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Brain impairment in well-nourished chronic alcoholics is related to ethanol intake.

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Brain Impairment in Well-nourished
Chronic Alcoholics Is Related to
Ethanol Intake
Josep M. Nicolb, MD,* Ram6n Estruch, MD,* Mane1 Salamero, MD,? Nuria Orteu, MD,$
Joaquim Fernandez-Sola, MD,* Emilio Sacanella, MD,* and Alvaro Urbano-M6rquez, MD*
To determine the influence of chronic ethanol intake on the central nervous system, we studied 40 asymptomatic,
well-nourished, chronic alcoholics (mean age, 42.6 -+ 9.1 years) and 20 age-, sex-, and education-matched control subjects. Studies included neuropsychological testing, visual and short-latency auditory evoked potentials, and morphometric
analysis of computed tomography scans. The mean daily ethanol consumption of the alcoholics was 204 gm over an
average of 26.4 years. Compared to control subjects, chronic alcoholics exhibited a significant prolongation of the PI00
latency of visual evoked potentials, and a prolongation and reduction in the amplitude of the latency of the V wave of
short-latency auditory evoked potentials. These abnormalities were related to the lifetime dose of ethanol consumed.
Brain morphometric analysis showed that alcoholics had a significantly greater degree of brain shrinkage with age,
compared to control subjects. The cortical atrophy index correlated significantly with the lifetime ethanol consumption.
Neuropsychological testing in alcoholics compared to controls revealed a significant impairment of frontal skills that was
related to age, degree of scholarship, and the presence of frontal atrophy. In conclusion, well-nourished chronic alcoholics exhibited significant brain impairment, as demonstrated by neuropsychological testing, evoked potentials, and
brain morphometric analysis, which was correlated with the lifetime dose of ethanol consumed.
Nicolis JM, Estruch R, Salamero M, Orteu N , Fernandez-Sob J, Sacanella E, Urbano-Mirquez A.
Brain impairment in well-nourished chronic alcoholics is related
to ethanol intake. Ann Neurol 1997;41:590-598
Ethanol misuse has been related to a wide range of
deleterious effects on the central nervous system [l-71.
Over the years, ethanol-related brain disorders have
been considered multifactorial, being attributed to the
neurotoxic effects of ethanol and its metabolites, malnutrition and vitamin deficiencies (alcoholic dementia,
Wernicke’s encephalopathy, and pellagra), water and
electrolyte disturbances (central pontine myelinolysis),
liver cirrhosis (hepatic encephalopathy), and head
trauma [3-7]. In addition, alcoholic patients may be
affected simultaneously by several of these disorders,
making it difficult to identify the cause of cognitive
dysfunction in chronic alcoholics. Brain lesions in alcoholics have been studied from different approaches
(neuropsychological testing, event-related potentials,
imaging, and isotopic assessment), often being conducted without complete knowledge of the underlying
pathological lesions and lacking the clinical, nurritional, or neuroradiological counterparts [ 5 ] . Since
most of the studies performed in chronic alcoholics did
not control these variables, the direct neurotoxic effect
of ethanol on brain impairment in asymptomatic
chronic alcoholics remains uncertain, as does the relation to factors such as nutritional status, vitamin deficiencies, and the frequency and amount of ethanol
The aim of the present study was ro evaluate a homogeneous population of asymptomatic, wellnourished, chronic alcoholic patients who were submitted to neuropsychological testing, evaluation of visual
and short-latency auditory evoked potentials, and morphometric analysis of computed tomography (CT)
scans, under controlled conditions. Alcoholics exhibited a significant neuropsychological impairment,
mainly in frontal task skills, which was related to frontal lobe atrophy. In addition, the structural and functional abnormalities observed in chronic alcoholics
were related to both the total lifetime dose of ethanol
consumed and the age of the patients.
From the Departments of *Internal Medicine, tClinical Psychology,
and $Neurophysiology, Hospital Clinic, Universitar de Barcelona,
Barcelona, Spain.
Received May 20, 1996, and in revised form Aug 5 and Sep 23.
Accepted for publication Sep 27, 1996.
Address correspondence to Dr Estruch, Department of lnternal
Medicine, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain.
Copyright 0 1997 by the American Neurological Association
Materials and Methods
Putient und Control Subject Selection
Over a 14-month period, 454 patients with
chronic alcoholism were seen in the Alcoholism Unit of the
Hospital Clinic of Barcelona. They fulfilled the diagnostic
criteria for alcoholism as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM 111-R) of the
American Psychiatric Association [ 8 ] .This unit treats only
ambulatory patients who seek assistance in terminating their
dependence on alcohol and have no signs or symptoms of
other diseases. Patients with overt alcohol-related diseases
such as liver disease, cardiomyopathy, and other disorders are
referred to other clinics. On Monday of each week, the first
male patient to register who was younger than 60 years and
who reported a daily ethanol consumption of more than 100
gm in the 2 years previous to the day of admission was selected for study. Initially, 58 chronic alcoholics were evaluated. Four patients with withdrawal syndrome, 2 with liver
cirrhosis, 1 who also reported consumption of benzodiazepine drugs during the last 6 months, and 1 with human
immunodeficiency virus infection were excluded. From these
50 patients, 10 (20%) had criteria of caloric malnutrition
(see below) and were also excluded from the study. Thus, 40
asymptomatic, well-nourished, chronic alcoholic patients
were finally included in the study. None of these patients
had disorders that cause brain damage other than alcoholism
or symptoms of Wernicke’s encephalopathy. No patient objected to being included in the study, and all gave informed
consent for the various procedures. The study protocol was
approved by the Institutional Review Board. Patients were all
white men of Spanish descent who lived with their families
in or around Barcelona and had histories of stable employment. About 60% were skilled laborers or office workers,
and the rest were unskilled workers. None of the patients
studied was indigent.
