this child in the next 15 minutes?

MS SMITH: I do not, to be frank, sir, but I could go on for 15 minutes.

THE CHAIRMAN: I think we will go on for 15 minutes longer, then.

MS SMITH: Going on to page 50, please, in the Royal Free records, this is the letter from Professor Walker-Smith to Dr Rosenbloom, explaining the decision-making. It is dated 18 July 1996.

“Dear Dr Rosenbloom

Thank you so much for sending the notes of [Child 3]. We are arranging his admission for Sunday the 8th September for colonoscopy, however the initial blood screens for bowel inflammation were negative, however Dr Wakefield is of the opinion that subtle changes in relation to inflammation may be present in such children, and we have arranged [Child 3]’s admission for a week to 10 days for a period of intensive investigation. We will let you know the results in due course and return his hospital notes to you then.”

He also wrote to the GP at page 51, giving much the same information.

“Dear Dr Sangyam

Many thanks for your query concerning [Child 3], our initial screen for Crohn's disease was quite negative. His C-reactive protein was within the normal range, his blood tests were all normal. However, we are pursuing further the relationship between bowel inflammation and autism and have arranged for [Child 3] to be admitted on Sunday the 8th September for colonoscopy and biopsy followed by further investigation.”

If, as would appear to be the case, this admission was motivated by Dr Wakefield’s opinion that subtle changes might be present in children with autism, Professor Booth, would you expect that to be a reason why clinically, as opposed to research purposes, Professor Walker-Smith would decide to admit this child who has no other symptom of bowel inflammation?
A No. I do not think there is any justification for admitting this patient for investigation for clinical reasons. That would be entirely outside accepted clinical practice and, as indicated, this was looking for subtle changes, and comes under the category of research.

Q We then get at page 45 a letter from Dr Casson to the little boy’s mother in the same terms as the letter you commented on before:

“This letter is to confirm that [Child 3] is to be admitted to Malcolm Ward on Sunday 8th September 1996 for colonoscopy.

Abnormality further investigations required will be decided on another occasion following consultation with Dr Wakefield.”

Again, you have already referred to the lack of clarity in the role that Dr Wakefield was playing. Does this underline that lack of clarity, or do you derive any assistance on why Dr Wakefield would decide on investigations if it is not clinical?
A It is very difficult to see why Dr Wakefield would be required to decide on further clinical relevant investigations. I cannot imagine a circumstance clinically where Dr Wakefield would provide relevant, useful clinical information to someone of Professor Walker-Smith’s experience.

Q The child was then admitted to the Royal Free Hospital. I am not going to take you to all the forms but there was a consent form for research biopsies that we have looked at with two previous patients, but just so the Panel know where the notes are, it is the Royal Free Hospital records at page 120. There is what you describe as the standard clinical consent form for colonoscopy at page 122. I would, however, like to take you to the endoscopy clerking sheet – that is prior to the endoscopy – which is at page 124. There is “Reason for Procedure” which says:

“? Crohn's disease (Severe constipation intermittent pr –

– is that rectal bleeding –

“from 8/12 [eight months] – 4 ½ years”.

I wanted to ask you this: that reference actually…. I am interrupting myself, but there is another note as well which goes with it which is at page 12, please, in the clinical records. That is the start of the note, and it is at the bottom of page 12 and the top of page 13:

“No abdominal pain – … no rash.”

Then:

“Suffers from constipation from the age of 4 m [months] - rectal bleeding with hard stools - not mucosy.”

That reference to rectal bleeding – what do you understand from that note?
A That the patient passes blood per rectum from time to time, and this would be a common symptom in patients with severe constipation who are passing hard stools.

Q Would it in itself be the kind of bleeding which might make you think in terms of colonoscopy clinically?
A No. Not as described here. It specifically says “rectal bleeding with hard stools”.

Q Is that a well known association?
A Yes, yes.

Q If we can just on the same subject go on to an earlier letter, which is in the GP records, page 105. As I say, this was a letter in February 1996 from the community paediatrician to the GP, and we see on page 106:

“He has a history of constipation and blood in stools. His parents have used Lactulose and micro-enemas on the advice of a specialist nurse. I now understand that he is waiting to be seen by the Specialist at the Royal Free Hospital, London, about his bowel problem.”

Is the description in that letter consistent with the history that is reported at admission to the Royal Free of the blood being associated with constipation?
A Yes. It strongly implies that they are linked, yes.

Q If we can return to the admission in September, the colonoscopy report at page 105 of the Royal Free Hospital records, please. We see a reference and the history to MMR and the report says:

“Normal to terminal ileum, but with increase in the number of lymphoid follicles in the terminal ileum.”

There are some handwritten notes in relation to the colonoscopy at 125:

“Normal to the terminal ileum. Lymphoid nodular hyperplasia not marked”

And then “Plan: other investigations as per the protocol.”

Then there were subsequent blood tests, and I would like to look at those so if you would go to page 73. You will see that the sample was received on 9 September 1996. Are there any significant abnormalities as far as those are concerned?
A No, I do not think so. One of the indices, the second one down, at 0.35 I cannot work out what that is, it is where a hole has been punched and it has been photocopied. It is fractionally low but it is not something that would be one of the indices that you would look at looking for evidence of inflammation.

Q Is the ESR normal?
A That is normal, yes, and the haemoglobin is normal.

Q So these are consistent with those taken prior to the admission, is that correct?
A Yes, they are.

Q Which we also know to be normal. Looking at the clinical notes for the rest of the investigations that were undertaken, page 15:

“10 September barium follow through tomorrow: MRI on Thursday”.

Then going the page we see on 11 September:

“Barium cancelled: ? Friday: MRI – [lumbar puncture] EEG and [evoked potentials] tomorrow.”

At the bottom of the page:

“EEG today: back from MRI scan: has had EEG awake: MRI scan under sedation.”

Samples were taken from the CSF, and amongst other things measles testing, and also bloods for measles testing. At the bottom of the page, “EEG under sedation.”

At page 16: we know he did indeed have the barium follow through, and we can see that at the top of the page, on 13 September. Going on, at 6 o'clock:

“Discussed with Mum – her main concern is over constipation”.

And there is a suggestion that liquid paraffin should be prescribed.

Turning on to the histopathology report on page 75, the comment at the end, page 76:

“Mild inflammatory and reactive changes in the small bowel samples, of uncertain significance on morphological grounds alone. No microbes or granulomas identified in any of these samples.”

And then the child was ultimately discharged from the Royal Free Hospital with prescriptions for Lactulose and Sytron. Are they constipation treatments?
A The Lactulose is a treatment for constipation and Sytron is an iron supplement.

MS SMITH: I am going to turn on now, sir, to the discharge summary, and then to various questions I have to ask Professor Booth as to his overall view on the case, so perhaps that would be a convenient moment?

THE CHAIRMAN: Yes indeed, it is 11.15 so we will now adjourn and resume at 11.35. Professor Both, you are still under oath and in the middle of giving your evidence so please do not discuss the case with anybody.

(Short adjournment)

THE CHAIRMAN: Ms Smith.

MS SMITH: Thank you. Professor Booth, going on with Child 3 would you turn to the discharge summary, which is at page 26. This is written by Dr Casson to the GP:

“[Child 3] was admitted for investigation of possible inflammatory bowel disease and a possible association of this with autism.”

It sets out his developmental history and the MMR and at the top of page 27:

“As regards bowel symptoms, he intermittently suffers from quite marked constipation. He has had occasional rectal bleeding although this does seem to accompany passage of a hard stool.”

The colonoscopy results, which we have already looked at, are set out, and the histology.

We see the investigations that Child 3 underwent in addition: blood tests, CSF results from the lumbar puncture, the barium meal and follow through, MRI, EEG and it says in conclusion:

“Therefore he does not appear to have significant bowel disease. There are several mildly aberrant blood results specifically an elevated blood lead and an elevated lactate. No other metabolic abnormalities were detected. The significance of the MRI findings are uncertain.

We will have to reconsider these findings when we review him again in clinic. as regards the protocol that patients who are being investigated as [child 3] is concerned, we have been unable to perform the Schilling test and the evoked potentials.”

We know there were some changes in this case, and I will go on to those in a moment but as far as these investigations are concerned, do they seem to you to accord with the investigations which were envisaged ultimately in the Ethics Committee application protocol?
A Yes.

Q I think you have dealt with this as we have gone along, but as far as the gastrointestinal investigations are concerned, the colonoscopy and the barium meal and follow through, do you regard them as being clinically indicated?
A No.

Q Going on with the chronology: there was then a change, as I say, in the histological findings. It is not clear what prompted that change or who made it but in this case the GP was informed of it, and I will return to the implications of that. If we look at page 25 of the Royal Free Hospital records, please, 31 December 1996, Professor Walker-Smith writes to Dr Shantha:

“… we sent a discharge summary to you on 4 October 1996. Further critical analysis of histology results has led to an amendment to the discharge summary, which I now am enclosing. Our final diagnosis is of indeterminate ileo-colitis with lymphoidnodular hyperplasia and we have no adequate explanation for his elevated blood lead or elevated lactate level. We sent him home on liquid paraffin. Since then I have not heard anything further concerning him although …”

That is not relevant:

“I have not seen [child 3] since discharge, I would be interested to hear concerning his progress. In the light of these histological findings and if gastrointestinal symptoms persist, treatment with a drug such as … (Mesalazine) might be of some therapeutic value. I look forward to hearing any comments that you may have.”

Accompanying that was a revised copy of the discharge summary, and that is at page 35. We see a diagnosis of “indeterminate ileo-colitis and lymphoidnodular hyperplasia” has been inserted.

The histology on page 36 has been amended to say that colonic histology, which was originally reported as within normal limits “revealed an increase of inflammatory cells” and the reference to the full blood count being normal has been omitted.

On page 37, again the diagnosis of “indeterminate ileo-colitis and lymphoidnodular hyperplasia” has been inserted.

The kind of phraseology of indeterminate ileo-colitis and lymphoidnodular hyperplasia, is that the sort of phraseology that you would expect to see an ordinary clinical histology report?
A Yes, that terminology would be used, yes.

Q If the amended histology revision was of clinical significance, the revision of the findings, would you expect to see that in an amended histology report in normal circumstances?
A Yes, you would normally see it in a report, and these sorts of changes are occasionally made to histology reports following discussion at the regular meeting that most units have with histopathologists, so the clinicians and the histopathologists look at the slides together and changes are occasionally made, and if they are substantial, particularly if they lead to changes in clinical management then the histopathologist would normally issue an amended report.

Q I think it is right, Professor Booth, that in light of the fact of the change in conclusion has been recorded in the records, albeit in a discharge letter, as we have just seen, you do not criticise that change, but all I really want to ask you is this: is it a usual event to see a change of this nature in a discharge summary to a GP?
A It is unusual. The fact that it has taken place after the discharge summary has been produced – and this is some months after the discharge summary was produced – would be very unusual. What is particularly unusual is that the source of the change has not been recorded. Histopathologists always sign their histopathology reports so that as a clinician you know who has done it and they take responsibility for the conclusions that they are reaching. In this case it is unclear what process has led to these changes, and the changes are not attributed to anybody, as far as I know.

Q As I say, I am spending a little time on this because we are going to be looking at other cases in contrast where you are critical of the fact that one cannot tell from the clinical records why a particular course of events has followed on but in this case, at least, I think you would acknowledge that it is at least clear that there has been a revision of the view?
A Oh yes, that is very clear from the amended discharge summary.

Q Going on to the follow up thereafter, and in particular you highlight a series of correspondence relating to Dr Wakefield: if we look at page 24, this is a letter from Dr Wakefield to Professor Walker-Smith:

“I spoke to [Mrs 3] yesterday. I am sure that he is one that should be included in the treatment protocol, since his biopsy showed clear evidence of colitis. He is currently on liquid paraffin but may well benefit from sulfasalazine.”

That is a letter that Dr Wakefield sent to Professor Walker-Smith in April.

Going on to page 21, a letter dated 30 March 1998, another letter from Dr Wakefield:

“Dear John,

[Child 3] is having continuing problems to the extent that he is now being taken into residential care in view of aggressive behaviour in association with his autism. The child psychiatrist … to whom I spoke today on the phone believes that he has Tourette’s …

One of [his] continuing gastrointestinal problems is severe constipation, and I think this may well be contributing … to his symptoms and signs. They have asked if there is a local paediatric gastroenterologist who could manage, on a day-to-day basis, the problem with his chronic constipation, and I said that I would write to you to endorse this recommendation. I am sure they would be very grateful for your advice.”

That is a letter from Dr Wakefield to Professor Walker-Smith.

Then if go to the GP records at page 89, this is a report from the senior specialist registrar in child and adolescent psychiatry.
A Could I check the page number?

Q It is page 89 in the GP records, which is a report from the St Helens & Knowsley Community Health.
A Yes.

