Three-Dimensional Mapping of Local Cerebral Perfusion in Alcoholic Encephalopathy With and Without Wernicke-Korsakoff Syndrome

Transcription

1 Journal o/ Cerebral Blood Flow and Metabolism 7: Raven Press, New York Three-Dimensional Mapping of Local Cerebral Perfusion in Alcoholic Encephalopathy With and Without Wernicke-Korsakoff Syndrome Takashi Rata, John Stirling Meyer, Norio Tanahashi, Yoshiki Ishikawa, Akira Imai, Tamotsu Shinohara, *Maria Velez, *William E. Fann, tprasab Kandula, and :j:fumihiko Sakai Cerebral Blood Flow Laboratory, Veterans Administration Medical Center, and the Departments of Neurology, *Psychiatry, and tradiology, Baylor College of Medicine, Houston, Texas, U,S,A., and :f:department of Internal Medicine, Kitasato University, School of Medicine, Sagamihara-City, Kanagawa, Japan. Summary: Seventeen severe chronic alcoholic patients with and without Wernicke-Korsakoff syndrome (WKS) were examined prospectively after being treated by withdrawal from alcohol. The WKS patients also received thiamine supplements. Three-dimensional measurements of local cerebral blood flow (LCBF) and local partition coefficients (LA) were made utilizing xenon contrast computed tomography (Xe CT-CBF). Results were displayed as color-coded brain maps before and after treatment and these were correlated with neurological and cognitive examinations. Before treatment chronic alcoholics without WKS (n = 10) showed diffuse reductions of LCBF values throughout all gray matter including hypothalamus, vicinity of nucleus basalis of Meynert, thalamus, and basal ganglia. Similar, but more severe, reduc- tions were seen in patients with WKS (n = 7), however, white matter perfusion was also reduced. In WKS, most prominent reductions of LCBF were also seen in hypothalamus and basal forebrain nuclei but thalamus, basal ganglia, and limbic systems were severely reduced. After treatment, both groups with alcoholic encephalopathy showed marked clinical improvement and cerebral perfusion was restored toward normal. Chronic alcohol abuse, in the absence of thiamine deficiency, reduces CBF by direct neurotoxic effects. If thiamine deficiency is also present, more severe and localized hemodynamic reductions are superimposed. Key Words: Alcohol-Cerebral blood flow-chronic alcoholism-nucleus basalis of Meynert-Wernicke-Korsakoff syndrome-xe CT CBF. The CNS is more sensitive to the deleterious effects of alcohol than other organs of the body. Ethanol (ethyl alcohol) affects the CNS as a metabolic and functional depressant, with certain systems being more sensitive to its cumulative effects than others. Ethanol rapidly passes the blood-brain barrier to depress neuronal activity. Electrophysiological studies in human subjects, as well as animal Received June 27, 1986; accepted September 24, Address correspondence and reprint requests to Dr. J. S. Meyer, Director, at Cerebral Blood Flow Laboratory, Veterans Administration Center, 2002 Holcombe Boulevard, Houston, TX 77211, U. S.A. Abbreviations used: ATPase, adenosine triphosphatase; CCS E, Cognitive Capacity Screening Examinations; CMR02, cerebral metabolic rate for oxygen; CT-CBF, computed tomography-cbf; LCBF, local CBF; LA, local partition coefficients; MABP, mean arterial blood pressure; PEC02, end-tidal CO2; PE02, end-tidal 02; PEXe', end-tidal stable xenon gas concentrations; WKS, Wernicke-Korsakoff syndrome; Xe, xenon. models, (Porjesz and Bergleiter, 1981; Walker et ai., 1981) show that brain stem, diencephalon and limbic systems are affected earlier than cerebral cortex. Chronic ethanol administration disorders conformations of membrane-bound lipids and proteins, altering Na + -K + adenosine triphosphatase (ATPase) activity of neuronal membranes (Lyon et ai., 1981), so that some investigators postulate that fluxes of calcium ions across neuronal membranes account for many of the neurological signs seen in chronic alcoholism (Durand and Carlen, 1984). It is generally agreed that chronic alcohol ingestion deranges the synthesis, release, uptake, and functioning of cerebral neurotransmitters and their receptors including acetylcholine, dopamine, norepinephrine, gamma-amino-butyric acid, and serotonin (Littleton, 1983; Martin et ai., 1984). For 22 years, cerebral blood flow (CBF) measurements have been used for functional assess- 35

