0145-6008/93/1701-0002$3.00/0
1
ALCOHOLISM: CLINICAL A N D EXPERIMENTAL
RESEARCH
Brain Lesions in Alcoholics
Michael E. Charness
Brain lesions in alcoholics are multifactorial in origin. Ethanol neu-
rotoxicity, Wernicke’s encephalopathy, hepatocerebral degenera-
tion, head trauma, central pontine myelinolysis, Marchiafava-Bignami
syndrome, pellagra, and premorbid pathological conditions, such as
fetal alcohol syndrome, may all contribute to cognitive dysfunction
in alcoholics. With the exception of ethanol neurotoxicity, all of these
conditions are associated with specific neuropathological lesions.
Wernicke’s encephalopathy, the neurological syndrome of thiamine
deficiency, is frequently overlooked during life and may cause global
dementia as well as the more familiar Korsakoff’s amnestic syn-
drome. Distinguishing ethanol neurotoxicity from nutritional defi-
ciency can be facilitated by magnetic resonance imaging, which can
visualize some of the specific macroscopic lesions of Wernicke’s
encephalopathy, central pontine myelinolysis, cerebellar degenera-
tion, and Marchiafava-Bignami syndrome. Computerized morpho-
metric studies of alcoholic brains have revealed ventricular enlarge-
ment, selective loss of subcortical white matter, and alterations in
neuronal size, number, architecture, and synaptic complexity. These
lesions tend to be more severe when there is coexisting nutritional
deficiency or liver disease, suggesting that ethanol neurotoxicity
may not be the sole cause. A search for similar lesions in nonalco-
holic Wernicke’s encephalopathy and nonalcoholic liver disease will
help determine the specificity of these lesions.
Key words: Alcoholism, Brain Lesions, Wernicke’s Encephalop-
athy, Magnetic Resonance Imaging.
MILD COGNITIVE IMPAIRMENT can be demon-
strated by neuropsychological testing in 50-70% of
detoxified alcoholics.’ Abstinence leads to a partial recov-
ery of function, particularly in the first weeks after the
cessation of drinking’.’; however, approximately 10% of
alcoholics exhibit stable and severe cognitive dysfunction
ranging from selective anterograde and retrograde amnesia
to dementia.
Brain damage in alcoholics is clearly multifactorial.
Ethanol and its oxidative metabolite acetaldehyde may
directly damage the developing and mature nervous sys-
t e m ~ . ~Nonoxidative
-~ metabolism of ethanol generates
fatty acid ethyl esters that accumulate differentially in
various tissues in a manner that correlates with suscepti-
bility to ethanol-induced damage.”“’ Ethanol is a rich
From the Dcymrttnent qj-Nmrology (Ni.iiro.sc.irnci~),Hurvurd Mcdiid
School; Division qf Neurolog), Brighum and W b m m :T Hospitul; und the
Section of Neiirologv ( I 27), U’est Rovhirry l‘i~tc~run 1s .4rlniiriistrution
Medkul CentcJr, U’c.st Ro.vhury. Mu.~sui~hiis~tt.s.
Reci*ivedfi,rpiiblicution Aiigiist 2 7, 1992; ucceptcd Octohiv 23. 1992
This stud!, M’US supported b), t h Nutionul
~ In.stitiitc on Alcohol .4hit.w
and Alcoholisin (AA06662) und [lie Medical Rcseurch Servic.cJ. Dcpurt-
men! of Viw-uns Aflairs.
Reprint reqiiests: Micliud E. Churness. M . D., Nurvurd hlcdit,ul
School.Veieruns Administrution Mcdicul Center (127). 1400 C‘FW’ Purk-
uuy, Cl’est Ro-ubiiry, MA 02132
Cop~~riglit0 1993 by The Reseurch Socicty on illcoholism.
2 4koliol C’hn E\[J R r , Vol 17. No I. 1993 pp 2-1 1
Vol. 17, No.
January/February 1993
source of nonnutritive calories, so that heavy drinking is
often complicated by malnutrition and vitamin defi-
ciency. “ . I 2 The diagnosis of Wernicke’s encephalopathy,
the neurological disorder of thiamine deficiency, is fre-
quently missed,I3 l 4 making it difficult to know whether
cognitive dysfunction in an alcoholic arises from malnu-
trition or ethanol neurotoxicity. This problem is com-
pounded by the lack of a specific pathological lesion of
ethanol neurotoxicity and the frequent coincidence of
several neurological complications of alcoholism, includ-
ing hepatocerebral degeneration, malnutrition and Wer-
nicke’s encephalopathy, head trauma, central pontine
myelinolysis, Marchiafava-Bignami syndrome, pellagra,
and premorbid pathological conditions, such as fetal al-
cohol syndrome.”,I5
Interactions among these conditions may also influence
brain damage in alcoholism. Acetaldehyde may acetylate
transketolase, reducing its activity.“ Thiamine deficiency
in turn accelerates ethanol metabolism and the production
of acetaldehyde by increasing alcohol dehydrogenase ac-
tivity. ‘’-Iy Chronic ethanol administration accelerates the
lesions of experimental thiamine deficiency.”) perhaps
by increasing N-methyl-D-aspartate (NMDA) receptor
expression and excitotoxicity.” Ethanol impairs the
recovery of function from neural injury of diverse etiol-
ogie~.”-’~Finally, genetic factors may also influence the
susceptibility of certain alcoholics to develop neurological
complications. For example, genetically determined ab-
normalities in the thiamine-dependent enzyme transke-
tolase may explain why only a subset of malnourished
alcoholics develop the Wernicke-Korsakoff syn-
drome. 19.26 27
The study of brain damage in alcoholism is an interdis-
ciplinary endeavor involving neuropsychological evalua-
tion, brain imaging, neuropathological examination, and
animal experimentation. Neuropsychological studies can
document the erosion of cognitive function over the life-
time of an alcoholic, but must be conducted without
complete knowledge of the pathologic lesions underlying
these changes. Imaging studies can visualize some of the
specific macroscopic lesions of Wernicke’s encephalop-
athy, central pontine myelinolysis, cerebellar degenera-
tion, and Marchiafava-Bignami syndrome, but cannot
identify the microscopic changes that characterize all Wer-
nicke’s cases or the subtle alterations in neuronal number,
size, architecture, and connectivity that may result from
ethanol neurotoxicity. Autopsy material presents a life-
time record of insults to the brain of an alcoholic, includ-
ing lesions unrelated to ethanol neurotoxicity, often in the
BRAIN LESIONS IN ALCOHOLICS
absence of data concerning premorbid cognitive function
and the extent and duration of drinking. Animal and
cellular models can control for nutritional deficiency and
liver disease, but may not be generalizable to different
species, including humans. Below, some of the important
pathological processes that underlie brain damage in al-
coholism are highlighted.
WERNICKE'S ENCEPHALOPATHY
Wernicke's encephalopathy is a common neurological
disorder caused by thiamine deficiency, and alcoholics
account for most cases in the Western world." Thiamine
deficiency in alcoholics results from a combination of
inadequate dietary intake, reduced gastrointestinal absorp-
tion, decreased hepatic storage, and impaired utilization."
Only a subset of thiamine-deficient alcoholics develop
Wernicke's encephalopathy, perhaps because they have
i ~ ~ h e r i t eord ~ ~ . ~ ~ abnormalities of the thiamine-
acquired28
dependent enzyme transketolase that reduce its affinity
for thiamine.
