Review
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► Additional supplemental
material is published online
only. To view, please visit
the journal online (http://​dx.​
doi.​org/​10.​1136/​pn-​2023-​
003817).
1
University of Glasgow,
Glasgow, UK
2
Queen Elizabeth University
Hospital, Glasgow, UK
3
Gartnavel Royal Hospital,
Glasgow, UK
Correspondence to
Professor John-­Paul Leach,
Queen Elizabeth University
Hospital, Glasgow, G51 4TF, UK;
j​ pleach246@​me.c​ om
Accepted 14 May 2023
© Author(s) (or their
employer(s)) 2023. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Wolfe M, Menon A,
Oto M, et al. Pract Neurol Epub
ahead of print: [please include
Day Month Year]. doi:10.1136/
pn-2023-003817
Alcohol and the central nervous system
Maytal Wolfe,1,2 Arun Menon,1,3 Maria Oto,2 Natasha E Fullerton,1,2
John-­Paul Leach ‍ ‍ 2
ABSTRACT
Ethanol use is common to most cultures but
with varying doses and to varying extents.
While research has focused on the effects
on the liver, alcohol exerts a range of actions
on the function and structure of the nervous
system. In the central nervous system (CNS) it
can provoke or exacerbate neurological and
psychiatric disease; its effects on the peripheral
nervous system are not included in this review.
Sustained alcohol intake can predispose to
acute neurochemical changes which, with
continued ingestion and incomplete treatment,
can lead to chronic structural changes in the
CNS: these include generalised cortical and
cerebellar atrophy, amnesic syndromes such as
Korsakoff’s syndrome, and specific white matter
disorders such as central pontine myelinolysis
and Marchiafava–Bignami syndrome. Alcohol in
pregnancy commonly and significantly affects
fetal health, though this receives less medical
and political attention than other causes of fetal
harm. This review looks at the range of disorders
that can follow acute or chronic alcohol use, and
how these should be managed, and we provide
a practical overview on how neurologists might
diagnose and manage alcohol addiction.
INTRODUCTION
Ethanol consumption is normalised in
most cultures around the world.1 It is one
of the substances of abuse that is toler-
ated, and in fact capitalised on by local
and regional governments, forming a
significant part of the economy of many
western democracies. The UK Institute
of Alcohol Studies reported in 2020 that
alcohol comprised around 2.5% of the
UK’s gross domestic product, totalling
around £46 billion, of which £11 billion
accrued directly from alcohol taxation.2
Unlike other drugs of abuse, the socio-
logical constructs and habits around
alcohol make its frequent use easy and
acceptable, and abstinence from alcohol
difficult to maintain. So, while the social
effects of alcohol at moderate doses may
be regarded as acceptable, increased
intake contributes to significant medical
Wolfe M, et al. Pract Neurol 2023;0:1–15. doi:10.1136/pn-2023-003817
and sociological harms. A recent survey
of UK drug users found that 32 out of 93
respondents had experienced more harm
from alcohol compared with many other
substances due to its ready availability,
potential for addiction, its risk of death
from acute and chronic effects, social
harms and the dangers of withdrawal.3
Excessive consumption often begins in
youth, but alcohol overuse is not the
preserve of the young, with UK surveys
showing that 38% of men and 19% of
women drink more than the recom-
mended limits of alcohol.4
Predictions of future consumption are
not encouraging. The decade up to 2019
saw a 19% rise in alcohol-­ related UK
hospital admissions to over 350 000 per
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year. People from the most deprived areas
(and especially men) were most likely
to be admitted to hospital with alcohol-­
related problems.5 In the same time
frame, the rate of alcohol-­related deaths
had increased by 7%, with indications of
increasing incidence in most but not all
countries.6–8
Most research and campaigning has
focused on hepatic damage, but the central
nervous system (CNS) is particularly
susceptible to the chemical chaos wrought
by excessive consumption both acutely
and chronically. The pattern of neurolog-
ical change is complicated by the multiple
medical, nutritional and sociological asso-
ciations of alcohol excess, many of which
can result from, or predispose to alcohol-­
related harm. While the medical harm
reflects the rate and extent of alcohol
intake, social factors increase this risk, as
do a range of as-­yet unidentified genetic
factors. Comorbidities influence the CNS
response, including general medical status
and nutritional state, prior liver disease,
head injury, underlying fetal alcohol spec-
trum disorder and underlying (and possibly
secondary) psychiatric diagnoses such as
depression, anxiety, schizophrenia and/or
concomitant antipsychotic and antianx-
iety medications.9 Additional complexity
comes from patients’ experiences of
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‘self-­managing’ their own mental health, particularly
since this may be difficult to detect. Left unchecked it
ultimately serves only to hamper treatment and moni-
toring of associated common psychiatric conditions or
neurological disorders, such as epilepsy and dementia.
Problematic alcohol use in a social/holistic context
Alcohol intake is more than a medical problem, and it is
very important to see the broader difficulties in context.
