Volume 168 Issue 11

Abstract Objective: To define recent trends (1993-1996) in incidence of endstage renal disease (ESRD) among Australian Aboriginal people in the Top End of the Northern Territory (NT). Design: Analysis of hospital and clinical records of the Darwin-based ESRD treatment program from 1993 to 1996 and comparison with data accumulated since 1978. Participants: All people entering the ESRD treatment program from 1978 to 1996. Main outcome measures: Number of patients treated for ESRD; their ethnicity, age and sex; comorbidities in Aboriginal patients; treatment methods and outcomes. Results: More Aboriginal people presented with ESRD between 1993 and 1996 (87) than in the previous 15 years of the program (68). The incidence of ESRD in Aboriginals reached 838 per million in 1996, and is doubling every 4 years. Aboriginal people presenting with ESRD are younger than non-Aboriginal people with ESRD, and, in contrast to non-Aboriginals, ESRD rates are higher in women than men. The numbers and proportions of Aboriginal ESRD patients who have hypertension, type 2 diabetes and cardiac disease are rising. Haemodialysis remains the most common form of treatment, and the number of dialysis treatments is doubling every 2.5 years. Only 9% of Aboriginal patients entering the program in 1993-1996 were treated with chronic ambulatory peritoneal dialysis and only 3% received transplants. Despite their younger age, survival of Aboriginal people on dialysis is low (median 3.3 years v. 6.5 years in non-Aboriginals), and graft survival after transplant is poor (37% at 5 years v. 88% in non-Aboriginals). Survival has not improved in the past 4 years, with fewer deaths from infection offset by more deaths from cardiovascular disease. Conclusions: The predicted doubling of ESRD incidence among Aboriginal people by the year 2000 will add an enormous burden to limited resources. Risk factors for renal disease underlie all the excess morbidity and mortality in NT Aboriginal adults, and arise out of accelerated lifestyle changes and socioeconomic disadvantage. Better living conditions and education, robust and integrated primary healthcare programs, and systematic screening for early renal disease and treatment of those with established disease are all matters of urgency. Introduction The high rate of endstage renal disease (ESRD) in Australian Aboriginal people is attracting increased attention.1-4 The Northern Territory (NT) faces particular challenges in dealing with this problem. It has the lowest population (179 000 people) and tax base of any Australian State, and the highest proportion of Aboriginal people (22% of the population, compared with 5%-6% for Queensland and Western Australia -- the States with the next-highest proportion). It has an area of 1 346 200 km2, and only two dialysis centres, 1500 km apart (one in Darwin and one in Alice Springs), which can scarcely accommodate the increasing numbers of Aboriginal people needing treatment. In a previous article,1 we reported the rising rates of ESRD among Aboriginal people in the Top End of the NT (Figure 1), with an average annual incidence of 440 per million from 1988 to 1993. Aboriginal patients were younger than their non-Aboriginal counterparts and, in contrast to the non-Aboriginal population, more women than men were affected. There was little use of chronic ambulatory peritoneal dialysis (CAPD), and the few transplants gave poor results. Comorbidities were high and there was a shorter survival time on treatment than in non-Aboriginal people. Tiwi people living on Bathurst and Melville islands had especially high rates of ESRD, but for other communities there were too few cases to allow calculation of population-adjusted rates. We present data for ESRD treatment in the Top End of the NT for the period 1993-1996, thus extending the period of analysed data to 19 years. The expanded data allow calculation of regional population-specific rates, and illuminate trends in diagnoses, comorbidities, treatment methods and survival. Methods Study population The total study population comprised all people entering the Top End ESRD treatment program from January 1978 to December 1996 inclusive. Our data sources were dialysis unit records and hospital files. We used Australian Bureau of Statistics aggregate and regional data from the 1987, 1991 and 1995 population censuses for the denominators for calculating ESRD rates for the 4-year intervals 1985-1988, 1989-1992, and 1993-1996.5The 1991 Aboriginal community census was used to calculate individual community rates for the three 4-year intervals. People moving to the NT from other countries or other States and becoming residents are potentially included in the census and thus the denominators. Statistical analysis We calculated age-standardised rates of ESRD with Epi-Info6 using aggregate Australian non-Aboriginal data from the 1996 Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) as the reference population.7χ2 tests