The detailed, regional pathology of Wernicke's enceph-
alopathy has been outlined by Victor and colleagues.1'
The characteristic lesions of Wernicke's encephalopathy
occur symmetrically in structures surrounding the third
ventricle, aqueduct, and fourth ventricle. The mamillary
bodies are involved in virtually all cases, and the dorso-
medial thalamus, locus ceruleus, periaqueductal gray, ocu-
lar motor nuclei, and vestibular nuclei are commonly
affected. Lesions occur less frequently in the colliculi,
fornices, septa1 region, hippocampus, and cerebral cortex,
which may show patchy, diffuse neuronal loss, and astro-
cytic proliferation. In about half of the cases, sagittal
sections through the cerebellum reveal selective loss of
Purkinje cells at the tips of the folia of the anterior superior
cerebellar vermis. These changes are identical to those
found in alcoholic cerebellar degeneration, where they can
occur in the absence of other Wernicke lesions.
Acute Wernicke lesions can be identified by endothelial
prominence, microglial proliferation, and occasional pe-
techial hemorrhages. In chronic lesions, there is demyeli-
nation, gliosis, and loss of neuropil with relative preser-
vation of neurons. Neuronal loss is most prominent in the
relatively unmyelinated medial thalamus. 12.29 Atrophy of
the mamillary bodies is a highly specific finding in chronic
Wernicke's encephalopathy and is present in up to 80%
of cases."
It is unclear how thiamine deficiency causes brain le-
sions. Thiamine is a cofactor for transketolase, a-ketoglu-
tarate dehydrogenase, pyruvate dehydrogenase, and
branched-chain a-ketoacid dehydrogenase,12and may also
function in axonal conduction and synaptic transmis-
ion.^' Thiamine deficiency produces a diffuse decrease in
cerebral glucose ~tilization.~' Shortly before the develop-
ment of structural brain lesions, vulnerable brain areas
exhibit a burst of metabolic activity accompanied by local
3
production of lactate."-32This burst of glucose utilization
could represent a shift from aerobic metabolism to rapid
glycolysis due to reduced pyruvate dehydrogenase activ-
it^.^' MK-801, a drug that blocks ion currents activated
by NMDA-preferring glutamic acid receptors,33 reduces
the neurological signs and the severity and extent of lesions
in experimental thiamine d e f i ~ i e n c yThese
. ~ ~ data suggest
that glutamate toxicity may cause structural lesions in
Wernicke's en~ephalopathy,~~ as happens in a variety of
other neurological disorder^.'^ Indeed, extracellular con-
centrations of glutamate increase up to 7-fold in the medial
thalamus and 3-fold in the hippocampus following sei-
zures in thiamine-deficient rats.36 The observation that
chronic ethanol treatment increases the density of NMDA
receptors in specific brain region^'^,^^ suggests a possible
mechanism whereby chronic ethanol ingestion could po-
tentiate the excitotoxicity of glutamate in Wernicke's en-
cephalopathy."
The distinctive nature of the pathological findings in
Wernicke's encephalopathy permits subclinical cases to be
diagnosed postmortem. Autopsy studies have consistently
revealed a higher (0.8-2.8%) incidence of Wernicke lesions
in the general population than is predicted by clinical
studies (0.04-0.13%). ".I4 The observation that acute Wer-
nicke's encephalopathy was correctly diagnosed before
death in only I of 22 patients13 suggests that the classic
clinical triad of encephalopathy, ophthalmoplegia, and
ataxia is either surprisingly rare13.14q39 or is not properly
elicited and recognized."q4'
In clinical studies, only one-third of patients with acute
Wernicke's encephalopathy present with the classic clini-
cal triad.I2 A majority of patients are profoundly disori-
ented, indifferent, and inattentive, and some exhibit an
agitated delirium related to ethanol withdrawal. Although
fewer than 5 % of patients present with a depressed level
of consciousness, the course in untreated patients may
progress through stupor and coma to death.12.41Ocular
motor abnormalities, including nystagmus, lateral rectus
palsy, and conjugate gaze palsies, occur in 96%, reflecting
lesions of the oculomotor, abducens, and vestibular nuclei.
Gait ataxia occurs in 87% and is likely due to a combi-
nation of polyneuropathy noted in 82% of cases, cerebellar
involvement, and vestibular pare~is.'~.~' In keeping with
the restriction of cerebellar pathology to the anterior and
superior vermis, ataxia of the arms and dysarthria or
scanning speech are each observed in less than 20% of
cases. I'
Autopsy-based series also suggest a very high incidence
(82%) of mental status abnormalities, but much lower
incidences of ataxia (23%), ocular motor abnormalities
(29%), and polyneuropathy ( 1 1 %).40 The classic triad of
clinical findings was identified retrospectively in only 17%
of autopsy cases and 19% showed none of the classic
elements. Stupor or coma, hypotension, and hypothermia
were predominant findings in unsuspected case^.'^.'^.^^
The discrepancy between prospective clinical and retro-
4 CHARNESS
spective, autopsy-based descriptions of Wernicke’s en-
cephalopathy is likely due to the exclusion of atypical
presentations in clinical series and the underestimation in
autopsy series of classic signs that were not properly elic-
ited, recognized, or recorded.
Computed tomography (CT) scanning occasionally re-
veals low-density diencephalic abnormalities in acute Wer-
nicke’s e n ~ e p h a l o p a t h y .In
~ ~some
, ~ ~ acute cases, magnetic
resonance imaging (MRI) demonstrates increased T2 sig-
nal surrounding the aqueduct and third ventricle, consist-
ent with the localization of the pathologic lesion^.^^.^'
Atrophy of the mamillary bodies can be identified by MRI
in approximately 80% of alcoholics with a history ofclassic
Wernicke’s encephalopathy4*(Fig. 1) and is not found in
control subjects, Alzheimer’s patients, or alcoholics with-
out a history of Wernicke’s e n ~ e p h a l o p a t h y Alcoholics
.~~.~~
with the Wernicke-Korsakoff syndrome have small mam-
illary bodies and normal hippocampal volumes, as deter-
mined by MRI, whereas the converse is true in nonalco-
holic amnestic patient^.^' The ability to detect specific
Wernicke lesions by MRI should prove valuable in study-
ing the cognitive disorders of a l c o h o l i ~ sThe . ~ ~ finding of
small mamillary bodies in a mentally impaired patient
will indicate that nutritional deficiency has likely played
a role in the cognitive disorder. This technique may also
prove useful in the diagnosis of atypical chronic cases of
Wernicke’s en~ephalopathy~~ and in elucidating prospec-
tively the full clinical spectrum of the disorder.
MR studies comparing amnestic alcoholics, nonamnes-
tic alcoholics, and controls identified increases in cerebro-
spinal fluid volume, ventricular enlargement, and reduc-
tions in cortical and subcortical grey matter structures in
both alcoholic g r o ~ p s . ~ The
’ , ~ *amnestic alcoholics showed
particularly large decreases in the anterior diencephalon,
mesial temporal, and orbitofrontal regions.51Neuropsy-
chological measures in the nonamnestic alcoholics did not
correlate with grey matter volume in a variety of brain
regions.
With prompt administration of thiamine, ocular signs
improve within hours to days, and ataxia and confusion
within days to weeks.” This early response likely repre-
sents recovery of a biochemical rather than a structural
lesion. A majority of patients are left with horizontal
nystagmus, ataxia, and a potentially disabling memory
disorder known as the Korsakoff amnestic syndrome.
These sequelae may result from the accumulation of le-
sions during repeated subclinical episodes of thiamine
deficiency,14,53-55 rapid development of irreversible lesions
during a single acute episode,54or inadequate treatment
of patients with low-afinity transketolase variants2’
Fig. 1. MRI of chronic Wernicke’s encephalop
athy. (A) Normal control and (B)chronic Wer-
nicke’s encephalopathy. T1-weighted sagittal
(left) and coronal (right) images in the plane of
the mamillary bodies (arrows). The Wernicke
patient shows shrinkage of the mamillary bod-
ies (arrows) and anterior superior cerebellar
vermis (arrowheads) and enlargement of the
third ventricle, lateral ventricles, interhemi-
spheric fissure, and cerebral sulci (arrowheads).