Richard Billingham’s book ‘Ray’s a Laugh’ provides
valuable insight into the extent and wide-­ranging phys-
ical, mental and social consequences of alcohol depen-
dence.10 The aim of addictions services is not solely
abstinence (although this may suit the majority): care
needs to be taken, since repeated alcohol withdrawal
has neurotoxic potential and has observable effects on
cognition.11 A pragmatic harm-­ reduction approach
may be required, and clinicians need to be mindful of
the complexity of patients with addictions and provide
person-­centred and trauma-­informed care.
In this article, we outline the nature and extent of
alcohol’s CNS effects and provide guidance on the
diagnosis and monitoring of alcohol-­ related neuro-
logical problems. However, we will not address the
significant peripheral neurological sequelae caused by
alcohol, such as neuropathy and myopathy.
EFFECTS OF ALCOHOL ON NEUROTRANSMISSION
Clinical manifestations of acute alcohol ingestion
were long held to relate to GABA receptor agonism
and glutamate receptor antagonism (particularly
the NMDA subtype). Variations in susceptibility of
GABA-­ A receptor subunits may explain why some
brain regions with high prevalence of delta subunits
are more affected at lower alcohol concentrations than
others.12 13 Acute adaptation in the CNS results in invo-
lution of GABA receptors in response to continued
effects of alcohol. The simultaneous upregulation of
NMDA receptor activity and reduced GABA receptor
function becomes problematic with abrupt cessation of
alcohol, when the resultant imbalance in neurotrans-
mitters leads to neurotoxicity and the rapid onset
of psychiatric difficulties and/or seizures described
below. Genetic variations in receptor pharmacology
may contribute to individual variations in response to
alcohol ingestion and withdrawal. Recognised factors
affecting acute response to alcohol include tolerance
mediated by chronic effects on GABA and NMDA
receptor expression and rate of ingestion. Positron
emission tomography has helped to understand other
broader neurochemical effects on neurotransmitter
function, which encompass opioid, dopaminergic and
serotonergic systems that may underly some of the
other features around addictive behaviour.12
DIAGNOSIS AND QUANTIFICATION OF ALCOHOL
EXCESS
A focused alcohol intake history is an essential part
of the neurological consultation. The WHO’s 11th
2 Wolfe M, et al. Pract Neurol 2023;0:1–15. doi:10.1136/pn-2023-003817
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revision of the international classification of diseases
(ICD 11) came into effect in January 2022 and is grad-
ually being incorporated into clinical practice.14 These
include updated definitions of alcohol use disorders.
Hazardous alcohol use substantially increases the risk
of harm to an individual’s physical or mental health or
risk of behaviour that harms others. A ‘harmful pattern
of use of alcohol’ is defined as repetitive use of alcohol
that has caused such harms, and which persists despite
this. Alcohol dependence is defined by the presence of
any two of three diagnostic criteria:
1. Impaired control over alcohol use.
2. Priority of alcohol use over other activities.
3. Physiological features of dependence (eg, tolerance,
withdrawal, and repeated alcohol use to alleviate with-
drawal symptoms).
Clinicians in the UK should also be familiar with the
Driver and Vehicle Licensing Agency (DVLA)’s definitions
of alcohol misuse and alcohol dependence that apply to
driving eligibility. These are not especially useful in clin-
ical practice but knowledge of them helps in advising
patients and other health professionals about the condi-
tions required for return of driving privileges.15
In terms of quantifying healthy limits of alcohol
use, although there is no absolute safe limit, the UK
government currently recommends a maximum of 14
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units per week, spread over 3 or more days, along with
several drink-­free days per week.16 In the UK, one unit
is defined as 10 mL or 8 g of pure ethanol. This can be
calculated by multiplying the total volume of a drink
in millilitre by the percentage alcohol by volume (the
percentage of volume of the drink that is pure ethanol).
England’s National Institute of Health and Care
Excellence (NICE) guidelines outline a strategy for
initial screening for alcohol use disorders.17 Assess-
ment should include formal tools, such as AUDIT (a
10-­question self-­report questionnaire with questions
on hazardous use of alcohol, dependence symptoms
and harmful use of alcohol).18 Due to its complexity,
despite its presence in the NICE guidelines, AUDIT is
not as easy for clinicians to remember and administer;
for this reason, the CAGE questionnaire has persisted
in clinical settings19 (see table 1). However, CAGE is
not sensitive to heavy drinking and does not distin-
guish between previous and current drinking.
Table 1  The CAGE questionnaire
C Have you ever felt you should Cut down on your drinking?
A Have people Annoyed you by criticising your drinking?
G Have you ever felt bad or Guilty about your drinking?
E Have you ever had a drink first thing in the morning to steady
your nerves or to get rid of a hangover (Eye opener)?
* A total of two or more ‘Yes’ answers is considered clinically
significant for diagnosis of problem drinking (Bradley 1992)

