- Email: [email protected]
Stillbirths among offspring of male radiation workers
CORRESPONDENCE
To support their suggestion that anencephaly can result from paternal preconceptional irradiation, Parker and colleagues cite a mouse experiment4 in which they state that anencephaly was seen in the offspring of male irradiated mice. Unfortunately, a mistake has crept in because this paper makes no mention of anencephaly. Some limitations of the study of radiation workers seem important. For example, there was no consideration of many possible factors in the mothers that would seem to be much more likely to affect stillbirth rates than paternal preconceptional irradiation. Paul B Selby Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830-6480, USA (e-mail: [email protected]) 1
2
3
4
Parker L, Pearce MS, Dickinson HO, et al. Stillbirths among offspring of male radiation workers at Sellafield nuclear reprocessing plant. Lancet 1999; 354: 1407–14. United Nations. Sources and effects of ionizing radiation. United Nations scientific committee on the effects of atomic radiation UNSCEAR 1993 Report to the General Assembly, with scientific annexes. New York: United Nations, 1993. Selby PB, Russell WL. First-generation litter-size reduction following irradiation of spermatogonial stem cells in mice and its use in risk estimation. Environ Mutagen 1985; 7: 451–69. Kirk KM, Lyon MF. Induction of congenital malformations in the offspring of male mice treated with x-rays at pre-meiotic and postmeiotic stages. Mutat Res 1984; 125: 75–85.
Authors’ reply Sir—In response to Pat Doyle and colleagues, as we reported, the crude stillbirth rates in the two groups are higher than those in the radiation workers largely because the children tended to be born in earlier years, when rates were higher, and to men of lower social classes. In comparison with the non-Sellafield cohort there were significantly more stillbirths than expected for the radiation worker cohort (115·0 stillbirths predicted [95% CI 100·6–129·3]; 130 observed). Our analysis was of stillbirth risk to radiation workers defined as men who had received an occupational radiation exposure in the time before conception. When moving from annual dose records (in the cohort study) to film badge records (in the case-control study), six births (five liveborn and one stillborn) included in the cohort study proved not to have had a dose in the preconception period and so were excluded from the study. Doyle and colleagues are mistaken in suggesting that men with a zero 90 day dose were excluded from the analyses. There were four men who each had two stillborn babies and, as reported, we looked at
THE LANCET • Vol 355 • February 5, 2000
familial effects by means of a variance components model, which showed little effect. We were concerned about the misclassification of birth order, especially in early years, and we have done several subanalyses and none suggested an undue influence. The results of the post 1961 analysis, in which misclassification of birth order was less of a difficulty, were very similar to those including the 1950s data (see table 5). Doyle and colleagues are concerned about identification of children. Respondents to the validation questionnaire included both past and present employees from Sellafield. The error rate, as reported, was less than 2%. This error rate was achieved by a careful process which included comparison of spouse information, occupation and, for parents born after 1969, place of birth. There were 278 mothers (501 liveborn children, six stillbirths) who were radiation workers before conception (dose range 0·08–159·9 mSv). With such small numbers and low exposure, we were unable to show a significant effect (odds ratio at 100 mSv 5·13 [95% CI 0·083–31·77], likelihoodratio-test statistic p=0·136). Paul Selby suggests that we claim the paternal preconceptional irradiation at Sellafield has led to a substantial increase in stillbirths. We reported a robust statistical association between father’s paternal preconceptional irradiation and stillbirth risk in radiation workers in whom there is a significant excess of stillbirths in comparison with the rest of Cumbria. Direct comparison of the human situation with animal models is extremely complicated, especially since there is no animal model in which the exposure pattern observed in long-term workers in the nuclear industry has been adequately replicated. The extrapolation of the association we have observed, over a dose range up to 910 mSv, to a dose of 5000 mSv is meaningless. We agree that we had little data on mothers, but consider that our careful consideration of social class, father’s age, and birth order did contribute to a consideration of some maternal factors to the analysis. To affect our results, any remaining maternal risk factor would need to be highly correlated with father’s radiation exposure independent of social class and the other covariates we considered. *Louise Parker, Alan W Craft, Mark S Pearce, Heather O Dickinson Department of Child Health, The Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK
Sir—The report by Louise Parker and colleagues1 of a dose-response relation between fathers’ preconception radiation dose and the subsequent risk of stillbirth is unusual and would be easier to assess if we knew whether or not there had been a significant excess of stillbirths among the radiation workers. We are told that the model they used, based on 3468 stillbirths of 235 316 total births in Cumbria to non-Sellafield workers, predicted 18·1 stillbirths to non-radiation workers at Sellafield against 21 observed and 99·9 stillbirths among children conceived before their fathers’ employment at Sellafield against 96 observed. However, we do not know how many stillbirths were predicted for the radiation workers whose babies were conceived after first employment against an observed number of 130. It would be helpful to know what the predicted number was and the 95% confidence limit of the resultant stillbirth ratio. Richard Doll CTSU, Harkness Building, Radcliffe Infirmary, Oxford OX2 6HE, UK 1
Parker L, Pearce MS, Dickinson HO, et al. Stillbirths among the offspring of male radiation workers at the Sellafield nuclear reprocessing plant. Lancet 1999; 354: 1407–14.
