351
Childhood deaths in Africa: uses and limitations of verbal autopsies
The verbal autopsy (VA) is an epidemiological tool that is widely used to ascribe causes of death by interviewing bereaved relatives of children who were not under medical supervision at the time of death. This technique was assessed by comparison with a prospective survey of 303 childhood deaths at a district hospital in Kenya where medically confirmed diagnoses were available. Common causes of death were detected by VA with specificities greater than 80%. Sensitivity of the VA technique was greater than 75% for measles, neonatal tetanus, malnutrition, and trauma-related deaths; however, malaria,
anaemia,
acute
respiratory-tract
infection,
and meningitis were detected with sensitivities of less than 50%. There may have been unwarranted optimism in the ability of VAs to detect some of the major causes of death, such as malaria, in African children. VA used in malaria-specific intervention trials should be interpreted with caution and only in the light of known sensitivities and specificities.
gastroenteritis,
Introduction Death rates in infancy and early childhood are unacceptably high in tropical Africa. Ironically, it is for this part of the world that least is known about the causes of childhood mortality. To allocate limited resources appropriately and to evaluate the effects of disease-specific interventions, it is important to know what proportion of childhood deaths in an area are due to specific, preventable
Although community-based disease-prevention are costly, their primary objectives, such as reducing particular causes of death, are rarely evaluated. In Africa, the paucity of reliable mortality data stems from a lack of comprehensive records of demographic events. Overall childhood mortality is usually estimated by indirect demographic techniques applied retrospectively to census causes.
programmes
and other survey data. Most childhood deaths occur at home and information on cause of death is not usually available. In some areas, cause-specific mortality has been estimated from data obtained by verbal autopsies (VAs). VAs are based on interviews with bereaved relatives by doctors, nurses, or lay persons. Questions are asked about the child’s symptoms during terminal illness and the information collected is reviewed independently by one or more physicians, who assign probable causes of death. It is common practice to have three doctors review the data and for cause of death to be attributed to a consensus between at least two of the reviewers.1 The VA technique has been used in descriptive studies2-9 and in controlled trials of disease-specific interventions.11’s
The World Health Organisation recommends that VAs are used to assign cause of death in trials of malaria-control strategies.16,17 Although this technique may be the only means of establishing levels of cause-specific mortality in parts of rural Africa, its reliability as a diagnostic tool has not been established. Three studies to validate VAs have been done, each of which used retrospective reviews of hospital records as the reference standard.18-2O In the Philippines, Kalter et all obtained the records of 164 children who had died in hospital from acute lower-respiratory-tract infection, measles, diarrhoea, or neonatal tetanus. The parents of these children were traced (between 7 and 304 days after the death) and a VA was administered. The hospital and VA derived diagnoses were compared by specific algorithms. The four disease conditions were diagnosed by VA with sensitivities and specificities greater than 78 %, except for acute lower-respiratory-tract infection which had a specificity of 41 %. Unfortunately, this study provides no information on several important African diseases, most notably malaria. Two studies from Africa are of limited value because of their small sample sizes (39 deaths in Kenya19 and 20 deaths in Liberia2O), incompleteness of follow-up, or lack of corroborative laboratory data. We report prospective surveillance of paediatric admissions and deaths in a Kenyan district hospital and subsequent testing of the VA technique with special reference to malaria.
Patients and methods
Prospective surveillance of children admitted to hospital Kilifi District Hospital is situated 60 km north of Mombasa on the Kenyan Coast. About 2750 patients aged 0-11 years are admitted to the paediatric ward each year. Between May, 1989, and July, 1991, all children were examined on admission and during their stay in hospital by a doctor from the Kenyan Medical Research Institute (KEMRI). The following details were recorded: age, presenting symptoms, clinical fmdings (including chest radiographs when done), and laboratory investigations. A blood sample for detection of malaria parasites and measurement of haemoglobin and total nucleated cells (Coulter Electronics, Luton, UK) was taken routinely on admission. Additional investigations, including lumbar puncture, blood culture, other microbiological investigations, and clinical chemistry, were done when indicated. When a child died in hospital, clinical and laboratory fmdings were reviewed by the clinical team who assigned up to two causes of death ADDRESSES Kenyan Medical Research Institute, Coastal Unit, Kilifi, Kenya (R W Snow, PhD, M. T. Winstanley, MD, V. M. Marsh, MRCGP, C R J C. Newton, MRCP, C. Waruiru, MB, I Mwangi, MB, P. A Winstanley, MRCP, K Marsh, MRCP); Nuffield Department of Clinical Medicine, Oxford University, John Radcliffe Hospital, Oxford, UK (R. W Snow, D Forster, PhD, C R. J C. Newton, P. A. Winstanley, K Marsh); and Tropical Health Epidemiology Unit, Department of Epidemiology and Population Sciences, London School of Hygiene and Tropical Medicine, London (J R. M. Armstrong, MSc). Correspondence to Dr Bob Snow, KEMRI Coastal Unit, PO Box 230, Kilifi, Kenya
352
that were coded according to the International Classification of Diseases (ICD).21 Two causes were assigned if they were judged to be either co-primary and separate (eg, measles and severe anaemia) or potentially related but distinct clinical entities (eg, kwashiokor and acute gastroenteritis). Underlying causes of death were recorded rather than physiological end-points such as cardiorespiratory arrest. When there was insufficient evidence to ascribe a cause of death confidently, the cause was classified as undetermined.
Development of VA
TABLE 1-HOSPITAL AND VA DERIVED CAUSES OF DEATH IN 303 CHILDREN ADMITTED TO HOSPITAL
interviews
to succeed, clinical and lay concepts of used to describe particular signs and symptoms must coincide. A detailed understanding of local languages is needed before a VA can be implemented. To reduce possible interview ambiguities pilot studies were done. A list of all likely symptoms and clinical signs was translated from English into the local vernacular by four hospital staff. These translations were then shown to five more staff who independently translated back into English. Phraseology was further refined by interviewing more than 600 mothers about symptoms noted during the child’s physical examination on admission to the paediatric ward. During these "recognition" interviews, clinical photographs were used as aide memoirs: these included jaundiced sclera, foot oedema, hair and skin changes of kwashiorkor, intercostal recession, desquamating measles rash, opisthotonic positioning, and pallor of the nail beds. The results of these studies were used to develop the vernacular for the VA interviews. Detailed results will be presented elsewhere.