As a result, attempts have been made to validate
an abbreviated version of AUDIT (named AUDIT-­C),
which includes only three items (typical frequency and
quantity of drinking and frequency of drinking six or
more drinks on one occasion) and has been shown to
be effective in screening for alcohol dependence or
heavy drinking warranting further assessment.20
LABORATORY TESTS OF EFFECTS OF ALCOHOL
INTAKE
Acute
Blood alcohol concentration
The use of one-­off measurement of serum alcohol fell
out of favour when results were used inappropriately
in legal arenas. Measurement can however be essential
(in assessing whether lowered conscious level may be
secondary to intoxication) and may help in non-­acute
situations, particularly where it is suspected that there
is ongoing use of alcohol. This should not be done
covertly.
Chronic
Liver function tests
As well as measuring serum alcohol, liver function tests
can help in assessing the long-­term effects of alcohol,
although these may be normal in the later stages of
liver disease. Serum gamma glutamyl transferase
(GGT) is the most sensitive of these routine tests, but
Figure 1  Unenhanced CT brain in a middle-­aged man with
alcoholic liver disease presenting to the emergency department
after a fall when intoxicated. The scan shows alcohol-­related
trauma. There are bilateral convexity subdural collections
(arrows) of various density in keeping with acute on chronic
subdural collections. There is further an extradural collection
overlying the right parietal lobe (asterix) with acute blood of
various densities, suggesting ongoing bleed, likely secondary to
coagulopathy. A small subcutaneous haematoma can be seen
from a recent fall overlying the right frontal bone (arrowhead).
Wolfe M, et al. Pract Neurol 2023;0:1–15. doi:10.1136/pn-2023-003817
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it is increased in around 10% of patients who also take
enzyme-­ inducing antiseizure medications. The full
blood count may include a raised mean corpuscular
volume (even with normal folate and vitamin B12),
and a reduced serum urea may also indicate impaired
hepatic function.
Carbohydrate-deficient transferrin
Transferrin is a transport protein for iron, and high
alcohol intake will increase the proportion of the
protein that has reduced sialic acid. This appears to
rise when alcohol intake exceeds four units per day.
Some studies have suggested that this carbohydrate-­
deficient transferrin (CDT) is a more sensitive and
specific marker of alcohol excess than GGT.21 CDT
is not routinely used in clinical practice but may be
required by some organisations (eg, DVLA) to provide
optimal evidence of abstinence in someone with a prior
diagnosis of alcohol misuse or alcohol dependence.
General health and nutritional assessment
Serum magnesium and phosphate can help in assessing
both the degree of metabolic upset caused by alcohol
and the need for replacement of these elements. Clini-
cians should consider the risk of refeeding syndrome
when admitting alcohol-­dependent patients to hospital.
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CLINICAL EFFECTS ON THE CNS—ACUTE
Intoxication
The acute CNS effects of alcohol are familiar across the
globe and include emotional instability impaired judge-
ment, inappropriate behaviour and cerebellar signs
(slurred speech, incoordination, ataxia, nystagmus).13
With higher doses, there may be memory impairment
and stupor at very high doses. Respiratory depres-
sion is a risk at serum alcohol concentrations above
300 mg/dL; death from alcohol intoxication can result
at concentrations above 500 mg/dL. Acute effects are
dose related, but the individual response is heavily
affected by individual tolerance and prior exposure.
In a patient presenting with a reduced level of
consciousness and smelling of alcohol, it may be
hazardous to assume that alcohol is the cause. It
is important to consider a differential diagnosis,
including subdural haematoma (with the possibility of
a higher risk of trauma combined with risk of possible
dysfunctional coagulation and cerebral atrophy),
metabolic abnormality (especially hypoglycaemia) and
a structural brain lesion.22 Evidence of trauma or focal
neurological signs should prompt imaging to exclude
another cause (figure 1).
Blackouts
The term ‘blackouts’ refers to episodic amnesia expe-
rienced after acute intoxication and usually indicates
that serum alcohol concentrations have been signifi-
cantly high. Although historically, blackouts have indi-
cated ‘alcoholism’, it is now clear that they happen in
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people with and without alcohol dependence. They
probably result from memory being disrupted before
motor control is lost with increasing intoxication.23
Interestingly, alcohol’s effects on memory may be
complex and there are reports of people who can
recall while drunk where they have secreted alcohol or
money, which they could not remember when sober.
CA1 pyramidal cells in the hippocampus are prob-
ably affected by alcohol in a dose-­dependent fashion,
leading to disruption of transfer of long-­term encoding
of short-­term memory. There are two documented
forms of blackout: en-­bloc blackouts in which there is
inability to remember events during a discrete period
of time, and fragmentary blackouts in which there
is incomplete disruption of recall. The most signifi-
cant risk factor for blackout is the rate of increase in
blood alcohol concentration. Adolescents and young
people may be particularly susceptible to blackouts,
not only due to their impulsive drinking patterns but
also due to the susceptibility of the developing hippo-
campus.24 Studies measuring blood alcohol concen-
trations compared with placebo show that younger
subjects perform poorly on tests of semantic and non-­
verbal memory when intoxicated compared with older
subjects. Women are also at increased risk of blackouts
and slower recovery from cognitive impairment.
Susceptibility to en-­bloc blackouts is also increased
with ingestion of other substances, including cannabis
and benzodiazepines.
Acute withdrawal state
An acute withdrawal state typically occurs within
6–48 hours of a sudden reduced intake in someone
with alcohol dependency.25 The neurological effects
result from the combination of chronically downregu-
lated GABA receptors and upregulated NMDA recep-
tors in the absence of alcohol. The relative deficiency
of GABAergic effects and excessive glutamatergic stim-
ulation lead to symptoms including confusion, rigidity,
tremor, anxiety and excessive sweating. The treatment
is with either fixed doses or as-­required dosing with
benzodiazepines when symptoms occur. NICE guide-
lines recommend giving symptom-­triggered benzodi-
azepines using a structured tool such as the revised
clinical institute withdrawal assessment alcohol scale
for withdrawal in hospital settings.17 Patients with
recent high alcohol intake and previous history of
severe withdrawal require a regular regimen.22
Delirium tremens
Where withdrawal is more severe, particularly on a
background of more severe dependence, the clinical
situation can progress to delirium tremens on the
third to fifth day after withdrawing. This state is char-
acterised by the acute onset of hallucinations, agita-
tion, autonomic hyperactivity, hand tremulousness
and nausea. Visual hallucinations are most common,
classically in the form of Lilliputian hallucinations of
4 Wolfe M, et al. Pract Neurol 2023;0:1–15. doi:10.1136/pn-2023-003817
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small creatures. Auditory and tactile hallucinations
can also occur. Generalised seizures can emerge.26
Perhaps 2%–5% of patients in hospital suffer from
delirium tremens, with a mortality rate of 1%–15%.27
Although symptoms commonly last between 1 and
7 days, they can persist for several weeks. Prolongation
is more common in those with a history of using illicit
substances (eg, benzodiazepines), comorbid dementia
or head injury. As with withdrawal, the mainstay of
treatment is benzodiazepines (often at very high
doses), but low doses of antipsychotics can be added to
help manage agitation associated with hallucinations.
Seizures
While some sources suggest that seizures can be
precipitated by high amounts of alcohol, this would be
an unusual result of excessive GABAergic stimulation
in adult humans. Sustained alcohol intake can reduce
the time spent in REM sleep, and the coingestion of
other compounds may play more of a part than the
alcohol itself. Low serum concentrations of phosphate
and magnesium may suggest a higher risk of electro-
lyte disturbance with refeeding, which in theory may
be proconvulsant, although this is probably rare in
alcohol detoxification.28 29 Subacute encephalopathy
with seizures in alcoholics (SESA) was first described
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in the 1980s, this syndrome includes patients with
prolonged confusion who have conditions along the
ictal-­
interictal spectrum, including non-­ convulsive
status.30 While SESA is not a necessary term, it acts
as a prompt for investigating with EEG or using EEG
monitoring in this situation.30
Seizures directly provoked by alcohol withdrawal
are usually self-­limiting and are an indication for
benzodiazepines, thiamine and glucose loading. Esca-
lation to use of antiseizure medications and, if neces-
sary, admission to an intensive care unit (ICU) may
still be required if immediate response is incomplete.
These ‘provoked seizures’ should not be regarded as
trivial. The 1-­year mortality after admission to ICU
with seizure is around 35% in patients with a history
of alcohol dependence or drug use.31 Continued
obtundation post-­ictally may justify EEG to exclude
non-­convulsive status epilepticus. Where seizures are
exclusively clearly related to alcohol withdrawal, each
one having attendant preceding withdrawal symptoms,
then the focus should ideally be on preventing future
occurrence of severe withdrawal to reduce risk of
long-­term neurotoxicity. Where there is an unclear or
at best tenuous relationship to withdrawal, antiseizure
medication will come into play for some. Where there
is such doubt, we feel it is safer to begin antiseizure
medication, a view justified by the risks of harm from
continued or prolonged seizures. There is no clear
evidence of benefit of any particular antiseizure medi-
cation in patients with provoked seizures, but given
the risk of incomplete adherence in patients prone to
excess alcohol intake, a reasonable strategy is slowly to