Sir—The radiation workers in Louise Parker and colleagues’ study1 had total cumulative external preconceptional doses in the range 0·01–911 mSv with a median of 30·1 mSv. Of the 9208 births to the partners of these men, 130 were stillborn and the statistical models derived by the researchers predict that up to 31·9 of these might be attributable to the radiation exposure received by the fathers. By contrast, studies on the offspring of the Japanese atomic bomb survivors have failed to find any significant association with parental radiation exposure for a range of adverse pregnancy outcomes and other measures of possible genetic effects.2 In the atomic bomb studies, stillbirths alone, with maternal age and parity taken into account, were analysed and no association with paternal dose was shown. Studies of somatic mutations in Sellafield workers, who received low dose chronic exposure, consistently indicate lower yields in comparison with similar studies on the acutely exposed Japanese atomic bomb survivors.3,4 Chromosome analysis of peripheral blood lymphocytes for stable aberrations revealed frequencies per unit dose a factor of six lower than those seen in atomic bomb survivors.3
493
CORRESPONDENCE
Studies of mutations in hypoxanthineguanine phosphoribosyltransferase and glycophorin A have shown no significant increases in the Sellafield workers3,4 in contrast with the raised frequencies seen in those exposed to radiation from the atomic bombs. Also, animal studies have established a reduction in effect for chronic exposure on gonadal cells, which indicates that the genetic effect of chronic exposure to spermatogonia is about a third that induced by acute irradiation.5 Thus, whether the statistical association found by Parker and colleagues represents a real biological effect is doubtful. E Janet Tawn Westlakes Research Institute, Cumbria CA24 3JY, UK 1
2
3
4
5
Parker L, Pearce MS, Dickinson HO, et al. Stillbirths among the offspring of male radiation workers at the Sellafield nuclear reprocessing plant. Lancet 1999; 354: 1407–14. Neel JV, Schull WJ. The children of Atomic bomb survivors. Washington DC: Natl Acad Press, 1991. Tucker JD, Tawn EJ, Holdsworth D, et al. Biological dosimetry of radiation wokers at the Sellafield nuclear facility. Radiat Res 1997; 148: 216–26. Cole J, Arlett CF, Green MHL, et al. Mutant frequencies in workers at the Sellafield installation. Health Phys 1995; 68: 388–93. United Nations scientific committee on the effects of atomic radiation, sources and effects of ionising radiation (UNSCEAR 1993 Report). New York: United Nations: 1993.
Thalamic perfusion in reflex sympathetic dystrophy syndrome Sir—Mitsutaka Fukumoto and colleagues (Nov 20, p 1790)1 used single photon emission computed tomography (SPECT) to visualise changes in thalamic perfusion contralateral to the side of pain in patients with reflex sympathetic dystrophy syndrome (RSDS). However, before postulating new central mechanisms of pathogenesis of RSDS, the implication that the sympathetic nervous system has a part in its aetiology needs to be reconsidered. The International Association for the Study of Pain has defined RSDS under a heading of complex regional pain syndrome (CRPS) type I as opposed to causalgia, involving nerve damage, which is CRPS type II.2 Hence, sympathetic instability would not be expected to correlate with thalamic perfusion as Fukumoto and colleagues found in their study.