For. the VA interview
terms
Implementation of the
VA
questionnaire
The VA questionnaire was divided into four parts: demographic details including date of birth and death; an open-ended section to record the mother’s unprompted description of the illness that led to the child’s death; a precoded section of prompted responses about specific symptoms and signs relating to the illness, where the clinical photographs were used as aide memoirs; and a section to record all relevant information from the health card (a card recording details of child welfare and clinic and vaccination attendances). Interviews were conducted in the first language of the interviewee by field workers fluent in that language and trained in the use of the appropriate vernacular. Field workers were unaware of the hospital diagnosis of the cause of death. Efforts were made to interview the relative who had closest contact with the child during the terminal illness, usually the mother. With the child’s identification information obscured, except for age and date of death, each completed questionnaire was reviewed independently by three doctors with local paediatric experience. Each ascribed one or two probable causes of death, from which consensus cause (or causes) of death was established when any two doctors agreed. Correspondence between the consensus diagnosis derived from the VA and the cause assigned at the time of death was analysed. Sensitivity, specificity, and positive predictive values were calculated. Neonatal deaths (within 28 days of birth) were considered separately, as is often done during community-based investigations of mortality.
*Defmrt)ons used to describe each diagnostic category will be provided by authors on request ARI =acute respiratory-tract infection flncludes 65 deaths in post-neonatal period and 12 neonates 7 children included in the undetermined category because no consensus was reached between any two clinicians
March, 1990, and 75% of all deaths from April, 1990, to November, 1991. This resulted in a slight over-
representation of malaria: 47 of 303 (16%) deaths in our study were due to malaria compared with 75 of 640 (11%) hospital paediatric deaths during the same period. This discrepancy was not known to the participating doctors. Of the 303 deaths, 226 (75%) had one and 77 (25%) had two causes of death recorded in hospital (23 co-primary diagnoses and 54 potentially related but distinct clinical entities). Causes of death were amalgamated to form broad categories for neonatal and post-neonatal deaths (table r). Deaths due to anaemia were classified as malaria if they occurred in relation to an acute illness with a peripheral parasitaemia and in the absence of any other clear cause for the anaemia; otherwise, they were classified as anaemia. The malnutrition category comprised kwashiorkor (60%), marasmic kwashiorkor (34%), and marasmus (6%). The measles category included children who died during an acute attack of measles, and others who presented with clear signs of recent measles but in whom the reason for admission TABLE II-SENSITIVITIES, SPECIFICITIES, AND PREDICTIVE VALUES OF VA INTERVIEWS COMPARED WITH
HOSPITAL DERIVED DIAGNOSIS*
Results Interviews with parents or guardians were completed for 303 deaths that occurred on the paediatric ward during the study period. Parents often stated that the health card had been destroyed after the child’s death and only 9 cards (3%) could be traced at home. Most interviews (92%) were conducted with one of the child’s parents; 8%, 35%, and 75 % were conducted’within 1 week,1 month, and 4 months, respectively, of death. VAs could only be done for children whose addresses were accurately recorded. Because of concurrent malaria research in the hospital, deaths for which accurate addresses were known before April, 1990, were predominantly caused by malaria. Thus, we followed up 47% of all deaths on the paediatric ward from May, 1989, to
*Calculations available from R. W S
353
and subsequent death was a post-measles complication such as acute respiratory-tract infection (ARI). When reviewing information recorded by the VA, a consensus was nearly always reached: 277 (91 %) had a single consensus diagnosis and 19 (6%) had a multiple consensus diagnosis. When considered in terms of the broad diagnostic categories, a consensus diagnosis was reached in 296 (98%) cases. For individual diagnoses, consensus was achieved in 283 (93%) cases. Table u shows the extent to which VA correctly identified (sensitivity) and correctly excluded (specificity) the broad categories of hospital diagnoses, and the positive predictive values of the VA technique. The doctors who reviewed the VA questionnaires were not asked to refine the malaria diagnoses into distinct clinical syndromes of cerebral malaria, malaria anaemia, and other forms of lifethreatening malaria. However, VA was more sensitive for cerebral malaria than the other types: VA detected as malaria 16 of 26 (62%) hospital diagnoses of cerebral malaria (comatose children who were unable to localise pain 23), but only 5 of the 12 (42%) deaths defmed in hospital as malaria anaemia.
Discussion The VA technique carries an underlying assumption that each disease category has a distinct pattern of symptoms and signs and that these can be reported accurately by lay respondents. The extent to which these assumptions could potentially alter the interpretation of VA fmdings is discussed in detail elsewhere.23 We have attempted to attribute cause of death unequivocably during a prospective surveillance of paediatric admissions to a Kenyan district hospital that has excellent laboratory facilities, and compared cause of death established in this way with that determined by VA. Only measles, neonatal tetanus, malnutrition, and accidents were detected by VA with sensitivities and specificities above 75 % and positive predictive values above 65%. Measles, neonatal tetanus, and accidents are welldefined syndromes that produce symptoms and signs that are readily recognised by the local population and VA may therefore be a useful tool to describe them during community-based surveys. In the Philippines, 18 VA had a sensitivity of 98% for measles and 100% for neonatal tetanus when compared retrospectively with hospital notes. The situation with malnutrition is more complex because the immediate cause of death can often be a supervening acute event such as septicaemia or respiratory infection. Nevertheless, in public-health terms it seems reasonable to concentrate on the underlying condition that appears to have distinct features that are well recognised by VAs. Maternal recognition and recall of malnutrition-related clinical signs may be less reliable in some communities, depending on the cultural interpretation of these states.23 In these situations, clinical photographs may prove a useful addition to VA by
promoting recognition. VA was less successful when applied to malaria, anaemia, gastroenteritis, meningitis, and ARI, which together account for 40% of the diagnoses of post-neonatal deaths at Kilifi hospital. Sensitivities were below 50% for each of these causes of death. These diseases often share symptoms. For example, of the 7 hospital-diagnosed malaria anaemia deaths misclassified by VA, 5 were recorded as ARI. Dyspnoea in young febrile children is common to both malaria anaemia and ARI and the distinction is difficult to make even with the help of laboratory investigations and
