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Jounal ofNeurology, Neurosurgery, and Psychiatry 1997;62:51-60 51 Operational criteria for the classification of chronic alcoholics: identification of Wemicke's encephalopathy

D Caine, G M Halliday, J J Kril, C G Harper

Abstract suggest that there can be a complete resolution Objectives-To establish better opera- of the underlying abnormality in tional criteria for the diagnosis of Wernicke's encephalopathy, similar to the res- Wernicke's encephalopathy. Current olution of neuropathology in hepatic criteria for diagnosing Wernicke's encephalopathy. However, unlike require the presence of encephalopathy, in which the clinical signs are three clinical signs (oculomotor abnor- a precursor of the pathology, many patients malities, cerebellar dysfunction, and an with the neuropathology of Wernicke's altered mental state), although it has encephalopathy do not have recorded signs of often been reported that most patients do the classic triad.' 2 This raises the question of not filfil all these criteria. whether the clinical correlates of the patholog- Methods-The clinical histories of 28 ical lesions are being missed during life or alcoholics with neurological and neu- whether the pathology represents clinically ropsychological assessments and defini- silent lesions. A similar situation is seen in tive neuropathological diagnoses were Alzheimer's , in which many non- examined to determine clinical signs for demented aged patients show a similar type use in a screening schedule. Operational and distribution of neuropathology to their criteria were then proposed for differenti- demented counterparts. 12 Recently research ating patients with Wernicke's into the pathophysiology of aging and encephalopathy alone or in combination Alzheimer's disease has been successfully with Korsakoff's or hepatic advanced by the use of operational criteria encephalopathy. The new criteria for which can be applied across clinics and labora- Wernicke's encephalopathy require two of tories.'3 14 The aim of the present study is to the following four signs; (1) dietary defi- propose operational criteria for the diagnosis ciencies, (2) oculomotor abnormalities, of Wernicke's encephalopathy. (3) cerebellar dysfunction, and (4) either Most patients world wide with Wernicke's an altered mental state or mild memory encephalopathy are alcoholics,'5 with 30%- impairment. Reproducibility and validity 80% of chronic alcoholics having the clinical testing of these criteria were performed or biochemical signs of thiamine deficiency.'6 on 106 alcoholics screened from a large Two extensive clinicopathological studies' 2 necropsy sample. found that the incidence of oculomotor abnor- Results-Despite rater variability with malities was low and therefore reliance on the Neuropsychology Unit, regard to specific symptoms, within and classic triad would result in significant under- Royal Prince Alfred between rater reliability for diagnostic recognition of these patients during life. Hospital, classification the Camperdown, 2050, using criteria retrospec- Because an altered mental state is also a com- Australia tively on patient records was 100% for mon neurological sign associated with hepatic D Caine three independent raters. Validity testing encephalopathy,'7 the overlap between the two Prince ofWales showed that Wernicke's encephalopathy poses substantial and often unrecog- Medical Research was underrecognised only when occurring nised difficulties for diagnosis. Operational Institute, High Street, cri- Randwick, 2031, with hepatic encephalopathy (50% sensi- teria for recognising and separating these Australia tivity). common conditions are needed. Therefore the G M Halliday Conclusions-By contrast with current aim of the present study was to devise and test Neuropathology criteria, the proposed operational criteria such operational criteria for classifying chronic Division, Departments show that the ofPathology, antemortem identification alcoholics for both treatment and research. We University of Sydney, of Wernicke's encephalopathy can be have assessed only alcoholics in order to 2006 and Royal Prince achieved with a high degree of specificity. analyse a large and relatively homogeneous Alfred Hospital, Camperdown, 2050, group of patients with Wemicke's encephal- Australia ( Neurol Neurosurg Psychiatry 1997;62:51-60) opathy. The criteria account for the diagnoses G M Halliday of other common medical complications asso- J J Kril ciated with this patient population.4 Key signs C G Harper Keywords: alcoholism; diagnostic criteria; neurological for operational criteria for Correspondence to: impairnent; Wernicke-Korsakoff diagnosis are pro- Dr G Halliday, Prince of posed and the reliability and predictive validity Wales Medical Research and Institute, Villa 2, High (specificity sensitivity) of using these crite- Street, Randwick. 2031, It is well known that the pathology of ria to classify chronic alcoholics tested. Australia. Wernicke's encephalopathy may not be associ- Received 25 March 1996 ated with the full clinical triad and that in the and in final revised form 30 August 1996 acute phase clinical symptoms may resolve Methods Accepted 2 September 1996 with thiamine treatment.'-" These findings To determine characteristic signs and 52 Caine, Halliday, Kril, Harper

symptoms for alcoholics with and without standardised administration and scoring of the Wernicke's encephalopathy, the histories of 28 following neuropsychological tests: Wechsler patients, well known to the neuropsychology memory scale, Rey auditory verbal learning unit, Royal Prince Alfred Hospital, who had test, Rey-Osterrieth complex figure test, trail died between 1989 and 1993 and had making test, and Stroop test.2' The diagnosis necropsy confirmation of their clinical diag- of Wernicke's encephalopathy, Wernicke- noses were examined. These had a variety of Korsakoff syndrome, hepatic encephalopathy, neurological presentations, including eight or related brain dysfunction was made patients with Wernicke's encephalopathy using the history obtained, information from (classic triad but with no evidence of a perma- referring agencies, the results of the clinical nent amnesic syndrome), six patients with the and neuropsychological examinations, and Wernicke-Korsakoff syndrome (alcoholics those of any additional tests which may have with Wernicke's encephalopathy fulfilling cur- been ordered. rent criteria for Korsakoffs psychosis'8 20)), nine patients with hepatic encephalopathy PATHOLOGICAL DIAGNOSIS (neurological abnormalities associated with A full necropsy was performed for all patients decompensated liver disease'7), and eight including macroscopic and microscopical patients with alcohol