CONTROL GROUP. This group comprised 20 asymptomatic men who did not report drinking of ethanol. They were
gathered from friends and relatives of the alcoholics. This
group was matched ( I control subject per 2 patients) for age
(t 2 years), sex (male), and sociocultural status with the
group of alcoholics. The members of this control group were
studied in the same manner as the alcoholics.
the patients or control subjects were on any medication before or during the investigation.
Clinicul Examination
For each patient a detailed history of ethanol intake and dietary habits was obtained by one of two physicians
(J. M. N., E. S.) using a structured questionnaire, and the
data were confirmed on consultation with family members.
Average quantity per year and frequency of ethanol intake
were recorded. Daily ethanol intake was considered as the
mean amount of ethanol consumed per day during the previous month. Life events such as marriage, military service,
and work posts were used as “anchor points” to help recollection (“time-line follow-back method”) [9].Total lifetime
dose of ethanol was estimated by multiplying the amount of
ethanol consumed per day by the number of years of each
alcohol intake period times 365, and adding the amounts of
these different periods. Withdrawal symptoms were evaluated
according to the Clinical Institute for Withdrawal Assessment (CIWA) scale [lo, 111, and a score equal to or higher
than 15 was considered as withdrawal syndrome. None of
LaborutoT and Nutritional Studies
Blood samples were obtained the day following admission,
for measurement of markers of alcohol intake and nutritional
status. These markers included hemoglobin, lymphocyte
count, total protein, albumin, prealbumin, retinol-binding
protein, transferrin, serum aspartate and alanine aminotransferases, gamma-glutamyl transpeptidase, ammonia, red cell
and serum folate, vitamin B,,, and erythrocyte transketolase
activity, which were measured by standard semiautomated
methods. Serological assays for the Venereal Disease Research
Laboratory test, fluorescent treponemal antibody absorption
test, and human immunodeficiency virus antibodies (ELISA)
were also done. Hepatic ultrasonography and percutaneous
needle liver biopsy were performed in all patients with a history of Iiver disease, heparomegaly on physical examination,
or laboratory data of chronic hepatocellular failure, or abnormally elevated serum aminotransferase levels for more than 2
months during which the patient had maintained complete
ethanol abstinence.
Overall nutrition was assessed in terms of the proportion
of actual to ideal weight [ 121. The lean body mass and muscular area of the arm were calculated from the circumference
of the upper nondominant arm and the thickness of the tricipital skinfold [13].The fatty area of the arm was calculated
from the thickness of the tricipital skinfold and was considered as indicative of total body fat [13].Patients were considered as having caloric malnutrition if their body weight
was less than 80% of their ideal weight or if the calculated
lean body mass was more than 10% below the normal value.
Protein malnutrition was diagnosed when the patients had
abnormal values of three of the following seven parameters:
hemoglobin, lymphocyte count, total protein, albumin, prealbumin, retinol-binding protein, and transferrin [ 14, 151.
Neuropsychological Testing
A neuropsychological test battery was performed 10 days after hospital admission to assess the intelligence quotient (IQ)
(Wechsler Adult Intelligence Scale [WAIS] subtests of vocabulary, similarities, and Kohs) [16, 171, basic attention span
(WAIS digit span) [16],logical and visual memory, delayed
recall and associate learning (Wechsler Memoiy Scale Logical
Memory and Visual Reproduction) [18, 191, as well as various “frontal lobe” skills such as the ability to form categories
(Weigl Color-Form Sorting Test) [20, 211 and visual conceptual and visuomotor tracking (Trail Making) [22].
Brain CT was performed
on a Somaton DR3 (Siemens, Erlangen, Germany) matrix 512 X 512, with 12 to 14 slices of
8-mm thickness parallel to the orbitomeatal plane. Each section was transferred to floppy disks and photographed on
100-mm spotfilms. For each patient, maximal width of the
frontal horns of the lateral ventricles (A), frontal brain width
(B), maximal width of the brain (C), frontal intracranial area
(D), and frontal lobe area (E) were measured by a Kontron
MOP-20 planimeter (Messgerate, Germany) using an enlarged picture of the CT slice at the caudate. nuclei, as re-
Nicolls et al: Ethanol-related Brain Impairment
ported elsewhere [ 1, 2, 231. The following combined indices,
considered as representative of frontal atrophy, were calculated from these measurements: frontal lobe index (AIB),
Evans ratio (A/C), and pericerebral frontal area considered as
the percentage of the difference of D minus E. In addition,
cortical atrophy was evaluated by the sum of the width of the
first eight sulci measured in a counterclockwise manner on
the semioval plane, as described elsewhere [2, 3, 241 (Fig 1 ) .