2 36 T. HATA ET AL. ment in chronic ethanolism. Cerebral blood flow, and less frequently cerebral metabolic rate for oxygen (CMR02), values reported have been consistently reduced (Hedlund et ai., 1964; Simojyo et ai., 1967; Berglund and Ingvar, 1976; Heiss et ai., 1976; Kruger and Hoyer, 1979; Berglund et ai., 1980; Berglund, 1981; J6hannesson et ai., 1982; Meyer et ai., 1985; Ishikawa et ai., 1986) and reductions correlate directly with estimates of neurological and cognitive impairments as well as estimates of brain atrophy (Meyer et ai., 1985; Ishikawa et ai., 1986). No information is available among patients with chronic ethanolism concerning local cerebral blood flow (LCBF) measured in the deep cerebral structures, which are probably most vulnerable to the toxic effects of ethanol, as judged by neuropathological studies and experiments in animal models (Berglund, 1981; Walker et ai., 1981). The present study reports three-dimensional measurements of CBF among patients with chronic ethanolism with and without Wernicke-Korsakoff syndrome (WKS) obtained by the use of stable xenon inhalation as a contrast medium for computed tomography (CT CBF). These were undertaken to determine whether there are LCBF differences between patients with neurotoxic effects of chronic ethanolism alone and those combined with the clinical signs of WKS. In previous communications, we reported two-dimensional measurements of CBF utilizing the xenon- 133 method in patients with ethanolic encephalopathy with and without Wernicke-Korsakoff syndrome (Meyer et ai., 1985; Ishikawa et ai., 1986). Three-dimensional CBF measurements now reported were successfully achieved in many of these patients. MATERIALS AND METHODS Tables la and b display relevant demography among 17 patients with longstanding ethanol dependency satisfying the diagnostic criteria established by the National Council on Alcoholism (1972). They were referred from the alcohol detoxification and rehabilitation ward by the psychiatric service of the Veterans Administration Medical Center, Houston, Texas. After treatment, they were followed by this laboratory as outpatients. The duration of excessive ethanol consumption ranged from 5 to 45 years (mean ± SD, 23.7 ± 10.8 years). The daily consumption of ethanol exceeded 80 g and ranged from 80 to 500 g/day (mean ± SD, 250 ± 140 g/day). Seven patients (Cases 1-7) had signs and symptoms fulfilling the diagnostic criteria for WKS established by Victor et al. (1971). The other patients (Cases 8-17) were admitted with symptoms and signs of neurotoxicity, including withdrawal symptoms but without fixed neurological signs, except for mild distal sensory neuropathy. The 17 patients listed in Tables la and b were part of a larger series in which measurements were attempted but were not always successful-because of problems with head movement. Among Cases 1-4 and 8-14, it was possible to measure CT-CBF values before and after treatment, which resulted in good recovery. Measurements were repeated 2-28 weeks after completion of treatment in patients with WKS, and 2-6 weeks after treatment in patients with signs of neurotoxicity but without WKS. Patients were excluded if there was any history of severe head injury, abuse of psychotropic drugs, the use of TABLE la. Demography of patients with ethanolic encephalopathy with or without Wernicke-Korsakoff syndrome Abnormal neurological findings Peripheral Eye signs Ataxia neuropathy CCSE scores Treatment Case no. Age Gender compliance Before After Before After Before After Before After 1 65 M E + IMP + + IMP M P + IMP + IMP M E + IMP + + IMP M P M E + IMP + IMP M E + IMP + IMP + IMP M P Mean ± SO 52.7 ± ± ± M E M E M E M E M E M E M E M E M ONR NE NE NE 29 NE 59 M ONR NE NE NE 29 NE Mean ± SO 52.7 ± ± ± 1.7 E, excellent; P, poor; ONR, did not return; IMP, improved; NE, not examined; CCSE, Cognitive Capacity Screening Examination. J Cereb Blood Flow Metab, Vol. 7, No.1, 1987

