Editorial note Unfortunately, an error of communication resulted in Dr Altmann et al not knowing that the letters in response to their paper were to be published in this issue, for which we apologise. A shortened version of the following reply will be published in the journal as soon as possible.
Esmonde, David, McMillan, and Murray et al make a number of comments
about the paper (1) in their separate letters, many of which are factually
incorrect and overlap.
Competing interests of authors
In our paper we openly acknowledged that the study was commissioned
by lawyers acting for the plaintiffs and funded through Legal Aid. This
legal action constrained the nature of our study but we do not believe it
biased our conduct. Indeed, our selection of automated testing systems was
intended to reduce investigator bias. The legal action affected, in
particular, our own wish to study other relevant groups of randomly
selected subjects such as those affected by anxiety, asymptomatic exposed
and non-exposed (to the water contamination) control subjects, as well as
randomly selected exposed individuals irrespective of symptoms. These
suggestions were made to the lawyers. It was also as a result of the legal
action that there was delay in publishing the work.
As we had to accept the constraints imposed upon us and mindful of
previous reports concerning Camelford complainants, we tried to design a
study in which the tests were as objective as possible and could be
compared with our previous studies of dialysis patients. In this way we
hoped to obtain data of clinical and scientific interest. If we had had a
completely free hand we would have studied the additional subjects
discussed above. We have not been engaged to represent the claimants we
studied or others in subsequent legal actions.
The question of competing interests was discussed at length with the
editorial staff of the BMJ before the paper went to print. The details
regarding the commissioning and funding of the studies are explicitly
discussed in the paper and there were no competing interests according to
the guidelines published by the BMJ.
Bias
In our paper we expressed our own concerns over the possibility of
experimental bias caused by the interests of participants who alleged they
were symptomatic. We emphasised that it was the pattern of the results
obtained in the psychometric testing, combined with the results of the
visual evoked responses and the similarity of these to our previous
findings in dialysis patients which was important and suggested that the
Camelford subjects had suffered from exposure to an acute toxic insult. We
therefore suggested that "aluminium poisoning must be considered a
possibility, although other contaminants may have contributed."
* In planning the study we anticipated Professor David's concern that
neuropsychological tests of the Camelford subjects might be influenced by
their affective state. This is one of the reasons why we used the battery
of tests from the Bexley Maudsley package (following advice from clinical
psychology colleagues) in a way which enabled us to compare the results
with those of our earlier studies on dialysis patients. The symbol digit
coding test is particularly sensitive to organic brain disease. In
addition, the manner in which it tests psychomotor function is subtle, to
the subject being tested, compared to the superficially more demanding
tests of memory such as the verbal recognition and visual spatial
recognition memory tests. Both in these and our previous studies, subjects
commented, after testing, that the visual spatial ability, visual
perceptual ability, verbal recognition memory and visual spatial
recognition memory tests were far more daunting and difficult than the
symbol digit coding test. No mention regarding the sensitivity of the
tests was ever made to the subjects and none had any prior knowledge of
what type of testing was going to be done. The tests were run in a calm
but most rigorous and uniform manner, and before each test the subject was
given time to rest and it was explained that they should perform as fast
and accurately as possible. Individuals who have early organic brain
disease exhibit the pattern of abnormality exactly as described in this
Camelford group - a pattern that has been described repeatedly in other
studies of psychomotor function in a variety of contexts including
potentially psychotropic drugs. If litigation-motivated bias had been
operating then one would expect the subject to under-perform on the tasks
most overtly related to memory rather than in the symbol digit coding
test. As this was not the case there is no evidence that such bias
affected these results.
* The purpose of choosing unexposed siblings, who denied exposure to
neurotoxins or psychotropic drugs of any type, was to provide genetic
(phenotypic) controls as this is a standard way of establishing
abnormalities which might be acquired rather than inherited. There were
only 15 available such siblings and so this was the number that we had to
accept - it would have been wrong not to proceed with or divulge this part
of the study and, indeed, we have not been criticised for this or the
statistics thereon by medical statisticians.