Q We see on page 91 a reference in the middle of the page about his past medical history, to the child’s referral to the Royal Free and Dr Wakefield’s belief that child 3’s autism and bowel problems are related to MMR. At page 94, under “Irregular bowel habit” which is one of the symptoms that the registrar had identified:

“I have discussed this issue with Dr Wakefield, consultant gastroenterologist at the Royal Free. He agrees that [Child 3’s] bowel condition (Non Specific Colitis) should be monitored locally and believes that [Child 3’s] bouts of constipation may well be exacerbating his behaviour problems. The prescribing of Salazopyrin and Ferrous Sulphate also needs to be reviewed. He will be writing to [Child 3’s] to request a local referral.”

Professor Walker Smith writes to the GP in the same records GP records, at page 86:

“Dear Dr Shantha

I understand that Child 3 is having a deterioration in his general behaviour. I wonder if it might be helpful to substitute the Sulphasalazine elixir for a therapeutic trial of the 5 ASA derivative Pentasa. I believe that this might be worthwhile although it may be practically difficult to administer Pentasa to this boy.”

That is the history of the follow up and description of anti inflammatories to this little boy. As far as the role of Dr Wakefield in that series of correspondence is concerned, given the matters you have already referred to – his apparent lack of paediatric qualification and the restrictions on any involvement in the clinical management of these patients, or any patients – are you surprised to see the letters in these terms?
A Yes, I am. I am very surprised and concerned.

Q One last letter, for completeness, on the gastrointestinal side. The problems with referral led to a letter to Dr Rosenbloom to Dr Casson, who was by then a consultant at the Alder Hey. If you turn to the GP records at page 69, Dr Casson says – and this is, by now, April 2002:

“I reviewed [Child 3] today.

The main concern is constipation. He had been seen at the Royal Free Hospital several years ago and a diagnosis of MMR associated colitis was made. Subsequently he had been treated with Sulphasalazine but there has been no follow up and there does not appear to be no useful outcome from this medication.

Presently he opens his bowels once a week...In himself he is otherwise well and there no signs of note.

I had a long discussion and have advised stopping the Sulphasalazine as it has obviously not been providing any relief. I started him on an aggressive anti constipation regime. This involves the use of liquid paraffin 20 30 mls tds with very, very gradual reduction. They should not stop the treatment as I suspect he will need it lifelong and need to achieve a dose that provides best results.

I will review him again in clinic in three months’ time.”

Thereafter he has remained under the care of Dr Casson. As a culmination of this child’s symptoms, Professor Booth, has there ever, as far as you can see, really been very much variation from what he has been suffering from?
A There does not seem to have been any convincing improvement in his symptoms on Sulphasalazine, which would in any case be a very unusual treatment indeed for constipation.

Q Overall, and in the light of that, what conclusions did you reach as to whether these gastrointestinal investigations, which were carried out in the Royal Free in 1996, were carried out for clinical or research reasons?
A As I said before, I have not been able to detect any clinical indication for the carrying out of colonoscopy in a patient with severe longstanding constipation and normal inflammatory indices. That, with references to protocols and case studies and so on, suggests very strongly that this patient was being investigated as part of a research study.

Q Were you able to find any independent confirmation of a diagnosis of disintegrative disorder in this child before the colonoscopy was performed? I can tell you that we have not been taken in this case to any evidence of Dr Berelowitz carrying out a behavioural assessment?
A No, I could not find anything.

Q Again, does it cause you concern that the apparent order of investigations was the invasive ones prior to the assessment of the eligibility for the study?
A Yes, absolutely. To be eligible for the research study, patients had to have disintegrative disorder.

Q I would now like to turn on to Child 4. You are going to need the GP and the Royal Free records. I think that is all in this case. Professor Booth, do tell me if you need a few minutes to remind yourself of which child it is with reference to your report. Just tell me and we will pause?
A Yes, I will.

Q Going again to the referral history first, GP records at page 125. This is a letter from Dr Wakefield to Child 4’s father dated 12 June 1996:

“Thank you very much for your letter regarding your son. I would be grateful if you could phone me or my secretary with your telephone number so that we can discuss this directly. It is much easier to answer many of the questions in this way. I look forward to hearing from you.”

There is a reference, to which we need not turn, in the GP records for a request by Mum for the matter to be discussed with a doctor in London. Then we get a referral letter from the GP to Dr Wakefield, which is in the Royal Free Hospital records at page 27. This is dated 1 July 1996 to Dr Wakefield:

“Following our recent telephone conversation, I would be grateful if you could arrange an appropriate ECR appointment for [Child 4] to undergo assessment regarding his possible autism and his bowel problems.”

The letter then sets out his longstanding behavioural difficulties and also bowel disturbance:

“His mother has always found it difficult to accept that there was no known cause for Child 4’s disorder. A few years ago she was chasing he idea with he might have a metabolic disorder and I enclose a copy of a letter I wrote to Dr Wraith in Manchester at that time, although his reply was he did not see any value in further tests along these lines. I am aware that you are looking at possible links between measles vaccine and various difficulties and [Child 4] certain had MMR in 1988. In general [his] mother thinks he develops normally initially and subsequently his problems worsened and he lost some of his milestones, but he subsequently improved on a restrictive exclusion diet. The professionals who have known [Child 4] since birth do not entirely agree with this however and there is a suggestion that some of [Child 4’s] problems may have started before vaccination.

... intermittent problems with his bowels with diarrhoea that [his mother relates to food intake He has had a negative test for coeliac disease and has on at least 2 occasions had giardia but he has had no further investigations regarding the cause of these symptoms.

As I say [his mother] is convinced that both his behaviour and his diarrhoea are triggered by h is diet and she has him on something of a restrictive exclusion diet. He has not gained weight and we have been very concerned about this. [His mother] feels that this is despite him being on a more normal diet. We have not made any assessment as to whether his failure to gain weight might be due to an inadequate diet or to possible malabsorption.

I would be grateful if you could arrange an appropriate appointment and would be very interested if you feel [Child 4] fits into the sort of category of patient that you are interested in looking at further.”

That was the referral letter. There is a reference in it, obviously, to gastrointestinal symptoms and, in particular, to two occasions of giardia. Can you assist us as to what that is?
A Giardia is an infection of the gut leading to diarrhoea, vomiting, loss of appetite, weight loss sometimes and can be persistent.

Q You highlight in your report that, in addition to that, he had had two episodes, one in 1993 of giardia and then in January 1994 an episode of dysentery due to a shigella infection.
A Yes.

Q Is that a similar organism?
A It is a bacterium that produces pain, blood and diarrhoea normally lasting for the week or so. It is a very unpleasant infection and in a minority of children leads to continuing episodes of abdominal pain and diarrhoea, so called post infective irritable bowel syndrome, but can go on for months and sometimes years even though the infection has cleared.

Q Given the fact that this child had had these infections, would that be something that was, at least, in your mind as a possibility?
A Yes.

Q The GP writes to Child 4’s mother. We have that letter in the GP records at page 123, just saying:

“I have received further information from the Royal Free which suggest that [Child 4] falls into a group of patients that are interested in looking at further.”

And that he has sent them a letter and they will be contacting her in due course.

We know that Dr Wakefield passed the referral on to Professor Walker Smith in the Royal Free records at page 26 on 4 July 1996:

“Dear John

Please can I pass on this referral which has come to me from Dr Tapsfield. [Child 4] sounds like a good candidate for our forthcoming study.”

Does the use of the word “study” in that context, and indeed the use of the words relating previously to falling into a group of patients they are interested in looking at further, does that have clinical or research implications?
A I think in Dr Tapsfield’s letter to the mother where he or she talks about Child 4 falling into a group of patients that they are interested in looking at further, it would be very unusual for a tertiary centre to express an interest only looking at certain groups of patients. Normally tertiary centres would be interested in seeing all patients referred to them, so it implies that there is a special interest in a particular group of patients. That is consistent with the wording of Professor Walker Smith’s letter to Dr Wakefield when he refers to this patient being a good candidate for a forthcoming study.

Q So that is the Royal Free Hospital records at page 26. If we go on to page Royal Free Hospital records at page 25, we see a letter in the terms we have seen before, 28 August 1996, to Mr and Mrs 4 from Dr Casson:

“This letter is to confirm that [Child 4] is to be admitted for colonoscopy. Any further investigations required will be decided on another occasion following consultation with Dr Wakefield.”

The comments you have already made in relation to that letter, do they apply in this instance as well?
A Yes, it would be unusual for a non clinician to be consulted about the need for further investigation in any case, but they might be consulted if it was within the context of a research study.

Q In this case we know that there was a letter and then the plan to admit. Generally speaking, if a GP makes a referral to a consultant in circumstances of this kind, do you expect the child to be seen prior to admission?
A Yes.

Q What is the normal pattern of events – indeed we have seen it in the previous cases?
A Normally, when a GP makes a referral, the patient is seen in the outpatient clinic. The history is taken, the patient is examined and on that basis, plus the information supplied by the GP, a decision is made about the differential diagnosis and what investigations would be appropriate. There are, perhaps, two exceptions to that in my experience. One is when a patient is severely ill at home and the patient gets admitted straight on to the ward. Another exception might be where a colleague within the region refers a patient who clearly needs a particular investigation. The classic example of that might be a patient who has positive tests indicating that they probably have coeliac disease and sometimes under those circumstances, in order to save time, one admits the patient as a day case, sees the patient before the investigation is done and then does the investigation. So you would see the patient first, but you would not necessarily waste time by seeing them in the outpatient clinic first. In a referral of a patient like this, it would be exceptional not to see them in the clinic first, I think.

Q Are you critical of that decision, simply to admit for a colonoscopy, on the basis of the symptoms that were available to the Royal Free at the time?
A Yes, I think Dr Tapsfield wrote a very good referral letter, but there is still a lot deal more information that you would require that you could obtain in an outpatient consultation first so that you could make sure that the appropriate investigations were done that were tailored to the particular differential diagnosis that you arrived at following the consultation.

Q What about screening tests, inflammatory markers, would you have expected those to be tested before admission for colonoscopy?
A If you felt that inflammatory bowel disease was within your differential diagnosis, then you probably would do, unless the patient had absolutely barn door symptoms and signs of inflammatory bowel disease which this patient did not have.

Q As we know, the child was admitted, in fact on 29 September. We can go to the admission clerking note which is on page 5 of the Royal Free records, please. We see at the top of the page:

“Admitted for study of disintegrative disorder /colitis /MMR.”

Then, underneath that:

“c/o [complaining of] Diarrhoea ? food related”

Also there are some behavioural symptoms and, at the bottom of those –

“Abdl [abdominal] pain.”

If we go down to “Development” at the bottom of the page, at eight months there seems to be some suggestion that there was some regression:

“Noted seemed to be losing words both vocally + understanding”.

Going over to the next page, mid-way down the first paragraph:

“Had had MMR 4/52 [4 weeks] before these loss of skills (N.B. had previous had measles at 15/12 [15 months].”

Then there is a list of the foods, just over half way down the page, which seemed to make him worse. Then there is a reference to dry which is on page 8:

“Diarrhoea became a problem between 1 - 1½ years.

No blood, no mucous.”

Then the fact that it contained undigested food. It says he deteriorated at four and a half years. Then it notes a response to diet. Down at the bottom of that passage:

“Presently – well most of time
If does get exacerbation seems to be related to new foods.”

It says that bowels open once or twice a day, normal, no straining. There is a reference again to various foods, with abdominal pain resolved. Then:

“Note ?Giardia x 2, proved on one occasion”

That must mean the presence of the infection was proved?
A Yes, yes.

Q There is a page that has been interposed, but the note continues on page 10. We see it says that the plan is colonoscopy, MRI, EEG and evoked potentials, lumbar puncture, various bloods as indicated and then a reference to an ECG and a chest X ray on the end. Again, I am not going to take you to them, but there are standard consent forms. When I say “standard” I am using the word you used – a standard clinical consent form for a colonoscopy, and biopsies, and a general consent form for research biopsies, and just for everybody’s records if they want them they are at the Royal Free Hospital records at page 79 and 80. Then we have a colonoscopy report which is at the Royal Free records at page 32. This is a colonoscopy report which was done by Dr Murch.

“Histology report to follow.

Mild granularity of rectum, with slight disturbance of vascular pattern (‘neovascularisation’). Normal colon, but ileum showed marked lymphoid nodular hyperplasia.

NB. Investigation performed because of disintegrative disorder variant of autism.”

Would that be an unusual thing to see on a colonoscopy report for a clinically indicated investigation?
A It would be exceptional for clinical report to indicate that the colonoscopy had been carried out because of disintegrative disorder.

Q Focusing on the information that the Royal Free had at the time, in other words the referral letter and the presentation at admission, is it your view that a colonoscopy was in fact clinically indicated in this case?
A I think particularly in view of the fact that no other test had been done and that stools and abdominal pain were better by the time the patient was admitted, I do not find an indication for doing a colonoscopy, clinically.

Q Are you critical of the reasons for which it appears that it was performed?
A It appears to have been carried out as part of the study into disintegrative disorder and I have not been able to satisfy myself that that diagnosis was confirmed before the patient was entered into the study and the intensive regimen of investigations begun.