related brain dysfunction examination of all organs. A detailed neu- (neurological or neuropsychological impair- ropathological examination was performed. ment, although not fulfilling the criteria for The external brain features were examined Wernicke's encephalopathy, Wernicke- before and after fixation in neutral buffered Korsakoff syndrome, or hepatic encephalopa- formalin for 14 days. The brain was then thy). Three patients had both Wernicke's embedded in 3% agar and sectioned at 3 mm encephalopathy and hepatic encephalopathy. intervals in the coronal plane with a rotary In all patients the clinical diagnosis matched slicer. The cut surfaces of each slice were the neuropathological diagnosis, patients with examined for neuropathological abnormalities. alcohol related brain dysfunction having no Standardised blocks of the superior frontal, neuropathological abnormality. superior parietal, inferior temporal, and parahippocampal cortices, hippocampus, STANDARDISED CLINICAL EXAMINATION amygdala, anterior and posterior basal ganglia Patients in the neuropsychology unit under- including the basal forebrain, thalamus, went a 90 minute clinical assessment by a con- mamillary bodies of the hypothalamus, mid- sultant neurologist or registrar, brain, pons, medulla oblongata, and cerebel- comprising a detailed history following a stan- lum (vermis, lateral cortices and dentate dard protocol, a complete general medical nuclei) were sampled for paraffin embedding. examination, and a detailed neurological Sections were cut at 10 mm and stained with examination including an examination of men- haematoxylin and eosin, luxol fast blue, and tal status. They also underwent clinical neu- silver stains before microscopical examination ropsychological assessment which included and diagnosis (by CGH). Other specialised stains were performed if required to exclude cerebral infarction, head injury, or degenera- Table 1 Schedule ofclinical signs and symptoms with domains highlighted (see textfor definitions) tive conditions such as Alzheimer's disease. Serious liver disease was diagnosed if liver cir- Previous history or atfirst Developed rhosis or was confirmed at necropsy. presentation subsequently At any time Hepatic encephalopathy was diagnosed if the Wernick's encephalopathy patient had serious liver disease and Alzheimer WE diagnosed clinically type II astrocytes in the brain (common in the Dietary deficiency Undernutrition basal ganglia, cerebral cortex, or pons). Vitamin deficiency Wernicke's encephalopathy was diagnosed Eye signs Ophthalmoplegia when mamillary body and periventricular lesions were evident.2223 In acute Wernicke's Gaze palsy con- Gerebellar signs encephalopathy the pathology was largely fined to abnormalities of blood vessels with Unsteady Cerebellar dysfunction petechial haemorrhages commonly occurring. Seresi=m In chronic Wernicke's encephalopathy neu- Frontal lobe ysfunction Planning deficit ronal loss and gliosis were evident in the Abstraction deficit mamillary bodies. A diagnosis of normal brain Mental rigidity Behavioural disturbance was made if no neuropathological abnormality was detected. Mild memory impairment Mild-moderate memory problems Confabulating EVALUATION OF CLINICAL SIGNS AND Altered mental state Disoriented SYMPTOMS Comatose A range of clinical signs and symptoms repre- Confused domains Digit span abnormal senting deficits in the major clinical Hepatic encephalopathy known to be affected in alcoholics4 was evalu- Diagnosed clinically Liver disease ated for establishing operational criteria. Jaundice Related clinical symptoms and alternative Haematemesis Melaena terms used to describe a sign or symptom were grouped together under each of these domains and a standardised schedule of the clinical Operational criteria for the classification ofchronic alcoholics: identification of Wernicke's encephalopathy 53

signs designed (table 1). For example, cerebel- ducted blind to the neuropathological diagnosis lar damage resulting in ataxia is commonly using the standardised schedule to record the present in alcoholics, but in the absence of for- presence or absence of clinical features at two mal testing it is often recorded as an unsteadi- time points: symptoms present at or before ini- ness. Therefore both ataxia and unsteadiness tial neurological examination and symptoms were used as indicators of cerebellar dysfunc- occurring after initial presentation. The clini- tion. The presence of either of these signs was cal domains were then categorised according sufficient to result in a positive score for cere- to pathological diagnosis. Operational criteria bellar abnormalities. for different diagnoses were devised on the Evaluation of the clinical profiles of the 28 basis of this information (table 2). patients disclosed 11 commonly encountered clinical domains. These were Wemicke's VALIDATING THE OPERATIONAL CRITERIA encephalopathy (diagnosed during life using Test population the classic triad), dietary deficiencies (a body All adult patients necropsied between 1986 mass index lower than 2 SD below normal as and 1994 from the Royal Prince Alfred evidence of undernutrition, a history of grossly Hospital, as well as 10% of necropsied impaired dietary intake, or an abnormal thi- patients from the New South Wales Institute amine status), eye signs (oculomotor abnor- of Forensic Medicine (referred for neu- malities such as ophthalmoplegia, nystagmus, ropathological examination), constituted the or gaze palsy), cerebellar signs (see above, or base from which the test samples were drawn abnormalities of past pointing, dysdiadokoki- (4600 patients). Of these 303 had a history of nesia, or impaired heel-shin testing), alcoholism (7% of sample) based on informa- (either as part of a withdrawal syndrome or in tion from telephone interviews to general prac- isolation, or a longstanding history of anticon- titioners, written questionnaires to relatives of vulsant medication), frontal lobe dysfunction patients, and clinical details from hospital (abnormalities in planning, insight, or abstrac- records. Alcoholism was established if greater tion with formal neuropsychological testing or than 80 g ethanol was consumed each day for when neurological examination elicited these most of their adult life (usually > 30 years) as characteristics), amnesia (a stable and persist- recorded from these multiple sources. ing inability to form new memories), mild Informant histories have been shown to pro- memory impairment (failure to remember two vide accurate assessment of alcohol intake.25 or more words in the four item memory test,24 Exclusion criteria were an average daily alco- or impairment on more elaborate neuropsy- hol consumption of less than 80 g ethanol, chological tests of