3 XE CT-CBF IN ALCOHOLIC ENCEPHALOPATHY 37 anticonvulsants, a history of chronic psychosis, and age exceeding 70 years. Seventeen age-matched normal volunteers underwent similar CT-CBF measurements and provided normative data that was pooled for purposes of comparison. The ages of normal volunteers ranged from 33 to 72 years (mean ± SD, 52.4 ± 11.5 years). They had normal neurological and cognitive examinations and were free from risk factors for stroke, consumed zero or less than 10 g of ethanol daily, and had normal EEGs and EKGs. Tables la and b summarize their age, gender, degrees of compliance with treatment, presence or absence of extraoccular movement disorder, nystagmus, presence or absence of ataxic gait, presence or absence of peripheral neuropathy, test scores, results of Cognitive Capacity Screening Examinations (CCSE) (Jacobs et ai., 1977), median daily intake of alcohol, duration of alcohol abuse, CBF values measured by the two-dimensional xenon-133 inhalation method, time intervals between CT-CBF measurements, and test results of performance before and after treatment. All patients underwent physical, neurological, and cognitive examinations at the time of CT CBF measurements before and after treatment. Complete blood counts, blood chemistries, urinalysis, and liver function tests were evaluated in all patients and cases were excluded if there were severe metabolic or hepatic dysfunctions. Therapy included detoxification by withdrawal of alcohol under medical and psychiatric supervision for 2-8 weeks, psychotherapy, counseling, and provision of a nutritious diet. Patients with WKS (Cases 1-7) were also administered oral thiamine supplementation in doses of 100 mg 3 times daily. Referral to the Cerebral Blood Flow Laboratory for neurological and CBF evaluations was delayed for 6-10 days until there was recovery from withdrawal symptoms. This was to exclude any acute effects of alcohol withdrawal and/or administration of tranquilizing drugs on CBF measurements and test performances. All sedative medications were discontinued for 48 h prior to referral to the CBF laboratory. Delirium tremens, seizures, and hallucinations were not present at the time of the CBF measurements. Local CBF and LA values were measured by the CT CBF method (Meyer et ai., 1980, 1981; Amano et ai., 1982). Normative values and standard deviations for LCBF and LA values are given in these and other publications (Meyer et ai., 1984; Tachibana et ai., 1984). The method was modified for computer analysis so that LCBF and LA values were provided as color-coded brain maps. Patients underwent neurological and cognitive testing 4-6 hours prior to CT -CBF measurements carried out with an EMI 1010 scanner. To reduce anxiety and potential hyperventilation, patients received a trial inhalation by wearing a face mask 4-6 h prior to CT-CBF measurements (Obrist et ai., 1985). Body nitrogen was displaced by inhalation of 100% oxygen for min prior to xenon inhalation. Inhalation mixtures of % xenon gas in oxygen were gradually incremented in the alveolar air over 7-9 min. It has been shown previously that % mixtures of xenon gas in oxygen cause minimal or no subanesthetic side-effects and that CBF values are not altered beyond the ± 15% error of the method (Meyer et ai., 1986). Furthermore, in the present study, xenon-l33 inhalation CBF measurements made on the same day in the same patients were in good agreement with Xe CT-CBF results (Meyer et ai., 1985; Ishikawa et ai., 1986). Four control scans were performed during the interval of denitrogenation (100% oxygen inhalation) followed by 3 or 4 serial scans during inhalation of TABLE lb. Demography of patients with ethanolic encephalopathy with or without Wernicke-Korsakoff syndrome Daily ethanol Duration of consumption drinking Case no. (g/day) (yrs) Before Fg CBF values by 133Xe inhalation method After Before Fw After Time interval between CT-CBF measurements (wks) NE 10.5 NE NE NE Mean ± SD 240 ± ± ± ± ± NE 19.4 NE ± NE NE 16.8 ± Mean ± SD 263 ± ± ± ± ± ± ± Xe, xenon-133; CT-CBF, computed tomography-cerebral blood flow; NE, not examined. J Cereb Blood Flow Metab, Vol. 7, No.1, 1987