These measurements were obtained by one physician (R. E.)
who had no knowledge of the clinical data. Frontal lobe atrophy was considered to be present when at least two of the
three frontal indices were 2 standard deviations (SDs) higher
than the control value. Similarly, cortical brain atrophy was
diagnosed when the sum of the sulci was 2 SDs higher than
the control value.
Evoked Potentials
Visual and auditory short-latency evoked potentials were
measured with a Nicolet Compact Four instrument (Nicolet
Biomedical Instruments, Madison, WI) 10 days after admission. Visual evoked potentials (VEPs) were recorded using
active electrodes at O,, O,, and O,, a reference electrode at
F,, and a forehead ground electrode. Stimulation consisted of
exposure to different black and white checkerboard patterns,
with the position of the black and white checks inverting
every 1.9 Hz. The checkerboard was displayed on a cathode
ray tube monitor placed 100 cm from the patient’s eye (monocularly), where each square pattern subtended angles of
66, 35, or 17 degrees. The electroencephalographic (EEG)
activity was amplified 20,000 times and filtered with a bandpass of 1 to 100 Hz. Each potential was obtained from the
average of 100 responses of 300 msec. For each subject the
amplitude and latency of PI00 at the different visual angles
for the scalp location 0, were obtained. Ipsilateral and contralareral short-latency auditory evoked potentials (SAEPs)
were obtained simultaneously by using reference electrodes
located on both earlobes, an active electrode at the vertex,
and the ground electrode placed on the forehead. Potentials
were evoked by monaural auditory stimuli consisting of
clicks of rarefaction polarity with an intensity of 90 decibel
peak equivalent pressure level during 100 psec, and a stirnulation frequency of 11.7 Hz. The signal was amplified
200,000 times and filtered with a bandpass of 150 to 3,000
Hz. Each potential was obrained from the average of 1,000
responses for a 10-msec period, and the amplitude and latencies of peaks I, 111, and V, and interpeak intervals 1-111,
111-V, and I-V were evaluated on both eats. T o avoid the
possible influence of circadian variations, all recording sessions took place between 11:OO AM and 2:OO PM, and the
room temperature was constant (22°C).
Statistical Analysis
Standard statistical methods from SPSS Statistical Analysis
System V4.0+ (SPSS, Chicago, IL) were used. Differences
between groups were analyzed using the two-tailed Student’s
t test. Correlation studies were obtained by Pearson’s correlation coefficient and regression analysis. When two or more
variables were significant in rhe univariate study, a multiple
regression analysis was performed. All variables are expressed
as mean ? SD, and a significance level of p < 0.05 was
Frontal lobe index
Evans ratio. _.___.._...__.__.
IPericerebralfrontal area
0 Frontal lobe area
Suici’ 1+2+3+4+5+6+7+8
Fig 1. Brain morphometric anabjes to assejs fiontal atrophy were fiontal lobe index (AIB), Evans ratio (AIC), and pericerebrnl
fiontal area considered as the percentage of the difference of D minus E. Cortical brain atrophy was assessed by measuring the
width of the Jirst eight rulci in a counterclockwise manner on the semioval plane.
592 Annals of Neurology
Vol 41
No 5
May 1997
Clinical, Laboratoy, and Nutritional Data
The 40 alcoholic patients had an average age of 42.6 +9.1 years (range, 27-60). The reported daily ethanol
consumption ranged from 100 to 350 gm (mean,
204 2 82) over a period of 26.4 t- 8.2 years, with a
total lifetime dose of ethanol of 23.5 +- 9.7 kg/kg (hlograms of ethanol/kilograms of body weight). The
drinking pattern was continuous, excessive ethanol intake as part of everyday life. Only occasional binges
were reported by the patients. Ethanol was consumed
mainly in the form of wine, beer, brandy, and less frequently, anisette, whiskey, or gin. No relationship was
observed between the type of beverage consumed with
any of the variables studied. Thirty-two (80%) of the
alcoholics and 15 (75%) of the control subjects had
smoked one to two packets of cigarettes a day since the
second decade of their lives. None of the subjects used
any other drugs.
Mild elevations of hepatic enzymes after 2 months of
ethanol abstinence were found in 3 alcoholic patients,
and structural abnormalities on hepatic ultrasonography in another 3. Fasting serum ammonia level was
normal in all patients (<50 pM/liter). Liver biopsy
was performed in these 6 patients and the following
diagnoses were made: normal liver in 3, fatty liver in 2,
and alcoholic hepatitis in the remaining subject. No
differences in these respects were found between the
group with and the group without abnormalities on
the CT scans, evoked potential studies, or neuropsychological tests. In relation to nutritional data, alcoholics exhibited a thinner tricipital skinfold, when compared to controls. None exhibited laboratory data of
protein malnutrition or thiamine deficiency (Table 1).