memory function), altered inadequate clinical history (no neurological mental state (disorientation in two of three examination or single admission only), or neu- fields, confused, an abnormal digit span, or ropathological evidence of a cerebral infarc- comatose); hepatic encephalopathy (grades 3 tion, head injury or neurodegenerative or 4, in which signs of impaired mental state condition (for example, Alzheimer's disease). range from to coma17), and liver dis- A total of 197 of the 303 alcoholics selected ease (signs of systemic abnormalities sec- were excluded, leaving 106 alcoholics for the ondary to chronic liver disease including study (35% of alcoholics, 2-3% of the total melaena, haematemesis, jaundice, ascites, or sample, 16 women and 90 men, including the asterixis). Abnormal liver function tests in iso- 28 patients used for establishing the opera- lation were not considered sufficient to have a tional criteria). The age range was 33 to 79 positive score for liver disease. In addition, years (mean 58 (SD 10)). poor performance on memory tests on only one occasion was only considered sufficient for INCLUSION CRITERIA AND DEFINITION OF a positive score for amnesia if the patient was PATIENTS unable to form any new memories. Inclusion criteria were consumption of greater than 80 g ethanol per day for most of their ESTABLISHING OPERATIONAL CRITERIA adult life, neurological assessment, clinical Retrospective patient note analysis was con- assessment at more than one time point, full necropsy, interview with general practitioner Table 2 Operational criteriafor the clinical diagnosis ofchronic alcoholics. See textfor or relatives, and an extensive and systematic definition ofclinical signs. Multiple diagnoses are possible neuropathological examination that excluded Clinical diagnoses conditions other than those directly attribut- No clinical Liver disease able to chronic alcohol consumption. Clinical domains signs only ARBD HE WE WKS WE Absent Absent Absent Absent Optional Optional TESTING THE OPERATIONAL CRITERIA Dietary deficiency Absent Absent t t The standardised schedule and operational Eye signs Absent Absent * 1t Cerebellar signs Absent Absent * t t criteria were applied to the longitudinal Seizures Absent Absent * patient records of all 106 Frontal lobe patients for clinical dysfunction Absent Absent * patient classification. About 30% of each Amnesia Absent Absent * Absent Absent Present patient type were randomly Mild memory selected for analy- impairment Absent Absent * t- t- ses of between and within rater reliability (32 Altered mental state Absent Absent Absent Present f . patients in total). These patients were classi- HE Absent Absent Absent Optional Absent Absent Liver disease Absent Present Present fied independently by three researchers blind to neuropathological diagnosis (DC, GMH, *Any one of these signs; tany two of these signs, but not both of those marked. ARBD = alcohol related brain dysfunction; HE = hepatic encephalopathy; WE = Wernicke's JJK). Symptoms and signs occurring at any encephalopathy; WKS = Wernicke-Korsakoff syndrome. stage were used for classification. The predic- 54 Caine, Halliday, Kril, Harper

tive validity of the clinical classification against alone had a definitive clinical diagnosis of the criterion of clinicopathological diagnosis is Wernicke's encephalopathy (classic triad) or expressed in terms of sensitivity and speci- clinical evidence of at least two of the four fol- ficity,26 where sensitivity = (true positives/ lowing signs; (1) dietary deficiencies, (2) eye (true positives + false negatives)) x 100% and signs, (3) cerebellar signs, and (4) either an specificity = (true negatives/(false positives + altered mental state or mild memory impair- true negatives)) x 100%. The microscopical ment; and Wernicke's encephalopathy at pathology for all patients with either a false necropsy. Amnesic patients and patients with clinical but positive pathological diagnosis or a a diagnosis of hepatic encephalopathy were true clinical but negative pathological diagno- excluded from this group. All patients had a sis (17% of all patients) was carefully progressive and usually short clinical course rechecked blind to the clinical classification (average of three years between first presenta- (by CGH). If discrepencies between diagnoses tion and death). At least two of the four signs of still existed (10 patients), the neuropathology Wernicke's encephalopathy were present at, or was rechecked by two independent researchers soon after, first presentation (patients 3 and 4, (GMH, JJK) and neuropathological diagnosis appendix). In many patients only a single sign determined by consensus agreement of all of the Wernicke's encephalopathy triad was three researchers. The original neuropatholog- noted initially, whereas at subsequent presen- ical diagnosis was confirmed in all of these tations there were usually additional neurolog- patients. ical signs. Most were still drinking at the time of death. It should be noted that clinically, many of these patients did not fulfill current diag- Results nostic criteria using the full clinical triad (eye DIAGNOSTIC GROUPS signs, cerebellar signs, and an altered mental Application of the operational criteria to the state). We found that patients with Wernicke's 106 patients confirmed the major diagnoses encephalopathy pathology had a minimum of identified in the 28 detailed patients and estab- two clinical signs which may have included lished a pattern for six different diagnostic dietary deficiencies. Thus some patients were groups. The clinical characteristics and pro- included with only one neurological abnormal- gression of symptoms for each group follow. ity in the presence of dietary deficiencies. This Alcoholics with compensated liver disease criterion differs substantially from the classic only had clinical evidence of compensated liver definition. disease in concert with the pathology for serious Alcoholics with the Wernicke-Korsakoff liver disease and a normal brain. patients were syndrome fulfilled the above criteria for the excluded if neurological impairment or dietary diagnosis of Wernicke's encephalopathy and deficiency was evident. These patients had one had documented evidence of amnesia and dis- or more of the symptoms of liver disease, but orientation in the absence of an acute confu- did not progress to develop all symptoms or sional state (patients 5 and 6, appendix). hepatic coma. These patients were often institutionalised due Alcoholics with hepatic encephalopathy had to their profound memory dysfunction and clinical evidence of decompensated liver disease therefore tended to have a longer history of (altered mental state) in concert with the neurological signs and symptoms (> 