4 38 T. HATA ET AL % stable xenon gas. A semiclosed partial rebreathing system was utilized to administer the gas mixtures so that a gradual rise time of xenon in alveolar air was achieved. End-tidal stable 38 xenon gas concentrations (PEXeS) were recorded throughout each inhalation by means of a Gow-Mac thermoconductivity gas analyzer. End-tidal xenon gas concentrations, which are known to be in equilibrium with arterial blood, were quantitated by means of a proportionality constant determined empirically. By these means, changes for concentrations of xenon gas in arterial blood were calculated in Hounsfie1d units and were utilized for correction of recirculation. Blood pressure was measured after CT -CBF measurements and end-tidal CO2 (PEcoz), end-tidal Oz (PEoz), EKG and EEG were recorded by means of a polygraph. Two back-to-back CT scans were serially examined before and during xenon in oxygen inhalation under standard conditions, utilizing 8 mm collimation, settings at 32 rna, and utilizing the rapid 120 kvp 60 s scanning mode. The total irradiation exposure to the center of the brain was 7-8 rads and the cornea of the eye was avoided. Computed tomographic image data were transferred from magnetic tapes to floppy diskettes and reconstructed by utilizing a microcomputer system (160 x 160 matrix). Data for each of the images, two before and during xenon enhancement were treated by unweighted 3 x 3 smoothing (presmoothing) without data compression before calculating LCBF and LA values. Effective cell areas covered were 3 x 3 of the original pixels, each corresponding to 20 mm of the brain sections and each voxe1 used for the calculations corresponded to 160 mm3 of brain tissue since each of the two slices were 8 mm thick. Thus, using this computer program for Xe CT-CBF measurements, the resolution is 160 mm3 The Xe CT CBF method has been reported previously to be capable of discriminating differences in flow between adjacent volumes as small as 80 mm3 (Meyer et ai., 1984). Data from these smoothed images (160 x 160 matrix) were used for LCBF and LA calculations. Four precontrast control scans were averaged and reconstructed as the average base line scan, and data for each of the enhanced scans were subtracted from it. Changes in Hounsfield units for each voxel were expressed as functions of time. On the second post-treatment visit, the patient's head was placed for the same two levels of the CT scanner using spot-lights attached to the scanner to locate the orbitomeatal line and Scout films were taken until images of both slices were superimposable on the pretreatment slices. The plane setting was never altered. Arterial input function was approximated as a first step exponential function, that is Ca(t) = Camax (1- e-mt), where Camax is the arterial xenon concentration at infinity and m is the rate constant for arterial xenon gas saturation over time (t). The values of Camax and m were estimated by using nonlinear least square fitting (Marquardt, 1963). Time dependent buildups for xenon concentrations in brain tissue were estimated by unweighted nonlinear least square fitting utilizing the damping Newton-Gauss algorithm or the Marquardt algorithm (1963). Analytical solution of Kety's formula (1951) was used as the model for fitting: Cj(n = AikJ Ca(t)e-k;(T-t)dt, Fj = Aiki, where Cj(n is the concentration of xenon in the specified region of interest at the time T and kj is the flow rate constant for that region of interest, Fj represents the regional cerebral blood flow to be derived and Aj is the partition coefficient for that region of interest. The double integration method of Amano et al. (1982), was omitted to simplify computer solutions. Scanning time was represented as the midscanning time for each 60 s scan. Results for LCBF and LA derived from this initial data processing (LCBF and LA) were reconstructed to the matrix of 160 x 160 voxels and a second unweighted 3 x 3 or 5 x 5 smoothing (postsmoothing) was used to decrease bias derived from instabilities of the fitting model. Smoothed LCBF and LA values (160 x 160 matrix) were now displayed on the CRT display by color-coding in 13 steps (LCBF values: mvloo g brain/min, LA values: 0-2.4). Local CBF and LA values could then be processed for any special region of interest by cursoring the precontrast plain CT images displayed next to the LCBF and LA maps. Region of interest values reported in this communication varied between 30 voxels (e.g., for head of caudate nucleus) to 300 voxels (e.g., for frontal cortex) as illustrated in Fig. 1. All data were calculated as the mean values ± standard deviations. Values for LCBF, LA, as well as neurological and cognitive test results were analyzed and compared between the two groups of chronic ethanolic patients with and without WKS, as well as between the group of age-matched normal volunteers utilizing the Mann-Whitney U test. Between group comparisons were also made before and after treatment utilizing the Wilcoxon signed rank test. Statistical significances were set at p < The consent forms and protocols for serial measurements of CBF by the CT -CBF method have been approved by the Institutional Review Boards of Veterans Administration Medical Center and Baylor College of Medicine, Houston, Texas. Informed consent was signed by all patients and volunteers prior to each CT-CBF measurement. RESULTS As previously reported (Meyer et ai., 1985), after treatment all patients in the WKS group showed improvements in tests of cognitive performance and their neurological deficits. The CCSE scores after treatment (26. 