titrate a well-­tolerated, non-­enzyme-­inducing antisei-
zure medication, with a moderate (eg, lamotrigine) or
long (eg, zonisamide) half-­life. Levetiracetam should
be avoided where there is an underlying acute or
chronic mood disturbance. Monitoring serum concen-
trations of long-­term antiseizure medication may help
to ensure adherence; ready access to laboratory facil-
ities may influence the choice of antiseizure medica-
tion if this is an important part of planned clinical
management.
Hallucinosis—alcohol-induced psychotic disorder
Hallucinations in the context of alcohol use
were described as a separate entity from delirium
tremens by Marcel in 1847. Bleuler coined the
term alcoholic hallucinosis in 1916, the modern
term being alcohol-­i nduced psychotic disorder. 14 32
Lifetime prevalence of alcohol-­induced psychotic
disorder ranges from 0.4% in Germany to 12.4% in
Nepal. By the ICD11 definition of alcohol-­i nduced
psychotic disorder, prominent psychotic symp-
toms occur during or shortly after intoxication or
withdrawal from alcohol, and symptoms should be
more than those usually found in alcohol intoxica-
tion or withdrawal. The symptoms should improve
and usually resolve with a significant period of
abstinence from alcohol.33 The literature highlights
characteristic features, including typical auditory
hallucinations of an acute onset, hallucinations
of derogatory voices and persecutory delusions.
These usually occur in clear consciousness and in
the absence of the thought-­d isorder typically seen
in other forms of psychosis, but around 10% may
have features of delirium in the acute stage of the
disorder. Alcohol-­i nduced psychotic disorder tends
to occur later in life and has a better prognosis than
other psychoses. Among 61 inpatients, the mean
Figure 2  Patient with alcohol-­related brain damage (ARBD) after prolonged alcohol abuse presenting with cognitive issues.
An unenhanced helical CT scan (A) shows disproportionate frontal lobe atrophy (arrows), a frequent finding after heavy alcohol
consumption. Tc-­99m HMPAO perfusion SPECT imaging (B) shows frontal cortical reduction in brain perfusion (arrows), which can be
seen secondary to chronic alcohol abuse or acute intoxication.
Wolfe M, et al. Pract Neurol 2023;0:1–15. doi:10.1136/pn-2023-003817
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duration of psychotic symptoms was 4 days, and
most reported hallucinations only when decreasing
their alcohol intake or abstaining from alcohol.32
The authors point out that twothirds of patients
had previous episodes of alcohol-­r elated psychosis,
highlighting risk of recurrence. There is no clear
consensus on the nature of alcohol-­ i nduced
psychotic disorder; some highlight similarities
with delirium tremens, for example, a tendency
towards physical symptoms and slight clouding of
consciousness, and others favour a conceptualisa-
tion closer to a schizophrenia-­like illness indicated
by auditory hallucinations in clear consciousness
and chronic course of the condition. 34 Alcohol-­
induced psychotic disorder has no accepted stan-
dard treatment, but improvement usually requires
abstinence from alcohol and use of antipsychotic
drugs to treat psychotic symptoms. Some have
suggested that initial treatment with benzodiaze-
pines helps in only some cases. 35
CLINICAL EFFECTS ON THE CNS—CHRONIC
Alcohol-related brain damage
Alcohol-­r elated brain damage is the unofficial, but
widely-­u sed term encompassing a wide spectrum
of pathology and cognitive impairment related to
Protected by copyright.
alcohol, including Wernicke-­Korsakoff syndrome,
and conditions resulting from direct toxic effects of
alcohol and also effects of head injury and stroke
related to alcohol.36 37 The lack of accepted defini-
tion can sometimes create difficulties. DSM-­V clas-
sifies alcohol-­r elated cognitive disorders as mild
and severe alcohol-­r elated neurocognitive disorder,
amnestic and non-­ a mnestic38 (see online supple-
mental case 1). This diagnosis is supported by
other signs of long-­term systemic effects of alcohol,
for example, cirrhosis, ataxia or peripheral sensory
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Figure 3  Appearances of Wernicke encephalopathy on MR brain scans from an elderly (A–C) and a middle-­aged man (D–F)
presenting with prolonged alcohol abuse, confusion and cognitive impairment, ataxia and falls and nystagmus and oculomotor