494
Fukumoto and colleagues found a strong correlation between contralateral thalamic perfusion and time since onset of symptoms, suggesting an initial increase in thalamic activity and then a gradual decrease. A similar spectrum of change in thalmic activity has been reported in other chronic pain conditions, from an increase in thalamic activity in central post-stroke pain3 to a decrease in thalamic activity in chronic neuropathic pain.4 Care must be taken when interpreting the results from one point in time and from a few patients. However, the possibility of temporal variation in thalamic activity with ongoing chronic pain may explain the variation in thalamic perfusion seen in other studies3,4 previously explained as heterogeneity of chronic pain pathophysiology. If such gross changes do occur in the central pain pathways over time, interpretation of functional brain imaging will be fraught with difficulties because results would be affected by time from onset of symptoms. Reversal of changes in thalamic activity by alteration of sensory input, rather than monitoring changes per se, may yield information on the pathogenesis of chronic pain. In a study by Di Piero and colleagues,5 perfusion in the contralateral hemithalamus was restored in five patients with unilateral, severe, chronic cancer pain by interrupting the ascending spinothalamic tract of the spinal cord. Hence, it may be difficult to separate changes in the thalamus from neuronal activity of afferent thalamic connections. Emma Chojnowska Pain Clinic, Frenchay Hospital, Frenchay, Bristol BS16 1LE, UK 1
2
3
4
5
Fukumoto M, Ushida T, Zinchuk VS, Yamamoto H, Yoshida S. Contralateral thalamic perfusion in patients with reflex sympathetic dystrophy syndrome. Lancet 1999; 354: 1790–91. Mersky H, Bogduk N, eds. Classification of chronic pain, 2nd edn. Seattle: ISAP Press, 1994. Cesaro P, Mann MW, Moretti JL, et al. Central pain and thalamic hyperactivity: a single photon emission computerized tomographic scan. Pain 1991; 47: 329–36. Iadarola MJ, Max MB, Berman KF, et al. Unilateral decrease in thalamic activity observed with positron emission tomography in patients with chronic neuropathic pain. Pain 1995; 63: 55–64. Di Piero V, Jones AKP, Iannotti F, et al. Chronic pain: a PET study of the central effects of percutaneous high cervical cordotomy. Pain 1991; 46: 9–12.
Sir—In their study involving singlephoton emission computed tomography (SPECT), Fukumoto and colleagues1 describe a correlation
between contralateral thalamic iodoamphetamine uptake index and time from onset of reflex sympathetic dystrophy syndrome (RSDS). Their findings help us understand more about RSDS and the plasticity of the brain in general. Their paper may have a widespread impact on the world of neuroscience. We urge Fukumoto and colleagues to test their findings in a larger patient group stratified in the different timely subgroups and to re-evaluate the data by Statistical Parametric Mapping (SPM) to be able to carry out the region-of-interest (ROI) analysis. This SPM software package, freely available via the Internet, comes from the Wellcome Department of Cognitive Neurology, London, UK, and has helped standardise measurement and data analysis in functional neuroimaging. This package not only spatially normalises the images to the stereotaxic atlas by Talairach and Tournoux,2 but can also carry out statistical analyses on study groups on a voxel-by-voxel basis.3 This package allows reliable and objective image handling that could improve interstudy variability, which often causes difficulties in ROI analysis. Cerebral reactions to peripheral diseases can also be found in patients with chronic symptoms after a distortion of the cervical spine. Such distortion can result in perfusion deficits in the posterior parietal occipital region, possibly because of nociceptive afferents from the upper cervical spine causing an increased vasopeptide production, which results in a vasoconstriction of the major cerebral arteries and the vulnerable posterior watershed region.4 Cerebral de-afferentiation phenomena can also be found in patients after a spinal cord injury. In such injuries glucose metabolism might be altered because of a reduction or loss of sensorimotor function and increased glucose metabolism in brain regions involved in attention and initiation of movement, possibly as a result of secondary disinhibition of these regions.5 Andreas Otte Obere Lachen 10, D-79110 Freiburg, Germany (e-mail: [email protected]) 1
2
3
Fukumoto M, Ushida T, Zinchuk VS, Yamamoto H, Yoshida S. Contralateral thalamic perfusion in patients with reflex sympathetic dystrophy syndrome. Lancet 1999; 354: 1790–91. Talairach J, Tournoux P. Co-planar Stereotaxic Atlas of the Human Brain. Stuttgart: Thieme, 1988. Friston KJ, Holmes AP, Worsley KJ, Poline JB, Frith CD, Frackowiak RSJ. Statistical parametric maps in functional imaging: a general approach. Hum Brain Mapping 1995; 2: 189–210.