7 ± 4. 1) increased significantly compared with scores before treatment (22. 1 ± 3.8; p < 0.05). Cases 2, 4, and 7 occasionally indulged in some ethanol after discharge; nevertheless, they ate well and took thiamine supplements. Cases 1 and 3 fully complied with treatment and recovered without any residual symptoms, signs, or cognitive impairments. Chronic ethanolic patients without WKS on admission to the study exhibited neurotoxic effects of ethanol without fixed neurological signs as reported previously (Ishikawa et ai., 1986) including tremor, confusion, and/or hallucinations and mild sensory peripheral neuropathy, which recovered after treatment in Case 8. Cognitive functions scored by CCSE were mildly impaired before treatment and their CCSE scores (n = 8) significantly improved (p < 0.05) after abstinence from alcohol. Table 2 compares LCBF and LA values in pa- J Cereb Blood Flow Metab. Vol. 7. No.1, 1987

5 XE CT-CBF IN ALCOHOLIC ENCEPHALOPATHY 39 FIG. 1. Brain map showing computed tomographic (CT) image and local cerebral blood flow (LCBF) values obtained in a 53-year-old, right-handed man suffering from neurotoxic effects of ethanol without Wernicke-Korsakoff syndrome (Case 13). The LCBF and local partition coefficient (LA.) values were calculated by cursoring any predetermined region of interest, in this instance the thalamus is cursored in purple on the CT image. This ensures correspondence of LCBF and LA. values to anatomical regions of interest. The number of pixels counted and the computed LCBF values and LA. values were averaged and printed out by computer. FIG. 2. Local cerebral blood flow (LCBF) and local partition coefficient (LA.) maps made in a 65-year-old, right-handed man (Case 1). Diffuse hypoperfusion is measured typical of the acute and severe ethanolic Wernicke-Korsakoff syndrome. In this case, LCBF values determined in two slices 8 mm apart were reduced in temporal cortex, thalamus, hypothalamus, vicinity of nucleus basalis of Meynert, cingulate gyrus, and white matter bilaterally. The LA. values remain normal except for the subcortical white matter of both frontal lobes which were reduced. PEC02 = MABP = mean arterial blood pressure. end-tidal CO2, FIG. 3. Local cerebral blood flow (LCBF) and local partition coefficient (LA.) maps printed out by computer in a 35-year-old, right-handed chronic ethanolic man, without Wernicke-Korsakoff syndrome (Case 14). End-tidal CO2 (PEco2) was 27.6 mm Hg and mean arterial blood pressure (MABP) was 83 mm Hg. There are diffuse reductions of cortical and basal ganglia CBF values, however, perfusion of left thalamus is higher than right. The LA. values shown in the map to the right are entirely normal except for a single low LA. area in the right internal capsule. FIG. 4. a: Local cerebral blood flow (LCBF) maps measured in a 65-year-old male patient (Case 1) with acute Wernicke-Korsakoff syndrome (WKS) (left) and after complete recovery with treatment (right). In the acute phases of WKS, his LCBF values measured in two slices 8 mm apart were severely reduced in both gray and white matter, including both temporal lobes, thalamus, hypothalamus, vicinity of nucleus basalis of Meynert, and cingulate gyrus. After treatment, CBF values were restored to normal. b: The LCBF maps measured in a 63-year-old, right-handed man (Case 12) who had neurotoxic effects of ethanol without WKS before (left) and after (right) withdrawal from ethanol. Before treatment, LCBF values are diffusely reduced but less severely so than among patients with WKS. Hypoperfusion is most evident in frontal, temporooccipital and thalamic regions. The LCBF values in white matter are within normal limits. After abstinence, LCBF values improved, including the thalamus and temporal lobes bilaterally.