10 years) pathology for serious liver disease and hepatic documented either in patient notes or inferred encephalopathy. Patients were excluded if from nursing home institutionalisation. Initial another encephalopathy was diagnosed clini- presentation was usually associated with the cally or if dietary deficiencies, eye signs, cere- effects of intoxication or withdrawal (including bellar signs, mild memory impairment, or seizures). There was progressive deterioration amnesia were evident, unless the patient had in both the range of neurological symptoms also been given a definitive clinical diagnosis of and the severity of cognitive symptoms hepatic encephalopathy. (patient 6). In particular, stable amnesia was The presence of of the liver was usually noted after detoxification at either the often not apparent until the patient presented initial or second presentation (within one with symptoms of decompensated liver disease. year). At this time institutionalisation usually Therefore these patients represent the more occurred and was associated with a reduction severe end of the range of patients with liver or cessation of drinking and improved nutri- disease. The most frequent symptoms included tional status. This is likely to contribute to the the combination of jaundice, ascites, melaena, relatively long survival time of these patients. and haematemesis, whereas asterixis was less Alcoholics with alcohol related brain dys- frequent (patients 1 and 2, appendix). The function had clinical evidence of neurological longest interval between initial presentation impairment in at least one domain (cerebellar with liver disease and death was 15 months signs, seizures, frontal lobe dysfunction, mem- (patient 2) and was independent of whether the ory impairment, altered mental state), but did patient ceased drinking during this time. not reach clinical criteria for any of the diag- Therefore, although these patients may have nostic groups above (patients 7 and 8, appen- had cirrhosis of the liver for an extended period, dix). These patients had no significant mortality seemed inevitable after the develop- neuropathology and usually presented with the ment of hepatic encephalopathy and was most full range of withdrawal symptoms (including commonly due to , gastrointestinal haem- seizures, patient 7) or with complex cognitive orrhage, or raised . deficits (dissimilar to the Wernicke-Korsakoff Alcoholics with Wernicke's encephalopathy syndrome in that memory impairment was Operational criteria for the classification ofchronic alcoholics: identification of Wernicke's encephalopathy 55

either mild (patient 8), or, if amnesic, associ- pathology, six were not clinically diagnosed ated with a longstanding history of seizures). using the operational criteria, whereas only Neither eye signs nor dietary deficiencies were nine patients fulfilled the classic clinical triad ever seen in these patients (patients 7 and 8). (22 5%). Using the operational criteria, two Most patients had longstanding histories of patients with Korsakoffs psychosis and a his- seizures (most had diagnosed in early tory of alcoholism were institutionalised for an adulthood) or neuropsychiatric abnormalities extended time and had no clinical record of with significant frontal lobe features (mostly the signs of Wernicke's encephalopathy. The coincident with their history of alcoholism). remaining patients had additional hepatic Alcoholics without neurological complica- encephalopathy clinically and pathologically, tions were defined by exclusion criteria. and the clinical signs of Wernicke's Patients were excluded if they fulfilled any of encephalopathy may have been less obvious. the criteria above or if dietary deficiencies, Altered mental state was found at some liver disease, or neurological, psychological, or stage in all encephalopathic patients and mild neuropathological abnormalities were evident. memory impairment was seen in most groups, These alcoholic patients usually presented but particularly those classified with alcohol with intoxication, unsteadiness, blackouts, or related brain dysfunction or Wemicke's withdrawal symptoms but without any perma- encephalopathy (either alone or in combina- nent sequelae; in particular, no neurological tion; table 3). Seizures were most prevalent in signs or cognitive dysfunction were evident patients with alcohol related brain dysfunc- (patient 9, appendix). tion, although the Wernicke-Korsakoff syn- Alcoholics with multiple diagnoses were drome group also had an above average also found. Some patients with neurological number of such patients (table 3). Ofparticular impairment also had evidence of liver disease. importance is the finding that cerebellar signs Compensated liver disease did not contribute concentrated in all patients classified with to the neurological signs in any patient. Wernicke's encephalopathy, although patients However, significant overlap in clinical signs with the Wernicke-Korsakoff syndrome had was evident in patients with hepatic eye signs more often than those with encephalopathy and Wernicke's encephalopa- Wemicke's encephalopathy or Wemicke's thy. In all such patients, the course of hepatic encephalopathy and hepatic encephalopathy encephalopathy followed that described above (table 3). Conversely, there was a high preva- for hepatic encephalopathy alone, although it lence of dietary deficiencies in patients with was somewhat more prolonged. In patients Wemicke's encephalopathy and Wernicke's with Wemicke's encephalopathy and hepatic encephalopathy plus hepatic encephalopathy encephalopathy diagnosed during life, the pre- compared with the Wemicke-Korsakoff syn- sentation of Wemicke's encephalopathy and drome. This is most likely due to the institu- hepatic encephalopathy occurred concurrently tionalisation of many in this group. Other (patient 10, appendix), possibly indicating a signs concentrated in particular alcoholic more classic presentation of the Wernicke's groups because of the inclusion/exclusion cri- encephalopathy triad in these patients. One teria. Dietary deficiencies and eye signs patient had a history of the Wernicke's occurred only in partients with Wernicke's encephalopathy triad and Korsakoffs psy- encephalopathy (with or without amnesia or chosis which preceded the complication of hepatic encephalopathy), amnesia was most hepatic encephalopathy (patient 11, appen- common in patients with the Wernicke- dix). Korsakoff syndrome, and liver disease and hepatic encephalopathy were common in RELIABILITY AND PREDICTIVE VALIDITY OF patients with these pathological diagnoses OPERATIONAL CRITERIA (table 3). In the 30% of patients randomly chosen for Table 3 also shows the specificity of the reanalysis of patient classification, rater