with Yates' correction were used to examine differences between groups. Kaplan-Meier survival analyses were performed by SPSS for Windows,8 and the log-rank test was used to compare the differences between the groups. Results In the period 1993-1996, 104 people entered the ESRD treatment program, making a total of 214 for the period 1978-1996. Of the total, 155 (72%) were Aboriginal, and 59 (28%) were non-Aboriginal. Incidence of treated ESRD Figure 2a shows the dramatic increase in incidence of ESRD in Aboriginal people over the three 4-year periods, with an average doubling time of about 4 years. More Aboriginal people (87) presented for treatment in the 4 years 1993-1996 than in the previous 15 years of the program (68). Within this most recent 4-year period, rates have continued to rise at an average of 22% per year, peaking at 838 per million9 in 1996 (compared with 39 per million in non-Aboriginal people in the NT). With age adjustment, the 1993-1996 average annual rate represents a 15-fold increase and the 1996 rate a 21-fold increase over ESRD rates in non-Aboriginal Australians nationwide. NT rates for non-Aboriginals, which did not change over this time period, are lower than Australian aggregate rates (62 per million from 1993-1996) because the NT has a younger population. All regions of the Top End are experiencing the same phenomenon, although current rates vary. Figure 2b shows the changes in incidence in Aboriginal people in the five regions with the highest current rates. The number of Aboriginal people receiving ESRD treatment (the prevalence), including those with functioning transplants, peaked at 2871 per million in 1996 versus 377 per million for non-Aboriginals. Finally, the number of dialysis procedures (which accrue most of the costs) is rising by 28% per year, or doubling every 2.5 years.9 Sex and age distribution of ESRD patients Ninety-three (60%) of the 155 Aboriginals with ESRD were women and 62 (40%) were men, compared with 23 (39%) women and 36 (61%) men among the 59 non-Aboriginal patients. Figure 2c shows the higher ESRD rates in Aboriginal women than men at each time period, resulting, in 1993-1996, in an age-adjusted relative risk of 31 in women versus 16 in men. On average, Aboriginal people were 5 years younger than non-Aboriginal people on entering the program (44 v. 49 years). However, the age distributions were quite different, with Aboriginal people most commonly presenting between the ages of 30 and 49 years, and non-Aboriginals between 50 and 69 years. Figure 3 shows that ESRD rates in Aboriginal people rose in most age groups over the life of the program, so that the average age and age distribution did not change appreciably. The age-specific incidence of ESRD in Aboriginal people peaked at age 50-59 years, and in non-Aboriginals at over 70 years. Renal failure causes and comorbidities in Aboriginals The Table compares the distribution of "causes" of ESRD in the two most recent 4-year intervals in those patients with documented causes. The proportion of ESRD in Aboriginal people attributed to (but not always solely due to) diabetes has almost doubled, that classified as glomerulonephritis has fallen by more than half, and the proportion in the "unknown" category has increased markedly. Aboriginal people with ESRD are more likely than non-Aboriginal people to have type 2 diabetes (48% v. 24%; P = 0.002) and hypertension (52% v. 32%; P = 0.01). Furthermore, these proportions have increased recently: for diabetes from 37% pre-1993 to 60% in 1993-1996 (P < 0.005); and for hypertension from 43% to 57% (P = 0.1); and for people with both diabetes and hypertension from 19% to 38% (P = 0.011). Treatment for ESRD Fifty-one per cent (30) of non-Aboriginal people, but only 17% (26) of Aboriginal people, have received transplants since 1978, and only 3% in the period 1993-1996. Potential reasons for this discrepancy include medical ineligibility, discouraging earlier results, distance to the transplant centre (in Adelaide), underservicing and difficulties in supervision of care in remote areas, lack of living related donors, and difficulties in HLA matching with donor organs. In 1996, only 11% of Aboriginal people with ESRD had functioning transplants versus 65% for non-Aboriginal people. Chronic ambulatory peritoneal dialysis (CAPD) rates in Aboriginal patients remain low, with only 5% of incident cases pre-1993 and 9% in 1993-1996 treated in this manner. Patient and graft survival Despite the younger age of Aboriginal patients with ESRD, their "integrated" survival (with all forms of treatment, ie, dialysis and transplantation) was significantly worse than that of non-Aboriginal people, with median survival times of 3.6 versus 12.3 years (P = 0.0025). This difference was reflected in those with and without diabetes. While survival on dialysis (CAPD and haemodialysis), as shown in Figure 4, tended to be lower in Aboriginal people (median 3.3 v. 6.5 years; P = 0.34), both graft and