Journal of Neurology, Neurosurgery, and Psychiatry 1983 ;46:593-598

The incidence of Wernicke's encephalopathy inAustralia-a neuropathological study of 131 cases

CLIVE HARPER

From the Department ofNeuropathology, Royal Perth Hospital, Perth, Australia

SUMMARY In a nine year necropsy study in Western Australia, the incidence of Wernicke'sencephalopathy was 2-8%. The incidence appears to be increasing. Although Wernicke'sencephalopathy is a nutritional disorder, the majority of cases occur in the alcoholic population.Only 20% of the 131 cases studied had been diagnosed clinically as Wernicke's encephalopathy.This large discrepancy between numbers of cases diagnosed clinically and pathologically suggeststhat chronic Wernicke's encephalopathy, which comprised 83% of the cases, may be the endresult of repeated subclinical episodes of Wernicke's encephalopathy. Thus, Wernicke'sencephalopathy could be considered a "progressive" disorder and as patients respond well tothiamine replacement therapy, early diagnosis is important. Alternatively, prevention by vitaminenrichment of alcoholic beverages may have to be considered in an attempt to minimise the socialand economic impact of Wernicke's encephalopathy on Western society.

Clinical and pathological studies throughoutAustralia indicate a high, and probably rising, inci-dence of a potentially preventable disease caused bythiamine (vitamin B1) deficiency-Wemicke'sencephalopathy or the Wemicke-Korsakoff syn-drome.'-5 A similar trend is apparent in other West-ern civilisations67 and probably exists even in ThirdWorld countries8 though largely overlooked becauseof lack of formal epidemiological studies. AlthoughWemicke's encephalopathy is caused by a nutri-tional deficiency of thiamine, it is seen today almostexclusively in the alcoholic population.'9 From aclinical point of view, the traditional triad of confu-sion, ataxia and ophthalmoplegia will only be evi-dent in a small percentage of cases and the diagnosishas been unsuspected prior to death in a significantproportion of cases.'01' In the acute stage of Wer-nicke's encephalopathy, there is a dramatic responseto parenteral thiamine. Thus, this disease is poten-tially preventable and the group at risk an obviousone, although not readily accessible.The Department of Neuropathology at the Royal

Perth Hospital provides a state wide service for the

Address for reprint requests: Dr Clive Harper, Department ofNeuropathology, Royal Perth Hospital, Box X 2213, GPO Perth,W.A. 6001, Australia.

Received 7 November 1982 and in revised form 10 February 1983.Accepted 10 February 1983

1 300 000 population. A relatively high proportionof the brains from those dying in the metropolitanarea are examined and cases of Wernicke'sencephalopathy have been studied in a prospectivefashion since 1973. Altogether, 131 cases have beenstudied and in most cases, medical records wereavailable for clinico-pathological correlation.

Results

In a post mortem study of Wernicke'sencephalopathy in Westem Australia between 1973and 1981, 131 cases were diagnosed pathologicallyfrom 4677 brains examined from patients over 20years of age. This is an overall incidence of 2 8%.There is some variation in the incidence from year toyear as shown in table 1. The Department ofNeuropathology at the Royal Perth Hospitalreceives material from many sources, the mostimportant for this study being the Perth City Coron-ers Department. Eighty-three cases of Wernicke'sencephalopathy were diagnosed from 1783 coronersnecropsies, an incidence of 4*7% compared to anincidence of 1.7% from necropsies performed inRoyal Perth Hospital.The age and sex distribution are shown in table 2.