Q Just following on for the inflammatory markers, Professor Booth, we have the results of the blood tests that were taken after the colonoscopy. They are at page 44. Can you just assist us as to whether there is anything on those results, which is significant so far as inflammatory markers are concerns?
A There is an albumin which is not low.

Q Sorry? Can you just tell us what you mean by that? It has an “H” by it; it is high.
A Yes.

Q Is that relevant?
A It is high. You would be looking for a low albumin, yes. The fact that the albumin was slightly high, the fact that the urea was slightly high, might indicate that this patient was a bit dehydrated when the sample was taken. It may have been taken following the bowel preparation, in which case the patient may have had quite a lot of diarrhoea. It is difficult to say.

Q Sorry – just so we are all clear. When you say you would be looking for a low albumin, you mean you would be looking for one if it was an indication of inflammation?
A Yes. If you were looking to see whether it helped you towards a diagnosis of inflammatory bowel disease, then a low albumin would be significant.

Q As far as any indications of inflammation are concerned, are there any of significance in that blood result?
A No, not on page 44.

Q If we go on to page 62, we get the rest of the results, I think. Are they sufficiently clear on your copy for you to be able to see what they are?
A I think the top, 14.8, probably refers to the haemoglobin as being high, very slightly. I do not think that is of any significance and I think 4 refers to the ESR.

Q Yes, it does.
A Yes – which is normal.

Q As I say, they were not done before the colonoscopy, and you are critical of that. They were undertaken post the colonoscopy during the admission, and they were normal?
A Yes.

Q Then returning to the chronology, there is a request for the further neuropsychiatric investigations for the EEG and the evoked potentials. That is at page 67. That is a form where the reason for the request is given as “disintegrative disorder and enteritis ? myelopathy.” It is signed by Dr Wakefield. You have made comments on this form previously, but does the same apply as far as this patient is concerned?
A Yes. It would not be appropriate for a non-clinician to be requesting clinical investigations, so I just make the comment that the reason for the investigation, disintegrative disorder, had not been substantiated.

Q We have the results of those investigations and the evoked potentials. As far as the EEG is concerned, it is at page 64 and indicates “Nothing definitely abnormal is evident”. Then at page 68, if you could turn to that, as far as the evoked potentials are concerned, we see:

“Normal waveform. We do not have latency values from control subjects for this test. One would guess this is a normal response.”

Do you have any particular observations in relation to that, Professor Booth?
A I think it is unacceptable to expose patients to investigations that are uninterpretable when they are reported on.

Q I am not trying to turn you into an expert on evoked potentials, but what is your understanding of what is said there, remembering we have lay members – they do not have values from control subjects for the test?
A It means that they have not established a normal range by looking at children with no neurological symptoms, so that when they get a result they do not know whether it lies within the normal range or not because they do not know what the normal range is.

Q Yes.
A So it is uninterpretable.

Q As far as the child is concerned, and whether it is research or clinical, could it possibly be of any benefit to him?
A It is difficult to see how, as it is uninterpretable.

Q Returning to the chronology, post the colonoscopy, page 9 please: this is the day after his colonoscopy, bottom of the page. We see:

“[Child 4] has been crying since 5 pm
Inconsolable
BO [bowel opening] x 2 with small amount of dark red blood mixed with stool.
Colonoscopy and biopsy yesterday.”

Is the blood that is recorded on that occasion associated with the colonoscopy and the biopsy he had undergone?
A I think if the bleeding was just on that occasion, which I think it appears to have been – I do not think there are further references to blood in the stool during the sub sequent part of the admission – it would be consistent with some bleeding into the colon following the biopsies. When you take a biopsy, there is always some associated blood loss.

Q Do you in fact, when a child normally has to have a colonoscopy and a biopsy for clinical reason, do you in fact warn the parents?
A Usually, yes.

Q That there may be some blood in the stool afterwards?
A Yes.

Q Then there is a clinical note for 2 October, that the child is to undergo a barium follow-through but in fact that was not undertaken until later. In this case there was a psychiatric assessment by Dr Berelowitz but he does not give any diagnosis. He simply says “a detailed report to follow”. Then, the little boy becomes unwell. That is why the investigations are postponed, if we look at page 12 of the clinical records. We see at the top of the page:

“Episodes of collapsing yesterday
Several vomits yesterday

MRI today
Postpone LP [lumbar puncture] to later date.”

Then on to page 13, in the middle of the page, 4 October:

“No well
No further vomiting

Explained to mum that need to wait for histology report + ? when will come back for further investigations.”

It is pointed out to me that I should have pointed out that Dr Berelowitz was seeing this child on 2 October, so after he had undergone a colonoscopy. He is discharged from the Royal Free. With regard to the histological analysis, that becomes apparent on the same day, in fact, after he is discharged. We have a note of the histology meeting in the records on page 13. This is the histology meeting. It says:

“Ileum - dense lymphoid pattern
- no acute inflammation
- normal architecture

Colon - prominent lymphoid follicles”

Then I think it is –

“No active inflammation.”

And at the bottom of the passage,

“No granulomas.”

We have recently – I mean during the course of this hearing – been provided with a copy of the clinical histology report. That is in the Royal Free records at page 33c. The comment at the bottom is:

“Large bowel series with terminal ileum, with no histopathological abnormality.”

Then after that, there is a discharge summary at page 21.

“Diagnoses: 1. Autism/developmental regression
2. Food related symptoms including diarrhoea, rashes and abdominal pain
3. Lymphonodular hyperplasia of the terminal ileum

[Child 4] was admitted to the Royal Free Hospital for further investigation of a possible link between a disintegrative disorder and colitis.”

It sets out his main problems and the gastrointestinal ones are diarrhoea and abdominal pain. It sets out the history and some indications of regression.

“At this time he began to lose various words and developmental disintegration appears to have taken place from then. This does not specifically correlate with his measles immunisation.

He had his measles immunisation initially at 15 months of age and a 2nd subsequent measles immunisations at … 2 ½ …”.

There was a change in his behaviour from then on. Then it sets that out.

“Socially mum noticed that behaviour responded to dietary variation.”

It sets out the various things.

“Since his dietary changes mum has noted he has become less aggressive, has less tantrums and is less hyperactive. He appears happier in himself.

The diarrhoea also appears to be food related. This became a problem at between 1-1½ years of age. His stool was initially loose and watery and then became increased in frequency. It contained no blood or mucuous and he has no peri-anal soreness. It generally contained undigested food. His diarrhoea became significantly worse from 4 ½ years of age. There was a marked increase in frequency and it became increasingly watery.”

He is put on an exclusion diet.

“On his present exclusion diet he remains well most of the time. If he does get an exacerbation of diarrhoea it does seem to be related to introduction of new foods. He now has his bowels open once or twice a day and this is of normal consistency. Abdominal pain has largely resolved. It is [noteworthy] that he had Giardia grown from his stool a year ago.”

Then it goes on and gives the investigations that he had – colonoscopy, barium meal and follow-through, MRI scan, lumbar puncture, Schilling test not performed, EEG and evoked responses. Blood results. Then at the bottom of the letter:

“Unfortunately because [child 4] had a period of vomiting and being generally unwell … it was impossible to complete all the investigations. We will therefore need to consider repeating these on a further occasion, i.e. barium meal, lumbar puncture.

… An echo cardiogram needs to be performed …”

As far as the histology is concerned, just going back in the discharge letter to page 23 – I am sorry, I may need to ask you some questions about this in a moment:

“Histology of the ileum showed a dense lymphoid aggregate with no obvious acute inflammation and normal architecture. Within the colon there was noted to be several prominent lymphoid follicules (sic) but again no active inflammation. Rectum was normal. There were no granulomas.”

That is how it was reported in the discharge summary.

In fact, although a plan was made to do a barium meal and follow through and a lumbar puncture at a later date, they were not undertaken, they never took place. Again, I have asked you this question in relation to other investigations which did not take place, if, whatever the kind of investigation, it is deemed necessary clinically would you expect the plan to be followed up, in other words for there to be consideration of whether the child did need a barium meal and follow through and a lumbar puncture?
A Normally if there is a plan for further investigations to be carried out on a separate occasion, the subsequent notes would either indicate that they had been done and what the results were or would include some discussion of why they had not taken place, the most usual example would be that the child had got better for some reason and it was not felt appropriate to carry out the investigations.

Q This is followed up apparently by a telephone discussion with Dr Wakefield and the GP and it is in the GP records at page 9, at the bottom of the page, 21 November 1996:

“Discussed Dr Wakefield” – over the page – “re GI abnormalities. ? new syndrome. ? related to susceptibility to abnormal reaction to MMR [arrow] modified inflammatory bowel disease [leading to] neural lesion [leading to] autism. No idea of treatment yet.”

That was Dr Wakefield was saying about the findings to the GP, and then following on there was a letter from Professor Walker-Smith to the GP at page 20 in the Royal Free records, a letter dated 20 March 1997:

“Dr Tapsfield,

In light of the histological finding of a colitis I believe a therapeutic trial of Mesalazine … or Salazopyrin suspension … may be useful. We have found some other children with similar features to [child 4] have both benefited from the effect on gastrointestinal symptoms and behaviour. The duration of such therapy would depend upon its clinical efficiency. If there is no response after a month it would not be worth continuing.”

Reminding ourselves for a moment, and keeping your finger in that, of the histological findings at page 33c of the Royal Free records:

“Large bowel series with terminal ileum, with no histopathological abnormality.”

Do you understand where the diagnosis of the histological finding of a colitis and the suggestions of anti-inflammatory treatment as a result of that, which is in Professor Walker-Smith’s letter on page 20, where that comes from?
A No, I have not been able to find any explanation for that change.

Q If there had been a change in diagnosis which apparently had treatment implications, would you expect to be able to detect why and by whom that change of diagnosis had come about?
A Yes, I think in the previous patient that we looked at there was a change in the discharge summary, although the source of the change was not clear, it was clear that a decision had been made to change the histological diagnosis, whereas here I have not been able to find any similar information in the notes.

Q Is that an important omission as far as you are concerned?
A I think it is important because it has obviously led to a major change in treatment. This patient’s therapy has been changed on the basis of a change in the histological diagnosis.

Q Are you critical of the opaqueness of the reason why Professor Walker-Smith (or someone) apparently thought that there was a colitis in this child?
A Yes, it should be made clear in the notes, yes.

Q I do not want to over-complicate matters but for reasons which will become apparent in the case of this child, I want to look at the ultimate description in The Lancet article of the histological findings, so would you go to bundle FTP2 page 784. The histological descriptions are given in the table at the top of the page, and if we go to child 4 we see that the description is chronic non-specific colitis and colonic lymphoid hyperplasia, reactive ileal and colonic lymphoid hyperplasia. Would it be fair to say that that description is not consistent with the clinical histological findings which we have just looked at in the records?
A Yes. The records indicate normal histology and The Lancet reference indicates abnormal histology.

Q Dr Davies, who as you know is the clinical histopathologist, her evidence was that the description in The Lancet resulted from a more detailed research analysis in contrast to the clinical analysis that had been undertaken previously, and it would appear to be the case that Professor Walker-Smith’s subsequent statement that there was a histological findings of colitis in the letter to the GP fits more closely with the research analysis reported in The Lancet, is that a fair way of putting it?
A Yes.

Q Do you have any comment on research findings of that kind resulting in, as apparently it did in this case, suggestions for treatment?
A I think from time to time when research investigations are being carried out on histological material new observations can certainly be made. I can think of a specific example in my own experience where observations were made following routine histopathology that led to a change in the patient’s treatment. What happens under those circumstances though it is made clear who has made the observation, on what basis, why they have made it, and it is recorded in the notes so that it is absolutely clear what is going on and why those decisions have been made. I think it becomes very dangerous when research observations leak back into the clinical record and there is no clear audit trail of why those subsequent clinical changes have been made.

Q When you say “dangerous”, can you tell us what you mean by that?
A There is lack of clarity about what is driving the management of the patient and who is driving it.

Q Turning lastly and very briefly to the follow-up in this case: I want to go into all the details of this. The Panel will recall that this is a case where the GP had some criticisms that he could not obtain any clarity from the Royal Free Hospital as to the investigations that child 4 had undergone at this time, and if we then look at the GP records at page 96. This is a letter from a Dr Berney who was the consultant psychiatrist to whom the child was referred, and on page 98, which is the only part I need to take you to, Dr Berney says:

“I will write to Dr Wakefield to see if I have any better luck at getting a summary of their investigations and conclusions. [Child 4] had a course of (I think) of Sulphasalazine after his investigation at the Royal Free. He became acutely distressed, apparently with abdominal pain and his autism and behaviour did not improve. It was therefore discontinued after a fortnight.”

Also in the GP records, later on in 1999 we see there continuing gastrointestinal problems, if we go to page 71, from a consultant paediatrician, Dr Colver, 20 April 1999, in the middle of the page:

“[Child 4] now has no abdominal pain and about once every three weeks he has an episode of diarrhoea.”

There seems to have been some resolution of that, if we go to page 70, the letter preceding it, dated 2 September 1999:

“I recently visited [child 4] …

He seems to be reasonably settled at the moment and in good health. He has had no diarrhoea or tummy pains and no rashes. He is eating well.”