patient survival after transplantation were clearly worse (Figures 5 and 6). Patient survival at 1 and 5 years after transplantation was 92% and 60% for Aboriginals, compared with 97% and 93% for non-Aboriginals (P < 0.001), and graft survival at 1 and 5 years was 73% and 37% for Aboriginal people, compared with 97% and 88% for non-Aboriginal people (P < 0.001). There has been no improvement in integrated survival, or in dialysis or transplant survival separately, in the period 1993-1996. Causes of death The causes of death in Aboriginal people have changed for the period 1993-1996. Deaths due to cardiac disease have increased from 33% before 1993 to 51% after 1993. Deaths due to voluntary withdrawal from treatment are unchanged (24% and 25%, respectively). In contrast, only one non-Aboriginal patient has ever withdrawn from treatment, and none in the past decade. Discussion These data for 1993-1996 confirm and further define the rise in incidence of renal failure among Aboriginal people in the Top End of the Northern Territory. No community is spared, and this pattern is repeated in Central Australian Aboriginals, who have even higher rates (1400 per million in 1996).4 Current incidence rates are now comparable with those of Afro-Americans and Native Americans (800 and 744 per million, respectively, in 1995); however, age-adjusted rates are much higher in Australian Aboriginals (due to their very youthful population) and are increasing much faster, with a doubling time less than 4 years versus 10 years for the US minority groups.10 These alarming figures are nonetheless underestimates, because some Aboriginal people, especially older people and those from very remote communities, decline treatment for ESRD or are medically unsuited. Most of the increase is real. It is not due to ageing of the Aboriginal population, as it is reflected across every age group; and it is not due to improved ascertainment, at least in the major communities, as awareness has been high since the mid 1980s. The disability and the personal, family and community disruption are great, and the resource requirement will be truly formidable if current rates of increase, which project up to 500 new cases between 1997 and 2004 (exponential progression), are sustained. The data confirm the younger age and female predominance of Aboriginal people with ESRD. The latter might be due, in part, to lower birthweights and the relatively higher adult body weights in women, with more marked insulin resistance and earlier onset of type 2 diabetes.11,12 Both occur also in Central Australia.4 Some of the change in attributed cause of ESRD over the most recent 8-year period reflects subjectivity in assignment criteria, but much reflects reassignment of the common finding of bland glomerulomegaly with absent or minimal inflammation13-15 from the "glomerulonephritis" category to the "unknown" category. The rise in renal failure attributed to diabetes is compatible with the dramatic increase in rates of diabetes and its complications in all Aboriginal communities,16 but clinical and biopsy data show that diabetes is more often a facilitating factor for disease expression and progression rather than the prime or sole cause of the underlying nephropathy.11,14 The increased incidence in all communities of Syndrome X (obesity, hypertension, dyslipidaemia, dysglycaemia and predisposition to cardiovascular disease), which is attributed to insulin resistance, likewise explains the increasing proportions of Aboriginal people presenting for ESRD treatment with diabetes and hypertension as comorbidities.11,16-18 These conditions are already generating more heart attacks, strokes, coronary angioplasties, coronary artery bypass graft procedures and cardiovascular deaths among Aboriginal ESRD patients. As the epidemic grows and the Aboriginal population ages, these complications will become more common, and further increase costs, complicate treatment and compromise survival. The persistently high rate of withdrawal of Aboriginal people from ESRD treatment reflects difficulties with chronic disability, the complex treatment regimen, and loss of social and family support and "land identity" associated with relocation from their community to Darwin for treatment.19,20 Initiatives to move treatment closer to home include attempts to promote CAPD, which has low rates of technical failure and peritonitis, but major problems with exit-site infections;20 a renewed focus on transplant (seven Aboriginal people received transplants in 1997); construction of the first community-based dialysis unit with seven stations on the Tiwi islands; and the possibility of placing haemodialysis stations in clinics in high risk remote areas. However, deliberations about efficient and equitable delivery of ESRD treatment must no longer be allowed to dominate the dialogue. Dialysis in the Top End currently costs $496 per treatment, which is about $75 000 per patient per year. This cost does not include