THE LANCET • Vol 355 • February 5, 2000
To support their suggestion that anencephaly can result from paternal preconceptional irradiation, Parker and colleagues cite a mouse experiment4 in which they state that anencephaly was seen in the offspring of male irradiated mice. Unfortunately, a mistake has crept in because this paper makes no mention of anencephaly. Some limitations of the study of radiation workers seem important. For example, there was no consideration of many possible factors in the mothers that would seem to be much more likely to affect stillbirth rates than paternal preconceptional irradiation. Paul B Selby Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830-6480, USA (e-mail: [email protected]) 1
2
3
4
Parker L, Pearce MS, Dickinson HO, et al. Stillbirths among offspring of male radiation workers at Sellafield nuclear reprocessing plant. Lancet 1999; 354: 1407–14. United Nations. Sources and effects of ionizing radiation. United Nations scientific committee on the effects of atomic radiation UNSCEAR 1993 Report to the General Assembly, with scientific annexes. New York: United Nations, 1993. Selby PB, Russell WL. First-generation litter-size reduction following irradiation of spermatogonial stem cells in mice and its use in risk estimation. Environ Mutagen 1985; 7: 451–69. Kirk KM, Lyon MF. Induction of congenital malformations in the offspring of male mice treated with x-rays at pre-meiotic and postmeiotic stages. Mutat Res 1984; 125: 75–85.
Authors’ reply Sir—In response to Pat Doyle and colleagues, as we reported, the crude stillbirth rates in the two groups are higher than those in the radiation workers largely because the children tended to be born in earlier years, when rates were higher, and to men of lower social classes. In comparison with the non-Sellafield cohort there were significantly more stillbirths than expected for the radiation worker cohort (115·0 stillbirths predicted [95% CI 100·6–129·3]; 130 observed). Our analysis was of stillbirth risk to radiation workers defined as men who had received an occupational radiation exposure in the time before conception. When moving from annual dose records (in the cohort study) to film badge records (in the case-control study), six births (five liveborn and one stillborn) included in the cohort study proved not to have had a dose in the preconception period and so were excluded from the study. Doyle and colleagues are mistaken in suggesting that men with a zero 90 day dose were excluded from the analyses. There were four men who each had two stillborn babies and, as reported, we looked at
THE LANCET • Vol 355 • February 5, 2000
familial effects by means of a variance components model, which showed little effect. We were concerned about the misclassification of birth order, especially in early years, and we have done several subanalyses and none suggested an undue influence. The results of the post 1961 analysis, in which misclassification of birth order was less of a difficulty, were very similar to those including the 1950s data (see table 5). Doyle and colleagues are concerned about identification of children. Respondents to the validation questionnaire included both past and present employees from Sellafield. The error rate, as reported, was less than 2%. This error rate was achieved by a careful process which included comparison of spouse information, occupation and, for parents born after 1969, place of birth. There were 278 mothers (501 liveborn children, six stillbirths) who were radiation workers before conception (dose range 0·08–159·9 mSv). With such small numbers and low exposure, we were unable to show a significant effect (odds ratio at 100 mSv 5·13 [95% CI 0·083–31·77], likelihoodratio-test statistic p=0·136). Paul Selby suggests that we claim the paternal preconceptional irradiation at Sellafield has led to a substantial increase in stillbirths. We reported a robust statistical association between father’s paternal preconceptional irradiation and stillbirth risk in radiation workers in whom there is a significant excess of stillbirths in comparison with the rest of Cumbria. Direct comparison of the human situation with animal models is extremely complicated, especially since there is no animal model in which the exposure pattern observed in long-term workers in the nuclear industry has been adequately replicated. The extrapolation of the association we have observed, over a dose range up to 910 mSv, to a dose of 5000 mSv is meaningless. We agree that we had little data on mothers, but consider that our careful consideration of social class, father’s age, and birth order did contribute to a consideration of some maternal factors to the analysis. To affect our results, any remaining maternal risk factor would need to be highly correlated with father’s radiation exposure independent of social class and the other covariates we considered. *Louise Parker, Alan W Craft, Mark S Pearce, Heather O Dickinson Department of Child Health, The Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK
Sir—The report by Louise Parker and colleagues1 of a dose-response relation between fathers’ preconception radiation dose and the subsequent risk of stillbirth is unusual and would be easier to assess if we knew whether or not there had been a significant excess of stillbirths among the radiation workers. We are told that the model they used, based on 3468 stillbirths of 235 316 total births in Cumbria to non-Sellafield workers, predicted 18·1 stillbirths to non-radiation workers at Sellafield against 21 observed and 99·9 stillbirths among children conceived before their fathers’ employment at Sellafield against 96 observed. However, we do not know how many stillbirths were predicted for the radiation workers whose babies were conceived after first employment against an observed number of 130. It would be helpful to know what the predicted number was and the 95% confidence limit of the resultant stillbirth ratio. Richard Doll CTSU, Harkness Building, Radcliffe Infirmary, Oxford OX2 6HE, UK 1
Parker L, Pearce MS, Dickinson HO, et al. Stillbirths among the offspring of male radiation workers at the Sellafield nuclear reprocessing plant. Lancet 1999; 354: 1407–14.