CT Data: Rehtion to Ethanol Intake
Significant differences between alcoholics and control
subjects were observed for the mean values of the
planimetric brain indices calculated (Table 2). According to the criteria mentioned above, 14 (35%) and 19
(47.5%) alcoholic patients, respectively, showed frontal
lobe and cortical atrophy, compared to only 1 control
subject ( p < 0.01, both). None of the subjects studied
disclosed focal cerebral lesions. Patients with frontal or
cortical atrophy were significantly older than those
without brain shrinkage ( p < 0.05, both). Indeed, age
significantly correlated with width of cortical sulci in
both alcoholics ( r = 0.52, p < 0.001) and control subjects ( r = 0.43, p < 0.05). However, interestingly, the
progression of cortical atrophy with age was significantly steeper in ethanol misusers, as observed when
comparing the slopes between alcoholics and control
subjects ( p = 0.04) (Fig 2).
Although daily ethanol intake was similar at admission, alcoholics with frontal and cortical lxain atrophy
reported a significantly prolonged duration of alcoholism ( p = 0.05, both) and a significantly higher total
lifetime dose of ethanol consumed than did their counterparts ( p < 0.01, both) (Table 3). Although a significant correlation between age and lifetime dose of ethanol consumption was observed ( r = 0.53, p <
0.001), in the multivariate analysis, the lifetime dose of
ethanol consumed and age remained as independent
factors determining the worsening of brain indices in
chronic alcoholics ( p < 0.01, all). In addition, in a
manner consistent with these findings, a highly significant correlation between the cortical brain shrinkage
and the total lifetime dose of ethanol was observed in
alcoholics ( r = 0.62, p < 0.001) (Fig 3), a correlation
Table 1. Labouatoyl and Nutritional Data (Mean t SO)
(n = 40)
(n = 20)
Ideal body weight (Yo)
Lean body mass (kg)
Tricipital skinfold (cm)
Arm circumference (cm)
Arm muscle area (cm')
Arm fat area (cm')
Hemoglobin (gmiliter)
Lymphocytes ( 106/lirer)
Total protein (gm/liter)
Transferrin (mg/dl)
Albumin (gmiliter)
Prealbumin (mg/dl)
Retinol-binding protein (mglliter)
Erythrocyte transketolase"
Aspartate aminotransferase (IU/liter)
Alanine aminotransferase (IU/liter)
Gamma-glutamyl transpeptidase (IU/liter)
t 13.9
t 4.4
i. 0.49
i 3.4
2 9.9
t 5.1
t 11
t 544
i 6.7
t 43
t 4.7
t 8.4
5 14
t 6.2
t 39
t 32
t 189
105.4 t 11.2
53.1 t 4.3
1.17 t 0.44
28.0 t 3.2
44.8 2 9.9
12.9 t 4.5
147 2 26
1,734 t 611
69.0 i 7.2
227 t 62
43.3 t 5.1
33.2 t 12.0
5 5 t 19
13.8 t 6.5
25 t 6
26 t 3
24 I 1 0
"Percentage difference between the enzymatic activity with and without the addition of thiamine pyrophosphate (TPP effect).
NS = not significant.
Nicolas et al: Ethanol-related Brain Impairment 593
Table 2. Neuropsychologicul Test and CT Dutu (Meun i SO)
Age (yr)
Education (yr)
Weigl Color-Form Sorting Test"
Trail Making test Ah
Trail Making test Bb
Digit span (age corrected)'
Logical memoryd
visual memory"
Associated learning'
Frontal lobe index
Evans ratio
Perifroiital area (Yo)
Cortical atrophy (mm)'
(n = 40)
42.6 +- 9.1
8.6 t 5.1
101.1 t: 17.6
4.5 ? 1.3
60.8 i 30.5
240 2 180
8.1 2 3.2
79.7 i 26.4
83.3 & 50.4
13.6 t 4.4
0.33 t 0.04
0.28 i 0.03
6.7 2 3.1
19.7 i 3.6
42.1 ? 10.4
8.8 t 4.5
102.4 i 12.4
5.3 t 1.0
45.6 i 20.0
124 2 53
8.2 ? 1.9
87.2 i 19.9
91.5 +- 12.3
14.4 i 3.0
0.28 0.02
0.25 ? 0.03
2.9 2 1.5
14.3 i 1.5
(n =
"Number of categories correctly identified.
hSeconds to complete the task.
'Direcr score.
'Percentage of retention.
'Sum of the width of the first eighr sulci in a counterclockwise direction on thc semioval plane
NS = not significant.
Fig 2. Correlution between cortical brain atrophy (width of
sub) and age in chronic alcoholics (closed circles) and controls (open circles). Notice that the slope of the regression between width of sulci and age in alcoholics (solid line) is
steeper than that in controls (dashed line) (p = 0.04).
that persisted after adjusting for the effect of age ( r =
0.50, p < 0.01).
Annals of Neurology
Vol 41
No 5
May 1997
Visual a n d Auditory Evoked Potentials: Relation to
Ethanol Intake a n d Brain Atrophy
None of the patients and control subjects studied reported a reduction in visual acuteness, and none presented an acuteness lower than 40/200 when evaluated
with the Snellen chart. Mean Iatency values of PI00 at
the lowest visual angle (17 degrees) in alcoholics were
significantly lengthened compared to control values.
Latencies at other checkerboard angles evaluated (66
and 35 degrees) were only slightly prolonged (Table 4).