Protected by copyright.
signs. MR scan of brain showing symmetrical, high signal on T2-­weighted and T2 FLAIR imaging, as well as on diffusion-­weighted
imaging affecting periaqueductal grey matter, medial thalamus, mamillary body and hypothalamus (arrows). Post-­contrast imaging
(C) shows corresponding enhancement (arrows). Brain atrophy for age is noted in the younger patient.

neuropathy, cardiac effects as well as evidence of
cerebellar atrophy on neuroimaging. According to
Oslin’s diagnostic criteria, the clinical diagnosis
should be made at least 60 days after the last expo-
sure to alcohol.39
Pathophysiology
In alcohol-­related brain damage, the frontal lobes
appear particularly vulnerable to glutamate excito-
toxicity, oxidative stress and disruption of neurogen-
esis.40 Cycles of bingeing and withdrawal probably
predispose to upregulation of NMDA receptors and
effects on cholinergic transmission in the basal fore-
brain. Almost 80% of alcohol-­ dependent people
have brain changes at postmortem, leading to frontal
lobe volume loss and atrophy. Functional imaging,
including 99mTc-­HMPAO SPECT assessing cerebral
perfusion and blood flow, can show decreased frontal
perfusion in alcohol abuse and alcohol-­related brain
damage (figure 2)
Clinical features
As suggested by the pathology, frontal cognitive
deficits are common. Compared with Alzheimer’s,
patients with alcohol-­
r elated brain damage have
better semantic and verbal memory and poorer
performance in visuospatial tasks. 36 The montreal
cognitive assessment is currently the most well-­
validated method of screening and distinguishing
alcohol-­
r elated brain damage from other causes
of cognitive impairment, although more detailed
neuropsychological assessment is required in making
the diagnosis and characterising difficulties.41
Treatment and prevention
Improvement or recovery in function can continue
following a substantial period of abstinence from
alcohol over a period of weeks to months.42 43
Repeated episodes of withdrawal probably contribute
to alcohol-­related brain damage, hence it is best to
avoid severe withdrawal syndrome and emergency
detoxes, and rather to plan detoxification.11 Planned
inpatient detoxification under addiction services is
very different to emergency detoxification in an acute
medical setting, which focuses on preventing acute
morbidity and mortality. Additional time, planning
and expertise is needed to promote long-­term absti-
nence with appropriate emphasis on general rehabili-
tation and long-­term care.
Wernicke/Korsakoff’s
Wernicke’s syndrome classically represents the acute
effects of CNS nutritional deficiency whereas Korsa-
koff ’s represents the chronic effects. However,