medicines, relocation and housing, transportation and hospitalisations.9 The allocation of resources of this magnitude to people with a median life expectancy of 3.3 years must be balanced by serious and sustained community-based initiatives to prevent and ameliorate the underlying problem. Most renal disease in Aboriginal communities is marked by albuminuria, and all renal failure arises in people with a history of progressive overt albuminuria.11Risk factors for renal failure include low birthweight and infant malnutrition, infections (scabies, poststreptococcal glomerulonephritis), increasing adult weight, high blood pressure, increasing glucose levels, insulin resistance, dyslipidaemia, and heavy drinking.11 Several risk factors can operate simultaneously, progressively compounding the decline in renal function that accompanies increasing age. The current epidemic is probably explained by the confluence of many risk factors over a short time period, associated with dramatic lifestyle changes and serious socioeconomic disadvantage. Ironically, the great fall in infant mortality between the late 1950s and late 1970s, a consequence of better hospital management of sick babies, means that those low birthweight babies now surviving to adult life are at high risk for renal and other chronic diseases.11,21 This multifactorial perspective on renal disease necessitates a rethinking of renal disease classifications.11 There is a need for a stronger focus on community and individual risk factor profiles and on pathophysiological interactions, and some de-emphasis of categorical definitions. It justifies a general preventive health services model, which will also reduce the diabetes, hypertension, cardiovascular disease, chronic lung disease and infections that contribute to the excess mortality in NT Aboriginal adults.17 In addition, screening programs to recognise early and established renal disease, and treatment (including angiotensin-converting enzyme inhibitors) to arrest disease progression, must be incorporated into regular adult healthcare in every Aboriginal community as a matter of urgency.22,23 Acknowledgements This study was supported by the National Health and Medical Research Council of Australia, and the Australian Kidney Foundation. We thank Dr David Pugsley, who led the way with renal services in the Northern Territory, and established the basis of these observations, and Dr Diane Howard and Dr Sid Selva-Nayagam, who have had the longest tenure of care of renal patients. We thank the staff of the Nightcliff Dialysis Unit and the Renal Unit at Royal Darwin Hospital for their excellent care and cooperation. Dr Zhiqiang Wang assisted with statistical analyses, and Ms Susan Jacups with clerical and graphic support. References Hoy WE, Mathews JD, Pugsley DJ. Treatment of end-stage renal disease in the Top End of the Northern Territory: 1978-93. Nephrology 1995; 1: 307-313. Hoy WE, Silva D. NT Top End Aboriginal end stage renal disease data and projections. Darwin, NT: Renal Strategy Committee, Territory Health Services, February 1997. Hoy WE. Renal disease in Aboriginal Australians. Med J Aust 1996; 165: 126-127. Renal disease in Central Australia -- challenges and opportunities for better health. Health Strategies, Deakin. Melbourne: Deakin University, September, 1997. Australian Bureau of Statistics. 1996 Census of population and housing. Aboriginal community profiles, small area data. Canberra: ABS, 1996. (Catalogue No. 2020.0.) Dean AG, Dean JA, Coulombier D, et al. Epi-Info, version 6: a word processing, database and statistics program for epidemiology on microcomputers. Atlanta, Ga: Centers for Disease Control and Prevention, 1994. Disney APS, editor. ANZDATA Report 1996. Nineteenth report of the Australian and New Zealand Dialysis and Transplant Registry. Adelaide: Queen Elizabeth Hospital, 1996. SPSS -- Statistical Package for the Social Sciences [computer program], release 6.1, standard version. Chicago: SPSS Inc, 1988. Margetts C, Morris E. Cabinet submission to the NT Legislature for renal services funding. Darwin: Royal Darwin Hospital, February 1998. United States Renal Data System (USRDS). Annual Data Report. Bethesda, MD: The National Institutes of Health, NIDDK, April 1997. Hoy WE, Mathews JD, McCredie DA, et al. The multidimensional nature of renal disease: findings in a high risk Australian Aboriginal community. Kidney Int 1998. In press. Hoy WE, Norman RJ, Hayhurst B, G Pugsley DJ. A health profile of adults in a Northern Territory Aboriginal community, with an emphasis on preventable morbidities. Aust N Z J Public Health 1997; 21: 121-126. Lloyd ML, Moore L, Pugsley DJ, Seymour AM. Renal disease in an Australian Aboriginal population: a pathologic study. Nephrology 1996; 2: 315-322. Howard DM, Davis J, Pugsley DJ, et al. Morphologic correlates of renal disease in a high risk Aboriginal community. Proceedings of the 31st Annual Scientific Meeting, Australian and New Zealand Society of