radiology. Similarly, both cerebral malaria and meningitis commonly present as short-duration febrile illnesses with seizures and coma. 6 of the 10 misclassified cerebral malarias in this study were recorded as meningitis by VA. The finding that despite low sensitivity, specificities for these common conditions were greater than 85% may lead to a misleadingly optimistic view of the success of VA because specificity is greatly increased by the inclusion of a group of syndromes (measles, malnutrition, and accidents) that are not likely to cause confusion. More relevant is the positive predictive value, a measure of how often a positive response is likely to be correct. Because the VA diagnosis is derived from the consensus of three doctors, the technique is likely to lack sensitivity in detecting multiple causes of death. Although 77 children in our study had two causes of death, only 10 (13%) were assigned two causes of death through VA. No combination of causes was common enough to enable us to assess sensitivity and specificity of VA for multiple causes of death. When analysis was restricted to children with single causes of death, the sensitivity of all categories except gastroenteritis increased, as might be expected. Specificity was, however, not much affected, suggesting that VA can correctly exclude a cause of death when children die of more than one underlying cause. Our primary interest in this study was to test the validity of the VA concept per se-ie, to determine whether it is possible to use historical information from bereaved parents to distinguish between common causes of death in childhood. Such a study could only be undertaken in a hospital population in which we were able to determine the true cause of death; however, the performance of VAs may be different when the technique is used in the
community One proposed use of VAs is to mortality rates. Before attempting
estimate cause-specific this it is undoubtedly useful to have an indication of which causes of death are likely to be suited to the VA approach. In Kilifi District VA surveys identified malnutrition-related deaths well (sensitivities, specificities, and positive predictive values above 85%), but performed poorly for ARI, gastroenteritis, and meninigitis. Caution should be excercised, however, in generalising these results to deaths occurring outside the hospital for two important reasons. Firstly, the natural history of terminal illness may be different for deaths in hospital and for deaths in the community. This cannot be known in advance, although it may become apparent if VAs in the community produce a pattern of symptoms quite different from that seen in hospital. Secondly, although it could be argued that taken as a whole VA at least produces an appropriate rank ordering of diagnoses (table I), it should be recognised that doctors are likely to be influenced by their experience of disease prevalence in hospitals when using VA. The prevalence of different causes of death may be different in the community; indeed, if it were not there would be no need for VAs as simple extrapolation from hospital-based data would be adequate. This is an area that requires further investigation even in the case of diagnostic categories that appear to be amenable to a VA approach. Another proposed use for VAs is for monitoring the impact of community-based interventions. Here the problem of accurately establishing true cause-specific death rates is less important than measuring the protective efficacy (PE) of an intervention from the ratio of death rates in two groups. A VA with specificity of 100%-ie, no false positives-and sensitivity of less than 100% will result in
354
Estimated
How and when should VAs be used? There is no single but there may have been an unwarranted degree of optimism over their general applicability. In this study, the performance of VAs in diagnosing several important causes of childhood mortality was disappointing. This may not disbar VA in specific circumstances, but use of VA should be based on locale-specific studies such as that described here and on an appreciation of the limitations inherent in the technique. For those causes of death that do not perform well with VAs, we need to consider other approaches. In community trials of interventions, hospital data may be more reliable in assessing effectiveness against specific
protective efficacy
answer
causes
of death.
This study was funded by the Overseas Development Administration Research Scheme R4672 and the Wellcome Trust. We thank Mr P. Warn and the other members of the laboratory support team at Kilifi, Ms Grace Bomu and Ms Christine Nyamawi for their sympathetic handling of interviews with bereaved relatives, and Dr Ben Were and Dr N. Peshu for their support of the KEMRI Kilifi unit. We also thank Prof Peter Smith, Mr Richard Hayes, and Dr Brian Greenwood for useful comments on the text. R. W. S. is a Well come Senior Fellow in basic biomedical sciences and K M is a Wellcome Senior Fellow in clinical science. This paper is published with the permission of the Director of KEMRI.
(UK)
REFERENCES 1.
True
10, 1990.
protective efficacy
Effect of sensitivity, specificity, and prevalence of PE in an intervention trial.
Gray RH, Smith G, Barass P. The use of verbal autopsies to determine selected causes of death in children. Baltimore: Johns Hopkins University School of Hygiene and Public Health Occasional Paper No
on
estimates
Figure shows true and estimated PE from a VA with 50% sensitivity and 90% specificity. Dashed line represents underestimation of PE for a disease that causes 20% of child deaths; dotted line is for a disease that causes 10% of deaths For reference, the solid line shows true PE equal to estimated PE (no bias). The relation between true and estimated PE depends on m, the proportion of the deaths due to a specific cause, sens (sensitivity of VA); and spec (specificity of VA) Thus estimated PE= (true PE x m x sens) - ([m x sens] + [1 - m] x [1 -spec]).
loss of power, but the estimate of PE will be unbiased.
However, if specificity is less than 100%, the PE estimate will be biased: it will be underestimated by a factor that depends on specificity, sensitivity, and the proportion of deaths due to the disease of interest (figure). The following hypothetical example illustrates the likely scale of effects. We found the sensitivity and specificity of VA for deaths due to malaria to be 46% and 89%, respectively. If 30% of all post-neonatal deaths in the local childhood population are due to malaria, and if the sensitivity and specificity from our hospital-based study were applied in the community, then a study designed to estimate a PE of 70% against malaria deaths would be expected to result in an estimated PE of only 45%. A recent trial of insecticide-treated bed nets in The Gambia" indicated a 63% and 70% PE for overall childhood mortality and malaria-specific mortality, respectively. After malaria, ARI was the second most reduced specific cause of mortality (B. Greenwood, personal communication). The authors suggest that the reduction in causes of death other than malaria was due either to malaria’s indirect contribution to other causes of death or to an underestimation of the true malaria mortality as described by the VA technique. Both are plausible explanations but our findings and the theoretical considerations discussed above lend support to the latter view.