6 Wolfe M, et al. Pract Neurol 2023;0:1–15. doi:10.1136/pn-2023-003817


Figure 4  (A–C) MR scan of brain in a patient in their late 40s, admitted with alcohol-­related problems, showing cerebellar, in
particular superior vermian and mamillary body atrophy (arrows).
in clinical practice, a mixed picture is much more
common. Chronic alcohol use leads to poor nutrition
and vitamin B1 deficiency causing symmetrical lesions
in thalamus, hypothalamus, mammillary bodies and
periaqueductal grey matter. Thiamine is a cofactor for
several enzymes in the Krebs cycle and involvement in
transketolase and glucose metabolism leads to build-­up
of toxic metabolites. The neuropathology is varied but
is usually associated with some degree of brain volume
loss.44 Wernicke’s pathology includes symmetrical
lesions around the third ventricle, aqueduct and fourth
ventricle, with mamillary body involvement in up to
80% of cases. Some studies identify particular effects
on white matter volume, although this is not a uniform
finding. Prefrontal white matter, and the genu of the
corpus callosum appear to be particularly suscep-
tible in Wernicke-­Korsakoff syndrome, the degree of
white matter loss probably correlating with the degree
of alcohol consumption. Figure 3 shows the typical
imaging findings.
Wernicke’s syndrome
Wernicke’s syndrome refers to the classic triad of
oculomotor signs (classically ophthalmoplegia),
cerebellar signs and altered mental state (See
online supplemental case 2). However, the classic
Wernicke’s triad occurs in only 10% of cases. Carl
Wernicke first described this syndrome in 1881 in
a case series.45 Of note, one of his cases was not
alcohol related but was a young woman with nutri-
tional deficiency due to pyloric stenosis. This high-
lights the role of thiamine deficiency in the clinical
manifestations and that Wernicke’s is not unique to
alcohol misuse but is a risk associated with malab-
sorption from any cause, including hyperemesis
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gravidarum and malignancy. People with alcohol
dependence are at particular risk of Wernicke’s due
to poor nutrition, decreased capacity for hepatic
Protected by copyright.
nutrient storage and decreased vitamin absorption.
A diagnosis of Wernicke’s is based on Caine’s clas-
sification requiring two of four features of dietary
deficiency, eye signs (ranging from subtle nystagmus
to complete ophthalmoplegia), cerebellar dysfunc-
tion and altered mental state.46 Altered mental
state is the most common feature and severity
can vary from disorientation to coma. Nutritional
replacement is vital and should be immediate if the
diagnosis is suspected. There is no international
consensus on optimal dosing with thiamine, but
in the UK, there is a widely accepted standard of
replacement doses 500 mg intravenous thiamine
three times per day for 2 or 3 days followed by
250 mg intravenously three times per day for the
next 2 or 3 days, followed by oral thiamine.47–49
Continuing disorientation would justify continuing
treatment with parenteral thiamine. Anaphylaxis
due to thiamine preparations is very rare. 22 Since
signs of Wernicke’s can be non-­s pecific, it is a good
practice to treat prophylactically if alcohol depen-
dence is suspected or detoxification is planned,
using once daily parenteral thiamine for 5 days.
Korsakoff’s
Korsakoff syndrome describes the syndrome of
persistent residual cognitive impairment, often where
Wernicke’s has been incompletely treated. There
is ongoing debate as to whether these are part of a
continuum of features that can be grouped with other
types of alcohol-­ related brain damage or whether
Korsakoff ’s is a pure syndrome related exclusively
7
Review
Figure 5  (A,B) MR scan of brain (sagittal and coronal)
showing corpus callosal changes of Marchiafava-­Bignami
disease. Images courtesy of Radiopedia.
to thiamine deficiency. The most important contrib-
utory factor is delay in thiamine replacement. In its
clinical features, Korsakoff syndrome has been defined
by a disproportionate impairment of declarative
memory (especially episodic and semantic) in an alert
patient. In addition, most of the memory loss tends
to be anterograde, with disproportionate loss of more
recent memories, known as Ribot’s law.50 This is well-­
illustrated in the case of Jimmy in Oliver Sacks’ book,
‘The Man Who Mistook his Wife for a Hat’.51 Other
features consistent with Korsakoff ’s include apathy,
executive dysfunction, lack of insight and confabula-
tion. There is no widely accepted treatment available
for Korsakoff ’s syndrome.
Dementia due to use of alcohol
ICD-­11 has this as a specific category of effect.14
There is an interesting ‘J-­shaped’ relationship between
patterns of alcohol use and dementias. This is thought
to be due to protective effects of low levels of alcohol
consumption, resulting from associated reduction in
platelet aggregation, inflammatory markers and lipids.
Meta-­analysis suggests that this protects only against
Alzheimer’s dementia but not vascular dementia.40 A
cohort study of people admitted to hospital over 5
years in France found that alcohol use disorders were
strongly associated with all risk factors for dementia
onset, particularly with early-­onset dementia.52
Cerebral and cerebellar atrophy
Light-­to-­moderate drinking in an elderly cohort may
lower the risk of cerebral atrophy especially if the
alcohol is taken as wine rather than beer or spirits,
but this has been countered in studies of younger
cohorts.53 54 Both nutritional deficiency and trauma
can exacerbate the generalised atrophic effects of
alcohol (figure 4). Mamillary body atrophy correlates
with the cognitive issues described above. In addition
to cortical atrophy, there may be particular mecha-
nisms for the effects of alcohol on the cerebellum.55
They lead to neuropathological effects more promi-
nent in the cerebellar vermis, and clinical effects more
8 Wolfe M, et al. Pract Neurol 2023;0:1–15. doi:10.1136/pn-2023-003817
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prominent in assessment of gait and the lower limbs.
The clinical features of a cerebellar ataxia may be exac-
erbated by a coincident peripheral neuropathy.
Marchiafava–Bignami disease
This is a rare and poorly understood clinical constella-
tion first described in the early 20th century. The most
common features include personality change, enceph-
alopathy, and gaze disorders, occasionally alongside
seizures.56 A corpus callosal syndrome may become
apparent with visual and tactile anomia, hemi-­alexia,
unilateral left-­sided apraxia and absence of interhemi-
spheric transference of unilateral somatosensory stim-
ulation of both hands.57 Other features of the damage
wrought by alcohol can include longstanding cognitive
decline, gait problems and incontinence. Focal neuro-
logical deficits such as hemiparesis, aphasia and apraxia
are less helpful in differentiating from other causes of
corpus callosal lesions. Imaging findings are usually
centred on the corpus callosum, with changes ranging
from oedema to cystic lesions. MR brain imaging
(figure 5) shows progressive demyelination and ulti-
mately necrosis of corpus callosum, affecting the body
of corpus callosum, followed by genu and ultimately
splenium, leading to classical imaging appearances of
callosal degeneration with cystic cavities. Occasionally
Protected by copyright.
similar lesions may also develop in the corticospinal
tracts, cerebellar peduncles and the hemispheric white
matter. Treatment involves avoiding alcohol and nutri-
tional replacement with thiamine alongside B12 and
folate. Some have suggested that prognosis is better in
those with unimpaired level of consciousness.58
Osmotic demyelination
Patients with chronic excessive alcohol consump-
tion are more prone to significant hyponatraemia via
various mechanisms including hypovolaemia, drinking
excessive salt-­
poor solutes (eg, beer), cerebral salt
wasting syndrome and reset osmostat syndrome.59
Rapid correction of this can cause acute onset of demy-
elination in some white matter tracts, most evident in
the pons. A recent review of clinical and neurolog-
ical features listed signs including most commonly
encephalopathy and dysphonia (50%), less so with
extrapyramidal symptoms and seizures. Neuroimaging
results (figure 6) showed central pontine myelino-
lysis in 11/18, in seven accompanied by extrapontine
myelinolysis. Five patients (27.8%) had extrapontine
myelinolysis only. The prognosis appeared better in
those presenting with encephalopathy rather than
focal neurological signs.60 Osmotic demyelination may
occur largely asymptomatically and be detected inci-
dentally during later imaging.61
Fetal alcohol spectrum disorder
The frequency and severity of this condition merits
further consideration. Given the range of neurochem-
ical effects exerted by alcohol, it is not surprising that
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Figure 6  CT and MRI images show central pontine myelinolysis (CPM) as part of an osmotic demyelination syndrome (ODS) in a
middle-­aged patient with a history of alcohol excess and an admission with severe hyponatraemia rapidly corrected on admission.
The initial CT scan (A) shows centrally low density changes at the level of the pons (asterix). In addition, well seen on the sagittal CT
images, there is cerebellar atrophy (arrowhead) reflecting alcohol-­related cerebellar degeneration. Further, there is some mamillary
body atrophy (arrows), related to thiamine deficiency in alcoholic liver disease, and cognitive dysfunction. The axial T2 TSE MRI
sequence (B,C) shows high signal centrally in the pons (asterixes) involving transverse pontine fibres, with sparing of the peripheral
and corticospinal tracts, leading to a three-­pronged spear appearance, described as a ‘trident sign’ found in CPM.