Images were acquired using TR 600, TE 25 (an
excellent description of MRI image acquisition,
T1, and T2 can be found in ref. 135. Repro-
duced with permission from Annals of Neurol-
ogy 22595400,1987.
 BRAIN LESIONS IN ALCOHOLICS
KORSAKOFF'S AMNESTIC SYNDROME
Approximately 80% of alcoholic patients recovering
from classic Wernicke's encephalopathy exhibit the selec-
tive memory disturbance of Korsakoff s amnestic syn-
drome," which is characterized by marked deficits in
anterograde and retrograde memory, apathy, an intact
sensorium, and relative preservation of other intellectual
a b i l i t i e ~ . 'Korsakoff
~.~~ s amnestic syndrome may also ap-
pear without an antecedent episode of Wernicke's enceph-
a l ~ p a t h y . ' ~Acute
.'~ lesions may be superimposed on
chronic lesions, suggesting that subclinical episodes of
Wernicke's encephalopathy may culminate in Korsakoff s
amnestic ~ y n d r o m e . ~ The
~ ,memory
~ ~ , ~ ~disorder correlates
best with the presence of histopathological lesions" and
areas of decreased density on CT scan5' in the dorsomedial
thalamus. However, Wernicke lesions have been confined
to the mamillary bodies in one reported case of Korsakoff s
amnestic syndrome.59
Whereas Korsakoff s amnestic syndrome is most readily
recognized as a relatively selective disorder of anterograde
and retrograde memory, some alcoholics with Wernicke
lesions exhibit a more global abnormality of higher cog-
nitive f ~ n c t i o n . ~Torvik"
' identified Wernicke's lesions at
autopsy in 20 alcoholics who had been evaluated by
psychiatrists during the course of their illness. Fifteen of
the 20 patients were felt to have a global dementia and
only 5 had a circumscribed memory disorder; conse-
quently, Korsakoff s amnestic syndrome was diagnosed in
only 3 of 20 patients, whereas Alzheimer's disease was
diagnosed in 8. Twelve of 15 patients diagnosed with
dementia showed only the lesions of Wernicke's enceph-
alopathy at autopsy, although subtle structural abnormal-
ities were not sought." The occurrence of global dementia
in Wernicke's encephalopathy and the absence of non-
Wernicke lesions in demented alcoholics has led some
investigators to conclude that most cases of dementia in
alcoholics are nutritional in rigi in."^'^^^^^('' Whether alco-
hol neurotoxicity plays a role in these cases can only be
determined by correlating computerized brain morphom-
etry with premorbid neuropsychiatric examination.
One of three patients in Wernicke's original report was
a nonalcoholic. I' Wernicke's encephalopathy has since
been described in nonalcoholic patients with malnutrition
due to hyperemesis, starvation, gastric plication, renal
dialysis, malignancy, and AIDS. 12,61-63Indeed, in one au-
topsy series, nonalcoholics accounted for I2 of 52 cases of
Wernicke's en~ephalopathy.~~
Korsakoff s amnestic syndrome is an infrequent sequela
of Wernicke's encephalopathy in n o n a l c o h ~ l i c s .This~~
observation has led to speculation that ethanol neurotox-
icity is an important contributing factor in the memory
disorders of alcoholic^.^^ Although it is certainly possible
that neurotoxic effects of ethanol may worsen the cerebral
disorder of thiamine deficiencv. it is also clear that Kor-
d ,
sakoffs amnestic syndrome can occur in the absence of
ethanol. Accounts of thiamine deficiency in prisoners of
5
war include descriptions of some individuals with endur-
ing disorders of mental function following treatment with
More recent cases provide clearer descrip-
tions of Korsakoffs amnestic syndrome following Wer-
nicke's encephalopathy in n o n a l c o h o l i ~ s Quantita-
.~~~~~~~~
tive brain morphometry (see below) in these uncommon
patients will indicate whether ventricular enlargement,
shrinkage of cerebral white matter, selective neuronal loss,
and simplification of dendritic arbors are specific lesions
of ethanol neurotoxicity or previously unrecognized man-
ifestations of thiamine deficiency.
CEREBELLAR DEGENERATION
Alcoholic patients may be aMicted by a chronic cere-
bellar syndrome related to the degeneration of Purkinje
cells in the cerebellar ~ o r t e x . ~
Midline
' cerebellar struc-
tures-especially the anterior and superior vermis-are
predominantly affected, a pattern that resembles the dis-
tribution of cerebellar pathology in Wernicke's encepha-
lopathy.'? The cause of alcoholic cerebellar degeneration
is not known with certainty, but its similarity to the
cerebellar lesion in Wernicke's encephalopathy suggests
that thiamine deficiency is likely to be an important
f a ~ t o r . ~ 'It. ~has
' also been proposed that alcoholic cere-
bellar degeneration, like central pontine myelinolysis. may
be related to electrolyte abn~rmalities.~' Evidence for a
direct toxic effect of ethanol as the cause is poor: cerebellar
ataxia in alcoholics does not correlate with daily, annual.
or lifetime consumption of ethan01,'~and animal models
of cerebellar degeneration induced by ethanol in the ab-
sence of nutritional deficiency show a somewhat different
pattern of cerebellar pathology, in which the granule cells
and molecular layer interneurons are more vulnerable
than Purkinje cells.75
Alcoholic cerebellar degeneration typically occurs only
after 10 or more years ofexcessive ethanol use. It is usually
a gradual, progressive disorder that develops over weeks
to months, but may also evolve over years or commence
a b r ~ p t l y . Mild
~ ' and apparently stable cases may become
suddenly worse. As in Wernicke's encephalopathy, ataxia
affects the gait most severely. Limb ataxia and dysarthria
occur more often than in Wernicke's encephalopathy,
whereas nystagmus is rare.71
The diagnosis of alcoholic cerebellar ataxia is based on
the clinical history and neurologic examination. CT or
MRI scans may show cerebellar cortical atrophy (Fig. I),
but one-half of alcoholic patients with this finding are not
ataxic on examination.'(' Whether these represent subclin-
ical cases in which symptoms will develop subsequently is
unclear.
HEPATOCEREBRAL DEGENERATION
Hepatic encephalopathy develops in many alcoholics
with liver disease. and is characterized by altered senso-
6 CHARNESS

rium, frontal release signs, asterixis. hyperreflexia, exten-

sor plantar responses, and occasional seizures. Whereas
some patients progress from stupor to coma and then
death, others recover and suffer recurrent episodes. Brains
of patients with hepatic encephalopathy show enlargement
and proliferation of protoplasmic astrocytes in the basal
ganglia, thalamus, red nucleus, pons, and cerebellum, in
the absence of neuronal loss or other glial changes.77
Occasional patients do not recovery fully after an epi-
sode of hepatic encephalopathy, but rather, go on to
develop a progressive syndrome of tremor, choreoatheto-
sis. dysarthria, gait ataxia, and dementia. Hepatocerebral
degeneration may progress in step-wise fashion, with in-
complete recovery after each episode of hepatic encepha-
lopathy, or slowly and inexorably, without a discrete epi-
sode of encephalopathy. Brain examination reveals astro-
cytic proliferation, as described, laminar necrosis in the
cortex, patchy loss of neurons throughout the cortex, basal
ganglia, and cerebellum, and cavitation of the cortico-
subcortical junction and superior pole of the p ~ t a m e n . ’ ~ , ~ ~

MARCHIAFAVA-BIGNAMI SYNDROME

Marchiafava-Bignami syndrome is a rare disorder of

demyelination or necrosis of the corpus callosum and
adjacent subcortical white matter, which occurs predom-
inantly in malnourished a l c o h o l i ~ sIn
.~~some cases there
are associated lesions of Wernicke’s encephalopathy or Fig. 2 Marchiafava-Bignami syndrome. The splenium of the corpus callosum shows
selective neuronal loss and gliosis in the third cortical an area of increased signal (arrow) (TR 2000, TE 40).