Nephrology; Perth, WA; March 5-8, 1996. Sydney: Australian and New Zealand Society of Nephrology, 1996. Bertram JH, Young RJ, Seymour AE, et al. Glomerulomegaly in Australian Aborigines. Nephrology 1998. In press. Markey P, Weeramanthri T, Guthridge S. Diabetes in the Northern Territory. Darwin: Diabetes Australia (Northern Territory), 1996. Cunningham J, Condon J. Premature mortality in Aboriginal adults in the Northern Territory, 1979-1991. Med J Aust 1996; 165: 309-312. Reaven GM. Insulin resistance and compensatory hyperinsulinemia: role in hypertension, dyslipidemia, and coronary artery disease. Am Heart J 1991; 121: 1283-1288. Willis J. Fatal attraction: do high technology treatments for end stage renal disease benefit Aboriginal people in Central Australia? Aust J Public Health 1995; 19: 603-609. . Snelling P. I hit beautiful serves -- but my partner keeps putting the ball in the net: renal transplantation in Aboriginal patients. Proceedings of the 10th Dialysis and Transplant Workshop of the Australian Kidney Foundation and the Australian and New Zealand Society of Nephrology; Launceston, Tasmania; October 1997. Sydney: Australian and New Zealand Society of Nephrology, 1997: 62-63 Barker DJP. Mothers and babies and disease in later life. London: BMJ Publishing Group, 1994. Hoy WE. Markers for cardiovascular and renal morbidity: expectations for an intervention program in an Australian Aboriginal community. Clin Exp Pharmacol Physiol 1996; 23 (Suppl 1), S33-S37. Hoy WE. Guidelines for screening and treatment of renal disease in Aboriginal communities. Nephrology 1998. In press. (Received 5 Jan, accepted 10 Mar, 1998) Authors' details Menzies School of Health Research, Darwin, NT. Janine L Spencer, FRACP, DTM&H(Lond), Paediatrician, Australian Kidney Foundation Research Fellow. Wendy E Hoy, BScMed, FRACP, NHMRC Senior Research Fellow, Director of Renal Program; and Renal Community Services Specialist, Territory Health Service. TVW Telethon Institute for Child Health Research, Perth, WA. Desiree T Silva, FRACP, MPH, Paediatrician. Royal Darwin Hospital, Darwin, NT. Paul Snelling, FRACP, Nephrologist, Royal Darwin Hospital, and Territory Health Service. Reprints will not be available from the authors. Correspondence: Dr W E Hoy, Menzies School of Health Research, PO Box 41096, Casuarina, NT 0811. E-mail: wendyATmenzies.su.edu.au Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia ".

Janine L Spencer · Desiree T Silva · Paul Snelling · Wendy E Hoy

Abstract Objective: To determine the prevalence of the Wernicke-Korsakoff syndrome (WKS) in Australia and compare this with previous studies. Design and setting: Prospective autopsy study at the New South Wales Institute of Forensic Medicine, 1996-1997. Methods: Brains of deceased people (aged over 15 years) derived from 2212 sequential autopsies performed between 1 January 1996 and 31 December 1997 were studied macroscopically and microscopically to identify cases of WKS. Main outcome measures: Standard histological criteria for WKS and any available clinical data. Results: Twenty-five cases of WKS were identified (prevalence, 1.1%), mostly among the 5.9% of the 2212 people who had a history suggestive of alcohol abuse. Only four cases (16%) had been diagnosed during life. Conclusions: There has been a significant reduction in the prevalence of WKS in Australia since the introduction of thiamine enrichment of bread flour. While the prevalence is still higher than in most other Western countries, further research is needed before adding thiamine to alcoholic beverages can be recommended. Introduction Wernicke-Korsakoff syndrome (WKS) is a potentially fatal neurological disorder caused by thiamine (vitamin B1) deficiency. It is easily treated by thiamine supplementation, with most people showing dramatic clinical improvement. Biochemical studies in the 1980s showed that 10%-20% of Australians had a low thiamine intake, with those who used alcohol excessively being particularly "at risk",1 and previous autopsy studies had shown that Australia had the highest recorded prevalence of WKS in the world, with most cases occurring among those who abused alcohol.2-5 To address these problems, the Australian Health Ministers' Council recommended the mandatory enrichment of bread flour with thiamine. Consequently, since 1991 bread flour in Australia has contained not less than 6.4 mg of thiamine per kilogram.6 Human thiamine requirements have been estimated to be 1.0-1.5 mg daily.7 The major food sources of thiamine are cereal products. Although thiamine is naturally present in the grains used to produce flour, much is removed during some types of processing, and thiamine enrichment of flour has been practised in a number of countries for many years.8,9 It is a mandatory requirement in the United Kingdom, Canada, and Denmark, while in the United States enrichment is not mandatory, but most flour is enriched. Since the introduction of thiamine enrichment of rice and flour, thiamine deficiency