prenatal exposure to alcohol affects the developing (table 2), comprising short palpebral fissures, smooth

brain. Fetal alcohol spectrum disorder describes a spec-
trum of physical and neurological abnormalities related
to prenatal alcohol exposure.62 This disorder probably
has a greater population impact than other syndromes of
prenatal harm; prenatal alcohol exposure globally affects
an estimated 7.7 per 1000 live births, with estimated UK
prevalence of fetal alcohol spectrum disorder of around
32.4 per 1000 live births. This is likely to be an under-
estimate, and there have been calls for coordinated and
standardised assessment and management of patients
affected by this condition.63 The pathophysiology of
prenatal damage is unclear, but MR imaging studies
have shown the effect of alcohol in the corpus callosal
anatomy.64 Whether this is a primary or secondary effect
is unknown.
Clinical features of fetal alcohol spectrum disorder
Around 10% of patients with fetal alcohol spectrum
disorder have characteristic or ‘sentinel’ facial features
Protected by copyright.
philtrum and thin upper lip.65
Standardised scales have been developed for
assessing physical signs. Studies suggest FASD
behavioural phenotypes score highly for hyperkinetic
behaviours as well as anxiety and emotional problems.
There is significant recognised overlap with attention-­
deficit hyperactivity disorder and autistic spectrum
disorders, and studies indicate that in those with good
language skills, difficulties with understanding and
social skills may remain well hidden. Given this vari-
ability and its high prevalence, it is highly likely that
FASD diagnosis may only become apparent in adult-
hood. Such patients may already be known to the
judicial system or mental health services. By the time
the diagnosis is made, the only measures required are
to treat the emergent symptoms. The recent guide-
lines describe a need for standardised and coordinated
multidisciplinary patient-­ centred assessment and
management.63