2. Greenwood BM, Greenwood AM, Bradlley AK, et al. Deaths in infancy and early childhood in a well-vaccinated, rural, West African population. Ann Trop Paediatr 1987; 7: 91-99. 3. Fivawo M. Indigenous concepts of malaria and malaria control in Tanzania. In: Buck AA, ed. Practical considerations on malaria vaccines and clinical trials. Washington: American Institute of Biological Sciences, 1986: 76-81. 4. Omondi-Odhiambo AM, Voorhoeve AM, Van Ginneken JK. Agespecific infant and childhood mortality and causes of death. In: Van Ginneken JK, Muller AS, eds. Maternal and child health in rural Kenya: an epidemiological study. Sydney: Croom Helm, 1984. 5. Gaurenne M, Fontaine O. Assessing probable causes of death using a standardised questionnaire. A study in rural Senegal. Seminar on comparative studies of mortality and morbidity: old and new approaches to measurement and analysis. Siena: International Union for the Scientific Study of Population and the Institute of Statistics, University of Siena, 1986. 6. Moir JS, Garner PA, Heywood PF, Alpers MP. Mortality in a rural area of Madang Province, Papua New Guinea. Ann Trop Med Parastitol 1989; 83: 305-19. 7. Chen LC, Rahman M, Sarder AM. Epidemiology and causes of death among children in a rural area of Bangladesh. Int J Epidemiol 1980, 9: 25-33. 8. Fauveau V, Wojtyniak B, Koenig MA, Chakraborty J, Chowdhury AI Epidemiology and cause of death among women in rural Bangladesh. Int J Epidemiol 1989; 18: 139-45. 9. Victora CG, Smith PG, Vaughan JP, et al. Evidence of protection by breast feeding against infant deaths from infectious diseases in Brazil Lancet 1987; ii: 319-21. 10. Greenwood BM, Greenwood AM, Bradley AK, et al. Comparison of two strategies for control of malaria within a primary health care programme in The Gambia. Lancet 1988; i: 1121-27. 11. Alonso PL, Lindsay SW, Armstrong JRM, et al. The effect of insecticide treated bed nets on mortality of Gambian children. Lancet 1991, 337: 1499-1502. 12. Spencer HC, Kaseje DCO, Mosely WH, et al. Impact on mortality and fertility of a community-based malaria control programme in Saradidi, Kenya. Ann Trop Med Parasitol 1987; 81 (suppl): 36-45. 13. Bang AT, Bang RA, Tale O, et al. Reduction in pneumonia mortality and total childhood mortality by means of community-based intervention trials in Gadchiroli, India. Lancet 1990; 336: 201-06. 14. Velema JP, Alihonou EM, Gandaho T, et al. Childhood mortality among users and non-users of primary health care in a rural West Afncan community. Int J Epidemiol 1991; 20: 474-79. 15. Mtango FDE, Neuvians D. Acute respiratory infections in children under five years. Control project in Bagamoyo District, Tanzania. Trans R Soc Trop Med 1986; 80: 851-58.
355
16. World Health Organisation. Guidelines for the evaluatin of Plasmodium falciparum asexual blood-stage vaccines in populations exposed to natural infection. Geneva: WHO Publication TDR/MAP/AVE/ PF189.5, 1989. 17. World Health Organisation. Guidelines for the development of protocols for studies to evaluate the impact of insecticide-impregnated bed-nets on mortality. Geneva: WHO, 1991. 18. Kalter HD, Gray RH, Black RE, Gultiano A. Validation of post-mortem interviews to ascertain selected causes of death in children. Int J Epidemiol 1990; 19: 380-86. 19. Mirza NM, Macharia WM, Wafula EM, et al. Verbal autopsy: a tool for
determining cause of death in a community. East Afr Med J 1990; 67: 693-98. 20. 21.
Pacque-Maragolis S, Pacque M, Dukuly Z, et al. Application of the verbal autopsy during a clinical trial. Soc Sci Med 1990; 31: 585-91. World Health Organisation. Manual of the International Statistical
Classification of Diseases, Injuries and Causes of Death. Geneva: 1977. 22. Warrel DA, Molyneux ME, Beales PF. Severe and complicated malaria. Trans R Soc Trop Med Hyg 1990; 84 (suppl 2): 1-65. 23. Snow RW, Marsh K. How useful are verbal autopsies to estimate childhood causes of death? Health Policy and Planning 1992; 7: 67-71.
WHO,
CLINICAL PRACTICE Classical
migraine: symptoms between visual aura and headache onset
The gap between the end of the visual aura and headache onset in classical migraine has been called the free interval. In a retrospective study of twentyfive migraineurs who had noted a gap, only three reported feeling normal at that time: twenty-two described alterations in mood, detachment from the environment or other people, fears, disturbances of speech or thought, or somatic symptoms. The interval lasted less than an hour in seventeen of the twenty-two but in five persisted for 1 to 5 hours. These symptoms suggest involvement of the frontal and temporal cortices as well as the hypothalamus; they do not conform to Leão’s spreading depression or a vascular mechanism, but are in keeping with a diffuse cerebral process with focal manifestations.
surroundings"; "away from everything"; "not with it"; "spread out-as though a barrier between me and others"; "curious feeling of unreality". One general practitioner said that she had never told anyone about the sensations during this phase of her migraines, because she felt herself to be insane during these intervals that in her case lasted 20-30 minutes; she expressed relief at discovering that she was not SYMPTOMS IN 25 PATIENTS BETWEEN END OF AURA AND BEGINNING OF HEADACHE
A colleague had migraine attacks only after competitive games of soccer: he described a visual aura lasting 20 minutes, followed by 30 minutes during which he felt
"euphoric and wrapped in cotton wool-less in contact with reality"; then his headache began. Until hearing and listening to this history, I had assumed that migraineurs were symptomless during the aura/headache interval (the "free interval") and paid no attention to this phase of attacks. Patients with migraine and a visual aura seen at initial or follow-up consultations were asked directly, "Does your headache begin during or immediately after the end of your visual aura?"; the same question was posed to medical colleagues known to have classical migraine. During four talks to general practitioners, those with classical migraine after the lecture and I put the same question to these. Twenty-five (about one-third of those interviewed) had experienced a gap between the end of the visual aura and the onset of headache. These individuals were asked to describe how they felt during that interval and to estimate its duration. The subjects were eight men and seventeen women aged 29-68 (mean 42) years. Twenty estimated the gap at 10-60 minutes, five at over 1 hour (up to 5 hours). Twenty-two subjects reported symptoms in the visual-aura/headache interval, but most had difficulty describing them, using expressions such as "very strange, unreal, removed from were
invited
to come
and
5 had 1 symptom, 11 had 2, 2 had
3, and 4 had
4
see me
alone. Another curious symptom was impaired body movement or clumsiness: two experienced car drivers would not drive during this interval fearing an accident; a 31-year-old physician perceived his limbs as being heavy and slow-moving. The symptoms in the affected twentytwo are listed in the table. In three individuals the symptoms in the gap resembled those during the premonitory phase before onset of the visual aura. ADDRESS National Hospital for Neurology and Neurosurgery, Queen Square, London WC1 N 3BG, UK (Dr J. N Blau, FRCP).