At the lowest angle, 7 (17.5%) chronic alcoholic patients disclosed a significantly prolonged PI 00 latency,
compared to none of the control subjects ( p < 0.05).
The mean PlOO amplitude was lower in alcoholics
compared to controls, but the differences did not reach
statistical significance. Alcoholics with a significant
lengthened latency of PlOO at a visual angle of 17 degrees were older, reported a significantly higher lifetime
dose of ethanol consumed, and showed significantly
greater cortical atrophy than did alcoholics with normal
optic evoked potentials ( p < 0.05, all). However, in the
multivariate analysis, the total amount of ethanol intake
remained as the only independent risk factor for the optic dysfunction in chronic alcoholics ( p < 0.01). In
addition, PI00 latency (angle of 17 degrees) correlated
significantly with the total lifetime dose of ethanol
intake in chronic alcoholics ( r = 0.61, p < 0.001).
In the SAEP evaluation, chronic alcoholics showed a
significant prolongation of the I, 111, and V latencies,
as well as a reduction in amplitude of the waves, and
prolongation of interpeak 1-111, 111-V, and I-V intervals (see Table 4). Thus, 11 (27.5%) alcoholics showed
a significant reduction in the V amplitude, and 7
Table 3. Clinical and Laboratory Data in Relation to the Presence of Cortical Brain Atrophy
in Chronic Alcoholics (Mean I
Cortical Atrophy
(n = 19)
Without Cortical Atrophy
(n = 21)
Age (yr)
Daily ethanol intake (gm)
Duration of alcoholism (yr)
Lifetime dose of ethanol consumed
(kg/kg of body weight)
Ideal body weight (%)
Lean body mass (kg)
Tricipital skinfold (cm)
Prealbumin (mg/dl)
Retinol-binding protein (mglliter)
Erythrocyte transketolase“
37.7 i 7.2
45.3 i 8.1
212 i 92
27.7 -+- 8.4
27.9 i 9.78
191 2 54
22.8 2 6.4
18.6 i 6.9
105.0 2
51.9 ?z
1.01 ?z
34.5 ?z
100.5 i 8.3
49.9 i 3.5
0.81 i 0.18
32.2 i 15.5
47 i 18
15.9 i 6.2
54 i 12
13.8 2 6.5
“Percentage difference between the enzymatic activity with and without the addition of thiamine pyrophosphate (TPP effect).
NS = not significant.
potentials in chronic alcoholics were not associated
with either age, nutritional status, or brain planimetric
indices of atrophy. Indeed, they were only related to
the total lifetime dose of ethanol consumed. Patients
with abnormal V latency reported a significantly higher
total lifetime dose of ethanol than did their counterparts (30.0 Ifr 7.6 vs 22.2 5 11.6 kg of ethanol/kg of
body weight, p < 0.05).
24 -
22 -
a O.
/ ,
Neuropsychological Test Data: Relationship with
Cortical Atrophy and Ethanol Intake
Although none of the patients exhibited a marked reduction in I Q as measured by WAIS, significant dif-
r = 0.623
a *
J d
p < 0.001
Lifetime ethanol consumption
(Kg ethanol / Kg body weight)
Fig 3. Correlation between cortical brain atrophy (width of
sulci) and total lifetime dose of ethanol consumed in asymptomatic chronic alcoholics.
(17.5%) had prolongation of the V latency, compared
to only 1 control subject for a reduction in V ampli-
tude and none for the latter parameter ( p < 0.05,
both). The abnormalities observed in auditory evoked
ferences in the frontal lobe tasks were observed between alcoholics and control subjects (see Table 2).
Alcoholics and control subjects showed a n impairment
in frontal skills with age. Interestingly, the impairment
of the alcoholics over time was significantly greater
than that observed in controls ( p < 0.05, all frontal
tests). Twelve patients had a significant impairment in
the Trail Making tests, compared to only 1 control
subject ( p < 0.05, both). Asymptomatic alcoholics also
showed some impairment in visual and logical memory, attention, and delayed recall, although the impairment did not achieve statistical significance. Alcoholics
with frontal atrophy showed a significant impairment
in frontal skills ( p < 0.05, all frontal tests). O n the
contrary, the alcoholics with cortical atrophy tended to
have nonsignificant poorer scores in the remaining tests
compared to their counterparts.