Sir—The radiation workers in Louise Parker and colleagues’ study1 had total cumulative external preconceptional doses in the range 0·01–911 mSv with a median of 30·1 mSv. Of the 9208 births to the partners of these men, 130 were stillborn and the statistical models derived by the researchers predict that up to 31·9 of these might be attributable to the radiation exposure received by the fathers. By contrast, studies on the offspring of the Japanese atomic bomb survivors have failed to find any significant association with parental radiation exposure for a range of adverse pregnancy outcomes and other measures of possible genetic effects.2 In the atomic bomb studies, stillbirths alone, with maternal age and parity taken into account, were analysed and no association with paternal dose was shown. Studies of somatic mutations in Sellafield workers, who received low dose chronic exposure, consistently indicate lower yields in comparison with similar studies on the acutely exposed Japanese atomic bomb survivors.3,4 Chromosome analysis of peripheral blood lymphocytes for stable aberrations revealed frequencies per unit dose a factor of six lower than those seen in atomic bomb survivors.3
493
CORRESPONDENCE
Studies of mutations in hypoxanthineguanine phosphoribosyltransferase and glycophorin A have shown no significant increases in the Sellafield workers3,4 in contrast with the raised frequencies seen in those exposed to radiation from the atomic bombs. Also, animal studies have established a reduction in effect for chronic exposure on gonadal cells, which indicates that the genetic effect of chronic exposure to spermatogonia is about a third that induced by acute irradiation.5 Thus, whether the statistical association found by Parker and colleagues represents a real biological effect is doubtful. E Janet Tawn Westlakes Research Institute, Cumbria CA24 3JY, UK 1
2
3
4
5
Parker L, Pearce MS, Dickinson HO, et al. Stillbirths among the offspring of male radiation workers at the Sellafield nuclear reprocessing plant. Lancet 1999; 354: 1407–14. Neel JV, Schull WJ. The children of Atomic bomb survivors. Washington DC: Natl Acad Press, 1991. Tucker JD, Tawn EJ, Holdsworth D, et al. Biological dosimetry of radiation wokers at the Sellafield nuclear facility. Radiat Res 1997; 148: 216–26. Cole J, Arlett CF, Green MHL, et al. Mutant frequencies in workers at the Sellafield installation. Health Phys 1995; 68: 388–93. United Nations scientific committee on the effects of atomic radiation, sources and effects of ionising radiation (UNSCEAR 1993 Report). New York: United Nations: 1993.
Thalamic perfusion in reflex sympathetic dystrophy syndrome Sir—Mitsutaka Fukumoto and colleagues (Nov 20, p 1790)1 used single photon emission computed tomography (SPECT) to visualise changes in thalamic perfusion contralateral to the side of pain in patients with reflex sympathetic dystrophy syndrome (RSDS). However, before postulating new central mechanisms of pathogenesis of RSDS, the implication that the sympathetic nervous system has a part in its aetiology needs to be reconsidered. The International Association for the Study of Pain has defined RSDS under a heading of complex regional pain syndrome (CRPS) type I as opposed to causalgia, involving nerve damage, which is CRPS type II.2 Hence, sympathetic instability would not be expected to correlate with thalamic perfusion as Fukumoto and colleagues found in their study.