6 40 T. HATA ET AL. TABLE 2. Local cerebral blood flow and partition coefficient values compared among patients exhibiting alcoholic encephalopathy with and without Wernicke-Korsakoff syndrome Age-matched Chronic alcoholics normal controls without WKS WKS Regions (n = 17) (n = 10) (n = 7) Gray matter LCBF D. LCBF D. LCBF D. Frontal cortex a a 1.10 ± 7.7 ± 0.03 ± 8.5 ± 0.16 ± 12.1 ± 0.25 Temporal cortex a a 1.00 ± 6.2 ± ± 10.8 ± 0.16 ± 8.0 ± 0.21 Occipital cortex a a 1.02 ± 7.0 ± 0.05 ± 12.0 ± 0.22 ± 6.1 ± 0.23 Cingulate gyrus a a,b 1.08 ± 4.4 ± ± ± 0.25 ± 3.4 ± 0.27 Hippocampal gyrus , c ± 9.3 ± 0.06 ± 7,9 ± 0.47 ± 10.3 ± 0.27 (n = 2) (n = 2) Caudate nucleus a a 1.04 ± 6.8 ± ± ± 0.19 ± 13.6 ± 0.33 Putamen a a 1.12 ± 7.0 ± 0.08 ± 13.1 ± 0.30 ± 19.3 ± 0.33 Thalamus a d 1.12 ± 5.6 ± 0,04 ± ± 0,32 ± 19.1 ± 0.31 Hypothalamus and nucleus basalis , lc 1.24 of Meynert region ± 7.6 ± ± 13.4 ± 0.54 ± 12.8 ± 0.39 (n = 2) (n 2) = p < White matter Internal capsule ± 3.8 ± 0,09 ± 7. 1 ± 0.42 ± 6.4 ± 0.43 Frontal lobe a 23.5a,b 1.05a ± 3,7 ± ± 7,2 ± 0.43 ± 1.8 ± 0.28 Occipital lobe 28, I l.13d a ± 3,5 ± 0,08 ± 6,2 ± 0.44 ± 2,6 ± 0,32 Age in years ± ,7 ± 8, ± 9.9 MABP in mm Hg 95,9 ± ± 10, ± 11.2 PEC02 in mm Hg 36,1 ± ± ± 5.7 WKS, Wernicke-Korsakoff syndrome; LCBF, local cerebral blood flow; LA, local partition coefficients; MABP, mean arterial blood pressure; PEC02, end-tidal carbon dioxide. a p < 0.01; b p < 0.01; cp < 0,05; dp < 0,05 (a,d-compared between alcoholic encephalopathy and normal controls; h,c-compared between patients with WKS and patients without WKS). tients showing neurotoxic effects of chronic ethanolism with and without WKS. The LCBF values for cortical gray matter of WKS patients were diffusely decreased by about - 35% compared with age-matched normal values (p < 0.01). Subcortical gray matter likewise showed marked hypoperfusion, particularly in the hypothalamus and the vicinity of the substantia innominata, which includes the nucleus basalis of Meynert in which values were decreased by - 60% compared with normative values. The LA. values of gray matter were slightly but not significantly higher than normative values. Local CBF and LA. values for white matter in patients with WKS were reduced compared to agematched normal volunteers. Perfusion was particularly reduced in frontal white matter and LA. values were reduced in frontooccipital white matter (p < 0.05). Typical CT-CBF maps measured in a 65- year-old man with WKS (Case 1) are illustrated in Fig. 2. Reductions of LCBF values in patients with WKS were significantly greater than in patients showing neurotoxic effects of chronic ethanolism without WKS. In WKS, LCBF reductions were most striking in the cingulate and hippocampal gyri, the hypothalamus, including adjacent nucleus basalis of Mey'nert, and frontal white matter where CBF reductions were greater than among patients without WKS (p < 0.05). There were no significant differences for LA. values between the two groups. Local CBF and LA. values in patients without WKS are also summarized in Table 2. The LCBF 'values of cortical gray matter were diffusely decreased compared with age-matched normal volunteers, but LA. values remained within normal limits. Local CBF values in subcortical gray matter were decreased diffusely, particularly in the hypothalamus and the vicinity of the nucleus basalis of J Cereb Blood Flow Metab, Vol. 7, No.1, 1987

7 XE CT-CBF IN ALCOHOLIC ENCEPHALOPATHY 41 Meynert where they were decreased by about - 50% compared with normative values. The L values in subcortical gray matter were slightly higher than the normative values, but these differences were not statistically significant. Local CBF values for white matter were normal but L values for frontal white matter, including adjacent parts of centrum semiovale and for occipital white matter, including the optic radiations, were reduced. Typical LCBF and L maps obtained from a 35-year-old man (Case 14) with neurotoxic effects of chronic ethanolism without WKS are illustrated in Fig. 3. All patients were right-handed, but there were no significant differences between dominant and nondominant hemispheres. Mean arterial blood pressures (MABP) and partial pressures for end-tidal carbon dioxide (PEco2), compared between groups of ethanolic patients with and without WKS and between normal volunteers, did not differ (Table 2). All 17 patients reported subjective experience of paresthesia during stable xenon inhalation