is said to have virtually disappeared in countries such as Japan and the US.10,11 Our aim was to establish whether this safe and simple public health measure has reduced the prevalence of WKS in Australia, and hence to determine whether we need to consider alternative public health measures such as adding thiamine to all flours used in food preparation or even to alcoholic beverages.12 Methods We prospectively studied all sequential autopsies of people aged over 15 years (as WKS is rare in a younger population in Western countries) from the NSW Institute of Forensic Medicine in Sydney during 1996 and 1997. In line with standard autopsy procedures, brains were fixed in 10% formol saline for at least two weeks. After careful external examination and removal of the brainstem and cerebellum, the brain was cut in the coronal plane, the first cut being made at the level of the anterior (ventral) tip of the mammillary bodies. The hemispheres were then cut at 10 mm intervals. The brainstem and cerebellum were separated by dividing the right and left cerebellar peduncles. The cerebellum was sectioned in the sagittal plane through the vermis and through the lateral hemispheres. The brainstem was sectioned in the horizontal plane at 3 mm intervals. The brain slices were examined, paying particular attention to the mammillary bodies and the regions around the third ventricle and the floor of the fourth ventricle. It has been shown that the mammillary bodies are abnormal on microscopic examination in 99%-100% of cases of WKS.3,13 The mammillary bodies were measured in three dimensions and brain slices were photographed if any macroscopic abnormality was noted. Blocks of tissue were taken for paraffin embedding and the preparation of histological sections. The principal block for this study incorporated both of the mammillary bodies and the walls of the third ventricle. Blocks from other regions of the brain were taken according to routine neuropathological protocols of the Institute of Forensic Medicine and the Neuropathology Department.4 These varied depending on the clinical history, cause of death, and general autopsy findings. Sections were cut at 10 mm and stained with haematoxylin and eosin. Brains were stored until each case was completed, so that, if necessary, additional blocks of tissue could be taken for further examination. This was particularly important if an abnormality was identified in the section of the mammillary bodies. A number of other diseases can affect the mammillary bodies, but these can usually be easily differentiated from WKS.5,14 All cases were examined microscopically by a neuropathologist (C H) without knowledge of the relevant clinical history or the macroscopic findings. In all cases in which WKS was suspected, the mammillary body section was also stained with reticulin, Weil myelin, glial fibrillary acidic protein, Perl's iron stain, Bodian silver impregnation, and Nissl stain for neurones. The purposes of these stains are summarised in Box 1. Clinical histories and general pathological data were correlated with the neuropathological findings. Statistical comparisons were made with data from a previous, similar study3 using chisquared statistics with Yates' correction factor and relative risk with 95% confidence intervals. Results We diagnosed 25 forensic cases of WKS from 2212 brains, giving an overall prevalence of 1.1%. Box 2 compares the prevalence data with those of a similar Australian study (including both forensic and hospital cases of WKS) undertaken by one of the authors (C H) from 1973 to 1981,3 and shows that there has been a statistically significant reduction in the prevalence of WKS. The mean age at death of the people with WKS was 55 years; 23 (95%) were men. Hospital medical records, located for 18 of the 25 deceased people with WKS, showed that alcohol appeared to have been a predisposing factor for WKS in 16 (89%). Of the remaining two, one was a man with paraplegia who was totally dependent and required gastrostomy feeding, and the other man had both lung and bowel cancer. Information available at autopsy indicated that 5.9% of the 2212 brains studied were from people with a history which suggested an alcohol problem, giving a prevalence of WKS in an Australian forensic population with a history suggestive of alcohol problems of 19%. A clinical diagnosis of WKS (Korsakoff's psychosis) during life had been made in only four (16%) of the 25 deceased whose WKS was identified at autopsy. However, two others had a diagnosis of alcohol-related brain damage. The hospital records located for 18 deceased people with WKS showed that four had severe amnesia (Korsakoff's psychosis), two others had memory problems and three had ataxia or unsteady gait. None were reported to have ophthalmoplegia or nystagmus, which are commonly described clinical signs in WKS.15 Three had a history of epilepsy. Eight (44%) had been given thiamine (vitamin B1) supplements during one or more of their hospital