Seventy-five per cent of the cases were male and25% female. The peak age incidence was in the fifthdecade. Twelve per cent (16) of the cases were ofaboriginal extraction. The aboriginal population

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Table 1 Wernicke's encephalopathy-Perth 1973-1981

Year Number of brains Number of cases of Incidenceexamined* Wernicke's encephalopathy

1973 505 6 1-2%1974 538 12 2 2%1975 601 18 3-0%1976 560 15 2-7%1977 486 10 2 1%1978 438 15 3-4%1979 532 9 1-8%1980 499 29 588%1981 518 17 3-3%Total 4677 131 2-8%

*Includes only "at risk" group (over 20 years)

Table 2 Sex and age distribution of 131 cases studied

Males ........... .... 98 (75%)Females ....................................... 33 (25%)

Ages (yr)30-39 ....................................... 940-49 ....................................... 1650-59 ....................................... 54 (41%)60-69 ....................................... 2570-90 ....................................... 27

makes up only 2-4% of the total Western Australianpopulation. In 90% of the 131 cases, alcoholism wasthe predisposing cause for the nutritional deficiency.One patient had malnutrition. Clinical informationwas not available on the other 12 cases, but most ofthese had other stigmata suggestive of alcoholismsuch as fatty livers or cirrhosis. Despite the fact thatthe majority of these cases had been examined inone of the teaching hospitals of Perth prior to theirdeath, often on numerous occasions, only 20% (26cases) had a clinical diagnosis of Wernicke'sencephalopathy or the Wemicke-Korsakoff syn-drome.From a pathological point of view, the cases of

Wernicke's encephalopathy can be readily classifiedas either acute, chronic or acute on chronic. Theincidence of these various stages of Wemicke'sencephalopathy are shown in table 3. Sixty-six percent were chronic, 17% acute and 17% acute onchronic. Commonly associated clinical problems inthese patients included epilepsy (11%), peripheralneuropathy (11%), alcoholic cardiomyopathy (4%)and 4% died with terminal hypothermia. Sixty percent had liver disease which included cirrhosis(37%), fatty liver (21%) and acute alcoholichepatitis (2%). Central pontine myelinolysis,although not diagnosed clinically, was found in twocases.

NEUROPATHOLOGYThe macroscopic neuropathological findings of the131 cases are listed in table 4. The most consistent

Harper

Table 3 Pathological classification ofthe 131 cases studied

Acute ................... 22(17%)Acute on chronic ........ ........... 23(17%)Chronic 86(66%)

macroscopic abnormality was shrinkage and browncolouration of the mamillary bodies (fig 1) which ischaracteristic of chronic Wernicke's encephalopathyand was seen in 75% of the cases. Ventricular dilata-tion, assessed subjectively, was noted in 34% ofcases. Periventricular haemorrhages (fig 2) werepresent in 5% of the cases and were seen only in theacute or acute on chronic stages of the disease.Frank necrosis of tissue was occasionally seen inacute Wernicke's encephalopathy in periventricularregions (fig 3). The lesions were characteristicallydistributed around the ventricular system, particu-larly in the walls of the third ventricle and the floorof the fourth ventricle. The incidence of involve-ment of these areas is listed in table 5.

Histologically, the acute lesion was characterisedby changes in and around blood vessel walls. Therewas extravasation of red blood cells (diapedesis)into the perivascular spaces and in some instancesthese extend outwards into the parenchyma to form"ball" microhaemorrhages (fig 4) or macroscopicallyevident haemorrhages (fig 2) as described above.The endothelial cells became hypertrophic. Tissuenecrosis also occurred in a periventricular distribu-tion, but was seen only in the most severe acute andacute on chronic cases.'2 In less severe cases, therewas a spongiosis of the affected areas suggestive ofoedema. An astrocytic reaction was recognised byTable 4 Neuropathological macroscopic findings (131 cases)

Incidence

Cerebral atrophy .....................21 %*Ventricular dilatation .................... 34%Mamiliary body atrophy .................... 75%Periventricular haemorrhage .................... 5%Cerebellar vermal atrophy ....................34%

*Includes three cases of Alzheimer's disease.