layer. A few cases have been described in nonalcohol-
i c ~ demonstrating
, ~ ~ - ~ ~ that ethanol alone is not responsible 10% of human cases also have symmetric extrapontine
for the lesion. The course may be acute, subacute, or lesions, most frequently in the striatum, thalamus, cere-
chronic, and is marked by dementia, spasticity, dysarthria, bellum, and cerebral white matter.84 Microscopic exami-
and inability to walk. Patients may lapse into coma and nation reveals demyelinated axons with preserved cell
die, survive for many years in a demented condition, or bodies except in the center of lesions, which may show
occasionally recover.” The disorder was formerly diag- cavitation. Myelinolytic lesions can be induced experi-
nosed only at autopsy, but lesions can now be imaged mentally by rapid correction of chronic hyp~natremia.”.~~
using CT or MRLX2MR typically shows areas of increased In rats, the lesions are primarily extrapontine in l~cation,’~
T2 signal (Fig. 2) or cystic areas of decreased T 1 signal whereas in dogs, a mixture of pontine and extrapontine
within the corpus callosum.” lesions is observed.8x The marked species differences in
the distribution of lesions in central pontine myelinolysis
CENTRAL PONTINE MYELINOLYSIS
illustrates one of the difficulties in generalizing patholog-
ical findings from experimental animals to humans.
Central pontine myelinolysis is a disorder of cerebral Symptoms and signs of central pontine myelinolysis
white matter that usually affects alcoholics, but also occurs may be absentx3 or obscured by associated conditions,
in nonalcoholics with liver disease, including Wilson’s such as ethanol withdrawal, Wernicke’s encephalopathy,
disease, malnutrition, anorexia, burns, cancer, Addison’s or hepatic encephalopathy. Treatment of these disorders
disease, and severe electrolyte disorders, such as thiazide- may lead to an initial improvement in mental status,
induced hyponatremia. Central pontine myelinolysis followed within days by confusion, lethargy, and coma
is frequently associated with a rapid correction of hypo- due to central pontine myelinolysis. Involvement of the
natremia; however, the majority of cases occur in alco- corticospinal tracts causes paraparesis or quadriparesis and
holics, suggesting that alcoholism may contribute to the demyelination of the corticobulbar tracts leads to dysar-
genesis of central pontine myelinolysis in as yet undefined thria, dysphagia, and inability to protrude the tongue. The
ways. tendon reflexes may be increased, decreased, or normal,
The most common macroscopic lesion is a triangular and Babinski signs may be present. Disorders of conjugate
region of pallor in the base of the pons. ApprGximately eye movement occur occasionally and may reflect exten-
BRAIN LESIONS IN ALCOHOLICS 7

sion of the lesion in the pons or associated Wernicke with postnatal de~elopment,'~ however, learning disabili-
lesions. Disproportionate involvement of motor function ties and hyperactivity p e r s i ~ t . ' ~ ~ ' ~
may produce the "locked-in" syndrome, with only limited Neuropathological examination in fetal alcohol syn-
ability to move the limbs or face despite a normal level of drome reveals microcephaly, cerebellar dysplasia, agenesis
consciousness." of the corpus callosum, and neuronal-glial heterotopi-
The lesions of central pontine myelinolysis can be vis- as,'8-'"" lesions consistent with the decreased proliferation
ualized using CT scanning or MRI (Fig. 3). MRI is more and disordered migration of neurons that have been dem-
sensitive than CT in imaging the pontine lesions'"; how- onstrated by in vivo ['Hlthymidine labeling studies in
ever, even MRI may be unremarkable early in the course rats. ""
of central pontine myelinolysis."' The most common MR In animal studies, gestational exposure to ethanol also
finding is an area of decreased TI signal or increased T2 causes microcephaly'O' and disrupts the cytoarchitecture
signal within the basis pontis. Other disorders, such as of cerebral cortex, hippocampus, cerebellum, and other
multiple sclerosis, multiinfarct dementia, and encephalitis, subcortical structures.1"1.10'-108 Alterations in the levels of
may show similar pontine MRI abnormalities, but also monoamines and acetylcholine in animals exposed to
cause significant periventricular abnormalities and a dis- ethanol in utero may derive from the failure of projection
tinctive clinical picture.") Serial CT or MRI studies indi- neurons to reach their targets.'" The pathological basis
cate that the radiographic lesions may resolve in parallel for mental retardation and learning disabilities may reside
with patient recovery'"~''; thus, the absence of lesions on in more subtle structural abnormalities, such as the sim-
MRI does not exclude the previous occurrence of central plification of hippocampal dendrites seen in animals ex-
pontine myelinolysis. posed to ethanol in utero.' "' Prenatal ethanol exposure
alters synaptogenesis and dendritic structure (reviewed in
ETHANOL NEUROTOXICITY IN THE DEVELOPING ref. 108) and reduces the density of parallel fibers in the
NERVOUS SYSTEM molecular layer of the cerebellum."'
Brain lesions in alcoholics may in some instances ante- MRI in a small number of children with fetal alcohol
date birth. Alcoholism runs in families, and many alco- syndrome has identified agenesis or hypoplasia of the
holics have been exposed to high concentrations of alcohol corpus callosum and selective reductions in the volume of
during critical stages of brain development. A n y attempt the cerebrum, cerebellum, and basal ganglia.'".'13 The
to understand the pathogenesis of subtle brain lesions in further elucidation of MR abnormalities in fetal alcohol
alcoholics must take into account the potential contribu- syndrome may help define the role of gestational exposure
tion of fetal alcohol exposure. to alcohol in the cognitive disorders of alcoholics.
The fetal alcohol syndrome is characterized by pre- and
postnatal growth retardation, microcephaly, neurological ETHANOL NEUROTOXICITY IN THE MATURE NERVOUS
SYSTEM
abnormalities, facial dysmorphology. and other congenital
an~malies.~." This full syndrome occurs in approximately Evidence that a direct neurotoxic effect may contribute
0.33 cases/ 1000 live births.'3 More often, heavy intrauter- to chronic cognitive dysfunction in alcoholics has been
ine exposure to ethanol is associated with a constellation adduced from imaging studies, neuropathological obser-
of less severe abnormalities "fetal alcohol effects," includ- vations, and animal experiments. CT and MRI show
ing mental retardation, intrauterine growth retardation, enlargement of the cerebral ventricles and sulci in a ma-
and minor, upgrouped congenital anomalies involving the jority of alcoholics"'; however. when corrected for the
cutaneous, genitourinary, musculoskeletal, and cardiac effects of aging, the radiographic indices do not correlate
systems.'2 Some dysmorphic features appear to recede consistently with either the duration of drinking or the

Fig. 3. Central pontine myelinolysis Arrows in-

dicate a midpontine abnormality that appears
as an area of decreased T I signal [sagittal
image (A)] (TR 600, TE 25) and increased T2
signal [horizontal image (B)] (TR 2000 TE 70)
 8 CHARNESS
severity of cognitive impairment.’’ The ventricles and
sulci become significantly smaller within about 1 month
of abstinence,’.’ 14-’ l 6 whereas brain water, estimated by
MRI”’ or chemical does not change con-
sistently. Based on these findings, it has been hypothesized
that changes in brain parenchyma, but not brain water,
may account for the reversible radiographic and cognitive
abnormalities of alcoholics.’,”’ In support of this hypoth-
esis are reports that chronic ingestion of ethanol by well-
nourished animals can reversibly reduce the complexity
ofdendritic arborization4and alter the density of dendritic
spines’ in the hippocampus.