Although such controls, out of loyalty, might strive to "give 110%"
in the psychological tests, it is noteworthy that the Bexley Maudsley
Automated tests and Symbol Digit Coding scores were not above normal and
it was the Symbol Digit Coding tests which differentiated the two groups.
Likewise their flash-pattern differences (which Professor David admits
would be less likely to be affected by their desire to achieve) were
significantly less than those of the Camelford subjects.
* We did not discuss the very small number of abnormal tap water
aluminium levels as no useful interpretation of them could be made. The
samples were posted to us by the subjects in containers that we gave them.
Because we were not in a position to sample their tap water ourselves we
felt that these data could not be regarded as reliable, and as there were
no elevated serum aluminium levels, we did not follow these up except to
recommend to the patients that they have their water systems overhauled.
* We addressed the issue of possible effects from anxiety not just
through the finding of relatively low levels of anxiety, but more
importantly by finding no relationship between the absolute levels of
anxiety, as measured by the SCL90 score, and the parameters we measured.
Flash-pattern differences
In response to Professor David's comments concerning technique we
merely wish to observe that Dr Dhanesha is a fully qualified clinical
neurophysiologist, having trained under the directorship of Professor G
Harding in the Clinical Neurophysiology Unit at Aston University,
Birmingham where she did her PhD studies on visual evoked subcortical
potentials (Aston University 1986). The wave forms were analysed in
exactly the same way as in our previous publications and in the manner
described in publications from Professor Harding's group.
* There is, as we stated, very little normative data published on
large series of visual evoked potential results, either flash stimulated
or pattern stimulated or the difference in timing between them.
It is possible that in a given subject the flash-pattern difference
may be large because of a quicker (i.e. shorter) pattern latency than
"normal". However, as there is surprisingly little normative data for
absolute flash and pattern visual evoked potential latencies, we chose to
use the difference between the two types of visual evoked potential and
not the absolute measures. In many studies looking at the relationship
between severity of dementia and visual evoked potentials, it is
noteworthy that it is the flash-pattern difference that correlates rather
than absolute values.
Indeed, the magnitude of the flash-pattern difference was
significantly correlated with the magnitude of the symbol digit coding
abnormality (but not the other Bexley Maudsley tests), as in dialysis
patients where it was also related to cumulative aluminium exposure.
If there was a functional relationship between the two types of
visual evoked responses one might expect the two measurements to
correlate, whereas if they were independent of each other there should be
little or no relationship. In our studies there was a very significant
relationship between these two parameters in normals, which was nearly
absent in the Camelford "victims" and completely absent in our dialysis
patients.
How aluminium exposure might lead to this effect on visual evoked
potential is not an area that we addressed in this or previous papers, but
there is no reason to suppose that aluminium toxicity is manifested solely
by causing neuronal death.
* We acknowledged the controversy about aluminium and Alzheimer's
disease, but there is no controversy about the potential for aluminium to
be neurotoxic. There are many published reports of visual evoked potential
abnormalities of the sort that we have discussed in dementias including
Alzheimer's disease, some of which were referred to in our paper.
* Professor David quotes terms from our paper that we never used -
"flash minus pattern evoked latency" and "patterned minus flash EP
difference". We beg to differ from his belief that our data "are totally
inadequate" We described our methods very clearly and published the
methods previously with illustrative waveforms (2). He also misquotes our
data in his table - we did not quote absolute latencies for the 55
Camelford adults - the 28 cases he quotes were part of a separate
methodological quality control study and he refers to SD (standard
deviation) where we used SE (standard error), and it is therefore unclear
whether the other data quoted in his table refers to means with SDs or
SEs. In addition there is no mention of the SDs or SEs in the bottom panel
of the table. Our dialysis studies included 16 patients (3), and to our
knowledge there are no descriptions of pathologically short pattern evoked
visual evoked responses in the world literature. The mean flash-pattern
difference of the sibling controls, using the same equipment and operator,
was very different from their Camelford relatives.