admissions. The diagnosis of WKS in this study was based on typical pathological abnormalities, which will not be described in detail as this information is available in current neuropathological texts.6 In brief, lesions are seen in a characteristic distribution -- in the mammillary bodies and around the walls of the third and fourth ventricles. Macroscopic findings vary depending on the stage of the disease (see Box 3). There were two acute cases, six acute-on-chronic cases (evidence of both acute and chronic damage to mammillary bodies), and 17 chronic cases. These data are compared with those of a previous study3 in Box 4. Discussion Our findings show a significant reduction in the prevalence of WKS in Australia compared with the findings of a similar study of forensic cases between 1973 and 1981 (see Box 2).3 The two forensic populations were similar, even though these two studies were conducted in different Australian States (New South Wales and Western Australia) and at different times. Laws relating to deaths which must be reported to the Coroner and undergo forensic autopsy are almost identical in these two States. Moreover, one of the authors (J H) was the Director of the Forensic Department in Perth, WA, at the time of the first study and is currently the Director of the NSW Institute of Forensic Medicine, where the current study was carried out; he commented that the profiles of cases in the two autopsy studies were very similar. The high prevalence of WKS at autopsy in Australia2-5 has been reflected in clinical studies, with, for example, 170 cases of WKS being identified among 1100 total inpatients at Queensland's largest hospital for the mentally ill.12 However, a retrospective study of records from 17 major Sydney hospitals from 1978 to 1993 showed that the number of acute cases of WKS was lower in 1992 and 1993 than in any of the other years.16 This suggests that dietary enrichment of bread flour with thiamine may have had an impact on the occurrence of acute cases of WKS. Our finding of fewer cases of acute WKS compared with the earlier WA study also supports this (see Box 4, above). As patients with acute WKS who are treated appropriately with parenteral thiamine respond within days, and signs and symptoms usually resolve completely, not all cases will progress to chronic disease. The development of chronic disease is not fully understood, but many chronic cases of WKS are likely to be the result of recurrent episodes of either clinical or subclinical thiamine deficiency.17 WKS is said in the medical textbooks to have a characteristic clinical picture of mental changes (confusion, obtundation), ataxia, and eye signs (nystagmus, ophthalmoplegia). However, as shown in this study and previously, analysis of clinical signs and symptoms of patients diagnosed with WKS post mortem reveals that a minority of cases have the full clinical picture and about a third exhibit only mental changes.15 Thus, the diagnosis can be easily overlooked. Many authors agree that WKS can develop as a result of repeated "subclinical" episodes of thiamine deficiency,18 so that studies of the prevalence of this disorder based on clinical findings are unsatisfactory and may underestimate the true incidence.15 Given that most of the cases of WKS we identified were chronic, some explanation must be sought for the significant reduction in the prevalence of this disease within six years of the introduction of thiamine enrichment of bread flour. There are four possible explanations: 1. A true reduction in the number of new (acute) cases of WKS as a result of the increase in dietary thiamine, and reduced numbers of "at risk" cases. 2. An improvement in the clinical status of patients who already have WKS and a reduced occurrence of further clinical or "subclinical" episodes of thiamine deficiency.17 This could result in an increase in the longevity of patients with existing WKS -- for example, through a reduction in the sudden unexpected deaths seen among chronic alcoholics. 3. A general improvement in the health status of the Australian population, independent of the introduction of thiamine supplementation. 4. Publication of the high prevalence of WKS in Australia may have led to an increased awareness, particularly among health professionals, of the necessity for thiamine treatment in "at risk" patients. Almost half of the 25 people whose WKS was identified at autopsy had been treated with thiamine in hospital. This increased awareness and therapeutic intervention may have played a role in the reduced prevalence. It is likely that each of these explanations played a part in reducing the prevalence of WKS. However, the relative importance of each will only be clarified with time and further study as the enrichment of bread flour with thiamine, has only been in place for six years. It should be noted that the results of this study may in fact underestimate the beneficial effect of the enrichment of bread flour with thiamine as