Pathological studies of the brains of alcoholics have
provided mixed evidence for ethanol-induced cerebral
atrophy.” Brain weight in alcoholics is reduced only
slightly as compared with that in nonalcoholics,”,’ ”).””
and some workers find no differences at all.”.”’ Brain
volume, estimated by the volume of the pericerebral
space-the cerebrospinal fluid-filled region between the
brain and skull-is reduced in alcoholics compared with
controls, but this indirect measure of cerebral atrophy is
most abnormal in alcoholics with liver disease or Wer-
nicke’s encephalopathy.’” Quantitative morphometry
suggests that alcoholics, including those with liver disease
and Wernicke’s encephalopathy, lose a disproportionate
amount of subcortical white matter as compared with
cortical gray matter.”” This loss of cerebral white matter
is also apparent when brains of nondemented alcoholics
with liver disease are compared with those from patients
with nonalcoholic liver disease; thus, liver disease cannot
be the sole cause of this selective loss of brain tissue. The
loss of cerebral white matter is evident across a wide range
of ages, is not accentuated in the frontal lobes,’”’and is of
sufficient magnitude (6- 17%)to account for the associated
ventricular enlargement.’”
The identification of selectively affected neurotransmit-
ter pathways could have important implications for the
management of dementia in alcoholics. Cholinergic neu-
rons in the nucleus basalis of the basal forebrain, which
innervate much of the cerebral cortex and are preferen-
tially depleted in dementia due to Alzheimer’s disease,
have also been reported to be lost in three patients with
Korsakoff s syndrome. I” Levels of the acetylcholine-syn-
thesizing enzyme choline acetyltransferase, which are re-
duced in the cerebral cortex in Alzheimer’s disease, are
also depleted in the brains of alcoholics, as reported in
some,123.124 but not all’25studies. Whether putative cholin-
ergic deficits in alcoholics are a consequence of thiamine
deficiency or direct ethanol neurotoxicity is unclear.
Long-term administration of ethanol to well-nourished
rats causes memory deficits, reductions in choline acetyl-
transferase levels and choline uptake, and a slight (17%)
loss of neurons in the nucleus basalis.6,’26 Transplantation
of cholinergic neurons into the hippocampus and neocor-
tex corrects both the cholinergic deficits and memory
abnormalities, suggesting that, at least in rats. ethanol can
directly damage cholinergic projection neurons. 122.126 Evi-
dence also exists for disruption of serotonergic and adre-
nergic pathways in amnestic alcoholics.~’7
The recent use of computerized morphometry has re-
vealed alterations in neuronal size, number, architecture,
and synaptic complexity in alcoholics. Neuronal density
in the superior frontal cortex was reduced by 22% in
alcoholics compared with nonalcoholic controls. Neu- ”’
ronal loss was accompanied by selective glial proliferation
in the superior frontal cortex and was more pronounced
in a subgroup of alcoholics with cirrhosis or Wernicke’s
encephalopathy. By contrast, neuronal counts in motor,
temporal, or cingulate cortex did not differ between the
two A decrease in neuronal area was also
observed in the superior frontal, cingulate, and motor
cortices. 17x.12y The complexity of basal dendritic arboriza-
tion of layer 111 pyramidal cells in both superior frontal
and motor cortices was significantly reduced in a group of
15 alcoholics compared with controls.’30Similarly, a sig-
nificant reduction in dendritic arborization of Purkinje
cells in the anterior superior vermis was observed in 4
alcoholics, 3 of whom also had lesions of Wernicke’s
encephalopathy or pe1lag1-a.l~’Finally, a group of five
alcoholics without lesions of nutritional deficiency showed
a decrease in the density of synaptic spines in layer V
cortical pyramidal cells when compared with control pa-
tients.‘”
These data demonstrate that there is selective neuronal
loss, dendritic simplification. and reduction of synaptic
complexity in different brain regions of alcoholics: how-
ever, it remains uncertain how these cellular lesions relate
to the selective loss of white matter described above. The
etiology of these cellular lesions is also unclear, because
patients often had coincident lesions of nutritional defi-
ciency or cirrhosis. In fact, the cellular lesions were often
most severe in the alcoholics with liver disease or Wernicke
lesions. There are three possible explanations for these
findings: ( 1 ) that liver disease and Wernicke lesions are
markers of worse alcoholism, greater ethanol intake, and
more severe ethanol neurotoxicity; (2) that liver disease
and thiamine deficiency potentiate the neurotoxic actions
of ethanol; or ( 3 ) that liver disease and thiamine deficiency
cause these lesions. The fact that the neurological syn-
dromes of liver disease and thiamine deficiency can de-
velop slowly suggests that lesions in these disorders may
also arise insidiously. Indeed, it is conceivable that some
of the subtle, nonspecific lesions identified in alcoholic
brains are early manifestations of malnutrition and liver
disease that precede more recognizable, specific lesions of
Wernicke’s disease and hepatocerebral degeneration. This
hypothesis can be tested easily by using computerized
morphometry to seek similar, subtle lesions in nonalco-
holic patients with Wernicke’s disease and hepatocerebral
degeneration. To date, all of the Wernicke patients studied
by computerized morphometry have been alcoholics,
some of whom have also had liver disease. In the mean-
BRAIN LESIONS IN ALCOHOLICS
time. evidence that ethanol is neurotoxic must come from
animal studies, where nutrition can be better controlled.
Here, the data suggest that ethanol is neurotoxic in various
murine species, in some instances producing lesions sim-
ilar to those observed in humans. Thus, with respect to
hippocampal neurons, chronic ethanol treatment
reduce^"^ or does not change4 cell number, reversibly
decreases4 or increases'34 dendritic ~ o m p l e x i t y and
, ~ re-
versibly decreases or increases the density of synaptic
spines,"5 depending on the cell type.
REFERENCES
1. Martin PR, Adinoff B, Weingartner H, et al: Alcoholic organic
brain disease: Nosology and pathophysiologic mechanisms. Prog Neuro-
Psychopharmacol Biol Psychiatr 10: 147- 164, 1986
2. Carlen PL, Wilkinson DA. Wortzman G. Holgate R: Partially
reversible cerebral atrophy and functional improvement in recently
abstinent alcoholics. Can J Neurol Sci 1 1 :44 1-446, 1984
3. Muuronen A. Bergman H. Hindmarsh T. Telakivi T: Influence
of improved drinking habits on brain atrophy and cognitive performance
in alcoholic patients: A 5-year follow-up study. Alcohol Clin Exp Res
13:137-141. 1989
4. McMullen PA. Saint-Cyr JA. Carlen PL: Morphological altera-
tions in rat CAI hippocampal pyramidal cell dendrites resulting from
chronic ethanol consumption and withdrawal. J Comp Neurol225: 1 I I -
118, 1984
5. King MA, Hunter BE, Walker DW: Alterations and recovery of
dendritic spine density in rat hippocampus following long-term ethanol
ingestion. Brain Res 459:381-385, 1988
6. Arendt T. Henning D, Gray JA. Marchbanks R: Loss of neurons
in the rat basal forebrain cholinergic projection system after prolonged
intake of ethanol. Brain Res Bull 2 1563-569. 1988
7. Streissguth AP. Landesman-Dwyer S. Martin JC. Smith DW:
Teratogenic effects ofalcohol in humans and laboratory animals. Science
209:353-361, 1980
8. Lieber CS: Biochemical and molecular basis of alcohol-induced
injury to liver and other tissues. N Engl J Med 3 19:1639-1650. 1988
9. Laposata EA, Lange LG: Presence of nonoxidative ethanol
metabolism in human organs commonly damaged by ethanol abuse.
Science 23 1:497-499, 1986
10. Bora PS, Lange LG: Molecular mechanism of ethanol metabo-
lism by human brain to fatty acid ethyl esters. Alcohol Clin Exp Res
17:28-30, 1993
1 1 . Thomson AD. Ryle PR. Shaw GK: Ethanol. thiamine. and brain
damage. Alcohol Alcohol 18:27-43. 1983
12. Victor M, Adams RA, Collins GH: The Wernicke-Korsakoff
Syndrome and Related Disorders Due to Alcoholism and Malnutrition.