Table 5 Neuropathological microscopic findings

Site Incidence of abnormalities

Mamillary bodies .............. 99%Third ventricular wall .............. 61%Thalamus .............. 61%Midbrain .............. 50%Pons .............. 50%Medulla..............33%

the third or fourth day. The neurons showed rela-tively little alteration, but myelin and axons areoften destroyed. By day 10, the most dramatic his-tological feature was hypertrophy and hyperplasia of

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The incidence of Wernicke's encephalopathy in Australia-a neuropathological study of 131 cases

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Fig 1 Coronal section ofthe cerebral hemispheres showingdark, shrunken mamillary bodies (arrow). This is the mostcharacteristic macroscopic fiding in chronic Wernicke'sencephalopathy.

Fig 3 A myelin stain ofa coronal section ofthediencephalon at the level ofthe red nuclei (RN) showingsymmetrcal necrosis (arrows) in the dorsomedial (DM) andcentromedian nuclei ofthe thalamus and also involving thethalamic fasciculus. This is seen only in the most acute cases

of Wernicke's encephalopathy.IIXTT~~----

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A76,63Fig 2 Coronal section ofthe cerebral hemispheres showingsmall haemorrhages in the mamillary bodies and walls ofthe third ventricle (arrow). The diagnosis ofacuteWernicke's encephalopathy was only made at necropsy.

40

endothelial cells and budding and proliferation ofcapillaries (fig 5). Apart from occasional histiocytes,there was generally no inflammatory reaction. Inchronic lesions, parenchymal elements were lost andreactive changes were largely restricted to astro-cytes. There was usually a slight increase in num-bers of blood vessels, but the endothelial cellsappeared normal. This change was recognised mosteasily in the mamillary bodies (fig 6). These struc-tures were abnormal in 99% of the cases and there-fore serve as the single most reliable area to examinehistologically when screening cases for Wernicke'sencephalopathy.

Cerebral atrophy was noted in 21% of the casesand this most commonly involved the frontal lobes.In a separate study which included a large number ofthese cases, it was shown that male patients with

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Fig 4 Paraffin section from the floor of the fourthventricle shows a small blood vessel surrounded by redblood cells in the penivascular space and parenchyma. Thisis a typical "ball" microhaemorrhage seen in theearly stages ofacute Wernicke's encephalopathy.(Haematoxylin & eosin x 400).

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Fig 5 Paraffin section from the mamillary body showingendothelial cell hypertrophy and hyperplasia (arrows) andcapillary proliferation. These changes are typical ofacuteWernicke's encephalopathy about 10 days after the onset ofthe disease. (Haematoxylin & eosin x 400).

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Fig 6 Reticulin stain ofthe mamillary body (MB) ofa case

ofchronic Wernicke's encephalopathy. There is shrinkageand central spongiosis and an apparent increase in thenumbers ofblood vessgls in the centre ofthe mamillarybody. (Reticulin stain x 40) III = third ventricle.

Wernicke's encephalopathy had a mean brainweight (at necropsy) which was 67 grams lighterthan the mean brain weight of a group of agematched controls.'3 Microscopically, there is a subtlepatchy cortical neuronal loss.

Cerebellar atrophy involving the anterior superiorpart of the vermis (fig 7) was noted in 34% of the

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Fig 7 Sagittal sections ofcerebellar hemispheres from anormal patient and a patient with cerebellar vermal atrophyassociated with chronic Wernicke's encephalopathy. Theatrophy is most severe in the anterior superior part ofthevermis where the foliae are shrunken.

cases. However, on microscopic examination, 44%of the cases were considered to have significant lossof Purkinje cells and proliferation of the Bergmannastrocytes which are the characteristic findings ofboth cerebellar atrophy as part of Wernicke'sencephalopathy and that which occurs in alcoholicsalone (alcoholic cerebellar degeneration).