* Professor David and Dr Murray refer to a study by Sloan and Fenton
and suggest that depression may have led to our observations on visual
evoked potentials, on the basis of the study by Sloan (4). This study
examined patients all over the age of 65 yr, considerably older than our
subjects, and we have observed that the flash-pattern difference increases
with age. Professor David incorrectly quotes data in his table from
Sloan's study; and it is not statistically correct to derive the flash-
pattern differences from averaged results of pattern and flash evoked
potentials, which we believe is how the data in David's table was derived.
Sloan found that the flash-pattern differences at the start of the
longitudinal study were 37.7 (23.3) ms (mean(SD)) in normal controls; 33.7
(21.1) ms in depressed patients and 45.0 (25.4) ms in those with
Alzheimer's disease. Although these are all considerably greater than
those measured by us, their study included patients over 65 years and the
mean age of all groups exceeded 70 years. The flash-pattern difference was
shorter in their depressed pateints than in controls. The only
statistically significant results in Sloan's paper were that the
Alzheimer's disease group had larger flash-pattern differences than the
controls; and that the regression coefficients with time of the flash P2
latency and the flash-pattern difference were significant in the Alzheimer
group. We could only find two other English language references to visual
evoked potentials in depression and both showed no significant change
(5,6).
Finally, of course one might expect an element of depression in the
Camelford group in response to their condition - but it would be
impossible to determine which came first.
Time interval between incident and our study
We strongly support Professor David's statement that incidents like
Camelford should trigger a rapid and co-ordinated response from
appropriate health professionals. Unfortunately this did not happen after
Camelford and as stated in our paper it was not until three years later
that we were asked to perform these studies, although at that time we
ourselves anticipated that such a delay would favour negative
investigation results. We were surprised by the results of our studies.
The ethics of medical publications
Finally, although we were concerned about the possible effects that
the publication of our paper might have on people who were involved in the
Camelford incident, it would have been wrong to withhold it. Had our
studies not been designed to provide scientifically useful information
(despite the inevitable limitations), and only been used to satisfy the
legal process, then the clinical and scientific communities would have
been deprived of results that we find interesting and worthy of debate,
and which we believe are valid.
It is unlikely that another Camelford will occur, so the opportunity
to study the effects will, we hope, not recur. We would welcome the
opportunity to carry out an objective follow-up study of the Camelford
subjects.
Paul Altmann
John Cunningham
James Thompson
Usha Dhanesha
Margaret Ballard
James Thompson
Frank Marsh
References
1. Altmann P, Cunningham J, Dhanesha U, Ballard M, Thompson J, Marsh
F. Disturbance of cerebral function in people exposed to drinking water
contaminated with aluminium sulphate: retrospective study of the Camelford
water incident. BMJ 1999; 319: 807-11.
2. Altmann P, Dhanesha U, Hamon C, Cunningham J, Blair J, Marsh F.
Disturbance of cerebral function by aluminium in haemodialysis patients
without overt aluminium toxicity. Lancet 1989; ii: 7-12.
3. Altmann P. The toxic effects of aluminium in haemodialysis
patients. MD Thesis, University of London, 1991.
4. Sloan EP, Fenton GW. Serial visual evoked potential recordings in
geriatric psychiatry. Electroencephalogr Clin Neurophysiol 1992; 84: 325-
31.
5. Jordan SE, Nowacki R, Nuwer M. Computerized electroencephalography
in the evaluation of early dementia. Brain Topogr 1989; 1: 271-82.
6. Swanwick GR, Rowan M, Coen RF, O'Mahony D, Lee H, Lawlor BA, et
al. Clinical application of electrophysiological markers in the
differential diagnosis of depression and very mild Alzheimer's disease. J
Neurol Neurosurg Psychiatry 1996; 60: 82-6.