Childhood deaths in Africa: uses and limitations of verbal autopsies
The verbal autopsy (VA) is an epidemiological tool that is widely used to ascribe causes of death by interviewing bereaved relatives of children who were not under medical supervision at the time of death. This technique was assessed by comparison with a prospective survey of 303 childhood deaths at a district hospital in Kenya where medically confirmed diagnoses were available. Common causes of death were detected by VA with specificities greater than 80%. Sensitivity of the VA technique was greater than 75% for measles, neonatal tetanus, malnutrition, and trauma-related deaths; however, malaria,
anaemia,
acute
respiratory-tract
infection,
and meningitis were detected with sensitivities of less than 50%. There may have been unwarranted optimism in the ability of VAs to detect some of the major causes of death, such as malaria, in African children. VA used in malaria-specific intervention trials should be interpreted with caution and only in the light of known sensitivities and specificities.
gastroenteritis,
Introduction Death rates in infancy and early childhood are unacceptably high in tropical Africa. Ironically, it is for this part of the world that least is known about the causes of childhood mortality. To allocate limited resources appropriately and to evaluate the effects of disease-specific interventions, it is important to know what proportion of childhood deaths in an area are due to specific, preventable
Although community-based disease-prevention are costly, their primary objectives, such as reducing particular causes of death, are rarely evaluated. In Africa, the paucity of reliable mortality data stems from a lack of comprehensive records of demographic events. Overall childhood mortality is usually estimated by indirect demographic techniques applied retrospectively to census causes.
programmes
and other survey data. Most childhood deaths occur at home and information on cause of death is not usually available. In some areas, cause-specific mortality has been estimated from data obtained by verbal autopsies (VAs). VAs are based on interviews with bereaved relatives by doctors, nurses, or lay persons. Questions are asked about the child’s symptoms during terminal illness and the information collected is reviewed independently by one or more physicians, who assign probable causes of death. It is common practice to have three doctors review the data and for cause of death to be attributed to a consensus between at least two of the reviewers.1 The VA technique has been used in descriptive studies2-9 and in controlled trials of disease-specific interventions.11’s
The World Health Organisation recommends that VAs are used to assign cause of death in trials of malaria-control strategies.16,17 Although this technique may be the only means of establishing levels of cause-specific mortality in parts of rural Africa, its reliability as a diagnostic tool has not been established. Three studies to validate VAs have been done, each of which used retrospective reviews of hospital records as the reference standard.18-2O In the Philippines, Kalter et all obtained the records of 164 children who had died in hospital from acute lower-respiratory-tract infection, measles, diarrhoea, or neonatal tetanus. The parents of these children were traced (between 7 and 304 days after the death) and a VA was administered. The hospital and VA derived diagnoses were compared by specific algorithms. The four disease conditions were diagnosed by VA with sensitivities and specificities greater than 78 %, except for acute lower-respiratory-tract infection which had a specificity of 41 %. Unfortunately, this study provides no information on several important African diseases, most notably malaria. Two studies from Africa are of limited value because of their small sample sizes (39 deaths in Kenya19 and 20 deaths in Liberia2O), incompleteness of follow-up, or lack of corroborative laboratory data. We report prospective surveillance of paediatric admissions and deaths in a Kenyan district hospital and subsequent testing of the VA technique with special reference to malaria.
Patients and methods
Prospective surveillance of children admitted to hospital Kilifi District Hospital is situated 60 km north of Mombasa on the Kenyan Coast. About 2750 patients aged 0-11 years are admitted to the paediatric ward each year. Between May, 1989, and July, 1991, all children were examined on admission and during their stay in hospital by a doctor from the Kenyan Medical Research Institute (KEMRI). The following details were recorded: age, presenting symptoms, clinical fmdings (including chest radiographs when done), and laboratory investigations. A blood sample for detection of malaria parasites and measurement of haemoglobin and total nucleated cells (Coulter Electronics, Luton, UK) was taken routinely on admission. Additional investigations, including lumbar puncture, blood culture, other microbiological investigations, and clinical chemistry, were done when indicated. When a child died in hospital, clinical and laboratory fmdings were reviewed by the clinical team who assigned up to two causes of death ADDRESSES Kenyan Medical Research Institute, Coastal Unit, Kilifi, Kenya (R W Snow, PhD, M. T. Winstanley, MD, V. M. Marsh, MRCGP, C R J C. Newton, MRCP, C. Waruiru, MB, I Mwangi, MB, P. A Winstanley, MRCP, K Marsh, MRCP); Nuffield Department of Clinical Medicine, Oxford University, John Radcliffe Hospital, Oxford, UK (R. W Snow, D Forster, PhD, C R. J C. Newton, P. A. Winstanley, K Marsh); and Tropical Health Epidemiology Unit, Department of Epidemiology and Population Sciences, London School of Hygiene and Tropical Medicine, London (J R. M. Armstrong, MSc). Correspondence to Dr Bob Snow, KEMRI Coastal Unit, PO Box 230, Kilifi, Kenya
352
that were coded according to the International Classification of Diseases (ICD).21 Two causes were assigned if they were judged to be either co-primary and separate (eg, measles and severe anaemia) or potentially related but distinct clinical entities (eg, kwashiokor and acute gastroenteritis). Underlying causes of death were recorded rather than physiological end-points such as cardiorespiratory arrest. When there was insufficient evidence to ascribe a cause of death confidently, the cause was classified as undetermined.
Development of VA
TABLE 1-HOSPITAL AND VA DERIVED CAUSES OF DEATH IN 303 CHILDREN ADMITTED TO HOSPITAL
interviews
to succeed, clinical and lay concepts of used to describe particular signs and symptoms must coincide. A detailed understanding of local languages is needed before a VA can be implemented. To reduce possible interview ambiguities pilot studies were done. A list of all likely symptoms and clinical signs was translated from English into the local vernacular by four hospital staff. These translations were then shown to five more staff who independently translated back into English. Phraseology was further refined by interviewing more than 600 mothers about symptoms noted during the child’s physical examination on admission to the paediatric ward. During these "recognition" interviews, clinical photographs were used as aide memoirs: these included jaundiced sclera, foot oedema, hair and skin changes of kwashiorkor, intercostal recession, desquamating measles rash, opisthotonic positioning, and pallor of the nail beds. The results of these studies were used to develop the vernacular for the VA interviews. Detailed results will be presented elsewhere.