The picture seemed to be a positive one, and, as I say, although there were subsequently some records relating to diet they are all between the general practitioner and other advisers and not with the Royal Free.

Can I ask you what is becoming a rather repetitive question: on this child, given all that we have looked at, what was your conclusion generally as to whether these were clinical or research activities at the Royal Free?
A I think these were research activities.

Q Do you have the same concerns in relation to the neuro-psychiatric assessment in this case by Dr Berelowitz, a psychiatric assessment by Dr Berelowitz, taking place after the investigative procedure were performed?
A Yes, there is no evidence that I am aware of that eligibility for inclusion in the research study was confirmed before the intensive invasive investigations were started.

MS SMITH: Sir, that concludes child 4, and I see it is almost ten to one and I suspect everyone is getting pretty tired so I wonder if that would be the appropriate moment to break for lunch.

Sir, if I may respectfully suggest, as I have when I was dealing with Professor Rutter, you may like to think about how many children’s cases you will face after the luncheon adjournment.

THE CHAIRMAN: I will come back to you with that answer when we resume.

MS SMITH: Thank you, bearing in mind, of course, that we are trying to stick to a timetable.

THE CHAIRMAN: Absolutely. We will now adjourn for lunch, and resume at ten to two. Professor Booth, please do not discuss this case over the adjournment, you are still in the middle of giving evidence.

(Luncheon adjournment)

THE CHAIRMAN: Good afternoon to you all and good afternoon to Professor Booth. Ms Smith, in answer to your question: we have been talking about it. The slight difficulty we have is not knowing, because I know there are some cases that you can take us through quickly because they are short cases, and then there are one or two others which are much longer cases, so would it be appropriate if we take stock in the afternoon break, then we will know exactly how we are feeling at that stage. One other factor we have to take into account is how Professor Booth is feeling. He has been giving evidence since yesterday morning and the time will probably come when he feels he has had enough for the day, so I think we will take stock in the break and take account of Professor Booth’s views as well.

MS SMITH: Thank you. (To the witness) I will turn now to child 6, and you will need the GP records and the additional hospital records. This is a case where, Professor Booth, you will recall that at the time of your original report we did not have all the relevant Royal Free Hospital records, but I think you have now had a chance to see the additional records, although obviously we cannot be sure that they are complete, so we have to treat them with some caution.

The referral letter is n the GP records at page 125. It is addressed to Dr Wakefield from the GP, dated 9 August 1996:

“Following our discussion over the phone the other day, [child 6] is a little boy with autism syndrome who does also suffer from bowel disorder. His mother is interested in entering him into your trial and I would be grateful if you could see her for discussion.”

As a result of that letter Dr Wakefield writes to Professor Walker-Smith and if you would go to the additional records, at page 2. this is a letter, dated 4 September, from Dr Wakefield to Professor Walker-Smith:

“Dear John,

I received this letter from a GP who has a child with autism and bowel disorder who may be suitable for our study and who, I am sure, would be appropriate to be seen by you in outpatients.”

Page 3 in those records is a letter dated 11 September to the GP from Professor Walker-Smith:

“I have been asked by Dr Wakefield to see [child 6] as I am the paediatric gastroenterologist associated with Dr Wakefield in our study on autism and bowel disorder. I have taken the liberty therefore of sending [Mr & Mrs 6] an appoint for [child 6]. I would be grateful if you could explain the situation to them.”

As far as that interchange of letters is concerned, the references to the child potentially being suitable for the study and Professor Walker-Smith’s letter to the GP talking about the study on autism and bowel disorder, is that consistent in your view with a normal clinical activity as opposed to a research activity?
A It implies very strongly that the patient is being referred for consideration for participation in a research study linking autism and bowel problems.

Q Professor Walker-Smith sees the child in outpatients, and we have got the records at page 38. They are difficult to read but I am sure someone will put me right if I get it wrong, but I think the relevant gastrointestinal symptoms are “abdominal pains and diarrhoea with blood in stools intermittently from 18 months. Blood and mucous” and I think … Sorry, these are extremely muddled, they start on page 38 and they go on to page 47, believe it or not, and I think, as I say, “From 18 months blood and mucous” and then I think it is “not fresh blood. Stools are usually soft” and then “not” and a word I cannot read but which could be “investigated”, “not investigated, has” and then going further down the page, “has abdominal pain at present”. We get a better note of that from what Professor Walker-Smith then wrote to the GP on 4 October 1996, which I think fairly faithfully reflects it, which is at page 6 in these notes:

“Many thanks for referring this boy, he certainly fits into the spectrum of a child diagnosed as autistic who also has bowel symptoms, as there is a history of recurrent abdominal pain and diarrhoea with passage of blood and mucous over several years. I am arranging for him to come in to have a colonoscopy and entering our programme of investigation of children with autistic problems.”

It then gives an admission date:

“In the meantime I have arranged for him to have simple screening for inflammatory markers. I will let you know the results in due course.”

As far as the symptoms that are exhibited in this case, Professor Booth, of abdominal pain with diarrhoea and the passage of blood and mucous over several years, would you agree that that is a presentation which suggests that a colonoscopy is indicated in this case?
A Yes.

Q As far as the picture that paints, is that a rather more classic one of the symptoms that you would expect to see in inflammatory bowel disease?
A Yes, it is.

Q Professor Walker-Smith had arranged inflammatory markers, but in view of that history, if he decided to admit for colonoscopy before the results of those blood tests had been obtained in any event would you in fact be critical of that?
A No, not at all.

Q Professor Walker-Smith writes to Dr Wakefield, and that is in the records at page 1. I should point out that the date at the top of the letter as 1995 is plainly a typographical error, as we can see from the last sentence of the letter, it should be 4 October 1996:

“I was very interested to see [child 6] in the clinic. This is a child who has been diagnosed as Asperger’s syndrome. In relationship to the MMR, he apparently had a measles rash a week before the MMR at the age of 15 months, but the doctor proceeded with the MMR injection. He had behaviour changes within a week although mother has only relatively recently associated the change of behaviour with the MMR. She also believes that he had a blotchy rash a week or so after MMR which lasted 2 days and she thinks was accompanied by fever and a cold. He subsequently was diagnosed as Asperger’s syndrome ... Mother is rather vague about precise details, but apparently he has had recurrent episodes of abdominal pain and diarrhoea with blood and mucous in his stool intermittently from the age of 18 months. She says she has seen several doctors about this. On examination his nutrition is good but he is clearly quite a disturbed boy. He fits well into the spectrum of children we need to investigate. I have arranged for him to be admitted …”

You have told us from Professor Walker-Smith’s point of view you are not critical of the decision in this case to perform a colonoscopy, Professor Booth, but does that erode overall the view that you have already expressed that he appears to be being admitted in the context of a research protocol nonetheless?
A Yes. The background to this is strongly suggested to be a research protocol. In this case you would be arranging to admit this child for further investigation, which would almost certainly need to be a colonoscopy irrespective of whether there was a research background or not.

Q He was admitted on 27 October until 1 November under Professor Walker-Smith, and in the light of the symptoms he was exhibiting and your views as to the colonoscopy I will not take you to the admission records, save to say that they echo the symptoms that you had already elicited in outpatients, is that correct?
A Yes.

Q A colonoscopy was indeed performed and the report of that is on page 43. This is one of the colonoscopies that was performed by Professor Murch:

“Endoscopic diagnosis: lymphoid hyperplasia of ileum. Low grade caecal and rectal changes on borderline of normality.”

Then we see that the other investigations which were intended, listed in the records at page 39. These are additional records in the middle of the page:

“MRI, EEG, evoked potentials on Thursday
Barium study tomorrow
Otherwise well.”

(written underneath it). We know that he underwent those investigations and the reports are available. There is an EEG report which I will not take you to, and there was a lumbar puncture on the same day because we have the CSF results. The clinical notes indicate that the child was seen by Dr Berelowitz with a letter to follow. That is on page 39 of the records. It is not very to see, but it is in the middle of the page:

“Seen by Dr Berelowitz, letter to follow.”

He is discharged from the Royal Free on 1 November 1996 and the procedures he had undertaken confirmed in the records, as I said, as being MRI, LP, EEG and evoked potentials. As far as that programme of investigations is concerned, does that fit with those described in the research protocol?
A Yes, it does.

Q With regard to Dr Berelowitz’s conclusions, there is not any report in the clinical record, but his conclusions are apparent from a later letter that Dr Wakefield wrote to mother and from Dr Berelowitz’s letter to Dr Wakefield and the assessment that he ultimately reached, which was some time after the submission of Asperger’s syndrome.

For the sake of completeness, it also appears that Dr Harvey saw the child at some point during the admission because he refers to it later on when he has some other dealings with the child. We can see that in the GP records at page 245. We do not know when, but we know he saw him because in 2001 get them him writing to the GP, Dr Harvey:

“When I was on the staff of the Royal Free I examined him neurologically at the request of my colleague, Dr Andrew Wakefield, who was investigating children with autism and the relationship with chronic inflammatory bowel disease.”

So he must have had the notes from the Royal Free with him then.

In addition to the investigations I have taken you to, there are also some neuropsychiatric assessments. You told us that the colonoscopy was, in your view, clinically indicated in the light of the symptoms. Does that apply equally to the barium meal and follow through?
A Yes, I think so, yes.

Q As far as the follow-up of this child is concerned, there is a very long history of follow-up and I am only going to take you to some signposts along the way. There is an outpatient’s appointment in November 1996 with Professor Walker Smith and after that a long discharge note from Professor Walker Smith to the GP. That is at page 10 of the additional records. That is apologising for the fact that there had not been a full discharge summary and setting out the general findings at that admission, saying that the child had been started on Olsalazine, an anti inflammatory, and indicating that he had not made any definite further appointment but that he would like to see Child 6 again at some point after the preliminary analysis of the results of the children with similar problems. We have further outpatient appointments with Professor Walker Smith in January 1997.

In the additional records at page 13, a letter to Dr Wakefield from Professor Walker Smith:

“This is just for the record to remind you that [Child 6] is on Olsalazine in a dose of 250mg three times a day. I am just starting his brother ...”

That is Child 7 who we have not yet got to, but, as you know, is one of the last of the 12:

“...on this because although the histology of the rectum was normal, he did have lymphoid nodular hyperplasia and it is at least worth a therapeutic trial as there is a continuing problem.”

Obviously I will ask you about Child 7 later, Professor Booth, but do you have any comments about Professor Walker Smith notifying Dr Wakefield as to the treatment that a child is being given?
A It would be normally very unusual for a clinician to write to a research histopathologist about changes in the patient’s management unless there was a joint research project being undertaken where patient outcome was of relevance to the study.

Q There is continuing involvement with outpatient appointments with Professor Walker Smith in July 1997 and January 1998, and then a letter to the GP from Professor Walker Smith at page 19:

“I reviewed [Child 6] again in outpatients. He continues on Olsalazine. Generally, his parents feel that this has had a good effect on his behaviour and he is overall more calm although recently there may be some deterioration in his behaviour. At the moment his mother’s main concern is that [Child 6] is incontinent and appears to have no control over his stools and this is obviously a considerable burden for her.”

Then he says:

“On examination the abdomen is soft and there are no palpable faeces but plain x ray of the abdomen does in fact show quite severe generalised faecal loading with distension of the rectum.

From a practical point of view the most difficult problem with this child is trying to achieve control over his constipation.”

He then goes through the steps that he has taken in relation to that. At the bottom of the letter:

“Dr Wakefield will be in touch in due course about the results of research and if there are any new problems emerging I would be happy to see the child again or give further advice about constipation. For the moment I have not given a further Outpatient appointment to be seen again in this clinic.”

That brought things to an end at that time. I should have read from the paragraph above:

“I do think in fact that further follow up should be done locally rather than here as basically we have nothing further to offer diagnostically.”

But there were, I think it is right to say, requests from the mother that the child continued to be seen at the Royal Free Hospital and a plan made to clear the bowel out for the constipation. If we turn to the additional records at page 64, we see the follow up continuing in May 1998 and again the Wakefield clinic stamp. Do you have the same comments as you made previously in relation to that stamp?
A Yes.

Q There is then an admission to the Royal Free for further management for constipation and to a preparation to clear out the bowel. I think I can just conclude it by saying that this child continues to be seen on and off by various people at the Royal Free Hospital until 2003.

If we turn on in the clinical records to page 68, there is a note by a clinician, who I think is a Dr Furman, at the Royal Free Hospital, and we see that that was an outpatient clinic in the Food Allergy Clinic. It concludes with the words “seen with Dr Wakefield today”, is that correct?
A Yes.

Q After that, if we look at the additional records at page 33, a letter to Dr Furman, Specialist Registrar in Paediatric Gastroenterology at the Royal Free wrote to the GP:

“I saw [Child 6] today together with Dr Wakefield. He was recently restarted him on Olsalazine which seems to have improved his behaviour. He requires 15 mls of liquid paraffin twice a day and sometimes this need to be increased....He continues to have some epigastric pain however.

Although he is still constipated and n view of the fact that he can not tolerate Picolax, he should continue on the liquid paraffin which should be increased from time to time.