The relationship between ethanol consumption and
cognitive performance in the chronic alcoholics was
also assessed. Alcoholics with significant impairment in
frontal tests reported a higher daily ethanol intake during the month prior to being admitted to the study
(249 2 80 vs 182 t 92 gm of ethanol, p < 0.05, for
part B of Trail Making) and throughout their lives
Nicolris et al: Ethanol-related Brain Impairment
Table 4. Wsual and Short-Latency Auditoly Evoked Potential Data in Alcoholics and Controls (Mean t SO)
Left Side
Visual evoked potentials
PlOO latency (66 degrees) (msec)
PI00 latency (35 degrees) (msec)
1'100 latency (17 degrees) (msec)
Auditory evoked potentials
I amplitude (pV)
I11 amplitude {pV)
V amplitude (pV)
1-111 latency (msec)
111-V latency (msec)
I-V latency (msec)
" p < 0.05 for alcoholics compdred
hp < 0.01 for alcoholics compared
(n = 40)
(n = 20)
(n = 40)
103.4 t 6.9
101.9 t 6.0
104.5 t 8.1"
101.9 2 3.2
100.9 2 2.8
101.1 5.2
102.6 2 6.9
102.4 2 6.8
103.9 2 6.8"
102.0 2 1.3
101.5 ? 3.2
100.8 t 5.3
t 0.12"
2 0.09"
t 0.12:'
t 0.19
t 0.19
2 0.19b
0.39 2 0.03
0.34 2 0.14
0.45 t 0.08
2.10 2 0.15
1.90 t 0.18
4.00 2 0.23
0.27 2 0.12b
0.24 i 0.09b
0.36 2 0.1 I "
2.15 i 0.17
1.99 2 0.20
4.14 2 0.19"
(n = 20)
0.37 t 0.18
0.36 ? 0.18
0.47 i 0.07
2.10 t 0.15
1.90 2 0.18
4.00 2 0.23
to controls for each side.
to controls for each side.
(29.2 2 8.4 vs 21.6 t 9.2 kg of ethanol/kg of body
weight, p < 0.05, for part B of Trail Making). Indeed,
the period of time used to complete part B of the Trail
Making test by the alcoholic patients correlated with
the total lifetime dose of ethanol consumed ( r = 0.39,
p < 0.05). Similarly, alcoholics with a Significant impairment in visual and logical memories reported a significantly higher intake of ethanol during the previous
month and throughout their lives ( p < 0.05, both).
No relation was found between neuropsychological
performance and nutritional variables. In the multivariate analysis, age, degree of scholarship, and the degree
of frontal atrophy resulted as the independent factors
determining the alteration of frontal skills in chronic
alcoholics ( p < 0.05, all). As shown above, brain atrophy was also related to the total amount of ethanol
consumed throughout life, and age.
For years, the pathogenesis of ethanol-related neurological disorders has been considered multifactorial and attributed to genetic predisposition, nutritional factors,
and neurotoxic effects of ethanol or its metabolites
[25].In the current study, we found evidence to support the latter postulation. In a relatively homogeneous
population of well-nourished alcoholics entering an
outpatient treatment program, nearly half of the patients exhibited morphometric evidence of cortical sulci
atrophy, approximately a third showed frontal lobe atrophy and significant cognitive impairment, and a few
patients disclosed a significant alteration in the evoked
potentials. Interestingly, a highly significant correlation
was obtained between the total lifetime dose of ethanol
consumed and the cortical brain atrophy. Moreover,
the results of the neuropsychological tests evaluating
frontal skills were also related to frontal lobe atrophy,
which in turn was related to the total lifetime dose of
596 Annals of Neurology
Right Side
Vol 41
No 5 May 1997
ethanol. Thus, it would appear that alcohol exerts a
dose-related toxic effect on the central nervous system.
An analogous dose-response relationship to ethanol has
been reported for the liver [26], heart [27],skeletal
muscle [27],and peripheral nerves [28, 291.
Malnutrition was formerly believed to be paramount
in the development of alcohol-related diseases [30-321.
In this study, no relationship was found between the
different parameters used to assess brain impairment
and the nutritional status of the patients. In fact, none
of the alcoholics showed evidence of gross malnutrition
and all had normal transketolase activity. The dietary
habits reported indicated that nutrition was adequate
in most of the patients and the independent reports of
food intake made by the members of the patients' families were in good agreement with the patients' own
reports. In addition, the means of nutrition factors between long-term alcoholics and control subjects differed little, as was also found between patients with
and those without brain shrinkage. Thus, the usually
recognized indicators of malnutrition do not explain
the occurrence of brain impairment in this population
of chronic alcoholics, nor is there any reason to believe
that gross malnutrition is a contributing factor. However, although chronic alcoholics did not report
marked changes in dietary habits over time and their
present nutritional data reflect good nourishment, past
episodes of malnutrition may not be totally excluded.
Another interesting point was the relationship observed between alcoholism, age, and brain atrophy.
Some authors postulated that older patients may be
more sensitive to the effects of ethanol on the brain,
whereas others agree that brain atrophy is a direct effect of heavy drinking [33-351. In the current study, a
significant correlation was obtained between brain atrophy indices and age in both chronic alcoholics and
control subjects. However, when we compared the
slopes of the regressions between cortical atrophy and
age, the slope for chronic alcoholics was considerably
steeper than that for the controls. Thus, the effects of
ethanol on the central nervous system seem to be relatively independent of age. Older alcoholic patients
present more severe brain impairment simply because
they have drunk more.