For. the VA interview
terms
Implementation of the
VA
questionnaire
The VA questionnaire was divided into four parts: demographic details including date of birth and death; an open-ended section to record the mother’s unprompted description of the illness that led to the child’s death; a precoded section of prompted responses about specific symptoms and signs relating to the illness, where the clinical photographs were used as aide memoirs; and a section to record all relevant information from the health card (a card recording details of child welfare and clinic and vaccination attendances). Interviews were conducted in the first language of the interviewee by field workers fluent in that language and trained in the use of the appropriate vernacular. Field workers were unaware of the hospital diagnosis of the cause of death. Efforts were made to interview the relative who had closest contact with the child during the terminal illness, usually the mother. With the child’s identification information obscured, except for age and date of death, each completed questionnaire was reviewed independently by three doctors with local paediatric experience. Each ascribed one or two probable causes of death, from which consensus cause (or causes) of death was established when any two doctors agreed. Correspondence between the consensus diagnosis derived from the VA and the cause assigned at the time of death was analysed. Sensitivity, specificity, and positive predictive values were calculated. Neonatal deaths (within 28 days of birth) were considered separately, as is often done during community-based investigations of mortality.
*Defmrt)ons used to describe each diagnostic category will be provided by authors on request ARI =acute respiratory-tract infection flncludes 65 deaths in post-neonatal period and 12 neonates 7 children included in the undetermined category because no consensus was reached between any two clinicians
March, 1990, and 75% of all deaths from April, 1990, to November, 1991. This resulted in a slight over-
representation of malaria: 47 of 303 (16%) deaths in our study were due to malaria compared with 75 of 640 (11%) hospital paediatric deaths during the same period. This discrepancy was not known to the participating doctors. Of the 303 deaths, 226 (75%) had one and 77 (25%) had two causes of death recorded in hospital (23 co-primary diagnoses and 54 potentially related but distinct clinical entities). Causes of death were amalgamated to form broad categories for neonatal and post-neonatal deaths (table r). Deaths due to anaemia were classified as malaria if they occurred in relation to an acute illness with a peripheral parasitaemia and in the absence of any other clear cause for the anaemia; otherwise, they were classified as anaemia. The malnutrition category comprised kwashiorkor (60%), marasmic kwashiorkor (34%), and marasmus (6%). The measles category included children who died during an acute attack of measles, and others who presented with clear signs of recent measles but in whom the reason for admission TABLE II-SENSITIVITIES, SPECIFICITIES, AND PREDICTIVE VALUES OF VA INTERVIEWS COMPARED WITH
HOSPITAL DERIVED DIAGNOSIS*
Results Interviews with parents or guardians were completed for 303 deaths that occurred on the paediatric ward during the study period. Parents often stated that the health card had been destroyed after the child’s death and only 9 cards (3%) could be traced at home. Most interviews (92%) were conducted with one of the child’s parents; 8%, 35%, and 75 % were conducted’within 1 week,1 month, and 4 months, respectively, of death. VAs could only be done for children whose addresses were accurately recorded. Because of concurrent malaria research in the hospital, deaths for which accurate addresses were known before April, 1990, were predominantly caused by malaria. Thus, we followed up 47% of all deaths on the paediatric ward from May, 1989, to
*Calculations available from R. W S
353
and subsequent death was a post-measles complication such as acute respiratory-tract infection (ARI). When reviewing information recorded by the VA, a consensus was nearly always reached: 277 (91 %) had a single consensus diagnosis and 19 (6%) had a multiple consensus diagnosis. When considered in terms of the broad diagnostic categories, a consensus diagnosis was reached in 296 (98%) cases. For individual diagnoses, consensus was achieved in 283 (93%) cases. Table u shows the extent to which VA correctly identified (sensitivity) and correctly excluded (specificity) the broad categories of hospital diagnoses, and the positive predictive values of the VA technique. The doctors who reviewed the VA questionnaires were not asked to refine the malaria diagnoses into distinct clinical syndromes of cerebral malaria, malaria anaemia, and other forms of lifethreatening malaria. However, VA was more sensitive for cerebral malaria than the other types: VA detected as malaria 16 of 26 (62%) hospital diagnoses of cerebral malaria (comatose children who were unable to localise pain 23), but only 5 of the 12 (42%) deaths defmed in hospital as malaria anaemia.
Discussion The VA technique carries an underlying assumption that each disease category has a distinct pattern of symptoms and signs and that these can be reported accurately by lay respondents. The extent to which these assumptions could potentially alter the interpretation of VA fmdings is discussed in detail elsewhere.23 We have attempted to attribute cause of death unequivocably during a prospective surveillance of paediatric admissions to a Kenyan district hospital that has excellent laboratory facilities, and compared cause of death established in this way with that determined by VA. Only measles, neonatal tetanus, malnutrition, and accidents were detected by VA with sensitivities and specificities above 75 % and positive predictive values above 65%. Measles, neonatal tetanus, and accidents are welldefined syndromes that produce symptoms and signs that are readily recognised by the local population and VA may therefore be a useful tool to describe them during community-based surveys. In the Philippines, 18 VA had a sensitivity of 98% for measles and 100% for neonatal tetanus when compared retrospectively with hospital notes. The situation with malnutrition is more complex because the immediate cause of death can often be a supervening acute event such as septicaemia or respiratory infection. Nevertheless, in public-health terms it seems reasonable to concentrate on the underlying condition that appears to have distinct features that are well recognised by VAs. Maternal recognition and recall of malnutrition-related clinical signs may be less reliable in some communities, depending on the cultural interpretation of these states.23 In these situations, clinical photographs may prove a useful addition to VA by
promoting recognition. VA was less successful when applied to malaria, anaemia, gastroenteritis, meningitis, and ARI, which together account for 40% of the diagnoses of post-neonatal deaths at Kilifi hospital. Sensitivities were below 50% for each of these causes of death. These diseases often share symptoms. For example, of the 7 hospital-diagnosed malaria anaemia deaths misclassified by VA, 5 were recorded as ARI. Dyspnoea in young febrile children is common to both malaria anaemia and ARI and the distinction is difficult to make even with the help of laboratory investigations and