On discussion with Dr Wakefield we have decided to give [Child 6] an open appointment and have not booked him for repeat follow up at this point.”

Does that inclusion of Dr Wakefield in outpatients clinics together with a paediatric registrar cause you concerns?
A Not automatically. Dr Wakefield may have been there because he was interested in this particular patient from his particular research perspective and wanted to find out what was happening. But what is concerning is that clinically relevant decisions about follow up were made with Dr Wakefield and I think that is an inappropriate activity for a non clinician to be undertaking.

Q Going on rather later into the history in October 2000, if you could turn to the GP records at page 331, this is a letter to Professor Neville, who is a paediatric neurologist at Great Ormond Street, from the GP in relation to the child having severe headaches and asking whether he would see him. The fourth paragraph down:

“He is one of the children who has been under the Royal Free and who has had his gut investigated and has the present of measles vaccine virus. The consultant involved in the research programme has rather frightened mum by suggesting that there is always a possibility of sub acute sclerosing panencephalitis with an insidious onset.”

Is that the SSPE?
A Yes.

Q That was an unknown childhood complication with measles:

“I am not certain whether that is a possibility, but given that the suggestion has been made and that [Child 6] remains unwell despite treatment for his migraine, I would be grateful if you could review him.”

Accepting that he does not identify the consultant involved in the research programme, as I must, nonetheless I would ask you, would you expect a researcher, as opposed to a clinician, having an involvement with the parents and making suggestions as to the particular diagnosis that might pertain to the child?
A I think this was Dr Wakefield who made the suggestion. He is referred to explicitly in other correspondence at 327.

Q Yes, you are quite right. This is a letter to consultant paediatrician at the Royal Alexander:

“I believe Dr LLoyd Evans of the Royal Free rang you regarding this autistic boy...”

He is the consultant developmental paediatrician at the Royal Free from whom we have heard:

“...who is suffering from recurrent moderately severe headaches over several months.

He was seen by Professor Walker Smith at the Royal Free who referred him to Dr Lloyd Evans, who rang me rather irately saying he didn’t want referrals from our local children for general paediatric matters.

I do see his point to some degree...

A neurology referral seemed a little excessive to me at the time but Andrew Wakefield who is the researcher into the MMR gut disorders spoke to me about him and suggested I needed to exclude sub acute sclerosing panencephalitis.

That seems rather dramatic to me but I am not an expert and therefore agree that he needs to be reviewed by someone who knows about these things.”

Repeating the question, again would you regard that as an appropriate role for a researcher who is not a paediatrician and who apparently has restrictions on clinical management of patients?
A No, it would not be appropriate and I think it is particularly inappropriate to apparently casually suggest to parents that their child might have sub acute sclerosing panencephalitis which certainly does begin insidiously but it is virtually a death sentence. Nearly 100 per cent of children are dead within three years of the diagnosis having been made.

Q That is a complication of measles?
A Yes, measles viruses identified in the brain.

Q I think I should go on to say that Professor Murch, in particular, went on being involved in the care of this child and, just to remind the Panel, this is the case where, ultimately, he, Professor Murch, go to XXX to see the child because there are concerns being expressed in relation to the myriad symptoms that the parents are reporting.

I have asked you what your overall view was about whether this was a research programme and you told us that, in your view, the admission was in relation to a research programme even though there were clinical indications for a colonoscopy. Again, is there any evidence that you could see of a diagnosis of disintegrative disorder being confirmed before the invasive investigations were carried out?
A No, I could not find that evidence.

Q That is all I have to ask you about [Child 6]. I am going on to Child 9. You will need local hospital records volume 2 and the Royal Free records.

THE CHAIRMAN: Is this volume 2?

MS SMITH: Local records volume 2 and the Royal Free records. Do you have your report on this child, Professor Booth, Child 9.
A Yes, I do.

Q Are you ready to go ahead?
A Yes.

Q Turning to the referral documents in the local hospital records at page 182. This is the letter to Dr Spratt, the consultant paediatrician, from Professor Walker Smith dated 11 September 1996:

“Dear Clifford

We have recently become aware of a syndrome of enteritis disintegrative disorder and autism. We have in fact investigated two children so far and during treatment they both had evidence of bowel inflammation. Whether this relates to Crohn’s disease or whether it is related to measles immunisation or measles itself is quite unclear. However, I have heard from Dr Wakefield that there is a child called [Child 9] who is resident in XXX whose parents would be quite keen for us to investigate the child in our protocol. I am just wondering whether you think this is at all appropriate. If you felt it appropriate, I would be happy to see the child. Just in case you may be interested, I am enclosing a copy of Dr Wakefield’s detailed proposal. I look forward to hearing your comments.”

Attached to that letter, as you know, between pages 183 and 203 is the scientific protocol in almost identical terms to that submitted to the ethics committee. Is this, as far as you are concerned, a normal way, a usual way, in which a clinical referral to another centre comes about?
A No, it would be very unusual.

Q Can you just tell us what is unusual about it?
A Normally the referral, the request for the patient to be seen in the tertiary centre, goes in the opposite direction, so it goes from the general paediatrician to the tertiary specialist.

Q Yes?
A It is pretty unusual for a tertiary specialist to request a patient to be referred.

Q Given the terms of the letter and the inclusion of the research protocol with it, does it point to you towards research or clinical activity?
A Towards research activity.

Q Dr Spratt responded to that letter, and his reply is at page 181. It is dated 25 September 1996.

“Thank you for your kind letter of 11th September, and enclosures.

I would of course be very pleased to have your opinion of [Child 9]’s distressing case history, and to take your advice about his proposed referral to Dr Wakefield’s service.

If convenient could I suggest you send his parents notice of a clinic appointment or short-stay admission to your ward – as you prefer – directly?”

There is no reference in that letter to gastrointestinal symptoms. Even given the circumstances in which the referral came about, which you dealt with, do you regard that as being an unusual omission?
A You would normally expect the paediatrician, who knew the patient, to provide some clinical details. It is a little surprising that Dr Spratt did not define what symptoms his patient had that made him think that the patient would be suitable for this research study.

Q Yes. If Dr Spratt had had concerns about gastrointestinal symptoms – himself had concerns about them – would you have expected him to enumerate them?
A You would have expected him to, yes. It may be that he felt that his patient exactly fitted into this syndrome of enteritis and disintegrative disorder, although I have to say at this point that these patients were being seen, I am not aware of any evidence that any patient in the study did have enteritis or disintegrative disorder.

Q We can gain a little insight into Dr Spratt’s views on that particular subject if we go back a little in time, because Dr Spratt wrote to Dr Cavanagh, who is the consultant paediatric neurologist at the Chelsea & Westminster Hospital, referring to an earlier letter from Dr Cavanagh following a previous admission to the Chelsea & Westminster. In the earlier letter, Dr Cavanagh had suggested a referral to Professor Walker-Smith in fact for further investigation of B12 impairment. That is 1995, ten months before the letters we have just been looking at. That is at page 206 and you see there, it is advised that he be referred to Professor Walker-Smith for further investigation of his impaired B12 absorption abilities. In fact, that never happened. If we then look at the letter in response, which is a very much longer letter, it is at page 205. We see it starts with an apology for the time lapse between November 1995 and September 1996.

“Dear Nick

I had intended to acknowledge your note to [Child 9]’s family doctor last November and apologise for my oversight now.

In the meantime John Walker-Smith has been in touch with me and I have invited him to see the boy and his parents soon. To the best of my knowledge he has never had any bowel symptoms and notwithstanding his very restricted diet of a few years ago I am not convinced he inhabits even the borderland of gastroenterology. But John will decide.

As you may know I do not see [Child 9] any more here and I wonder if he is still attending with you in London. Could you confirm – and in passing let me know whether or not you came to accept the clinical diagnosis of autism in his case? I would be most grateful.”

So that seems to suggest that at least when Dr Spratt was seeing the child, he was not convinced of his having bowel symptoms?
A Correct.

Q And going back to the question I was asking you before, Professor Booth, he made this referral, obviously, and we have seen the circumstances in which he did it. Can I ask you again, does that point to a clinical or a research intent?
A Dr Spratt was of the view that this patient did not have gastrointestinal disease, and would indicate that he was referring Child 9 on the basis of consideration for inclusion in a research study on enteritis and disintegrative disorder?

Q Yes. As a result of Professor Walker-Smith contacting Dr Spratt in the circumstances we look at to begin with, the child was seen by him in outpatient clinic, and the notes are at page 17 in the Royal Free Hospital records. We see the reference, as best I can read it, towards the bottom of the page in relation to gastrointestinal symptoms:

“Screams ? pain in abdomen”

And then there was reference to chocolate, and then “on floor” in inverted commas, which is obviously a description that was given of his response to that.

“From age of 2 yrs – one loose stool & has had undigested food. We cut out foods from diet.”

Professor Walker-Smith then wrote a little more detailed account, or a clearer one, of the symptoms. Before I go on to that, it does not appear that at that outpatients clinic any inflammatory markers were ordered, any screaming tests were done for inflammatory markers. Is it your view that those should have been carried out in this case?
A I think if you were entertaining a possible diagnosis of inflammatory bowel disease in the presence of symptoms that were by no means typical, and you were considering a colonoscopy, it would be appropriate to check the inflammatory markers first before coming to definite decision.

Q We have seen exactly what the symptoms were set out to be. Would you go to page 36 in the Royal Free records. This is Professor Walker-Smith’s letter back to Dr Spratt, dated 8 November.

“Dear Clifford

I duly saw [Child 9] in outpatients. From a gastrointestinal point of view it is interesting that he does pass 1 loose stool a day which in fact seems to be his pattern from the age of 2. He also has screaming attacks which are clearly related to food which his parents attribute to abdominal pain, it is difficult to interpret this. As you know his diet has become severely limited but despite this he is gaining weight and growing to above average with height and weight both above the 90th centile. We have now seen several children with autism and gastrointestinal symptoms, all of whom on gastrointestinal investigation have proved to”

- and I think it should be “have” –

“some kind of bowel inflammation. It is quite difficult to relate this directly to autism. Dr Wakefield as you know, believes that immunisation may play some part, although I remain neutral on this issue for the moment. However the parents are keen that we should endeavour to investigate [Child 9], and I have therefore arranged for him to come in to have a colonoscopy. He will be admitted on 17th November we will then … endeavour to follow this by barium meal and follow through and also to do a repeat lumbar puncture. We will let you know the results of these investigations.”

It is clear from that that Professor Walker-Smith was aware, as indeed was the case, that this child had already had a lumbar puncture during his admission to the Chelsea & Westminster in 1995. He is making a decision to admit this child, both for that investigation and for gastrointestinal investigations and colonoscopy and a barium meal and follow through. In the light of the history that he had elicited from the parents of one loose stool a day and query abdominal pain, but difficult to interpret, do you think that decision to admit for those investigations was consistent with clinical care?
A No, I do not think a colonoscopy or a barium meal would be the first line investigations that one would carry out in a patient with no symptoms. There would be other investigations, less invasive, that you would do first.

Q The screening tests that you have already referred to?
A It would include those screening tests, but there would be other investigations as well.

Q What kind, Professor Booth, are you referring to?
A You would probably carry out some blood tests, which would include the inflammatory indices. You would perhaps carry out a screening test for coeliac disease. You may well check stool culture, and microscopy for Giardiasis. You might also submit stool for looking for excess fat in the stool and carry out some tests on the stool to look for pancreatic disease. There would be a number of non-invasive things that one might well do before proceeding to a colonoscopy in this particular patient.

Q You say “one might well do,” and of course there must always, one assumes, be some difference of opinion between clinicians. Are you actually critical of the decision that was made not to undertake any further investigations save for the invasive ones you have referred to?
A Yes. I cannot really on the basis of the clinical presentation, understand the undue haste for carrying out a colonoscopy.

Q The child was admitted, we know, from 17 November till 22 November. I have already been to the records which indicate that that was under the care of Professor Walker-Smith. He was admitted indeed for a colonoscopy, and we can see that from the record at page 7. We see:

“6 yr old [admitted] for Colonoscopy.”

I think the next line is a reference to a B12 deficiency. Is that correct? I am sorry – are you with me?
A Sorry. Page 7?

Q Yes.
A “Admitted for colonoscopy.”

Q Yes. Underneath that is a B12 deficiency?
A Yes.

Q And query “autistic behaviour” and “? diarrhoea”. There are the consent forms that I have asked you about before – consent form for research biopsies and a consent form for colonoscopy under sedation in the terms that you have already described as being standard. Then we have the colonoscopy report at page 73. This is one that was carried out by Dr Thomson, and we see:

“Histology not taken.

Disintegrative disorder. No abnormality up to terminal ileum except for a small area at the hepatic flexure which was erythematous. There was a small increase in the size and number of prominent lymphoid nodules.”

Then the clinical notes after the colonoscopy set out rather more history. We go back to page 9. As I say, we must remember, this is after the colonoscopy. Look at the middle of the page:

“Loose stools around the age of 2 – 3Y [years].
1 stool / day No blood, No mucous.
? Abdominal pain. Screaming episodes which last 10 – 30 minutes.
Thriving well.”