Competing interests:
No competing interests
12 May 2000
P Altmann
J Cunningham, U Dhanesha, M Ballard, J Thompson, F Marsh
Rapid Response:
Authors' reply to Camelford correspondence
Editorial note
Unfortunately, an error of communication resulted in Dr Altmann et al not knowing that the letters in response to their paper were to be published in this issue, for which we apologise. A shortened version of the following reply will be published in the journal as soon as possible.
Esmonde, David, McMillan, and Murray et al make a number of comments
about the paper (1) in their separate letters, many of which are factually
incorrect and overlap.
Competing interests of authors
In our paper we openly acknowledged that the study was commissioned
by lawyers acting for the plaintiffs and funded through Legal Aid. This
legal action constrained the nature of our study but we do not believe it
biased our conduct. Indeed, our selection of automated testing systems was
intended to reduce investigator bias. The legal action affected, in
particular, our own wish to study other relevant groups of randomly
selected subjects such as those affected by anxiety, asymptomatic exposed
and non-exposed (to the water contamination) control subjects, as well as
randomly selected exposed individuals irrespective of symptoms. These
suggestions were made to the lawyers. It was also as a result of the legal
action that there was delay in publishing the work.
As we had to accept the constraints imposed upon us and mindful of
previous reports concerning Camelford complainants, we tried to design a
study in which the tests were as objective as possible and could be
compared with our previous studies of dialysis patients. In this way we
hoped to obtain data of clinical and scientific interest. If we had had a
completely free hand we would have studied the additional subjects
discussed above. We have not been engaged to represent the claimants we
studied or others in subsequent legal actions.
The question of competing interests was discussed at length with the
editorial staff of the BMJ before the paper went to print. The details
regarding the commissioning and funding of the studies are explicitly
discussed in the paper and there were no competing interests according to
the guidelines published by the BMJ.
Bias
In our paper we expressed our own concerns over the possibility of
experimental bias caused by the interests of participants who alleged they
were symptomatic. We emphasised that it was the pattern of the results
obtained in the psychometric testing, combined with the results of the
visual evoked responses and the similarity of these to our previous
findings in dialysis patients which was important and suggested that the
Camelford subjects had suffered from exposure to an acute toxic insult. We
therefore suggested that "aluminium poisoning must be considered a
possibility, although other contaminants may have contributed."
* In planning the study we anticipated Professor David's concern that
neuropsychological tests of the Camelford subjects might be influenced by
their affective state. This is one of the reasons why we used the battery
of tests from the Bexley Maudsley package (following advice from clinical
psychology colleagues) in a way which enabled us to compare the results
with those of our earlier studies on dialysis patients. The symbol digit
coding test is particularly sensitive to organic brain disease. In
addition, the manner in which it tests psychomotor function is subtle, to
the subject being tested, compared to the superficially more demanding
tests of memory such as the verbal recognition and visual spatial
recognition memory tests. Both in these and our previous studies, subjects
commented, after testing, that the visual spatial ability, visual
perceptual ability, verbal recognition memory and visual spatial
recognition memory tests were far more daunting and difficult than the
symbol digit coding test. No mention regarding the sensitivity of the
tests was ever made to the subjects and none had any prior knowledge of
what type of testing was going to be done. The tests were run in a calm
but most rigorous and uniform manner, and before each test the subject was
given time to rest and it was explained that they should perform as fast
and accurately as possible. Individuals who have early organic brain
disease exhibit the pattern of abnormality exactly as described in this
Camelford group - a pattern that has been described repeatedly in other
studies of psychomotor function in a variety of contexts including
potentially psychotropic drugs. If litigation-motivated bias had been
operating then one would expect the subject to under-perform on the tasks
most overtly related to memory rather than in the symbol digit coding
test. As this was not the case there is no evidence that such bias
affected these results.
* The purpose of choosing unexposed siblings, who denied exposure to
neurotoxins or psychotropic drugs of any type, was to provide genetic
(phenotypic) controls as this is a standard way of establishing
abnormalities which might be acquired rather than inherited. There were
only 15 available such siblings and so this was the number that we had to
accept - it would have been wrong not to proceed with or divulge this part
of the study and, indeed, we have not been criticised for this or the
statistics thereon by medical statisticians.