radiology. Similarly, both cerebral malaria and meningitis commonly present as short-duration febrile illnesses with seizures and coma. 6 of the 10 misclassified cerebral malarias in this study were recorded as meningitis by VA. The finding that despite low sensitivity, specificities for these common conditions were greater than 85% may lead to a misleadingly optimistic view of the success of VA because specificity is greatly increased by the inclusion of a group of syndromes (measles, malnutrition, and accidents) that are not likely to cause confusion. More relevant is the positive predictive value, a measure of how often a positive response is likely to be correct. Because the VA diagnosis is derived from the consensus of three doctors, the technique is likely to lack sensitivity in detecting multiple causes of death. Although 77 children in our study had two causes of death, only 10 (13%) were assigned two causes of death through VA. No combination of causes was common enough to enable us to assess sensitivity and specificity of VA for multiple causes of death. When analysis was restricted to children with single causes of death, the sensitivity of all categories except gastroenteritis increased, as might be expected. Specificity was, however, not much affected, suggesting that VA can correctly exclude a cause of death when children die of more than one underlying cause. Our primary interest in this study was to test the validity of the VA concept per se-ie, to determine whether it is possible to use historical information from bereaved parents to distinguish between common causes of death in childhood. Such a study could only be undertaken in a hospital population in which we were able to determine the true cause of death; however, the performance of VAs may be different when the technique is used in the
community One proposed use of VAs is to mortality rates. Before attempting
estimate cause-specific this it is undoubtedly useful to have an indication of which causes of death are likely to be suited to the VA approach. In Kilifi District VA surveys identified malnutrition-related deaths well (sensitivities, specificities, and positive predictive values above 85%), but performed poorly for ARI, gastroenteritis, and meninigitis. Caution should be excercised, however, in generalising these results to deaths occurring outside the hospital for two important reasons. Firstly, the natural history of terminal illness may be different for deaths in hospital and for deaths in the community. This cannot be known in advance, although it may become apparent if VAs in the community produce a pattern of symptoms quite different from that seen in hospital. Secondly, although it could be argued that taken as a whole VA at least produces an appropriate rank ordering of diagnoses (table I), it should be recognised that doctors are likely to be influenced by their experience of disease prevalence in hospitals when using VA. The prevalence of different causes of death may be different in the community; indeed, if it were not there would be no need for VAs as simple extrapolation from hospital-based data would be adequate. This is an area that requires further investigation even in the case of diagnostic categories that appear to be amenable to a VA approach. Another proposed use for VAs is for monitoring the impact of community-based interventions. Here the problem of accurately establishing true cause-specific death rates is less important than measuring the protective efficacy (PE) of an intervention from the ratio of death rates in two groups. A VA with specificity of 100%-ie, no false positives-and sensitivity of less than 100% will result in
354
Estimated
How and when should VAs be used? There is no single but there may have been an unwarranted degree of optimism over their general applicability. In this study, the performance of VAs in diagnosing several important causes of childhood mortality was disappointing. This may not disbar VA in specific circumstances, but use of VA should be based on locale-specific studies such as that described here and on an appreciation of the limitations inherent in the technique. For those causes of death that do not perform well with VAs, we need to consider other approaches. In community trials of interventions, hospital data may be more reliable in assessing effectiveness against specific
protective efficacy
answer
causes
of death.
This study was funded by the Overseas Development Administration Research Scheme R4672 and the Wellcome Trust. We thank Mr P. Warn and the other members of the laboratory support team at Kilifi, Ms Grace Bomu and Ms Christine Nyamawi for their sympathetic handling of interviews with bereaved relatives, and Dr Ben Were and Dr N. Peshu for their support of the KEMRI Kilifi unit. We also thank Prof Peter Smith, Mr Richard Hayes, and Dr Brian Greenwood for useful comments on the text. R. W. S. is a Well come Senior Fellow in basic biomedical sciences and K M is a Wellcome Senior Fellow in clinical science. This paper is published with the permission of the Director of KEMRI.
(UK)
REFERENCES 1.
True
10, 1990.
protective efficacy
Effect of sensitivity, specificity, and prevalence of PE in an intervention trial.
Gray RH, Smith G, Barass P. The use of verbal autopsies to determine selected causes of death in children. Baltimore: Johns Hopkins University School of Hygiene and Public Health Occasional Paper No
on
estimates
Figure shows true and estimated PE from a VA with 50% sensitivity and 90% specificity. Dashed line represents underestimation of PE for a disease that causes 20% of child deaths; dotted line is for a disease that causes 10% of deaths For reference, the solid line shows true PE equal to estimated PE (no bias). The relation between true and estimated PE depends on m, the proportion of the deaths due to a specific cause, sens (sensitivity of VA); and spec (specificity of VA) Thus estimated PE= (true PE x m x sens) - ([m x sens] + [1 - m] x [1 -spec]).
loss of power, but the estimate of PE will be unbiased.
However, if specificity is less than 100%, the PE estimate will be biased: it will be underestimated by a factor that depends on specificity, sensitivity, and the proportion of deaths due to the disease of interest (figure). The following hypothetical example illustrates the likely scale of effects. We found the sensitivity and specificity of VA for deaths due to malaria to be 46% and 89%, respectively. If 30% of all post-neonatal deaths in the local childhood population are due to malaria, and if the sensitivity and specificity from our hospital-based study were applied in the community, then a study designed to estimate a PE of 70% against malaria deaths would be expected to result in an estimated PE of only 45%. A recent trial of insecticide-treated bed nets in The Gambia" indicated a 63% and 70% PE for overall childhood mortality and malaria-specific mortality, respectively. After malaria, ARI was the second most reduced specific cause of mortality (B. Greenwood, personal communication). The authors suggest that the reduction in causes of death other than malaria was due either to malaria’s indirect contribution to other causes of death or to an underestimation of the true malaria mortality as described by the VA technique. Both are plausible explanations but our findings and the theoretical considerations discussed above lend support to the latter view.