and all patients developed respiratory irregularities, especially respiratory slowing after 5 min of inhalation (Obrist et ai., 1985). Heart rate of all patients compared before and during CT-CBF measurements, but there is no significant change of heart rate as per our previous report (Meyer et ai., 1981). Table 3 shows effects of treatment on cerebral perfusion among both groups of patients with chronic ethanolism. In those without WKS, LCBF values increased diffusely throughout the brain after abstinence from ethanol. In patients with WKS, LCBF values increased more prominently than in patients without WKS after abstinence and thiamine supplementation. Improvements of cerebral perfusion were most marked in the hypothalamus plus the vicinity of nucleus basalis of Meynert, cingulate gyrus, hippocampal gyrus, and basal ganglia, all of which exceeded + 40%. The hypothalamus and nucleus basalis of Meynert were increased by + 64%. Local CBF values in white matter also increased diffusely throughout the brain after treatment. After treatment, pooled values for both types of ethanolic encephalopathy showed significant increases for LCBF in the regions including the hippocampal gyrus, thalamus, hypothalamus and adjacent nucleus basalis of Meynert, and the white matter of occipital lobes increased about +20%. Diffuse increases of CBF correlated with improvements of cognitive performance for both groups. Significant relationships were not found between residual cognitive impairments that persisted in one case after treatment of WKS (Case 2). Increases of LCBF values after treatment for any particular region did not appear to correlate any better with cognitive improvements than the diffuse increases measured in diencephalon, nucleus basalis of Meynert, temporal cortex, and limbic systems. All patients with WKS showed marked improvements of brain perfusion as did all but two patients with neurotoxic effects of ethanol (Figs. 4a, b, 5). DISCUSSION In the present study, the xenon contrast CT-CBF method has been utilized for measurements of local TABLE 3. Effects of treatment (abstinence, thiamine) on regional cerebral perfusion Chronic alcoholics without WKS (n = 7) WKS (n = 4) Both groups pooled (n = II) Regions Before After Before After Before After Mean CBF of slices Frontal cortex Temporal cortex Occipital cortex Cingulate gyrus Hippocampal gyrus Caudate nucleus Putamen Thalamus Hypothalamus and nucleus basalis of Meynert region Internal capsule Frontal lobe Occipital lobe 51.5 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 9. 4a 51.7 ± ± ± ± ± ± ± ± ± ± 6.1a 49.5 ± ± ± ± ± ± 14.4a 49.0 ± ± 17.5a 29.7 ± ± ± ± ± ± 7.0a WKS, Wernicke-Korsakoff syndrome. a p < J Cereb Blood Flow Metab, Vol. 7, No.1, 1987

8 42 T. HATA ET AL. Mean CBF Cortical Gray Matter Subcortical Gray Matter White Matter 90 '" ".. > U::]. 60 "'8.:: o iii.c 50 ca g 0.c f::;::. a E 40.. g..j i+p< i+p< i+p<o.ol-1 I- N.S.--I I I I I I I I I Before After Before After Before After Before After I Mean ± S.D. FIG. 5. Graph to show improvement of local cerebral blood flow values before and after treatment in the two categories of chronic ethanolic encephalopathy. Pooled gray matter values for cortex include frontal, temporal, and occipital cortex plus cingulate gyrus, and hippocampus. Pooled subcortical gray matter values include caudate, putamen, thalamus, hypothalamus, and vicinity of nucleus basalis of Meynert. Before treatment, cases with Wernicke-Korsakoff syndrome (WKS) indicated by closed circles, were more severely reduced than cases without WKS (open circles). Abstinence Abstinence Abstinence Abstinence cerebral blood flow and local partition coefficients. This method has certain advantages for investigating the pathophysiology of alcoholic encephalopathy. It makes possible measurements of local CBF of the deep brain structures such as the hypothalamus, substantia innominata, and adjacent regions in which the basal nuclei of the forebrain are located, as well as thalamus and limbic systems, which judging from studies in animal models, should be primarily affected by ethanol (Walker et ai., 1981; Lishman, 1986). It is also possible to detect changes in lipid composition of cerebral tissues by measuring alterations of local partition coefficients (Radue and Kendall, 1978). Changes of the lipid composition of the brain have been reported at autopsy among patients dying with chronic alcoholism (Lesch et ai., 1972). The greatest disadvantage of utilizing the method among chronic ethanolic patients is head movement probably associated with mild confusion and/or agitation. As discussed by several investigators, the CT -CBF method has some theoretical limitations (Gur et ai., 1982). However, the computer program described here for calculating and mapping LCBF and L.