Discussion

The incidence of Wernicke's encephalopathy in thenine year necropsy study from 1973 to 1981 inPerth, Western Australia was 2*8% of all brains ofpatients older than 20 years. The incidence in theCleveland Metropolitan General Hospital from1963 to 1976 was 2-2% of 3548 consecutive necrop-sies performed in adults (18 years and older).6Cravioto et al in 196114 studied 1600 brains frompatients coming to necropsy at the Bellevue Hospi-tal over three years and the incidence of Wernicke'sencephalopathy was 1-7%. Torvik et al,9 in a recentnecropsy study in Oslo, Norway found an incidenceof 0-8%. Thus, the incidence of Wernicke'sencephalopathy in Western Australia appears to behigher than elsewhere. This may, however, reflectthe inclusion of brains from coroners' necropsies inwhich the incidence of Wernicke's encephalopathywas 477%. No similar study exists in the literature.The material from the Coroners' Department isobviously a very different population sample fromthat of a teaching hospital. However, it should benoted that 15% of patients were found to havealcohol-related reasons for their admission to hospi-tal in a recent Australian study.'5 It is of interest to

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The incidence of Wernicke's encephalopathy in Australia-a neuropathological study of 131 cases

note the fluctuation in incidence from year to year(table 1) and to speculate on the cause. The suddendrop in incidence in 1979 corresponded to theauthor's absence from Perth. This may have beencoincidental, but as shown in a previous paper,' thebrains of cases of Wernicke's encephalopathy oftenappear normal macroscopically and unless approp-riate blocks are examined microscopically, approxi-mately 30% of cases will be missed. There doesappear to be a trend towards an increase in the inci-dence of Wernicke's encephalopathy over the nineyear period. What possible explanation can beoffered to explain this trend? The estimated averagealcohol consumption in Australia has increased from5784 grams/head per year in 1977 to 7424 grams/head per year in 1981.2 The pattern of drinkinghabits has changed, with greater amounts of winebeing consumed. At the same time, the cost of livinghas increased disproportionately to salaries andsocial security allowances so that the averagealcoholic will have less money to spend in 1981compared to 1973. The implication is that thealcoholic will forgo the "lesser necessities of life"such as food rather than change his drinking habits.At the Royal Perth Hospital approximately

0-04% of all admissions are diagnosed as Wer-nicke's encephalopathy. In the last three years, therewas an average of 14 new cases diagnosed clinicallyeach year.' This figure is comparable with the Mas-sachusetts General Hospital where the figure wasabout 0-05 %.6 In a recent study from Sydney, NewSouth Wales, Truswell and Apeagyei2 showed thatthe annual incidence of Wernicke-Korsakoff diseasehad increased five fold in the last 15 years whereasthe population had only increased 1*3 times. Con-sidering that only 7% of people over the age of 20years dying in Western Australia have necropsystudies of their brains and an average of 14 cases ofWernicke's encephalopathy are diagnosed patholog-ically each year, there appears to be a relativelylarge discrepancy between numbers of cases ofWernicke's encephalopathy diagnosed clinically andpathologically. This was also confirmed by clinico-pathological analysis in that although the majority ofthe 131 cases had been seen in the teaching hospitalsof Perth, only 20% were diagnosed clinically asWernicke's encephalopathy. Why are so few cases ofthis syndrome diagnosed clinically? It is probablethat the chronic form of the disease, which com-

prised 83% of the cases, can develop after repeatedepisodes of a subclinical encephalopathy in whichthe usual signs of mental confusion, ataxia, oph-thalmoplegia, nystagmus and memory loss might beabsent. Lishman'° in his lecture on "Cerebral Disor-ders in Alcoholism" agreed with and expanded upon

this hypothesis. Thus, it would seem that an accurate

assessment of the incidence of Wernicke'sencephalopathy in the population can only beachieved through pathological studies. However, itseems likely that detailed neurological assessment,including psychometric testing, will bring to lightmore clinical cases of Wernicke's encephalopathy.