Although such controls, out of loyalty, might strive to "give 110%"
in the psychological tests, it is noteworthy that the Bexley Maudsley
Automated tests and Symbol Digit Coding scores were not above normal and
it was the Symbol Digit Coding tests which differentiated the two groups.
Likewise their flash-pattern differences (which Professor David admits
would be less likely to be affected by their desire to achieve) were
significantly less than those of the Camelford subjects.
* We did not discuss the very small number of abnormal tap water
aluminium levels as no useful interpretation of them could be made. The
samples were posted to us by the subjects in containers that we gave them.
Because we were not in a position to sample their tap water ourselves we
felt that these data could not be regarded as reliable, and as there were
no elevated serum aluminium levels, we did not follow these up except to
recommend to the patients that they have their water systems overhauled.
* We addressed the issue of possible effects from anxiety not just
through the finding of relatively low levels of anxiety, but more
importantly by finding no relationship between the absolute levels of
anxiety, as measured by the SCL90 score, and the parameters we measured.
Flash-pattern differences
In response to Professor David's comments concerning technique we
merely wish to observe that Dr Dhanesha is a fully qualified clinical
neurophysiologist, having trained under the directorship of Professor G
Harding in the Clinical Neurophysiology Unit at Aston University,
Birmingham where she did her PhD studies on visual evoked subcortical
potentials (Aston University 1986). The wave forms were analysed in
exactly the same way as in our previous publications and in the manner
described in publications from Professor Harding's group.
* There is, as we stated, very little normative data published on
large series of visual evoked potential results, either flash stimulated
or pattern stimulated or the difference in timing between them.
It is possible that in a given subject the flash-pattern difference
may be large because of a quicker (i.e. shorter) pattern latency than
"normal". However, as there is surprisingly little normative data for
absolute flash and pattern visual evoked potential latencies, we chose to
use the difference between the two types of visual evoked potential and
not the absolute measures. In many studies looking at the relationship
between severity of dementia and visual evoked potentials, it is
noteworthy that it is the flash-pattern difference that correlates rather
than absolute values.
Indeed, the magnitude of the flash-pattern difference was
significantly correlated with the magnitude of the symbol digit coding
abnormality (but not the other Bexley Maudsley tests), as in dialysis
patients where it was also related to cumulative aluminium exposure.
If there was a functional relationship between the two types of
visual evoked responses one might expect the two measurements to
correlate, whereas if they were independent of each other there should be
little or no relationship. In our studies there was a very significant
relationship between these two parameters in normals, which was nearly
absent in the Camelford "victims" and completely absent in our dialysis
patients.
How aluminium exposure might lead to this effect on visual evoked
potential is not an area that we addressed in this or previous papers, but
there is no reason to suppose that aluminium toxicity is manifested solely
by causing neuronal death.
* We acknowledged the controversy about aluminium and Alzheimer's
disease, but there is no controversy about the potential for aluminium to
be neurotoxic. There are many published reports of visual evoked potential
abnormalities of the sort that we have discussed in dementias including
Alzheimer's disease, some of which were referred to in our paper.
* Professor David quotes terms from our paper that we never used -
"flash minus pattern evoked latency" and "patterned minus flash EP
difference". We beg to differ from his belief that our data "are totally
inadequate" We described our methods very clearly and published the
methods previously with illustrative waveforms (2). He also misquotes our
data in his table - we did not quote absolute latencies for the 55
Camelford adults - the 28 cases he quotes were part of a separate
methodological quality control study and he refers to SD (standard
deviation) where we used SE (standard error), and it is therefore unclear
whether the other data quoted in his table refers to means with SDs or
SEs. In addition there is no mention of the SDs or SEs in the bottom panel
of the table. Our dialysis studies included 16 patients (3), and to our
knowledge there are no descriptions of pathologically short pattern evoked
visual evoked responses in the world literature. The mean flash-pattern
difference of the sibling controls, using the same equipment and operator,
was very different from their Camelford relatives.