Philadelphia, F. A. Davis. 1989
13. Torvik A. Lindboe CF, Rodge S: Brain lesions in alcoholics. A
neuropathological study with clinical correlation. J Neurol Sci 56933-
248, 1982
14. Harper CG: The incidence of Wernicke's encephalopathy in
Australia-A neuropathological study of I3 I cases. J Neurol Neurosurg
Psychiatr 46:593-598, 1983
15. Tarter RE, Edwards KL: Multifactorial etiology of neuropsycho-
logical impairment in alcoholics. Alcohol Clin Exp Res 10: 128- 135.
I986
16. Pratt OE, Rooprai HK. Shaw GK. Thomson AD: The genesis
of alcoholic brain tissue injury. Alcohol Alcohol 25:2 17-230. 1990
17. Martin PR. Majchrowicz E, Tamborska E. et al: Response to
ethanol reduced by past thiamine deficiency. Science 227: 1365- 1368.
I985
18. Impeduglia G. Martin PR. Kwast M. et al: Influence of thiamine
deficiency on the response to ethanol in two inbred rat strains. J Phar-
macol Exp Ther 240:754-763. 1987
5,
19. Martin PR. McCool BA. Singleton CK: Genetic sensitivity to
thiamine deficiency and development of alcoholic organic brain disease.
Alcohol Clin Exp Res 1731-37.1993
20. Zimitat C. Kril J. Harper CG. Nixon P F Progression of neuro-
logical disease in thiamin-deficient rats is enhanced by ethanol. Alcohol
71493-50 I . I990
2 1 . Lovinger DM: Excitotoxicity and alcohol-related brain damage.
Alcohol Clin Exp Res 17: 19-27. 1993
22. West JR. Lind MD, Demuth RM. et al: Lesion-induced sprout-
ing in the rat dentate gyrus is inhibited by repeated ethanol administra-
tion. Science 2 I8:809-8 10, I982
23. Lind MD. Goodlett CR, West JR: Time course and reversibility
of ethanol's suppressive effects on axon sprouting in the dentate gyrus of
the adult rat. Alcohol Clin Exp Res 12:433-439. 1988
24. Tjossem HH. Goodlett CR. West JR: Sprouting responsiveness
in the dentate gyrus is reduced by ethanol administered following but
not preceding an entorhinal lesion. Exp Neurol 97:441-453. 1987
25. Orona E. Hunter BE. Walker DW: Ethanol exposure following
unilateral enterorhinal deafferentation alters synaptic reorganization in
the rat dentate gyrus: A quantitative analysis of acetylcholinesterase
histochemistry. Exp Neurol 101:l 14-131, 1988
26. Blass JP, Gibson GE: Abnormality of a thiamine-requiring en-
zyme in patient with Wernicke-Korsakoff syndrome. N Engl J Med
29711367-1370. 1977
27. Mukherjee AB. Svoronos S. Ghazanfari A. et al: Transketohse
abnormality in cultured fibroblasts from familial chronic alcoholic men
and their offspring. J Clin Invest 79:1039-1043. 1987
28. Jeyasingham MD. Pratt OE. Burns A. et al: The activation of
red blood cell transketolase in groups of patients especially at risk from
thiamin deficiency. Psycho1 Med 17:3 1 1-3 18. 1987
29. Torvik A: Two types of brain lesions in Wernicke's encephalop-
athy. Neuropathol Appl Neurobiol 11:179-190. 1985
30. lwata H: Possible role of thiamine in the nervous system. Trends
Pharmacol Sci 3: I7 I - 173. 1982
31. Hakim AM, Pappius HM: Sequence of metabolic. clinical. and
histological events in experimental thiamine deficiency. Ann Neurol
13:365-375. 1983
32. Hakim AM: The induction and reversibility of cerebral acidosis
in thiamine deficiency. Ann Neurol 16:673-679. 1984
33. Choi DW: Glutamate neurotoxicity and diseases of the nervous
system. Neuron I :623-634. I988
34. Langlais PJ. Man RG: Protective effects of the glutamate antag-
onist MK-80 1 on pyrithiamine-induced lesions and amino acid changes
in rat brain. J Neurosci 10:1664-1674, 1990
35. Butterworth RF: Effects of thiamine deficiency on brain metab-
olism: Implications for the pathogenesis of the Wernicke-Korsakoff
syndrome. Alcohol Alcohol 24:27 1-279. 1989
36. Langlais PJ, Henderson SW. Zhang SX: Increased extracellular
glutamate in thalamus and hippocampus of acutely thiamine deficient
rats. soc Neurosci 18: 1599. 1992
37. Grant KA. Valverius P, Hudspith M. Tabakoff B: Ethanol
withdrawal seizures and the NMDA receptor complex. Eur J Pharmacol
I76:289-296. 1990
38. Gulya K, Grant KA. Valverius P. et al: Brain regional specificity
and time-course of changes in the NMDA receptor-ionophore complex
during ethanol withdrawal. Brain Res 547:129-134, 1991
39. Reuler JB. Girard DE. Cooney TG: Wernicke's encephalopathy.
N Engl J Med 312:1035-1039. 1985
40. Harper CG, Giles M, Finlay-Jones R: Clinical signs in the
Wernicke-Korsakoff complex: a retrospective analysis of 131 cases diag-
nosed at necropsy. J Neurol Neurosurg Psychiatr 49:341-345. 1986
41. Wallis WE. Willoughby E. Baker P: Coma in the Wernicke-
Korsakoff syndrome. Lancet 2:400-401, 1978
42. Ghez C: Vestibular paresis: A clinical feature of Wernicke's
disease, J Neurol Neurosurg Psychiatr 32: 134-1 39. 1969
43. Lindboe CF. Loberg EM: Wernicke's encephalopathy in non-
alcoholics: An autopsy study. J Neurol Sci 90: 125-129, 1989
 10
44. McDowell JR, LeBlanc HJ: Computed tomographic findings in
Wernicke-Korsakoff syndrome. Arch Neurol 4 1:453-454, 1984
45. Mensing JWA, Hoogland PH, SloofJL Computed tomography
in the diagnosis of Wernicke’s encephalopathy: A radiological-neuro-
pathological correlation. Ann Neurol I6:363-365, I984
46. Gallucci M, Bozzao A, Splendiani A, et al: Wernicke encepha-
lopathy: MR findings in five patients. Am J Neuroradiol I1:887-892,
1990
47. Yokote K, Miyagi K, Kuzuhara S, et al: Wernicke encephalop-
athy: Follow-up study by CT and MR. J Comput Assist Tomogr 15:835-
838, 1991
48. Charness ME, DeLaPaz R L Mamillary body atrophy in Wer-
nicke’s encephalopathy: Antemortem identification using magnetic res-
onance imaging. Ann Neurol22:595-600, 1987
49. Charness ME, DeLaPaz R L Periodic alternating nystagmus in
an alcoholic with small mamillary bodies. Neurology 38(Supp1):42I ,
I988
50. Squire LR, Amaral DG,Press GA: Magnetic resonance imaging
of the hippocampal formation and mammillary nuclei distinguish medial
temporal lobe and diencephalic amnesia. J Neurosci 10:3 106-3 I 17, I990
5 1. Jernigan TL, Schafer K, Butters N, Cermak LS: Magnetic reso-
nance imaging of alcoholic Korsakoff patients. Neuropsychopharmacol-
ogy 4: 175-186. 1991
52. Jernigan TL, Butters N, DiTraglia G. et al: Reduced cerebral
grey matter observed in alcoholics using magnetic resonance imaging.