Chronic Wernicke's encephalopathy could beconsidered as a "progressive disorder", each acuteclinical or subclinical episode of Wemicke'sencephalopathy causing cumulative damage, and itis therefore important to identify early cases, treatand prevent further progression. It is a matter ofhuman nature that many of these patients, often wellknown in the outpatient and emergency units, aregiven a rather cursory examination and subtle signsof Wernicke's encephalopathy could be missed. Redblood cell thiamine assays, which reflect tissue levelsof thiamine, are now available in the Royal PerthHospital.'6 These may prove useful in the earlydiagnosis of thiamine deficiency states and the man-agement of such patients.The sex incidence (male:female = 3:1) probably

reflects the drinking pattern of Australians and therehas been no change over the nine year period.' Dis-turbing features are the number of young men andwomen dying with this disease and the high inci-dence of Wernicke's encephalopathy in the aborigi-nal community.Although this disease is largely restricted to the

alcoholic population, there are other specific situa-tions which can predispose to acute Wernicke' sencephalopathy and can cause sudden death.'2These include prolonged intravenous feeding with-out adequate vitamin supplements," 17 fasting forobesity,'8 and hunger strikes. In these instances, theclinical course may be that of confusion and obtun-dation progressing fairly rapidly to coma."l The clas-sical clinical signs of Wernicke's encephalopathymay not be apparent or may be masked by the coma.The neuropathological findings of these 131 cases

are similar to those of Victor, Adams and Collins'9in their monograph on the Wernicke-Korsakoffsyndrome. Routine neuropathology is unlikely tohelp our understanding of the distinctive periven-tricular distribution of the lesions. Likewise, ananalysis of the neuropathological findings in the 11cases which had been diagnosed clinically as Kor-sakoff's psychosis, has shown no significant differ-ences in the distribution or severity of lesions fromthe 15 cases diagnosed clinically as Wernicke'sencephalopathy.One neuropathological aspect which deserves

further attention is cerebral cortical atrophy whichwas present in 34% of cases (including three cases ofAlzheimer's disease). Although this finding is basedon a subjective assessment of the external appear-

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ance and slices of the fixed brain, an analysis of freshbrain weights of a group of these cases (66) showedthat the mean brain weight of males with Wernicke'sencephalopathy was 67 grams less than that of anage matched normal control group.'3 This was asignificant difference (p < 0.001). Interestingly, themean brain weight of 61 male alcoholics who had nohistological evidence of Wernicke's encephalopathy,was 75 grams less than the control group (p <0.001). Torvik et al9 also showed a mean brainweight difference of 31 grams in comparing 545male alcoholics with 586 controls. They concludedthat this confirmed the existence of a generalisedalcoholic brain atrophy. From our study, bothalcoholics with Wernicke's encephalopathy andthose with no evidence of a nutritional deficiencyhad low mean brain weights. This suggests thatalcohol, the factor common to both groups, is moreimportant than nutritional deficiencies in causing areduction in brain weight and cerebral cortical atro-phy. Recent radiological studies202' have also dis-closed a high incidence of cerebral cortical "shrink-age", but some of these changes appear to be revers-ible.2' 22

Having stressed the extraordinary frequency ofthis disease, it is obvious that it creates a significantsocial and economic burden to our community. Cen-terwall and Criqui23 showed a significant cost-benefitin an analysis of the economic feasibility of prevent-ing this disease by fortification of alcoholic bever-ages with thiamine. Certainly, these patientsrespond dramatically to thiamine supplements in theearly or acute stages of the disease.24 However, theoptimal approach is prevention rather than cure.

I am grateful to the Perth City Coroners' Depart-ment for their continued cooperation in providingmaterial for our examination. Mr Rick Timm pre-pared the figures and Mrs Patsy Cunningham typedthe manuscript.

References

'Harper CG. Wernicke's encephalopathy: A more com-mon disease than realised. J Neurol NeurosurgPsychiatry 1979;42:226-31.