* Professor David and Dr Murray refer to a study by Sloan and Fenton
and suggest that depression may have led to our observations on visual
evoked potentials, on the basis of the study by Sloan (4). This study
examined patients all over the age of 65 yr, considerably older than our
subjects, and we have observed that the flash-pattern difference increases
with age. Professor David incorrectly quotes data in his table from
Sloan's study; and it is not statistically correct to derive the flash-
pattern differences from averaged results of pattern and flash evoked
potentials, which we believe is how the data in David's table was derived.
Sloan found that the flash-pattern differences at the start of the
longitudinal study were 37.7 (23.3) ms (mean(SD)) in normal controls; 33.7
(21.1) ms in depressed patients and 45.0 (25.4) ms in those with
Alzheimer's disease. Although these are all considerably greater than
those measured by us, their study included patients over 65 years and the
mean age of all groups exceeded 70 years. The flash-pattern difference was
shorter in their depressed pateints than in controls. The only
statistically significant results in Sloan's paper were that the
Alzheimer's disease group had larger flash-pattern differences than the
controls; and that the regression coefficients with time of the flash P2
latency and the flash-pattern difference were significant in the Alzheimer
group. We could only find two other English language references to visual
evoked potentials in depression and both showed no significant change
(5,6).
Finally, of course one might expect an element of depression in the
Camelford group in response to their condition - but it would be
impossible to determine which came first.
Time interval between incident and our study
We strongly support Professor David's statement that incidents like
Camelford should trigger a rapid and co-ordinated response from
appropriate health professionals. Unfortunately this did not happen after
Camelford and as stated in our paper it was not until three years later
that we were asked to perform these studies, although at that time we
ourselves anticipated that such a delay would favour negative
investigation results. We were surprised by the results of our studies.
The ethics of medical publications
Finally, although we were concerned about the possible effects that
the publication of our paper might have on people who were involved in the
Camelford incident, it would have been wrong to withhold it. Had our
studies not been designed to provide scientifically useful information
(despite the inevitable limitations), and only been used to satisfy the
legal process, then the clinical and scientific communities would have
been deprived of results that we find interesting and worthy of debate,
and which we believe are valid.
It is unlikely that another Camelford will occur, so the opportunity
to study the effects will, we hope, not recur. We would welcome the
opportunity to carry out an objective follow-up study of the Camelford
subjects.
Paul Altmann
John Cunningham
James Thompson
Usha Dhanesha
Margaret Ballard
James Thompson
Frank Marsh
References
1. Altmann P, Cunningham J, Dhanesha U, Ballard M, Thompson J, Marsh
F. Disturbance of cerebral function in people exposed to drinking water
contaminated with aluminium sulphate: retrospective study of the Camelford
water incident. BMJ 1999; 319: 807-11.
2. Altmann P, Dhanesha U, Hamon C, Cunningham J, Blair J, Marsh F.
Disturbance of cerebral function by aluminium in haemodialysis patients
without overt aluminium toxicity. Lancet 1989; ii: 7-12.
3. Altmann P. The toxic effects of aluminium in haemodialysis
patients. MD Thesis, University of London, 1991.
4. Sloan EP, Fenton GW. Serial visual evoked potential recordings in
geriatric psychiatry. Electroencephalogr Clin Neurophysiol 1992; 84: 325-
31.
5. Jordan SE, Nowacki R, Nuwer M. Computerized electroencephalography
in the evaluation of early dementia. Brain Topogr 1989; 1: 271-82.
6. Swanwick GR, Rowan M, Coen RF, O'Mahony D, Lee H, Lawlor BA, et
al. Clinical application of electrophysiological markers in the
differential diagnosis of depression and very mild Alzheimer's disease. J
Neurol Neurosurg Psychiatry 1996; 60: 82-6.
Competing interests: No competing interests