If we go on in that note to page 11. At “colonoscopy” we see bloods and then the indication that they are to be in accord with the protocol. Lumbar puncture, and then the words:

“Parents refused lumbar puncture.
Colonoscopy normal
No blood results so far”

And lastly:

“Barium follow through.”

Given that you are critical of the decision to carry out a colonoscopy at all, but we know it was normal, was there any reason that you can see for proceeding to a barium meal and follow through?
A No. I do not think I would have done. I cannot see any indication for doing a follow through.

Q And with regard to the blood tests which were subsequently reported, there is a full blood count at page 82. It is the column which is headed “18 November”, Professor Booth. Can you tell us what the results convey to you?
A Yes. The ESR is normal; haemoglobin is normal. The white count is normal. The MCV, I think that must be a recording error: the normal range would be 72, 74, up to about 90, so 6.1 is obviously a problem, unless it is 61, which would be very low, Platelet count is normal. So those are the inflammatory indices that were measured, and they were normal.

Q But, of course, measured subsequent to the colonoscopy ---
A Yes.

Q --- rather than as a screening procedure before it. Then continuing with the chronology of the admission, we see that a barium meal was carried out. Would you go back to page 11 at the bottom of the page:

“Barium: [Normal] terminal ileum [normal]”

A Yes.

Q And the child was discharged on 22 November. There was subsequently some histology findings after the discharge. At page 48, which is the histopathology report we see the two descriptions at the bottom of the page:

“Specimen I: Small bowel mucosa showing no histological abnormality.

Specimen II-VII. Large bowel mucosa showing prominent lymphoid follicles but no histological abnormality.”

Then we have the notes of the histology meeting. This is when, as we have already discussed, the histology report is discussed between the histopathologist and the clinicians.
That is at page 48a. You will see child 9 is No. 8 in that list and the consensus apparently was that there was nothing abnormal detected.

That is backed up again by the clinical records at page 8 which indicate the histology again, “No active inflammation: no crypt distortion.” That was the position that was reached as far as the histology was concerned.

Then there was a second admission, which was on 9 December 1996, and again I will not take you to it, you have been to it on a number of occasions before but the child was admitted under the care of Professor Walker-Smith, and if we look at the clinical notes at page 12 we see the reason for that was: “Readmitted for MRI, lumbar puncture, bloods” and then the MRI was said to be under general anaesthetic: “Basically well – autism.”

There was a consent form for both those procedures, MRI and lumbar puncture under general anaesthetic, I would like to look at this one, which is at page 44: again, is that a standard consent form as opposed to a research consent form?
A Yes, it is the normal standard consent form.

Q The child also had an EEG. I will not trouble to take you to that (it is at page 86 of the Royal Free records if anybody wants the reference) and we know that he also had a lumbar puncture because we have the cerebrospinal fluid results at page 53 of the Royal Free records. Then the child was discharged home.

I want to now revert to the issue of the histopathology. Professor Walker-Smith then wrote to Dr Spratt, and the letter is at page 33, dated 31 December 1996:

“Dear Clifford,

[Child 9] was duly admitted. Endoscopy revealed a marked increase in size and number of prominent lymph nodes in the terminal ileum, i.e. lymphoid nodular hyperplasic. The colon was endoscopically normal except for an area at the hepatic flexure which was slightly erythematous.

Histologically there was an increase in chronic inflammatory cells throughout the colon with a moderate increase in intra-epithelial lymphocytes.

Other investigations were however normal and are being collected and you will have a discharge summary soon.

Our diagnosis is indeterminate colitis with lymphoid nodular hyperplasia.

A therapeutic trial of Mesalazine (Asacol) may be worthwhile.

We have now studied seven children all of whom have had some evidence of enterocolitis and disintegration disorder following MMR. Two of these may have Crohn’s disease. One of these has improved significantly on enteral feeding.

Clearly this is a difficult group of children and our work is only beginning but we will keep you informed.

I wonder if you have seen any other similar cases in XXX.”

If we can just remind ourselves, Professor Booth, if we go back to the clinical histology report at page 48, that indicates no histological abnormalities.
A Correct, yes.

Q As you know, it also indicates on the next page, 48a, that when the matter was discussed between the clinicians and the histopathologists nothing abnormal was detected. In the light of that, is the statement that is made by Professor Walker-Smith in the letter on page 33 -

“Histologically there was an increase in chronic inflammatory cells throughout the colon with a moderate increase in intra-epithelial lymphocytes.”

- consistent with those findings that are documented in the records to which I have just taken you?
A They are directly contradictory statements.

Q Is the reason for that contradiction and that change in histological description and the consequent change in diagnosis apparent from any of the other clinical notes?
A No.

Q This is similar to the situation that has already arisen and we have already dealt with today in the case of child 4. You have already addressed the next question that I am going to ask you but at the risk of being tedious I ask you again, would you expect the reason for this apparent change in histological descriptional diagnosis to be ascertainable from the clinical records for the child?
A Yes, it is not clear why this change was made. It is a relevant change because it appears to have led to an indication for using an anti-inflammatory agent so it is not a minor discrepancy, it is a complete change in the interpretation of the biopsies.

Q It is contained, of course, in the letter which is being sent to the general paediatrician who has referred the child. Is it important for a doctor who has referred the child, albeit apparently referred at invitation, to understand why it is that the tertiary referral centre has come to a conclusion and given a treatment?
A Yes, probably but I think it is more important for the inpatient record for the series of decisions that have been made about the histology to be available. I think that if there are changes in interpretation within the hospital they would not necessarily all have to be communicated to the referring paediatrician or the GP but I think it is important from the point of view of the patient record that they are trackable. You may be referring to a completely different patient, for example, in the letter to the paediatrician, we just do not know.

Q You have already told us that weekly histology meetings are a common occurrence in gastroenterology departments, with communication between clinician and histopathologist. We see that that did not yield a different interpretation because that also records a normal conclusion, so can you see any way at all how this diagnosis has fetched up being made?
A Presumably someone or some other people have had a further look at the slides by themselves and come to a separate conclusion.

Q If we go to – and this is the same exercise that I did with child 4 – FTP2, The Lancet paper so we can see what the description was there, that is page 784, it is the same table and if you run your finger down to child 9 you will see the description is “chronic non-specific colitis; reactive ileal and colonic lymphoid hyperplasia”. That is obviously inconsistent with the clinical histology findings as we have seen them in the records where there is a report of normality, is that correct?
A That is correct, yes.

Q But as I mentioned in the case of child 4, Dr Davies’s evidence, the clinical histopathologist, was that the description in The Lancet resulted from a more detailed research analysis, in contrast to the clinical analysis that had been undertaken previously, and Professor Walker-Smith’s subsequent histological description to Dr Spratt of indeterminate colitis with lymphoid nodular hyperplasia, does that fit with the research analysis as reported in The Lancet?
A Well, chronic non-specific colitis could be used as a synonym for indeterminate colitis, yes.

Q And …
A And the lymphoid nodular hyperplasia.

Q Again we dealt with this with child 4 but do you have the same concerns in relation to research findings driving treatment?
A Yes, as I have said before, I think occasionally research findings are perfectly valid in changing treatments but it is important that everybody understands why those changes have been made and that the person or people responsible for coming to that conclusion are clearly identified, for the same reason that histopathologists sign their reports, and radiologists sign their reports, for example.

Q Returning to the subsequent history, we go on to Professor Walker-Smith’s letter, you will recall, indicating a diagnosis of indeterminate colitis and then Dr Spratt replied to this letter at page 29, thanking Professor Walker-Smith for his letter:

“Clearly your findings are interesting and I shall be pleased to take your advice about the details of any useful therapeutic trial of mesalazine in [child 9]’s case. Please let me know.

For my part I have no evidence to link the little boy’s history of severe developmental delay and learning difficulties within a significant gastrointestinal history – nor, indeed, for that matter, his receipt of immunising agents in his first two years of life. I shall of course be interested to follow his gastrointestinal story from a bit of a distance in future months/years and to learn more of your research in due course. In particular, the source of your control material for the studies you are undertaking at the moment.

In an historical way would also be grateful for your opinion about the boy’s present and likely past vitamin B12 status – in the context of what I interpret as likely fairly mild terminal ileal inflammation, long-running significant dietary ‘deficiency’ and the general cognitive characteristics which I at least without any semantic allegiance have considered a form of autism.

If you could respond with reference to trial use of medical treatment soon I would be most grateful. I will take your further reply as my cue to try to re-establish clinical contact with the little boy’s parents and their family doctor in XXX.”

So that was the reply, and we then have following on from that a discharge summary at page 31 repeating the diagnosis of autistic spectrum, indeterminate colitis and lymphoid nodular hyperplasia and setting out his history and indicating the investigations that he had had, or some of the investigations that he had had:

“All his investigations were normal except very high lead level … I’ll be obliged if you can repeat this. As part of the investigation protocol he also had an MRI of his brain, which was normal.

In summary, the gastroenterological investigation suggested a diagnosis of indeterminate colitis and lymphoid nodular hyperplasia. A therapeutic trial of Asacol may be useful. We have not arranged a follow up appointment for the moment.”

I say “some of the investigations” because there is not in that letter a reference to the lumbar puncture, I think I am right in saying, that was undertaken.

The very briefly the follow up, again there are quite a number of letters, particularly from Dr Spratt to Professor Walker-Smith both giving and seeking information. We can see the first of those letters, January 1997, page 28, which is the response to the letter that I have just read:

“I am afraid I cannot answer your query about his likely past vitamin B12 status as I find this confusing. However, I would now recommend a trial of Mesalazine …”

– that is the anti-inflammatory, is that correct?
A That is correct, yes.

Q “I will be interested to hear if there is a response”. Thereafter there is a lengthy correspondence. In May 1997, the local hospital records volume 2, page 171, a letter was sent by Dr Spratt to Dr Smith, the GP, in relation to the sulphalazine saying his physical growth has been impressive:

“I am sure no-one would expect him to be a small fellow; but given at least his nutritional – if not also his suspected gastrointestinal – history he looks good value for his no doubt excellent general care. Nor, you will be pleased to know, is he showing any clinical evidence of ill effects due to the use of his new medication.

His parents report no overt change in his bowel habit to date either. He still passes one stool of unpredictably variable consistency most days.”

Then at page 170 in the same bundle, blood tests were taken, and in the middle of the page says:

“I am obviously unsure where to go from here and will write to Professor Walker-Smith (with the lead result) soon. Logically since the diagnosis of [child 9]’s colitis was achieved by laboratory means – in the virtual absence of symptoms – his follow-up should involve endoscopy and re-biopsy at a convenient time. And yet that might take us even further away from the reasonable limits of clinical medicine and the interests of the child. I really don’t know. I wonder have you got a view?

Assuming normal laboratory data later this week I have not asked to meet again routinely.”

Then he writes to Professor Walker-Smith in relation to the high lead levels and does ask if he wants him to have another colonoscopy and that is at page 64. The rest of the letter deals with the blood test results and the last paragraph reads:

“Could you also advise whether to carry on with anti colitic therapy as the boy has never had specific gastrointestinal symptoms and neither his bowel habit nor his autism seems to have altered in response to his use of medication over the past three months. Would you want him to have another colonoscopy and biopsy at a future date. Please let me know.”

Professor Walker Smith’s response to that at page 163.

“I have discussed the situation with Dr Andy Wakefield. If there has been no change in symptoms on Sulphasalazine therapy, I would stop the drug. Ideally perhaps one would consider repeating endoscopy but without any symptomatic improvement this does not seem to be relevant. Later on as our knowledge of this disorder develops we may indeed need to repeat endoscopic and biopsy studies.”

He then deals with the lead levels and asking whether the child has a PICA.

“Sorry not to have been of more help. I would be interested to hear from time to time about [his] subsequent progress.”

What are your comments on that interchange of correspondence as far as whether this is research or clinical medicine?
A I think Dr Spratt thought that his patient was taking part in a research project. He referred in one of his letters to Professor Walker Smith to trial use of medical treatment, for example, and his views on the virtual absence of gastrointestinal symptoms, and yet the patient being extensively investigated, including colonoscopy, would fit, I would think, more with his view that this was a research study rather than investigations carried out on this patient on the basis of clinical need.

Q Is that a view you share on the basis of the documents you have seen?
A Yes.

Q As far as page 163 is concerned, the letter indicating a discussion of the situation with Dr Wakefield, when Professor Walker Smith is asked whether this child should be taken off anti inflammatories or left on them, would you expect Professor Walker Smith, as an experienced clinician, to be making decisions in conjunction with Dr Wakefield if Dr Wakefield’s role is solely research?
A No, it is most puzzling.

Q Are you critical of it?
A I cannot think of a clinical circumstance where Professor Walker Smith would need to discuss with someone like Dr Wakefield, as a non clinician and histopathologist, whether to continue with an anti inflammatory treatment.