retest- operational criteria and the percentage of over- ing gave the same diagnosis in all patients lapping clinical signs in each alcoholic group. (100% accuracy) even with test-retest intervals The false positive rate for clinical classification of up to four months. Further, despite can be obtained by subtracting the specificity between rater agreement for individual signs value from 100. Interestingly, only in patients and symptoms on the standardised schedule of classified with hepatic encephalopathy or liver only 83%, it was 100% for diagnostic classifi- disease could the diagnosis not be substanti- cation in all instances. This indicates that ated on pathological grounds. Of the 18 grouping symptoms and signs into broad patients classified with hepatic encephalopathy domains for patient classification is reliable using the operational criteria, no Alzheimer and reproducible with regard to overall diag- type II astrocytes could be found in the nosis while allowing for interrater differences of two patients. Both patients had serious liver with regard to specific signs and symptoms. pathology, and examination of the clinical Table 3 shows the sensitivity of the opera- records showed evidence of decompensated tional criteria and the percentage of patients liver disease. Yet despite this, hepatic with different clinical signs in each alcoholic encephalopathy could not be confirmed neu- group. Only the diagnosis of Wernicke's ropathologically, although death occurred encephalopathy in combination with amnesia without longstanding coma in both patients or hepatic encephalopathy proved problematic (within three hours of coma onset). Of the 11 for retrospective classification. Out of 40 patients fulfilling the operational criteria for patients with Wemicke's encephalopathy compensated liver disease only, four had no 56 Caine, Halliday, Kril, Harper

Table 3 Specificity and sensitivity ofthe clinical diagnosis based on pathological criteria and the proportion ofpatients with different clinical signs. Clinical signs which concentrate in particular alcoholic groups are in bold Clinical diagnoses No clinical Liver disease All 106 signs only ARBD HE WE WKS WE+HE patients (n = 22) (n = 11) (n = 15) (n = 18) (n = 16) (n = 16) (n = 8) Sensitivity 94 100 100 100 100 100 88 50 Specificity 99 100 96 100 98 100 100 100 Mean number of signs (/11) 2 0 1 2 3 3 *5 *5 Clinical domains: WE 8 0 0 0 0 *31 13 *25 Dietary deficiency 9 0 0 0 0 *25 13 *38 Eye signs 19 0 0 0 0 31 *56 25 Cerebellar signs 36 0 0 36 17 *81 *81 50 Epilepsy 1 6 0 0 *50 11 19 *32 0 Frontal lobe dysfunction 14 0 0 14 0 *31 *44 13 Amnesia 17 0 0 14 0 0 *100 0 Mild memory impairment 29 0 0 50 6 *63 50 50 Altered mental state 29 0 0 0 56 31 56 *63 HE 22 0 0 0 *89 0 0 *88 Liver disease 47 0 *100 21 *100 44 31 75 For abbreviations see table 2. * > Twice the proportion seen in all 106 patients. Values apart from mean number are %.

serious liver pathology. Seven of 16 patients The validation of the criteria relies on ade- classified with Wernicke's encephalopathy also quate testing procedures. The test population fulfilled the criteria for liver disease, although studied was derived from both hospital and three of these patients had no serious liver forensic sources, representing a broader cross pathology. All seven patients with a false posi- section of patients than those from a single tive diagnosis for liver disease using the opera- source. The use of forensic material minimised tional criteria had clinical symptoms and signs the bias of patient selection towards those with that could be attributed to concomitant gas- overt neurological complications, as all sudden trointestinal disease (for example, gastric or accidental deaths are subject to forensic ulcer) producing melaena or haematemesis. necropsy in Australia. In addition, patients with a wide variety of neurological diseases were initially selected for neuropathological Discussion evaluation and from these, alcoholics were The operational criteria reported here can be chosen for study. Pathological diagnoses were used to classify accurately alcoholics with neu- revalidated for all patients that were clinically rological deficits. The criteria were designed to mismatched. Because of the retrospective differentiate alcoholics with and without the analysis and inclusion criteria, a proportion of Wemicke-Korsakoff syndrome, and to differ- patients at the lower end of hazardous alcohol entiate Wemicke's encephalopathy from consumption may not have been included in hepatic encephalopathy as these represent our alcoholic population. However, these longstanding diagnostic difficulties in alcohol patients are least likely to have medical com- research.17 28 31 Other medical complications plications due to their alcoholism and may often encountered in alcoholics, but which do only have neurological deficits disclosed by not result in CNS deficits, were not incorpo- detailed neuropsychological assessment.32 We rated. By grouping together signs and symp- are therefore confident of the validity of our toms into clinical domains and redefining sample and test populations and that our current diagnostic criteria for Wernicke's methodology has not produced substantial encephalopathy, the overall accuracy of the bias towards alcoholics with neurological proposed criteria is high and the need for point impairment. to point agreement on individual signs is min- imised. DIFFERENTIATION OF DIAGNOSTIC GROUPS The existing clinical triad for Wernicke's Using the operational criteria, we have been encephalopathy was modified so that the diag- able to clinically define alcoholics with nosis only required any two of the following Wemicke's encephalopathy neuropathology. signs; eye signs, cerebellar dysfunction, altered Only two institutionalised (> 15 years) alco- mental state, and dietary deficiencies. This holics with Korsakoffs psychosis had modification produced highly specific and Wemicke's encephalopathy neuropathology non-overlapping diagnoses for Wemicke's without enough clinical evidence of the disease encephalopathy, the Wemicke-Korsakoff syn- (false positive rate of 6% excluding patients drome, hepatic encephalopathy, and with hepatic encephalopathy ). This substan- Wernicke's encephalopathy plus hepatic tially reduces the current rate (> 80%) of neg- encephalopathy (98%-100% specificity). ative clinical diagnosis,' 2 and the use of the Furthermore, sensitivity for the diagnosis of operational criteria prospectively is likely to Wemicke's encephalopathy was improved eliminate this error altogether. The high rate from 31% using the classic triad to 100% with of negative clinical diagnosis of Wernicke's the proposed criteria. The use of the proposed encephalopathy in patients with positive neu- operational criteria for the classification of ropathology in past studies strongly suggests neurological impairment in chronic alcoholics that most patients with clinical Wemicke's will allow Wemicke's encephalopathy to be encephalopathy go undetected during life, diagnosed with a high degree of confidence. rather than the alternative explanation of Operational criteria for the classification of chronic alcoholics: identification of Wernicke's encephalopathy 57