2. Greenwood BM, Greenwood AM, Bradlley AK, et al. Deaths in infancy and early childhood in a well-vaccinated, rural, West African population. Ann Trop Paediatr 1987; 7: 91-99. 3. Fivawo M. Indigenous concepts of malaria and malaria control in Tanzania. In: Buck AA, ed. Practical considerations on malaria vaccines and clinical trials. Washington: American Institute of Biological Sciences, 1986: 76-81. 4. Omondi-Odhiambo AM, Voorhoeve AM, Van Ginneken JK. Agespecific infant and childhood mortality and causes of death. In: Van Ginneken JK, Muller AS, eds. Maternal and child health in rural Kenya: an epidemiological study. Sydney: Croom Helm, 1984. 5. Gaurenne M, Fontaine O. Assessing probable causes of death using a standardised questionnaire. A study in rural Senegal. Seminar on comparative studies of mortality and morbidity: old and new approaches to measurement and analysis. Siena: International Union for the Scientific Study of Population and the Institute of Statistics, University of Siena, 1986. 6. Moir JS, Garner PA, Heywood PF, Alpers MP. Mortality in a rural area of Madang Province, Papua New Guinea. Ann Trop Med Parastitol 1989; 83: 305-19. 7. Chen LC, Rahman M, Sarder AM. Epidemiology and causes of death among children in a rural area of Bangladesh. Int J Epidemiol 1980, 9: 25-33. 8. Fauveau V, Wojtyniak B, Koenig MA, Chakraborty J, Chowdhury AI Epidemiology and cause of death among women in rural Bangladesh. Int J Epidemiol 1989; 18: 139-45. 9. Victora CG, Smith PG, Vaughan JP, et al. Evidence of protection by breast feeding against infant deaths from infectious diseases in Brazil Lancet 1987; ii: 319-21. 10. Greenwood BM, Greenwood AM, Bradley AK, et al. Comparison of two strategies for control of malaria within a primary health care programme in The Gambia. Lancet 1988; i: 1121-27. 11. Alonso PL, Lindsay SW, Armstrong JRM, et al. The effect of insecticide treated bed nets on mortality of Gambian children. Lancet 1991, 337: 1499-1502. 12. Spencer HC, Kaseje DCO, Mosely WH, et al. Impact on mortality and fertility of a community-based malaria control programme in Saradidi, Kenya. Ann Trop Med Parasitol 1987; 81 (suppl): 36-45. 13. Bang AT, Bang RA, Tale O, et al. Reduction in pneumonia mortality and total childhood mortality by means of community-based intervention trials in Gadchiroli, India. Lancet 1990; 336: 201-06. 14. Velema JP, Alihonou EM, Gandaho T, et al. Childhood mortality among users and non-users of primary health care in a rural West Afncan community. Int J Epidemiol 1991; 20: 474-79. 15. Mtango FDE, Neuvians D. Acute respiratory infections in children under five years. Control project in Bagamoyo District, Tanzania. Trans R Soc Trop Med 1986; 80: 851-58.
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16. World Health Organisation. Guidelines for the evaluatin of Plasmodium falciparum asexual blood-stage vaccines in populations exposed to natural infection. Geneva: WHO Publication TDR/MAP/AVE/ PF189.5, 1989. 17. World Health Organisation. Guidelines for the development of protocols for studies to evaluate the impact of insecticide-impregnated bed-nets on mortality. Geneva: WHO, 1991. 18. Kalter HD, Gray RH, Black RE, Gultiano A. Validation of post-mortem interviews to ascertain selected causes of death in children. Int J Epidemiol 1990; 19: 380-86. 19. Mirza NM, Macharia WM, Wafula EM, et al. Verbal autopsy: a tool for
determining cause of death in a community. East Afr Med J 1990; 67: 693-98. 20. 21.
Pacque-Maragolis S, Pacque M, Dukuly Z, et al. Application of the verbal autopsy during a clinical trial. Soc Sci Med 1990; 31: 585-91. World Health Organisation. Manual of the International Statistical
Classification of Diseases, Injuries and Causes of Death. Geneva: 1977. 22. Warrel DA, Molyneux ME, Beales PF. Severe and complicated malaria. Trans R Soc Trop Med Hyg 1990; 84 (suppl 2): 1-65. 23. Snow RW, Marsh K. How useful are verbal autopsies to estimate childhood causes of death? Health Policy and Planning 1992; 7: 67-71.
WHO,
CLINICAL PRACTICE Classical
migraine: symptoms between visual aura and headache onset
The gap between the end of the visual aura and headache onset in classical migraine has been called the free interval. In a retrospective study of twentyfive migraineurs who had noted a gap, only three reported feeling normal at that time: twenty-two described alterations in mood, detachment from the environment or other people, fears, disturbances of speech or thought, or somatic symptoms. The interval lasted less than an hour in seventeen of the twenty-two but in five persisted for 1 to 5 hours. These symptoms suggest involvement of the frontal and temporal cortices as well as the hypothalamus; they do not conform to Leão’s spreading depression or a vascular mechanism, but are in keeping with a diffuse cerebral process with focal manifestations.
surroundings"; "away from everything"; "not with it"; "spread out-as though a barrier between me and others"; "curious feeling of unreality". One general practitioner said that she had never told anyone about the sensations during this phase of her migraines, because she felt herself to be insane during these intervals that in her case lasted 20-30 minutes; she expressed relief at discovering that she was not SYMPTOMS IN 25 PATIENTS BETWEEN END OF AURA AND BEGINNING OF HEADACHE
A colleague had migraine attacks only after competitive games of soccer: he described a visual aura lasting 20 minutes, followed by 30 minutes during which he felt
"euphoric and wrapped in cotton wool-less in contact with reality"; then his headache began. Until hearing and listening to this history, I had assumed that migraineurs were symptomless during the aura/headache interval (the "free interval") and paid no attention to this phase of attacks. Patients with migraine and a visual aura seen at initial or follow-up consultations were asked directly, "Does your headache begin during or immediately after the end of your visual aura?"; the same question was posed to medical colleagues known to have classical migraine. During four talks to general practitioners, those with classical migraine after the lecture and I put the same question to these. Twenty-five (about one-third of those interviewed) had experienced a gap between the end of the visual aura and the onset of headache. These individuals were asked to describe how they felt during that interval and to estimate its duration. The subjects were eight men and seventeen women aged 29-68 (mean 42) years. Twenty estimated the gap at 10-60 minutes, five at over 1 hour (up to 5 hours). Twenty-two subjects reported symptoms in the visual-aura/headache interval, but most had difficulty describing them, using expressions such as "very strange, unreal, removed from were
invited
to come
and
5 had 1 symptom, 11 had 2, 2 had
3, and 4 had
4
see me
alone. Another curious symptom was impaired body movement or clumsiness: two experienced car drivers would not drive during this interval fearing an accident; a 31-year-old physician perceived his limbs as being heavy and slow-moving. The symptoms in the affected twentytwo are listed in the table. In three individuals the symptoms in the gap resembled those during the premonitory phase before onset of the visual aura. ADDRESS National Hospital for Neurology and Neurosurgery, Queen Square, London WC1 N 3BG, UK (Dr J. N Blau, FRCP).