Q I will not take you to the rest of the correspondence, save to say there is continuing correspondence between Professor Walker Smith and Dr Spratt, certainly until the middle of 1998. Overall, you have indicated to us that you feel that the gastro intestinal investigations are research motive rather than clinical motive. Is that correct?
A Yes.

Q Again the question I have asked you before, there does not appear to have been any neuropsychiatric assessment prior to the colonoscopy being carried out on this child. Are you, for the reasons you have already given in relation to the previous patients, critical of that?
A Yes, I have not been able to find any evidence that a preliminary assessment was carried out before colonoscopy.

MS SMITH: Sir, that brings me to the end of a child and I see it is 3.15 pm. I wonder whether that would be the moment for us to have a short break?

THE CHAIRMAN: I think before we take a break, can I ask Professor Booth at this stage, how do you feel for this afternoon now? Do you feel you would wish to continue?
A Yes.

THE CHAIRMAN: Would you be able to deal with one more child?
A Yes.

THE CHAIRMAN: It is now 3.15 pm. We will adjourn and resume at 3.25 and, hopefully, we will be able to take one more child after that and then Professor Booth will take some rest. Thank you.

(The Panel adjourned for a short while).

THE CHAIRMAN: Ms Smith.

MS SMITH: We turn to Child 5. The Panel will need the GP records and the Royal Free records. I am going to go through them in the same way with Professor Booth, with the referral and then the admission, then your comments on the clinical indication. Page 106 of the GP records please. This is a handwritten note from one of the partners in the general practitioner’s practice to the other. It says:

“Re [Child 5]

Dr Wakefield consultant gastroenterologist Royal Free rang and gave very lengthy and convincing case for [Child 5] to be referred to Professor John Walker Smith as they have findings suggesting there is an association between inflammatory bowel disease/enteritis causing a failure to absorb B12 which is needed to myelinate till age 10 leading to neurological problems and autism.”

Is that a little thumbnail summary of the science in the ethics committee application you may not recall it?
A I cannot just remember about the B12, but, essentially, yes, I think so.

Q
“Measles vaccine may be implicated but that is being researched and uncertain of implications. Anyway – see fax – parents are keen – will you refer – presumably is extra contractual.”

As you know, I am going to be asking you questions about the methods of referral overall when I ask you later about descriptions in The Lancet article, but at this stage can I ask you, as I have asked in respect of the some of the other children, is that in your experience a normal way for a clinical referral to start off, with a telephone call from the tertiary referral centre giving a lengthy and convincing case for referral?
A No, it is very unusual.

Q In the GP notes there is a further note by the GP, Dr Shillam, simply saying that there was to be a referral to Professor Walker Smith by Dr Wakefield and the information set out again. He writes, Dr Shillam to Professor Walker Smith, on page 105, on 1 October 1996:

“This 7¾ year old autistic child’s parents have been in contact with Dr Wakefield, and have asked me to refer him to yourself regarding your current study into association between autism and childhood bowel problems.

[Child 5] has presented with developmental delay, and severe communication problems and autism was diagnosed when he was three.”

It sets out the difficulties in his behaviour. It then says that he has been seen by a consultant clinical psychologist, consultant paediatrician, child guidance clinic and another consultant psychologist at the Oxford Radcliffe Hospital. Then it says:

“His parents are concerned about an association they have read in the ‘Daily Mail’ between MMR vaccine, childhood enteritis and possible brain damage. [Child 5] had his MMR vaccine on 10.04.90. He did not have pertussis vaccine, but received three doses of diptheria, tetanus and polio followed by another dose at 3½ years.

Thank you for seeing this child.”

Again, given that this is a referral to a paediatric gastroenterologist, is there anything striking to you about the symptoms, or lack of them, that are communicated in that letter?
A The striking thing is the absence of any gastroenterological symptomatology.

Q In your experience as a gastroenterologist receiving referrals of this kind on a regular basis, is that an uncommon occurrence, to receive a referral letter containing no reference to GI symptoms?
A Yes, it is very uncommon and you would wonder if the letter had been addressed to the right consultant.

Q Just one thing in passing on this letter, and I could have asked it about any of the others we have looked at so far, it may not have any mention of gastrointestinal symptoms, but is it a reasonably detailed letter in terms of its length?
A Oh yes, it provides quite a lot of information in the second paragraph about his symptomatology and who he has also seen in the third paragraph, so it is not by any means a sort of sketchy, skimpy referral letter.

Q Professor Walker Smith replied and he simply indicated that he would be pleased to see the child and arranged for an outpatient appointment. He did attend an outpatient’s appointment. That is on page 40 of the Royal Free records. Again, I think the gastrointestinal symptoms started just over half way down the page where we can see it says that the child has bouts of diarrhoea, that he has been treated by Dr Bricher with Nystatin which makes him constipated and then it says:

“He has one soft stool a day and episodes of diarrhoea once a month.”

I am sorry I missed out, inadvertently in the line above, a reference to abdominal pain. I cannot read the rest of it but there is a reference to abdominal pain as well as to bouts of diarrhoea. What is Nystatin, what is that treatment for?
A It is a medication for infection with candida, sometimes known as thrush.

Q After that outpatient’s appointment Professor Walker Smith wrote to Dr Shillam, the GP, and we can see what he elicited in terms of history rather more clearly. That is at page 361:

“Many thanks for referring this child with autism and disturbed behaviour. He demonstrated how difficult his behaviour can be when I saw him in the clinic and we did not proceed with any blood tests. He has a number of episodes which have been interpreted as abdominal pain when he draws up his legs and appears to suffer from abdominal pain. He has intermittent episodes of diarrhoea which apparently responded in part to Nystatin which has been prescribed over the past year. Several of these children with autism have had gastrointestinal symptoms and on investigations have proved to have gastrointestinal pathology. I am arranging for him to come in for a colonoscopy on Sunday 1 December 1996.”

It appears that blood tests were considered by Professor Walker Smith, but they were not proceeded with because of the difficulties in this child’s behaviour and then he proceeded in any event to arrange a colonoscopy. What was your view as to that course of action?
A First, it is a lot easier for the patient and the doctor to have blood tests than it is to come in for a colonoscopy, so I cannot quite understand, if the feeling was that blood tests were indicated, why they were abandoned and a colonoscopy carried out anyway. Secondly, the symptoms that this patient had would not immediately suggest that a preliminary investigation, the first thing you would do, would be a colonoscopy.

Q In those circumstances, do you think a blood test should in fact be carried out?
A I think if you are undecided whether or not the patient may or may not need a colonoscopy because the symptoms are not typical of a colitic illness, you would certainly want to do some blood tests and, as I said, it is more acceptable to the patient to have a blood test than it is to have a colonoscopy.

Q Then the child is admitted to the Royal Free on 1 December. We can see the reasons given for that on the endoscopy clerking sheet on page 456. We see the reason for the procedure is for autism and behavioural problems, recurrent abdominal pain and diarrhoea and to rule out gastrointestinal pathology.

There are consent forms and, again, if anybody needs to refer to them, they are page 457 and page 458, a consent form for a diagnostic colonoscopy and for research biopsies. Then we can see a clinical note at page 38. It says at the top of page 38:

“Autism : Since 2 years
Diarrhoea
Abdominal pain on and off since last” – I think it is – “6 years”.

Then turning over to the next page:

“Diarrhoea: Having bouts of diarrhoea off and on since he was”

– and I think that is “4 years old.”

“No blood or mucus in the stool.

Abdominal Pain: Having episodes last 6 years when he suddenly clutches his abdomen and”

– I think it is “groans”.

“Lasts for about 10 minutes to one hour.”

That was the other indication of the symptoms that the child was suffering from. Then there is a colonoscopy report, page 424. This one is one that was carried out by Dr Murch.

“Colonoscopy for investigation of autism with diarrhoeal features. There was mild proctitis, with a granular mucosa and loss of vascular pattern, but no friability or ulceration. The colon was normal throughout otherwise, while the caecum showed patchy loss of vascular pattern without ulceration. There were prominent follicles in the ileum, but not sufficient to call lymphoid hyperplasia. The ileal mucosa appeared fully normal.”

Without labouring the point, Professor Booth, do your same views apply in relation to the responsibilities of Dr Murch as the endoscopist carrying out the procedure?
A Yes.

Q Blood was taken on that same day, and the results were reported, but it would appear that that was after the colonoscopy had been undertaken. They were actually subsequently reported in the discharge summary. Perhaps I can just go to that and ask you just what they showed rather than to the actual record. It is page 351, I think. Please go to page 352. Can you just tell us, as far as those blood results, as I say, which were undertaken, but were undertaken after the colonoscopy, what they indicate as far as the inflammatory markers were concerned?
A The CRP is normal. The haemoglobin is normal. Platelets are normal. White count and ESR are normal.

Q So no indications of inflammation?
A No abnormality.

Q Just returning to the history of the admission, the next thing was on 2 December, the day after admission, the Royal Free Hospital records at page 453, there was a request for an EEG. It is signed by Dr Wakefield and requesting an EEG and evoked potentials. The reason given was disintegrative disorder and autism. You have already indicated in general terms the consequence of being the doctor who signs a request for an investigation, and your view on Dr Wakefield ordering such investigations. Are your observations the same in this case?
A They are the same, but just an additional observation; that Dr Wakefield appears to be one of two responsible consultants now for this patient.

Q Do you base that on the request source?
A Yes.

Q The indication?
A It says “Consultant”.

Q Which says “Harvey/Wakefield”?
A “Harvey/Wakefield”.

Q Are you critical of him apparently awarding himself that status?
A Yes. My understanding is that he does not have clinical consultant status at the Royal Free at that time.

Q Then returning to the history of the admission, we know that on 3 December – so that is after the colonoscopy – Dr Berelowitz sees the child. You need not go to it, but just for everyone’s records, that is in the Royal Free records at page 9. Then he writes the next day to Dr Wakefield, and the letter he wrote is on page 354, which I would like you to turn to. It is to Dr Wakefield.

“Dear Andy,

Thank you for asking me to see [Child 5]. I saw his mother and observed [him] briefly on 3rd December 1996.”

It then sets out the history and says he was diagnosed as autistic at the age of three, and that Dr Berelowitz thinks that the likely diagnosis is a developmental disorder such as autism. He says:

“However, I thought he was a slightly unusual looking child and so obviously the usual chromosomal studies need to be done.”

And on the same day as that letter, 4 December, there is a histopathology report, which is at page 429. It sets out the various specimens that were taken.

“Microscopic Description

Specimen I consists of fragments of small intestinal mucosa which includes lymphoid follicles but which is without pathological abnormality.

Specimens II, III & IV are large bowel mucosa fragments with normal crypt architecture. There is at best a minimal increase in chronic inflammatory cells within the superficial lamina propria. No active inflammation is seen.

Specimens III & IV show minor crypt architectural distortion including occasional bifid forms. Paneth cell metaplasia is not seen. No excess chronic inflammatory cells are seen. A very occasional polymorph is seen within surface crypt epithelium. No ova granulomas or parasites are seen in any of these biopsies.”

And the comment is:

“Large bowel series; minor changes the significance of which are uncertain but do not amount to the diagnosis of inflammatory bowel disease.”

That was signed by Dr Davies. Before I go to the handwritten note on that, would you just keep your finger in that, we have the notes of the histology meeting at the hospital on 6 December. That is at page 430a, the next page. Child 5 is the first. We see that Dr Davies has written by his name, “Measles – minor”.

MR MILLER: Sir, I apologise for interrupting. I think we have to be careful about this line of questioning because my recollection of Dr Davies’ evidence was that she could not say whether or not she had written that before the histology meeting or after the histology meeting. That applies to the previous child to whom this witness was taken. We will have to look at the transcript, perhaps overnight, but my understanding was that she said she could not say when she had written it. It may have been in preparation for the histology meeting rather than as a result of it. Just for Mr Evans, it is page 5, Day 32.

MS SMITH: Would you just excuse me for a moment? (After a pause) I am sorry, sir. The point I was just trying to ascertain was a previous case to which Mr Miller has referred, there was actually a note in the clinical records of the histology meeting making the same point as is on the histology meeting list. I accept the point in relation to this one, where there is not a histology meeting in the clinical records as well.

On that note, can I turn back, please, to the manuscript note that has been written at page 430, Professor Booth?
A Yes.

Q
“NB. Report when seen by Prof W.S. [Professor Walker-Smith] – seemed to be more significant inflammation than indicated”

- I think that is -

“in this report.”

Is that correct?
A Yes, yes.

Q You have told us already that it is known, although unusual, to reach a different conclusion than was originally reached in the histopathology report. In these circumstances, where there is a clear explanation on the face of the records, that an identified someone – Professor Walker-Smith – on looking at these thought that there was more inflammation. I think it is right that you do not, in fact, criticise that change?
A No, absolutely not. It is clearly recorded in the clinical record and it is clear who has made that decision, and it is appropriate for Professor Walker-Smith, if he felt that that was the case, to come to that conclusion.