many of the cases of chronic WKS will have developed before the enrichment program commenced. Further prevalence studies should be carried out in, say, another five years, and this information, together with biochemical studies of the thiamine status of the Australian population, will enable rational decisions to be made with regard to other public health programs, such as fortification of alcoholic beverages with thiamine. Our findings neither support nor confirm the prediction of Price and Theodorous that many people who abused alcohol would not be protected by a flour enrichment program because alcoholic beverages are, "for a hazardously long period of their lives, their only form of caloric intake".12 However, they had suggested, on the basis of this prediction, that thiamine supplementation of alcoholic beverages might be a more effective preventive measure, and in reviewing this proposal Connelly and Price noted that fortification of beverages, rather than bread flour, would be more cost-effective by a factor of 20-40-fold.19 Although there has been a significant decrease in the prevalence of WKS in Australia since the introduction of thiamine enrichment of bread flour in 1991, the rate is still higher than in most other Western countries5 and there is a need to maintain vigilance in the management of patients, particularly those with known or suspected alcohol problems. Acknowledgements This research was supported by the Australian Brewers' Foundation and by the National Health and Medical Research Council (Grant number 943302). We are grateful to all the staff at the NSW Institute of Forensic Medicine for their assistance and cooperation. References Wood B, Breen KJ. Clinical thiamine deficiency in Australia: the size of the problem and approaches to prevention. Med J Aust 1980; 1: 461-464. Harper C. Wernicke's encephalopathy: a more common disease than realised. J Neurol Neurosurg Psychiatry 1979; 42: 226-231. Harper CG. The incidence of Wernicke's encephalopathy in Australia -- a neuropathological study of 131 cases. J Neurol Neurosurg Psychiatry 1983; 46: 593-598. Harper CG, Gold J, Rodriguez M, Perdices M. The prevalence of the Wernicke-Korsakoff syndrome in Sydney, Australia: a prospective necropsy study. J Neurol Neurosurg Psychiatry 1989; 52: 282-285. Harper C, Fornes P, Duyckaerts C, et al. An international perspective on the prevalence of the Wernicke- Korsakoff syndrome. Metab Brain Dis 1995; 10: 17-24. Harper C, Butterworth R, editors. Nutritional and metabolic disorders. 6th ed. London: Arnold, 1997: 601-664. Freeman RM, editor. Rational use of vitamins in practice. Toronto: JB Lippincott, 1979: 115-122. Axford DWE, Williams DA. Flour enrichment around the world. Br Flour Milling Baking Res Assoc 1981; 4: 156-163. Bauerfeind JC. Nutrification of food. In: Shiks ME, Young VR, editors. Modern nutrition in health and disease. 7th ed. Philadelphia: Lea and Febiger, 1988. Figueroa WG, Sargent F, Imperiale L, et al. Lack of avitaminosis amongst alcoholics. J Clin Nutrition 1953; 1: 179-199. Sebrel WH. Enrichment: good gift of yesterday. Cereal Science Today 1966; 11: 228-230. Price J, Theodorus MT. The supplementation of alcoholic beverages with thiamin: a necessary preventative measure in Queensland. Aust N Z J Psychiatry 1979; 13: 315-320. Victor M, Adams RD, Collins GH. The Wernicke- Korsakoff Syndrome. Philadelphia: Davis, 1989. Schubert T, Friede RL. Transneuronal mammillary atrophy. J Neurol 1979; 221: 67-72. Harper CG, Giles M, Finlay-Jones R. Clinical signs in the Wernicke-Korsakoff complex -- a retrospective analysis of 131 cases diagnosed at autopsy. J Neurol Neurosurg Psychiatry 1986; 49: 341-345. Ma JJ, Truswell S. Wernicke-Korsakoff syndrome in Sydney hospitals: before and after thiamine enrichment of flour. Med J Aust 1995; 163: 531-534. Lishman WA. Cerebral disorders in alcoholism. Syndromes of impairment. Brain 1981; 104: 1-20. Lishman WA. Alcohol and the brain. Br J Psychiatry 1990; 156: 635-644. Connelly L, Price J. Preventing the Wernicke-Korsakoff syndrome in Australia: cost-effectiveness of thiamin-supplementation alternatives. Aust N Z J Public Health 1996; 20: 181-187. (Received 7 Aug1997, accepted 16 Feb 1998) Authors' details Department of Pathology, University of Sydney, and Royal Prince Alfred Hospital, Sydney, NSW. Clive G Harper, MD, FRCPA, Professor; Donna L Sheedy, BA, Research Assistant; Ana I Lara, Technical Assistant. Network for Brain Research into Mental Disorders, Prince of Wales Hospital, Sydney, NSW. Therese M Garrick, RN, BNurs, Research Assistant. New South Wales Institute of Forensic Medicine, Sydney, NSW. John M Hilton, MB ChB, FRCPA, Director; Jack Raisanen, MD, Forensic Neuropathologist. Reprints: Professor C G Harper, Department of Pathology, University of Sydney, NSW 2006. E-mail: clivehATpathology.su.oz.au Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia ".

Clive G Harper · Donna L Sheedy · Ana I Lara · Therese M Garrick · John M Hilton · Jack Raisanen