Alcohol Clin Exp Res I5:4 18-427, I99 1
53. Lishman WA: Cerebral disorder in alcoholism. Syndromes of
impairment. Brain 104: 1-20. I98 I
54. Witt ED, Goldman-Rakic PS: Intermittent thiamine deficiency
in the rhesus monkey. I. Progression of neurological signs and neuroan-
atomical lesions. Ann Neurol I3:376-395, 1983
55. Bowden SC: Separating cognitive impairment in neurologically
asymptomatic alcoholism from Wernicke-Korsakoff syndrome: Is the
neuropsychological distinction justified? Psycho1 Bull 107:355-366, I990
56. Ekhardt MJ, Martin PR: Clinical assessment of cognition in
alcoholism. Alcohol Clin Exp Res 10: 123- 127. I986
57. Harper CG: Wernicke’s encephalopathy: A more common dis-
ease than realised. J Neurol Neurosurg Psychiatr 42:226-231, 1979
58. Shimamura AP, Jernigan TL, Squire LR: Korsakoffs syndrome:
Radiological (CT) findings and neuropsychological correlates. J Neurosci
814400-4410, 1988
59. Pittella JE, de Castro LP: Wernicke’s encephalopathy manifested
as Korsakoff’s syndrome in a patient with promyelocytic leukemia. South
Med J 83:570-573, 1990
60. Lishman WA: Alcoholic dementia: A hypothesis. Lancet
I : I 184-1 186, 1986
61. Davtyan DG,Vinters HV: Wernicke’s encephalopathy in AIDS
patient treated with zidovudine. Lancet 1:919-920, 1987
62. Acker W, Aps EJ, Majumdar SK, Shaw GK: The relationship
between brain and liver damage in chronic alcoholic patients. J Neurol
Neurosurg Psychiatr 45:984-987, 1982
63. Bjorneboe G-EA, Johnsen J, Bjorneboe A, et al: Some aspects
of antioxidant status in blood from alcoholics. Alcoholism Clin Exp Res
12:806-810, 1988
64. Freund G: Chronic central nervous system toxicity of alcohol.
Ann Rev Pharmacol I3:2 17-227, 1973
65. de Wardener HE, Lennox B: Cerebral beriberi (Wernicke’s en-
cephalopathy). Lancet 1 :1 1- 17, 1947
66. Cruickshank EK: Wernicke’s encephalopathy. Q J Med 19:327-
338. 1950
67. Parkin AJ, Blunden J. Rees JE, Hunkin NM: Wernicke-Korsak-
off syndrome of nonalcoholic origin. Brain Cogn 15:69-82, 1991
68. Becker JT, Furman JM, Panisset M, Smith C: Characteristics of
the memory loss of a patient with Wernicke-Korsakoffs syndrome
without alcoholism. Neuropsychologia 28: 17 1-179, 1990
69. Engel PA, Grunnet M, Jacobs B: Wernicke-Korsakoffs syn-
CHARNESS
drome complicating T-cell lymphoma: Unusual or unrecognized? South
Med J 84:253-256, 1991
70. Beatty WW, Bailly RC, Fisher L: Korsakoff-like amnesic syn-
drome in a patient with anorexia and vomiting. Int J Clin Neuropsychol
11:55-65, 1988
71. Victor M, Adams RD, Mancall EL: A restricted form of cere-
bellar cortical degeneration occumng in alcoholic patients. Arch Neurol
76:579-688, I956
72. Mancall EL, McEntee WJ: Alterations of the cerebellar cortex
in nutritional encephalopathy. Neurology I5:303-3 13, 1965
73. Kleinschmidt-DeMasters BK, Norenberg MD: Cerebellar degen-
eration in the rat following rapid correction of hyponatremia. Ann Neurol
101561-565, 1981
74. Estrin WJ: Alcoholic cerebellar degeneration is not a dose-
dependent phenomenon. Alcohol Clin Exp Res 11:372-375, 1987
75. Tavares MA, Paula-Barbosa MM, Cadete-Leite A: Chronic al-
cohol consumption reduces the cortical layer volumes and the number
of neurons of the rat cerebellar cortex. Alcohol Clin Exp Res 11:315-
319, 1987
76. Hillbom M, Muuronen A, Holm L, Hindmarsh T: The clinical
versus radiological diagnosis of alcoholic cerebellar degeneration. J Neu-
rol Sci 73:45-53, 1986
77. Victor M, Adams RD, Cole M: The acquired (non-Wilsonian)
type of hepatocerebral degeneration. Medicine 44:345-395, I965
78. Brion S: Marchiafava-Bignami syndrome, in Vinken PJ, Bruyn
GW (eds): Metabolic and Deficiency Diseases of the Nervous System,
Part I . Amsterdam, North-Holland Publishing Company, 1976, pp 3 17-
329
79. Leong ASY: Marchiafava-Bignami disease in a non-alcoholic
Indian male. Pathology I1:241-249, 1979
80. Kosaka K, Aoki M, Kawasaki N, et al: A non-alcoholic Japanese
patient with Wernicke’s encephalopathy and Marchiafava-Bignami dis-
ease. Clin Neuropathol 3:23 1-236, 1984
81. Delangre T, Hannequin D, Clavier E, et al: Maladie de Mar-
chiafava-Bignami d’evolution favorable. Rev Neurol (Paris) 142:933-
936, 1986
82. Kawamura M, Shiota J, Yagishita T. Hirayama K: Marchiafava-
Bignami disease: Computed tomographic scan and magnetic resonance
imaging. Ann Neurol 18:103-104, 1985
83. Adams RD, Victor M, Mancall EL: Central pontine myelino-
lysis. A hitherto undescribed disease occurring in alcoholic and mal-
nourished patients. Arch Neurol 8 l : 154- 172, I959
84. Wright DG, Laureno R, Victor M: Pontine and extrapontine
myelinolysis. Brain 102:361-385, 1979
85. Norenberg MD, Papendick RE: Chronicity of hyponatremia as
a factor in experimental myelinolysis. Ann Neurol 15:544-547, 1984
86. Illowsky BP, Laureno R: Encephalopathy and myelinolysis after
rapid correction of hyponatremia. Brain I 10:855-867, 1987
87. Kleinschmidt-DeMasters BK. Norenberg MD: Rapid correction
of hyponatremia causes demyelination: Relation to central pontine mye-
linolysis. Science 21 1:1068-1070, 1981
88. Laureno R: Central pontine myelinolysis following rapid correc-
tion of hyponatremia. Ann Neurol I3:232-242, 1983
89. Messert B, Omson WW, Hawkins MJ, Quaglieri CE: Central
pontine myelinolysis. Considerations on etiology, diagnosis, and treat-
ment. Neurology 29: 147- 160, I979
90. Miller GM, Baker HL, Okazaki H, Whisnant JP: Central pontine
myelinolysis and its imitators: MR findings. Radiology I68:795-802.
1988
9 1. Charness ME, Diamond I: Alcohol and the nervous system, in
Appel SH (ed): Current Neurology. New York, Wiley. 1984, pp 383-421
92. Rosett HL, Weiner L: Alcohol and the Fetus. New York, Oxford
University Press, 1984
93. Abel EL, Sokol RJ: A revised conservative estimate of the
incidence of FAS and its economic impact. Alcohol Clin Exp Res 15:
5 14-524, I99 I
BRAIN LESIONS IN ALCOHOLICS
94. Spohr HL, Steinhausen HC: Follow-up studies of children with
fetal alcohol syndrome. Neuropediatrics 18: 13- 17, 1987
95. Streissguth AP, Martin DC,Barr HM, et al: Intrauterine alcohol
and nicotine exposure: attention and reaction time in 4-year old children.
Dev Psycho1 26533-541, 1984
96. Streissguth AP, Barr HM, Sampson PD, et al: Attention, distrac-
tion and reaction time at age 7 years and prenatal alcohol exposure.