2 Truswell AS, Apeagyei F. Alcohol and cerebral thiamindeficiency. In: Jelliffe EFP, Jelliffe DB, eds. AdverseEffects of Foods. New York: Plenum Press,1982;253-58.

3Brown J. Alcoholic psychoses in Queensland psychiatrichospitals. In: Prevention of Alcohol-Related BrainDamage. Report of Workshop April 5-6. Canberra,Australia: Commonwealth Department of Health,1979:48.

4Price J, Theodoros MT. The prevention of Korsakoff'spsychosis. Med J Aust 1979;1:285.

' Wood B, Breen KJ. Clinical thiamine deficiency inAustralia: The size of the problem and approaches toprevention. Med J Aust 1980;1:461-4.

6Victor M, Laureno R. Neurologic complications ofalcohol abuse: epidemiologic aspects. In: SchoenbergBS, ed. Advances in Neurology Vol 19. New York:Raven Press, 1978.

7 Wilkinson P. Possible measures to reduce the prevalenceand severity of alcohol and drug-related cerebraldamage. In: Rankin JG, ed. Alcohol, Drugs and BrainDamage. Ontario, Canada: Addiction ResearchFoundation, 1975:81-8.

8 Edwards G. Drinking problems. Putting the Third Worldon the map. Lancet 1979;2:402-4.

9Torvik A, Lindboe CF, Rodge S. Brain lesions inalcoholics. A neuropathological study with clinicalcorrelations. J Neurol Sci 1982; In Press.

'° Lishman WA. Cerebral disorder in alcoholism: Syn-dromes of impairment. Brain 1981;104:1-20.

" Harper CG. Sudden, unexpected death and Wemicke'sencephalopathy. A complication of prolongedintravenous feeding. Aust NZ J Med 1980;10:230-5.

12 Harper CG. Confusion, coma and death from a prevent-able disease. Med J Aust 1981;2:219-21.

'3 Harper CG, Blumbergs PC. Brain Weights in Alcohol-ics. J Neurol Neurosurg Psychiatry 1982;45:838-40.

4 Cravioto H, Korein, J, Silberman J. Wernicke'sencephalopathy. A clinical and pathological study of28 autopsied cases. Arch Neurol 1961;4:510-19.

"5 Williams AT, Harding Bums F, Morey S. Prevalence ofalcoholism in a Sydney teaching hospital. Med J Aust1978;2:608-1 1.

16 Icke GC. The microbiological assay of thiamine and itsclinical significance. M Sc Thesis, University of West-ern Australia, 1980.

7 Wallis WE, Willoughby E, Baker P. Coma in theWemicke-Korsakoff syndrome. Lancet 1978;2:400-1.

18 Drenick EJ, Joven CB, Swendseid ME. Occurence ofacute Wernicke's encephalopathy during prolongedstarvation for the treatment of obesity. N Engl J Med1966;274:937-9.

'9 Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff syndrome. Philadelphia: Davis, 1971.

20 Cala LA, Mastaglia FL. Computerised axial tomographyin the detection of brain damage. 1. Alcohol, nutri-tional deficiency and drugs of addiction. Med J Aust1980;2: 193-8.

21 Carlen PL, Wartzman G. Holgate RC, Wilkinson DA,Rankin JG. Reversible cerebral atrophy in recentlyabstinent chronic alcoholics measured by computedtomography scans. Science 1978;200:1076-8.

22 Artman H. Reversible Enlargement of Cerebral SpinalFluid Spaces in Alcoholics. Annual Journal ofNeuroradiology 1981;2:23-7.

23 Centerwall BS, Criqui MH. Prevention of theWemicke-Korsakoff syndrome. A cost-benefitanalysis. N Engl J Med 1978;299:285-9.

24 Phillips GB, Victor M, Adams RD. A study of the nutri-tional defect in Wernicke's syndrome: the effect of apurified diet, thiamine, and other vitamins on the clin-ical manifestations. J Clin Invest 1952;31:859-71.

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