patients with a clinical episode of Wernicke's with treatment. That is, alcoholics with the encephalopathy having resolving neuropathol- Wernicke-Korsakoff syndrome can be differ- ogy. entiated from alcoholics with Wernicke's The question of whether Wernicke's encephalopathy but without Korsakoffs psy- encephalopathy is both clinically and neu- chosis by the severity and stability of memory ropathologically resolvable can be assessed in loss regardless of other cognitive deficits. It is those alcoholics with neurological symptoms important to distinguish permanent memory but no neuropathology. In the present study loss in alcoholics who are sober and thiamine 48 out of the 106 patients examined had no replete from memory loss in intoxicated, thi- neuropathological abnormality. Most of these amine deficient alcoholics. One important test (69%) also had no signs of Wernicke's of this distinction may be memory recovery encephalopathy in their medical records or with thiamine supplementation. In agreement from informant interviews with general practi- with our definition, past studies define the tioners or family members. Of the remaining Wernicke-Korsakoff syndrome clinically as an patients (alcohol rated brain dysfunction) amnesic syndrome in the presence of pre- most were epileptic from young adulthood or served intelligence and learned behav- had longstanding neuropsychiatric . iour. 18-203637 In particular, alcoholics with Although it cannot be discounted that some of Wernicke-Korsakoff syndrome have a consis- these neurologically impaired patients may tent loss of anterograde episodic memory.'8 36 38 have had a past episode of clinical Wernicke's whereas many past studies have not empha- encephalopathy without any permanent brain sised the underlying signs of Wernicke's damage (true negatives), none had any evi- encephalopathy in patients with the Wernicke- dence or history of dietary deficiency, eye Korsakoff syndrome, most support the sugges- signs, or an altered mental state, suggesting tion that the Wernicke-Korsakoff syndrome that overt encephalopathy is unlikely to have is the inevitable outcome of Wernicke's been missed. Mild memory impairment was encephalopathy. 18 29 39 Interestingly, in our test common in these patients and cerebellar dys- population this occurred only in the propor- function was seen in 36%, although coexistent tion of alcoholics whose survival time was epilepsy and longstanding treatment with anti- extended by institutional intervention, as pre- convulsants may account for these symp- viously suggested.40 The inclusion of toms.33 Therefore, it seems unlikely that a Wernicke's encephalopathy as a prerequisite in significant number of alcoholics have had our criteria for the Wernicke-Korsakoff syn- Wernicke's encephalopathy clinically without drome was useful in excluding patients with evidence of permanent . memory deficits from other causes and did not The finding that Wernicke's encephalopa- significantly decrease diagnostic sensitivity. thy and hepatic encephalopathy occur together However, the use of Wernicke's encephalopa- in some alcoholics has important implications thy as an essential inclusion criterion for for the acute management and treatment of Wernicke-Korsakoff syndrome was a source of patients with suspected hepatic encephalopa- error for retrospective analysis in a small pro- thy. It is well established that the most com- portion of patients. mon and often isolated sign of Wernicke's We were unable to identify a subset of alco- encephalopathy is a disturbed mental state' 2 holic patients with a -like process and that some patients present in coma34 35 when degenerative neuropathology and head making differential diagnosis difficult. The injury were excluded. This supports other prospective use of the operational criteria out- pathological studies which have not been able lined should improve diagnostic classification to define pathological characteristics for alco- of patients with these life threatening holic dementia.284' The absence of alcoholic encephalopathies. In particular, previous cere- dementia in the present sample suggests that bellar signs or mild memory impairment are coincident neurodegenerative conditions con- more common in Wernicke's encephalopathy tribute to this clinical profile. Alcoholic than hepatic encephalopathy, with dietary dementia has been used to describe those who deficiencies and eye signs distinguishing have a gradual cognitive decline,29 whereas the patients with Wernicke's encephalopathy. In term Korsakoffs psychosis has been used for addition, alcoholics with both ence- patients whose onset of memory loss is rapidly phalopathies were notable for having physical acquired. The Wernicke-Korsakoff syndrome signs in many domains. Our results indicate is generally diagnosed in younger patients than that in patients suspected of having alcoholic those with alcoholic dementia.29 42 43 After hepatic encephalopathy in the presence of or excluding degenerative conditions, the alco- with a history of neurological abnormalities, a holics studied had a mean age (SD) of 58 (10) strong suspicion of Wernicke's encephalopa- years and none had gradual cognitive decline. thy should be entertained and appropriate Careful clinicopathological studies have yet to treatment measures taken. substantiate the existence and aetiology of this Using the operational criteria descibed, proposed condition. alcoholics with Wernicke's encephalopathy can be distinguished from those with the IMPLICATIONS FOR PATHOGENESIS Wernicke-Korsakoff syndrome with a high The association between the reversible degree of sensitivity and specificity. In the pre- encephalopathic symptoms of Wernicke's sent study, two factors distinguished between encephalopathy and permanent brain damage the diseases: an amnesic syndrome with (1) a is not well understood. The neuropathology clear sensorium and (2) which does not remit underlying Wernicke's encephalopathy can 58 Caine, Halliday, Kril, Harper