Neurobehav Toxicol Teratol 8:7 17-725, 1986
97. Streissguth AP, Barr HM, Sampson PD, et al: IQ at age 4 in
relation to maternal alcohol use and smoking during pregnancy. Dev
Psycho1 25:3-1 I , 1989
98. Jones KL, Smith DW: Recognition ofthe fetal alcohol syndrome
in early infancy. Lancet 2:999-1001, 1973
99. Clarren SK, Alvord EJ, Sumi SM, et al: Brain malformations
related to prenatal exposure to ethanol. J Pediatr 92:64-67, 1978
100. Siebert JR, Astley SJ, Clarren SK: Holoprosencephaly in a fetal
macaque (Macaca nemestrina) following weekly exposure to ethanol.
Teratology 44:29-36, I99 I
101. Miller MW: Effects of alcohol on the generation and migration
of cerebral cortical neurons. Science 233: 1308- 131 I , 1986
102. Diaz J, Samson HH: Impaired brain growth in neonatal rats
exposed to ethanol. Science 208:751-753, 1980
103. West JR, Hodges CA, Black AJ: Prenatal exposure to ethanol
alters the organization of hippocampal mossy fibers in rats. Science
21 1~957-959, 1981
104. West JR, Hodges SC: Permanent hippocampal mossy fiber
hyperdevelopment following prenatal ethanol exposure. Neurobehav
Toxicol Teratol 5: 139- 150, 1983
105. Miller MW: Effect of prenatal exposure to alcohol on the distri-
bution and time of origin of corticospinal neurons in the rat. J Comp
Neurol257:372-382, 1987
106. Miller M W Effect of ethanol on cell proliferation and neuronal
migration, in Miller MW (ed): Development of the Central Nervous
System: Effects of Ethanol and Opiates. New York, Wiley-Liss, Inc.,
1992, pp 47-69
107. Kotkoskie LA, Norton S: Prenatal brain malformations follow-
ingacute ethanol exposure in the rat. Alcohol Clin Exp Res 12:831-836,
1988
108. Pentney RJ, Miller MW: The effects of ethanol on neuronal
morphogenesis, in Miller MW (ed): Development of the Central Nervous
System: Effects of Ethanol and Opiates. New York, Wiley-Liss, Inc.,
1992, pp 71-107
109. Druse MJ: Effects of in utero ethanol exposure on the develop-
ment of neurotransmitter systems, in Miller MW (ed): Development of
the Central Nervous System: Effects of Ethanol and Opiates. New York,
Wiley-Liss, Inc., 1992, pp 139-167
110. Davies DL, Smith DE: A Golgi study of mouse hippocampal
CA 1 pyramidal neurons following perinatal ethanol exposure. Neurosci
Lett 26:49-54, 198 1
I 1 I . Smith DE, Davies D L Effect of perinatal administration of
ethanol on the CI pyramidal cell of the hippocampus and the Purkinje
cells of the cerebellum: An ultrastructural survey. J Neurocytol 19:708-
717, 1990
112. Mattson SN, Riley EP, Jernigan TL, Jones EK: Magnetic reso-
nance imaging of children with fetal alcohol syndrome. Alcohol Clin
Exp Res 16:369, 1992
113. Gabrielli 0, Salvolini U, Coppa GV, et al: Magnetic resonance
imaging in the malformative syndromes with mental retardation. Pediatr
Radio1 2 I :16- 19, I990
114. Carlen PL, Wortzman G, Holgate RC, et al: Reversible cerebral
II
atrophy in recently abstinent chronic alcoholics measured by computed
tomography scans. Science 200: 1076-1078, 1978
1 15. Schorth G, Naegele T, Klose U, et al: Reversible brain shrinkage
in abstinent alcoholics, measured by MRI. Neuroradiology 30:385-389,
1988
116. Zipursky RB, Lim KO, Pfefferbaum A: MRI study of brain
changes with short-term abstinence from alcohol. Alcohol Clin Exp Res
131664-666, 1989
I 17. Harper C, Kril JJ, Daly JM: Brain shrinkage in alcoholics is not
caused by changes in hydration: A pathological study. J Neurol Neuro-
surg Psychiatr 51:124-127, 1988
118. Harper CG, Kril JJ, Daly J: Does a “moderate” alcohol intake
damage the brain? J Neurol Neurosurg Psychiatr 5 1:909-913, 1988
119. Harper CG, Kril JJ: Brain atrophy in chronic alcoholic patients:
A quantitative pathological study. J Neurol Neurosurg Psychiatr 48:211-
217, 1985
120. Harper CG, Kril JJ, Holloway R L Brain shrinkage in chronic
alcoholics: A pathological study. Br Med J 290501-504, 1985
I2 1. de la Monte SM: Disproportionate atrophy of cerebral white
matter in chronic alcoholics. Arch Neurol 45:990-992, 1988
122. Arendt T, Bigl V, Arendt A, Tennstedt A: Loss of neurons in
the nucleus basalis of Meynert in Alzheimer’s disease, paralysis agitans
and Korsakoffs disease. Acta Neuropathol (Berl.) 61:IOl-108, 1983
123. Antuono P, Sorbi S , Bracco L, et al: A discrete sampling tech-
nique in senile dementia of the Alzheimer type and alcoholic dementia:
Study of the cholinergic system, in Amaducci L, Davison AN, Antuono
P (eds): Aging of the Brain and Dementia. New York, Raven Press, 1980,
pp 151-158
124. Nordberg A, Adolfsson R, Aquilonius SM, et al: Brain enzymes
and Ach receptors in senile dementia of Alzheimer type and chronic
alcohol abuse, in Amaducci L, Davison AN, Antuono P (eds): Aging of
the Brain and Dementia. New York, Raven Press. 1980, pp 169-17 1
125. Smith CJ, Perry EK, Perry RH, et al: Muscarinic cholinergic
receptor subtypes in hippocampus in human cognitive disorders. J Neu-
rochem 502347-856, 1988
126. Arendt T, Allen Y, Sinden J, et al: Cholinergic-rich brain trans-
plants reverse alcohol-induced memory deficits. Nature 332:448-450,
1988
127. Charness ME, Simon RP, Greenberg DA: Ethanol and the
nervous system. N Engl J Med 32 I :442-454, 1989
128. Harper CG, Kril J, Daly J: Are we drinking our neurons away.
Br Med J 294534-536, 1987
129. Kril JJ, Harper CG: Neuronal counts from four cortical regions
of alcoholic brains. Acta Neuropathol 79:200-204, I989
130. Harper C, Corbett D: Changes in the basal dendrites of cortical
pyramidal cells from alcoholic patients-A quantitative Golgi study. J
Neurol Neurosurg Psychiatr 53356-86 1, 1990
13I . Ferrer 1. Fabregues I, Pineda M, et al: A Golgi study of cerebellar
atrophy in human chronic alcoholism. Neuropathol Appl Neurobiol
101245-253, 1984
132. Ferrer I, Fabregues I, Rairiz J, Galofre E: Decreased numbers of
dendritic spines on cortical pyramidal neurons in human chronic alco-
holism. Neurosci Lett 69: 1 15-1 19, 1986
133. Walker DW, Barnes DE, Zornetzer SF, et al: Neuronal loss in
hippocampus induced by prolonged ethanol consumption in rats. Science
209:711-713, 1980
134. Durand D, Saint Cyr JA, Gurevich N, Carlen PL: Ethanol-
induced dendritic alterations in hippocampal granule cells. Brain Res
4771373-377, 1989
135. Pfefferbaum A, Lim KO, Rosenblum MA: Structural imaging
of the brain in chronic alcoholism, in Zakhari S , Witt E (eds): Imaging
in Alcohol Research. Rockville, MD, Department of Health and Human
Services, 1992, pp 99-120