494
Fukumoto and colleagues found a strong correlation between contralateral thalamic perfusion and time since onset of symptoms, suggesting an initial increase in thalamic activity and then a gradual decrease. A similar spectrum of change in thalmic activity has been reported in other chronic pain conditions, from an increase in thalamic activity in central post-stroke pain3 to a decrease in thalamic activity in chronic neuropathic pain.4 Care must be taken when interpreting the results from one point in time and from a few patients. However, the possibility of temporal variation in thalamic activity with ongoing chronic pain may explain the variation in thalamic perfusion seen in other studies3,4 previously explained as heterogeneity of chronic pain pathophysiology. If such gross changes do occur in the central pain pathways over time, interpretation of functional brain imaging will be fraught with difficulties because results would be affected by time from onset of symptoms. Reversal of changes in thalamic activity by alteration of sensory input, rather than monitoring changes per se, may yield information on the pathogenesis of chronic pain. In a study by Di Piero and colleagues,5 perfusion in the contralateral hemithalamus was restored in five patients with unilateral, severe, chronic cancer pain by interrupting the ascending spinothalamic tract of the spinal cord. Hence, it may be difficult to separate changes in the thalamus from neuronal activity of afferent thalamic connections. Emma Chojnowska Pain Clinic, Frenchay Hospital, Frenchay, Bristol BS16 1LE, UK 1
2
3
4
5
Fukumoto M, Ushida T, Zinchuk VS, Yamamoto H, Yoshida S. Contralateral thalamic perfusion in patients with reflex sympathetic dystrophy syndrome. Lancet 1999; 354: 1790–91. Mersky H, Bogduk N, eds. Classification of chronic pain, 2nd edn. Seattle: ISAP Press, 1994. Cesaro P, Mann MW, Moretti JL, et al. Central pain and thalamic hyperactivity: a single photon emission computerized tomographic scan. Pain 1991; 47: 329–36. Iadarola MJ, Max MB, Berman KF, et al. Unilateral decrease in thalamic activity observed with positron emission tomography in patients with chronic neuropathic pain. Pain 1995; 63: 55–64. Di Piero V, Jones AKP, Iannotti F, et al. Chronic pain: a PET study of the central effects of percutaneous high cervical cordotomy. Pain 1991; 46: 9–12.
Sir—In their study involving singlephoton emission computed tomography (SPECT), Fukumoto and colleagues1 describe a correlation
between contralateral thalamic iodoamphetamine uptake index and time from onset of reflex sympathetic dystrophy syndrome (RSDS). Their findings help us understand more about RSDS and the plasticity of the brain in general. Their paper may have a widespread impact on the world of neuroscience. We urge Fukumoto and colleagues to test their findings in a larger patient group stratified in the different timely subgroups and to re-evaluate the data by Statistical Parametric Mapping (SPM) to be able to carry out the region-of-interest (ROI) analysis. This SPM software package, freely available via the Internet, comes from the Wellcome Department of Cognitive Neurology, London, UK, and has helped standardise measurement and data analysis in functional neuroimaging. This package not only spatially normalises the images to the stereotaxic atlas by Talairach and Tournoux,2 but can also carry out statistical analyses on study groups on a voxel-by-voxel basis.3 This package allows reliable and objective image handling that could improve interstudy variability, which often causes difficulties in ROI analysis. Cerebral reactions to peripheral diseases can also be found in patients with chronic symptoms after a distortion of the cervical spine. Such distortion can result in perfusion deficits in the posterior parietal occipital region, possibly because of nociceptive afferents from the upper cervical spine causing an increased vasopeptide production, which results in a vasoconstriction of the major cerebral arteries and the vulnerable posterior watershed region.4 Cerebral de-afferentiation phenomena can also be found in patients after a spinal cord injury. In such injuries glucose metabolism might be altered because of a reduction or loss of sensorimotor function and increased glucose metabolism in brain regions involved in attention and initiation of movement, possibly as a result of secondary disinhibition of these regions.5 Andreas Otte Obere Lachen 10, D-79110 Freiburg, Germany (e-mail: [email protected]) 1
2
3
Fukumoto M, Ushida T, Zinchuk VS, Yamamoto H, Yoshida S. Contralateral thalamic perfusion in patients with reflex sympathetic dystrophy syndrome. Lancet 1999; 354: 1790–91. Talairach J, Tournoux P. Co-planar Stereotaxic Atlas of the Human Brain. Stuttgart: Thieme, 1988. Friston KJ, Holmes AP, Worsley KJ, Poline JB, Frith CD, Frackowiak RSJ. Statistical parametric maps in functional imaging: a general approach. Hum Brain Mapping 1995; 2: 189–210.
THE LANCET • Vol 355 • February 5, 2000