When we analyzed each part of the study, our results
did not differ much from those obtained in the literature. Previous studies demonstrated a loss of neurons
mainly in the frontal cortex [I, 31, which apparently
correlates with other CT [36, 371, single-photon emission computed tomography [2, 381, neuropsychological, and pathological findings suggesting that the frontal lobes are more susceptible to ethanol damage than
are other brain regions [3, 391. In our sample, almost
one third of asymptomatic chronic alcoholics with active ethanol consumption showed a significant cognitive impairment, mainly in frontal lobe skills. Prior
neuropsychological studies showed that chronic alcoholics initially manifest deficits in abstraction, problem
solving, and tasks involving speed and complex
perceptual-motor response [4, 241, whereas functions
that depend on memory are affected at a later period
[35]. In fact, only very advanced heavy drinkers with
alcoholic dementia reveal a global neuropsychological
impairment [4].Although the subdivision of the cerebrum into different lobes has only limited functional
validity [40],difficulties in categorizing and inflexibility of thinking, as assessed by different tools such as
the Weigl Color-Form Sorting Test and Trail Making
tests, are very consistent with selective frontal lobe dysfunction, especially in the absence of severe global impairment [41-431. Our sample of alcoholics reflected
this situation, when compared to age-, sex- and
education-matched control subjects. In addition, the
neuropsychological impairment of frontal lobe tasks
was significantly related to the morphometric indices of
frontal lobe atrophy. However, no significant relation
was observed between the index of cortical sulci atrophy and assessment of distributed cognitive functions
such as attention or memory. This may be explained
by the fact that the heavy drinkers studied were relatively young and none exhibited significant signs of
global neuropsychological impairment. Further studies
with more advanced alcoholics may show different results.
As in other studies, visual and auditory evoked potentials were also altered in alcoholics [7, 44-46]. In
our series, asymptomatic, well-nourished, chronic alcoholics showed a significant prolongation of the latency
PI00 at the angle of 17 degrees, a prolongation of V
latency, and a reduction in the amplitudes of the
evoked auditory waves. These observations are consistent with the previous literature, except for a lower
prevalence. The variability of these results probably de-
pends on the neurological impairment, degree of alcoholism, and the presence of Wernicke’s syndrome.
There is little information on the factors involving the
alterations of evoked potentials in alcoholics without
thiamine deficiency. In the current study, although
only few patients exhibited abnormalities in the evoked
potentials, they were found to be related to the total
lifetime dose of ethanol, in absence of malnutrition.
There is no adequate experimental model for alcoholic brain damage, and the morphological changes
produced by the consumption of ethanol in rodents
and other species are reversible [25]. This fact reinforces the importance of studies in an ethnically homogeneous population of chronic alcoholics who may be
subjected to careful clinical measurements under controlled conditions. In this context, we observed that
ethanol-related brain shrinkage is common among
well-nourished chronic alcoholics, and concluded that
alcohol seems to be toxic to the central nervous system
in a dose-dependent manner. The key question, however, concerns the mechanism of lesions due to ethanol. It remains to be discovered whether chronic neurological damage depends on changes in membrane
ionic channels, alterations in membrane fluidity, alcohol metabolites, the formation of oxygen free radicals
[25],or the effects of ethanol hitherto unknown.
1. Harper CG, Kril JJ. Brain atrophy in chronic alcoholic patients.
A quantitative pathological study. J Neural Neurosurg Psychiatry 1985;48:211-217
2. Nicolis JM, Catafau AM, Estruch R, et al. Regional cerebral
blood flow-SPECT in chronic alcoholism: relation to neuropsychological testing. J Nucl Med 1993;34:1452--1459
3. Harper CG, Kril JJ. Neuropathology of alcoholism. Alcohol Alcohol 1990;25:207-2 16
4. Tarter RE, Edwards KL. Multifactorial etiology of neuropsychological impairment in alcoholics. Alcohol Clin Exp Res
5. Charness ME. Brain lesions in alcoholics. Alcohol Clin Exp Res
6. Chick JD, Smith MA, Engelman H M , er al. Magneric resonance imaging of the brain in alcoholics: cerebral atrophy, lifetime dose consumption, and cognicive deficits. Alcoholism
(NY) 1989;13:5 12-5 18
7. Cadaveira F, Grau C, Roso M, Sanchez-Turet M. Multimodaliry exploration of event-related potentials in clironic alcoholics.
Alcohol Clin Exp Res 1991;15:607-611
8. American Psychiatric Association. Diagnostic and statistical
manual of mental disorders. 3rd ed. Washington, DC: American Psychiatric Press, 1987
9. Sobell LC, Maisto SA, Sobell MB, Cooper AM. Reliability of
alcohol abusers’ self-reports o f drinking behaviour. Behav Res
Ther 1979;17: 157-160
10. Fay A. The management of alcohol withdrawal. Med J Ausr
11. Foy A, March S, Drinkwater V. Use of an objective clinical scale
in the assessment and management of alcohol withdrawal in
a large general hospital. Alcohol Clin Exp Res 1988;12:360-364
12. Jelliffe DB. The assessment of the nutritional status of the com-
Nicolls et al: Ethanol-related Brain Impairment
munity. Monograph Series No. 53. Geneva: World Health Organization, 1966
Kudman D. Assessment of nutritional status. In: Braundwald
AB, lsselbacker KJ, Petersdorf RG, et al, eds. Harrison's principles of internal medicine. 11th ed. New York: McCraw-Hill,
Estruch R, Nicolk JM, Villegas E, et al. Relationship between
ethanol-related diseases and nutritional status in chronically alcoholic men. Alcohol Alcohol 1993;28:543-550
Nicolk JM, Estruch R, Anturiez E, et al. Nutritional status in
chronically alcoholic men from the middle socioeconomic class and
its relation to ethanol intake. Alcohol Alcohol 1993;28:551-558
Wechsler D. Manual for Wechsler Adult Intelligence Scale.