vary in type (acute v chronic) and extent,23 and Notably, Wernicke's encephalopathy neu- some of these differences may account for the ropathology was found in a significant number reversible nature of some symptoms and signs, of patients with hepatic encephalopathy, sug- in particular the eye signs. Lesions in brain- gesting that these have a high risk of additional stem periventricular regions are likely to Wemicke's encephalopathy and should be account for the eye signs with the type and treated with parenteral thiamine. extent of damage determining their clinical This study was funded by the National Health and Medical resolution."' By contrast, cerebellar dysfunc- Research Council of Australia. We are grateful for the assis- tion is seen as a permanent neurological sign tance of the staff of the Histopathology Laboratory, Department of Pathology, University of Sydney, and to in alcoholics.' 4'10 The coexistence of cerebellar Professors RF Butterworth and J Willoughby and Dr JDG abnormalities and poor nutritional state in Watson for their comments on the manuscnrpt. many patients with Wernicke's encephalopa- thy supports the suggestion that thiamine defi- ciency is important in the pathogenesis of cerebellar damage.3 44 Although often termed alcoholic cerebellar degeneration, a direct neu- Appendix rotoxic effect of alcohol has not been shown. BRIEF HISTORIES OF REPRESENTATIVE PATIENTS Furthermore, malnourished non-alcoholics Alcoholics with hepatic encephalopathy Patient 1 was a 51 year old male alcoholic who had had have also been reported to have cerebellar the signs and symptoms of hepatic encephalopathy for degeneration.44 In addition, a proportion of the preceding two months with two hospital admis- alcoholics with a history of seizures have per- sions. He initially presented with bleeding oesophageal manent cerebellar degeneration which may be varices and was discharged one month later when sta- due to either repeated hypoxic episodes bilised. He was readmitted one week later drowsy, caused by seizures or to longstanding medica- jaundiced, and dehydrated. For the next three weeks he had recurrent variceal bleeds and resistant ascites with tion with .33 increasing encephalopathy. Six days before death he Patients with Wernicke's encephalopathy had a large haematemesis and became hypotensive. He had a progressive and relentless course with a was resuscitated, but his condition remained grave maximum survival time of three years. By con- until death. trast, patients with the Wemicke-Korsakoff Patient 2 was a 65 year old male alcoholic who had syndrome had considerably longer disease had three major hospital admissions over the preceding 15 months for the management of his alcoholic liver durations due to substantial institutionalised disease. He was abstinent for this time period. About care. The importance of rehabilitation in the one year before death he presented with several days successful long term management of patients history of weakness, confusion, and disorientation and with the Wernicke-Korsakoff syndrome has was admitted to hospital for management of his hepatic been noted previously.4046 The increased sur- encephalopathy. During the next nine months he had vival time of institutionalised patients with the further short hospital stays for increased ascites. On final admission he presented semiconscious and Wemicke-Korsakoff syndrome suggests that hypothermic with evidence of aspirant in the right lung the brain damage underlying the disorder may and ascites. He was rousable and responded to name be related to cessation of alcohol or correction but had low blood pressure, was acidotic, and had of thiamine deficiency. Interestingly, in some ascites with a very high white cell count. Antibiotics patients with Wemicke's encephalopathy were started and CT ordered to discount intracranial seizures precede the amnesia necessary for a haemorrhage; however, on rewarming he deteriorated diagnosis of the Wernicke-Korsakoff syn- and died despite intubatation. drome (all patients with the Wemicke- Alcoholics with Wernicke's encephalopathy alone Korsakoff syndrome with seizures also had Patient 327 was a 51 year old male alcoholic who had Wemicke's encephalopathy neuropathology). had increasing periods of binge drinking accompanied This suggests that the Wernicke-Korsakoff by poor diet over the preceding three years. Three days occur different pathogenic before death he was admitted to hospital, heavily intox- syndrome may by icated, with , confusion, and agitation. He mechanisms: brain damage in association with showed ophthalmoplegia, , and strabismus severe thiamine deficiency alone (the major- . He was given thiamine and became alert and ity), or the combined brain damage due to thi- oriented briefly before vomiting large amounts of blood amine deficiency and seizures. and bile and aspirating. Patient 4 was a 59 year old male alcoholic who had no major alcohol related diseases besides Wernicke's encephalopathy. When first assessed in 1985 for a Summary noticeable Spigelian hernia, he was able to give a We have devised operational criteria to signifi- detailed, informative family and personal history. He cantly improve the identification of patients was immediately admitted to hospital and underwent with Wemicke's encephalopathy. The use of successful surgery but became confused and disori- these proposed criteria for the differential ented in time and place but not person over the next alcoholics our week and experienced some indicative of diagnosis of may improve alcohol withdrawal. He was discharged one month understanding of the underlying aetiological later. Two years before death he was admitted to hospi- factors contributing to their neurological tal for detoxification, showing signs of nystagmus, oph- impairment. The existing classic triad was thalmoplegia, and confusion. He was seen at the modified to include the presence of dietary neuropsychology unit and tested after seven days sobri- deficiencies and required only two rather than ety. At this time he showed poor planning and con- a clinical this struction and scored 26/38 on the short mental status three signs for diagnosis. Using examination despite scoring only 1/4 for simple calcula- criterion, the diagnosis of Wernicke's tions, 1/3 for similarities, and 0/4 for construction. He encephalopathy either alone or with amnesia was able to learn four objects after two trials and could (Wemicke-Korsakoff syndrome) or hepatic remember two of four objects after a five minute delay. encephalopathy improved from 22% to 85%. Because of defective vision, all memory tests were given Operational criteria for the classification ofchronic alcoholics: identification of Wernicke's encephalopathy 59 in the auditory mode. One month before death, he was sions to detoxification units. On neuropsychological admitted to hospital during an acute Wernicke's assessment 18 months before death no impairment was encephalopathy episode with ocular signs, confusion noted. He scored 37/38 on the