\ allows optimal correlations of disordered cognitive function with measurements throughout different systems of the brain (by cursoring regions of interest on the CT image) and the use of single compartmental analysis permits studies of small volumes of brain, despite problems of time dependent noise when relatively slow scanners are used (Ip et ai., 1983). Present results indicate diffuse and significant reductions of gray matter LCBF values throughout the entire cerebral cortex and deeper brain struc- tures among chronic ethanolic patients suffering from neurotoxic effects without WKS. Several investigators have described acute toxic effects of administration of ethanol on CBF and metabolism (Battey et ai., 1953; Fazekas et ai., 1955), but there are relatively few reports of CBF measurements among chronic alcoholic patients without WKS (Berglund and Ingvar, 1976; Heiss et ai., 1976; Kruger and Hoyer, 1979; Berglund et ai., 1980; J6- hannesson et ai., 1982; Ishikawa et ai., 1986). In these reports, two-dimensional methods were used. These did not permit analysis of any possible changes in perfusion of the hypothalamus and adjacent regions of basal forebrain nuclei or limbic systems and thalamus. The CT-CBF measurements make possible correlation of LCBF changes in these structures with neurocognitive status. In the present study, patients with WKS showed more severely reduced LCBF values than in chronic ethanolics without WKS. This is to be expected since thiamine deficiency also reduces neuronal activity and disturbs neurotransmitter function (McEntee and Mair, 1978; Martin et ai., 1984). Local CBF reductions in white matter appear to be characteristic of WKS and were not observed in chronic ethanolism without WKS. Possibly LCBF reductions reflect effects of thiamine deficiency by reducing transketolase activity of the oligodendrocytes, an important enzyme for lipid and protein synthesis (Dreyfus, 1965; Noble and Tewari, 1973; Tewari et ai., 1978; Sharp et ai., 1982). Recently, Lishman has discussed different types of cognitive impairments in chronic alcoholics and difficulties in separating some from Alzheimer's disease. Impaired recent memory is a feature of J Cereb Blood Flow Metab, Vol. 7, No. 1, 1987

9 XE CT-CBF IN ALCOHOLIC ENCEPHALOPATHY 43 both types of dementia and was evident in the present series of WKS patients. Lishman (1986) offers a unifying hypothesis to account for the pathogenesis of both Alzheimer's disease and WKS, postulating that alcohol exerts toxic effects on the basal forebrain nuclei, causing diffuse cortical cholinergic deficiencies, similar to those known to Alzheimer's disease. This would then account for the loss of recent memory in alcoholic dementias. Neuropathological studies support this hypothesis (Arendt et ai., 1983). Present LCBF measurements also support the Lishman hypothesis. Diffuse cortical CBF reductions were accompanied by more severe hypoperfusion in hypothalamus and adjacent regions of the substantia innominata which has been reported to harbor the cells of nucleus basalis of Meynert (Saper and Chelim sky, 1984). Damage to these basal forebrain nuclei would impair their cholinergic projections resulting in diffuse reductions in cortical and subcortical blood flow similar to CBF changes in Alzheimer's disease reported from this laboratory (Amano et ai., 1982; Tachibana et ai., 1984). Assuming that chronic consumption of ethanol, with or without WKS, exerts neurotoxic effects on the nucleus basalis of Meynert and adjacent systems, diffuse cortical reductions of CBF would be expected to result with maximal hypoperfusion in the hypothalamus and substantia innominata harboring the basal nuclei of the forebrain. Furthermore, if this assumption is correct, the CBF reductions should be rapidly reversible after abstinence from ethanol. In fact, this is what was observed in both groups of chronic ethanolic patients with and without WKS. Acknowledgment: This work was supported by the Veterans Administration, Washington, DC and by grants from Mr. and Mrs. Harry K. Smith, Mr. Albert K. 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