New York: Psychological Corporation, 1955
Silverstein AB. Reappraisal of the validity of WAIS, WISC, and
WPPSI short forms. J Consult Clin Psychol 1970;38:3442
Wechsler D. A standardized memory scale for clinical use.
J Psychol 1945;19:87-95
Russell EW. A multiple scoring method for the assessment of
complex memory functions. J Consult Clin Psychol 1975:43:
Weigl E. On the psychology of so-called processes of absrraction. J Abnormal Social Psychol 1941;36:3-33
Goldstein KH, Scheerer M. Abstract and concrete behavior:
and experimental study with special tests. Psychol Monogr
Reintan RM. Validity of the Trail Making Test as an indication
of organic brain damage. Percept Mot Skills 1958;8:271-276
Pascual-Leone A, Dhuna A, Anderson DC. Cerebral atrophy in
habitual cocaine abusers: a planimetric C T study. Neurology
Parsons OA, Stevens L. Previous alcohol intake and residual
cognitive deficits in detoxified alcoholics and animals. Alcohol
Alcohol 1986;2l :137-1 57
Charness ME, Simon RP, Greenberg DA. Ethanol and the nervous system. N Engl J Med 1989;321:442-454
Lelbach WK. Cirrhosis in the alcoholic and its relation to the
volume of alcohol abuse. Ann NY Acad Sci 1975;252:85-105
Urbano-Mrirquez A, Estruch R, Navarro-Lopez F, et al. The
effects of alcoholism on skeletal and cardiac muscle. N Eiigl
J Med 1989;320:409-415
Villalra J, Estruch R, Antunez E, et al. Vagal neuropathy in
chronic alcoholics: relation to ethanol consumption. Alcohol
Alcohol 1989:24:421428
Monforte R, Esrruch R, Valls-Sole J , et al. Autonomic and peripheral neuropathies in chronic alcoholics: a dose-relared toxic
effect of ethanol. Arch Neurol 1995:52:45-5 1
598 Annals of Neurology
Vol 41
No 5
May 1997
30. Patek AJ, Toth MG, Saunders GA, et al. Alcohol and dietary
factors in cirrhosis: an epidemiological study of 304 alcoholic
patients. Arch Intern Med 1975;135:1053-1057
31. Jacobs RM, Sorrel1 MF. The role of nutrition in the pathogenesis of alcoholic liver disease. Semin Liver Dis 1981;1:224-253
32. Mendenhall CL, Anderson S, Weesner RE, et al. Protein-calorie
malnutrition associated with alcoholic hepatitis. Am J Med
33. Pfefferbaum A, Rosenbloom MJ, Crusan K, Jernigan TI,. Brain
CT changes in alcoholics. The effects of age and alcohol coilsumption. Alcohol Clin Exp Res 1988:12:81-87
34. Sullivan EV, Marsh L, Mathalon DH, et al. Anterior hippocampal volume deficits in nonamnesic, aging chronic alcoholics. Alcohol Clin Exp Res 1995;19:110-122
35. Bergman H. Brain dysfunction related to alcoholism: some results from the KARTAD project. In: Parsons OA, Butters N,
Nathan PE, eds. Neuropsychology of alcoholism: implications
for diagnosis and treatment. New York: Guilford, 1%7:2 1-44
36. Jernigan TL, Butters N, DiTraglia G, et al. Reduced cerebral
grey matter observed in alcoholics using magnetic resonance
imaging. Alcohol Clin Exp Res 1991;15:418-427
37. Carlen PL, Penn RD, Fornazzari L, et al. Computerized tomographic assessment of alcoholic brain damage and its potential
reversibility. Alcohol Clin Exp Res 1986;10:226-232
38. Melgaard B, Henriksen L, Danielsen UT, et al. Regional cerebral blood flow in chronic alcoholics measured by single photon
emission computerized tomography. Acta Neurol Scand 1990;
39. Waugh M, Jackson M, Fox GA, et al. Effect of social drinking on
neuropsychological performance. Br J Addict 1989;84:659-667
40. Adams RD, Victor M. Principles of neurology. New York:
McGraw-Hill, 1989
4 1. Tamkin AS. The Weigl Color-Form Sorting Test as an index of
cortical function. J Clin Psychol 1980;36:778-781
42. Tamkin AS, Kunde JT. Construct validity of the Weigl ColorForm Sorting 'lest. Percept Mot Skills 1982;55:105-106
43. Lezak MD. Neuropsychological assessment. 2nd ed. New York:
Oxford University Press, 1983
44. Kelley WR, Pena Y, Reilly EL, et al. Effects of age and alcohol
abuse on pattern reversal evoked potentials. Clin Electroencephalogr 1984; 1 5: 102-1 09
45. Chan YW, McLeod JC, 'l'uck RR, Feary PA. Brain stem auditory evoked responses in chronic alcoholics. J Neurol Neurosurg Psychiatry 1985;48:1107-1 112
46. Chu N, Squires K, Starr A. Auditory brain stem responses in
chronic alcoholic patients. Electroencephalogr Clin Neurophysiol 1982;54:418-425
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