short mental state (disoriented in time and place, with no recall of the examination and had insight into his alcohol problem. previous nights events), and severe ataxia. He did not He remained cognitively stable until death, which was improve with thiamine therapy (100 mg daily). Formal due to acute alcohol intoxication. testing disclosed global impairment with the examiners concluding that Wernicke's encephalopathy had par- Akoholics with multiple diagnoses tially resolved with thiamine therapy. However, Patient 10 was a 46 year old woman who presented reassessment 10 days later showed substantial improve- with hepatic encephalopathy after a 27 year history of ment in attention span, alertness, and ability to follow consuming about one bottle of scotch a day. Two and a simple commands. He was discharged three weeks half years before death she was admitted for one month later. The next week he was readmitted with back pain after a short history of weight loss, vomiting, anorexia, and was again confused and disoriented in time and and increasing jaundice with hepatomegaly and raised place. Just before death, his memory skills were poor serum transaminases. Three months before death, she and he was grossly confused, although the memory was admitted with hepatomegaly and jaundice, but no lapses were not continuous nor of sufficient degree or evidence of oesophageal varices or peptic ulceration. nature to be consistent with a diagnosis of Korsakoff3s Peripheral neuropathy and cerebellar dysfunction were psychosis. This history indicates a persisting confu- evident. Clinical evidence of encephalopathy returned sional state related to heavy ethanol intoxication and after reduction of dietary protein content. She had a thiamine deficiency. short history of auditory and visual hallucinations. She had asterixis, spider naevae, pronounced jaundice, Alcoholics with the Wemnicke-Korsakoff syndrome clubbing of fingers and toes, and hepatosplenomegaly. Patient 5 was a 78 year old female alcoholic who had Investigations disclosed anaemia, hyponatraemia, high been under constant institutionalised care for eight serum, and urinary osmolarity, and pulmonary years before death and had been diagnosed with oedema. She was assessed by the neuropsychology unit Korsakoff3s psychosis before admission. Estimates of denying any symptoms of cognitive impairment or neu- alcohol intake were in excess of 100 g per day from the rological dysfunction. Bilateral nystagmus was present age of 20 without adequate diet. The first report of on lateral gaze and there was generalised muscle wast- memory impairment was 20 years before death. She ing. She had an abnormal tandem gait and abnormal was persistently disoriented in time and place and had heel-shin test although she was not clinically nystagmus, cerebellar ataxia, and severely impaired encephalopathic. On short mental state examination declarative memory. She was unable to remember her she scored 20 out of 38 with problems in digit span, doctor from week to week despite being in his care for learning, calculations, information, similarities, con- six years. Disorientation and amnesia persisted until struction, and recall. On full neuropsychological assess- death despite documentation of abstinence from alco- ment she showed severe memory impairment and hol for the final eight years. This neuropsychological pronounced impairment of higher order cognitive func- profile indicates the persisting, stable memory impair- tions. Confusion developed and hepatic failure with ment diagnostic of Korsakoffs psychosis. malaena became evident, although renal failure super- Patient 6 was a 60 year old chronic alcoholic who vened. was admitted to hospital in 1980 for severe , Case 11 was a 46 year old male alcoholic with a 10 when it was noted that he had problems with his mem- year history of alcohol-related diseases including bleed- ory. In 1983, he was admitted to hospital with chest ing gastric ulcers, chronic liver disease, nystagmus, pains and during investigations was noted to have nys- tremor, memory blanks and a five year history of ataxia tagmus and ataxia. His memory, however, was and frequent vomiting. He was first noted to have regarded as normal. He was readmitted to hospital in memory problems in early 1990 when he returned to 1990 because of suicidal intention with bilateral nystag- his doctor's surgery having forgotten his prior atten- mus and a broad based ataxic gait. Neuropsychological dance that morning. In the final year of his life, he was testing showed him to be a man of average to above still living independently although he was often disori- average intelligence, with a normal immediate memory ented in time and place and showed gross memory loss span (short mental state 30/38). However, he was and unsteady gait. He was admitted to hospital with unable to learn any new material (structured or epigastric pain one month before death, was confused, unstructured) beyond his immediate memory span. He disoriented in time and place, and had poor short term recalled none of four words after five minutes, and memory. His family reported an increase in mental there was nearly total loss of information after interfer- impairment over the previous fortnight. He was for- ence. He was unable to recall personal events from the mally tested two weeks later and was found to have a previous 10 years. He was institutionalised without general amnesic syndrome. Although alert and coopera- improvement in memory function for almost three tive, he showed perserveration and . He years until his death by suicide. This neuropsychological could do no calculations and could not remember facts profile indicates the persisting, stable memory impair- from personal or historical events. He was last admitted ment of Korsakoffs psychosis. to hospital in hepatic coma, surviving for three days. This history indicates an amnesic deficit of at least 12 Alcoholics with alcohol related brain dysfunction months duration with intermittent episodes of Patient 7 was a 58 year old male alcoholic who devel- Wernicke's encephalopathy related to heavy ethanol oped epilepsy a year before death with no CT abnor- intoxication and thiamine deficiency followed by a mality. Three months before death he was diagnosed rapidly decompensating liver disease. with carcinoma of the lung and declined treatment. He had several grand mal seizures in the two days before 1 Harper CG, Giles M, Finlay-Jones R. Clinical signs in the death. Wemicke-Korsakoff complex: a retrospective analysis of 131 patients diagnosed at necropsy. J Neurol Neurosurg Patient 8 was a 66 year old male alcoholic who had- Psychiatry 1986;49:341-5. drank heavily since the age of 18. 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