Q Returning to the chronology, the child subsequently, on 5 December, was seen by Dr Harvey. That is on page 39. We just looked at that before for the note above. He simply reports that as far as he can get near him, there was nothing abnormal detected about the central nervous system. The parents have no doubt about the relationship of MMR. He had normal previous development. We know that the child then underwent an MRI, and that is at page 451. No abnormality was recorded. At EEG on page 454, and that was in accordance with the request that had been made earlier by Dr Wakefield, which we dealt with earlier. The conclusion was within normal limits. He also had a barium meal and follow through and there was a question raised as to that, and that is at page 452. It was thought at that time – and I underline that because as we will see later it was not the case – that there was a tight stricture and that the appearances were highly suggestive of Crohn’s disease, is that right?
A Yes.

Q As I say, we will return to that later but so we are clear as we go along, I think that was ultimately decided to be an anatomical peculiarity rather than indicative of Crohn’s disease, is that correct?
A When the investigation was subsequently repeated there was no evidence of Crohn’s or of a stricture.

Q We will come on to that but I want to ask you as far as that first admission was concerned, in light of the child’s presentation at outpatients and on admission and the history that had been relayed to the Royal Free, is it your view that the gastrointestinal investigations, in other words the colonoscopy and the barium meal and follow through were clinically indicated in this case?
A No, I do not think they were, not as preliminary investigations. This patient was getting, on the admission clerking, episodes of severe colicy abdominal pain lasting up to 10 minutes. He was clutching his abdomen and groaning and colonoscopy would not be the preliminary investigation of a patient with that constellation of symptoms.

Q We looked at the literature when we were looking at some general material yesterday which referred to how common a symptom abdominal pain was in children: is that correct?
A Yes. This abdominal pain that he was having was in association with previous episodes of diarrhoea so certainly investigation of the symptoms would be important, but there would be some preliminary non-invasive investigations to be done before going on to a colonoscopy I think.

Q In fact, certainly as far as the screening tests were concerned, we know the were subsequently normal but they were not carried out before this decision was made, and you have already indicated earlier on in my questioning that you are critical of that, is that correct?
A That, and also I think in someone with this type of abdominal pain, you would want to perhaps get a plain abdominal film to make sure they did not have a kidney stone or a stone in their urethra or a gallstone. You would probably do an ultrasound examination for the same reason, and probably do a plain abdominal film also to see if they were constipated, which could also explain this constellation of colicy abdominal pain and intermittent diarrhoea.

Q This child was discharged on 6 December, and we see the discharge notification which sets out the procedures at page 360: colonoscopy, MRI, barium meal and follow through, EEG and evoked potentials. Also there was a prescription given of liquid paraffin, is that a treatment for constipation?
A Yes, it is.

Q And Salazopyrin which would be the anti-inflammatory, is that correct?
A Yes. In the middle is sodium picosulphate, which is also a laxative for constipation and Salazopyrin is an anti-inflammatory agent.

Q As far as the Salazopyrin is concerned, there is a note that the prescription is on the basis of “X ray evidence of Crohn’s and histological colitis”.
A Yes.

Q We know Salazopyrin was prescribed – I will not take you to the reference but it is in the GP records at page 17 – and then subsequently a full discharge summary was sent by Dr Casson, and that is at page 351:

“[He] was admitted to our ward … for assessment of his persistent diarrhoea.”

It sets out his developmental history and then the gastro-intestinal symptoms that we have already looked at:

“His parents feel that the onset of his neuro-developmental symptoms stems from the period 2 months after having had the MMR vaccination … April 1990. A few months subsequent to this he started losing his skills.

He had a colonoscopy performed under sedation … blood tests … We are still awaiting results of his central nervous system, MRI scan and lumbar puncture.”

Above that the barium meal and follow through to demonstrate a stricture.

He says on the next page that they need to consider these findings at greater length when he is reviewed in clinic.

I should have mentioned the colonoscopy, which I omitted, at page 352:

“He had a colonoscopy performed under sedation. This demonstrated a mild proctitis with a granular mucosa and loss of the vascular pattern, but there was no friability or ulceration. The colon was otherwise normal throughout. There did appear to be a slight loss of vascular pattern in the caecum without any ulceration. There was prominent lymphoid follicles within the ileum. The ileal mucosa appeared normal. Biopsies showed normal crypt architecture. There was very minimal increase in the chronic inflammatory cells within the superficial laminar propria although no active inflammation was seen. Very occasional polymorphus were seen within the surface crypt epithelium. No granulomas were seen. Overall it appears that these are minor changes, the significance of which is uncertain.”

That would appear to accord with the clinical histology report prior to the notes from Professor Walker-Smith.

As I say, at the end of the letter they were going to consider all the findings at a greater length when they reviewed him in clinic.

There was then a second admission for a repeat barium meal and follow through under sedation because of the previous suspected stricture, and in fact on that occasions also a lumbar puncture was performed, and that is at the bottom page 7, there is reference to a lumbar puncture and we see that the cerebrospinal fluid was sent out for measles analysis. Above that, at the top of the page: “Admission for barium meal and follow through under sedation.” There is reference to a possible stricture.

If you then turn to page 363 we will see the ultimate conclusion from that barium meal and follow through, that there was no evidence of a small bowel stricture or of Crohn’s disease, is that correct?
A That is right, yes.

Q There is a record in the clinical notes, at page 8, of a long discussion with the parents and the reason for the treatment: “Long discussion with mum and dad”, we see at one: treat constipation with liquid paraffin: two, inflammation in the large bowel is significant as estimated when professor and Alan [Philips]” reviewed the treatment and the decision to start to start the anti-inflammatory Mesalazine, and then there is a discharge notification. I will not go to it but it sets out the procedures for that admission of barium meal, follow through and lumbar puncture. In fact just so we are reminded, this is a case where there was an aftermath from the lumbar puncture. I will not take you to the notes but there was undoubtedly a complication which arose from it. Then as far as follow up is concerned, Professor Booth, the follow up in respect of this child is extremely lengthy and perhaps I can just summarise it and then refer to one or two of the notes. I think it is right that the child had a significant problem with constipation and he appeared to obtain considerable relief from the treatment with laxatives, is that correct?
A Yes, that is correct.

Q But then the position was significantly complicated because he had to have abdominal surgery because of his pica, his inappropriate eating of foreign objects, and a number of procedures were carried out, including a laparotomy, open surgery to remove those objects, is that correct?
A That is correct, yes.

Q Just taking you to one or two of the references that summarise that, page 350, and there Professor Walker-Smith is saying:

“… it is interesting that liquid paraffin and Picolax has had a remarkable effect on his gastrointestinal symptoms.”

Just to underline it, they are the treatments for constipation, not the anti-inflammatories:

“He is no longer having diarrhoea and has three loose stools per day. I think the vicious cycle of chronic constipation with overflow has been broken.

Of more interest is that when his mother subsequently gave him Mesalazine there was a further symptomatic improvement with the disappearance of his abdominal pain and apparent general improvement in his behaviour and wellbeing. As you know, we did find some evidence of microscopic colitis and we have had several children who have now responded remarkably well to Mesalazine.”

Then he says the method of administration was unsatisfactory and had been changed:

Q
“I would suggest that he continues on this medication definitely for the moment and if there is a measurably sustained improvement he should continue on his. I have not made an appointment to see this child again in the outpatients and will leave it to you and the parents to decide how long he needs to go on Mesalazine for the moment.

In relation to the research that is being done concerning this group of children I suggest that you or [Mrs 5] should be directly in touch with Dr Andy Wakefield who is directing the research aspect of this study. If you have any further queries please do not hesitate to contact me.”

Page 349 is the GP to Professor Walker Smith asking for a follow up appointment:

“Mum is rather hesitant about continuing him on Mesalazine indefinitely without attending your clinic again.”

and referring to the way in which to get in touch with Dr Wakefield. I need not take you to the letter but Professor Walker Smith did indeed arrange an outpatient appointment to be sent and sees the child in outpatient’s and then writes back to the GP on page 348:

“I saw [Child 5] again. He does not seem to be doing so well on the Pentasa treatment as well as he was formerly. I think it might be helpful if we try a Sulphasalazine suspension....

In relation to Picolax I do not think he needs any more Picolax. When I examined him today he did not appear to be faecally overloaded and I would for the moment just continue on liquid paraffin.”

Then giving the various symptoms and at the bottom of the page saying:

“Although the overall diagnosis is not totally clear, therapeutic strategy of using 5 ASA derivatives [anti inflammatories] and related drugs has made a measurable difference to [Child 5’s] symptoms. I think it would be helpful if I did go on seeing him and I have given his parents an appointment for six months.”

At 320 a letter from the Allergy Clinic to the GP in relation to a referral there for [Child 5]. If we go on to the second page:

“The recent admission of [Child 5] to the Royal Free Hospital ... Gut behaviour is abnormal in these children and the Pentasa that he has been given has also had an interesting and beneficial effect. [Child 5] has changed from being very pale to being quite pink as a result of a few weeks of this treatment....

I would mention all these threads in the investigation of autistic children and if you agree I will send a copy of this letter to Dr Wakefield so that we can coordinate the therapy. My view would be that Nystatin is generally useful in these children and is unlikely to conflict with Pentasa. I will, however, ask Dr Wakefield for his opinion.”

He says:

“He should have nutritional supplements and he is going to discuss that with Dr Wakefield.”

Then we see a further outpatient clinic at page 34 of the Royal Free. Again, Professor Booth, we see the stamp “Wakefield Clinic”. Would you repeat your previous comments in relation to the appearance of Dr Wakefield’s name on a stamp in this way?
A Yes, I would.

MR COONAN: I am sorry to interrupt, and I know it is late in the afternoon. We have jumped twelve months and omitted to look at page 319. In the interests of not being selective, I do suggest that care is paid to this sequence so Professor Booth is not mislead.

MS SMITH: I hope I have prefaced all this by saying that I am doing my absolute best to retain the sanity of the Panel in relation to incredibly detailed clinical records and not to be unfair to these doctors. I have tried very hard not to be selective in any way which may be detrimental to anything they want to say. If I have missed a letter, I am sorry, it is inadvertent and I am very happy to go to it. It is page 319. This is the letter to Dr Brostoff, who is at the Allergy Clinic, from Professor Walker Smith:

“Your letter to Dr Wakefield was sent to me. I am the clinician involved. Dr Wakefield is overall directing a research. I enclose a copy of [Child 5’s] Discharge Summary.

We are very interested by the non specific colitis we have been seeing in these children and the good response to Mesalazine.

I am happy for [Child 5] to have nutritional supplements but wonder about adding Nystatin at present without any evidence of current yeast infection until we have had a longer time to evaluate the effect of Pentasa.”

That was on 12 June 1997. If I may go back to page 34, which is by now in July 1998. We see the stamp “Wakefield Clinic” in the clinical records. Can I ask you again, do you repeat your previous comments in relation to that clinical record?
A Yes, to have a clinic stamp of your own for an outpatient clinic implies that you are taking clinical responsibility for everything that is transacted in that clinic.

Q If we go on to page 171, which is a letter to Professor Walker Smith in 1999 from the parents. It expresses concerns over the child’s condition – lost over a stone in weight, very pale, sick daily experiencing great pain, walking with a stoop:

“I would ask you please to give us as much time with you and Dr Wakefield as possible as I think he is in need of a very thorough examination. Doctors have been called in over the last month and are ensuring he doesn’t become dehydrated. We are unsure of whether to take him off Pentasa or not. Please advise if you feel this is necessary.”

And saying that there could be communication by fax:

“Please ring to advise and we will switch over to fax mode. I believe Dr Wakefield also wanted to see [Child 5].”

That is the beginning of the series of admissions which led to surgery and ultimately the discovery of foreign bodies in the child’s abdomen. Is that correct?
A That is correct.

Q I am not going through the long pursuing history, save to make clear that he remained under the care of the Royal Free Hospital until 2003, in so far as we can trace it in the records. As far as the original investigations were concerned, Professor Booth, you told us that you did not feel a third colonoscopy at that stage was clinically indicated and you were critical of that. As far as those two admissions were concerned and the procedures that were carried out, did it appear to you that they were – the gastrointestinal investigations at least – were carried out for clinical or research reasons?
A I think the notes make it clear that this was part of a research study. The letter that we looked at on 350 referred to a research study, for example. It would also be very unusual indeed for a histopathologist to make a clinical referral for a clinical neuropsychiatric assessment to Dr Berelowitz, as indeed Dr Wakefield did, unless it was part of a research study.

Q With reference to Dr Berelowitz, we know the child had not been reviewed by him at the time of the colonoscopy. So as far as any entry into a study of disintegrative disorder was concerned, was it justified on the basis of the research protocol?
A No, the eligibility of this patient for inclusion in that research protocol had not been established before the colonoscopy took place.

MS SMITH: Thank you very much, sir. That is all I have to ask about Child 5.

THE CHAIRMAN: Thank you very much. We will now adjourn. Tomorrow is a non sitting day, so we will resume at 9.30 on Thursday morning. Professor Booth, that does mean you are going to be under oath for the next two days at least and perhaps longer.
A I understand.

THE CHAIRMAN: Please make sure you do not the case with anyone. We will meet again at 9.30 Thursday morning.

(The Panel adjourned until 9.30am on Thursday 11 October 2007)

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