Table 2  Fetal alcohol spectrum disorder (FASD) diagnostic criteria

FASD with sentinel features
All three sentinel facial features (short palpebral
features, smooth philtrum, thin upper lip)
Prenatal exposure to alcohol confirmed or unknown
Severe impairment in three or more
neurodevelopmental areas
FASD without sentinel features
No sentinel facial features
Prenatal alcohol exposure confirmed
Severe impairment in three or more
neurodevelopmental areas
At risk
Prenatal alcohol exposure confirmed
Diagnostic criteria for FASD not met
Some indication of neurodevelopmental
disorder but does not meet criteria for
significant impairment

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Protected by copyright.
Figure 7  Woman with alcohol excess and known liver disease. MR scan of brain (A–D) shows features suggestive of hepatic
or hyperammonaemic encephalopathy (arrows). High T1-­weighted signal globus pallidus in keeping with mineral deposition
(arrowheads). Symmetrical high FLAIR signal involving basal ganglia, affecting caudate and to a lesser degree lentiform nuclei,
further thalamus, posterior limbs of the internal capsule, and also cingulate gyrus, insula and splenium, in addition to centrum
semiovale and corona radiata. Subtle peri-­aqueductal and mamillary body high T2-­weighted signal also noted in addition to some
mamillary body atrophy and marked frontal lobe atrophy (asterixes).

INDIRECT EFFECTS OF ALCOHOL ON THE CNS— there is persisting disorientation or encephalopathy,

ACUTE
Trauma
The impaired motor skills and disinhibition of acute
intoxication lead not only to more risky behaviours
but also the reduced ability to enact protective reflexes.
Alcohol excess in itself probably increases the chances
of direct traumatic brain and neurological injury,
and any sign of trauma or focal neurological deficit
should prompt further neurological monitoring and/
or investigation.
Exposure to other substances
Patients prone to alcohol excess commonly ingest
other substances. In 2020, the Office for National
Statistics noted that the proportion of adults reporting
drug use increased substantially with higher alcohol
use; nearly 15% of people drinking on more than
3 days per week reported use of any drug, over 10%
reported cannabis use and over 5% reported cocaine
use.66 As with alcohol use, this may not be volunteered
and may be deliberately concealed. Such substances
might contribute to the clinical presentation and might
reduce or attenuate the clinical recovery.67 Where
it may be justified to screen for other substances that
might be perpetuating any psychiatric or neurological
features, as this could help with prognostication and
perhaps with treatment.
INDIRECT EFFECTS OF ALCOHOL ON THE CNS—
CHRONIC
Hepatic encephalopathy
The liver’s role in dealing with products of protein
breakdown clears the body of many tertiary and
quaternary amines. Where this is impaired, this
leaves the normal CNS function compromised by
false neurotransmitters, manifests as hepatic enceph-
alopathy.68 An acute-­ on-­
chronic overuse of alcohol
can provoke this, but other sudden metabolic stress
(systemic infection, gastrointestinal bleed causing an
acute ‘protein load’ or localised peritoneal infection)
should not be overlooked. Clinicians should suspect
the diagnosis in someone with a prior history of hepatic
disease, developing a subacute delirium or reduced
conscious level. Blood testing will show deranged liver
function tests and raised serum ammonia. Imaging is

10 Wolfe M, et al. Pract Neurol 2023;0:1–15. doi:10.1136/pn-2023-003817


Figure 8  MR spectroscopy shows a Glx complex (blue circle) including glutamine and glutamate peaks between 2.2 and 2.5 ppm
in lesional voxels and ‘normal’ white matter—a finding in hepatic encephalopathy secondary to brain hyperammonaemia. MR
spectroscopy overall would be compatible with hepatic encephalopathy.
usually normal, and EEG shows generalised slowing.
Despite long-­ held belief about the specificity of
triphasic waves, the EEG findings are usually non-­
specific and not always easily differentiated from EEG
in encephalopathy of other causes. However, EEG can
help in excluding non-­ convulsive status epilepticus,
and it may help with long-­term prognosis of hepatic
failure.69 MR brain imaging findings are shown in
figure 7 along with an example of MR spectroscopic
changes (figure 8).
Box 1  Practical considerations when assessing a
patient with alcohol addiction expressing low mood
► Alcohol intoxication may lead to suicidality through
disinhibition, impulsiveness and an exacerbation of
depressive thoughts, most of which will resolve with
sobriety.
► Suicide risk is significantly increased in people with
alcohol dependence; it is important to enquire about
suicidal ideation and plans.
► Depression is the most common psychiatric mental
illness in people with alcohol use disorder.
► Depressive symptoms associated with heavy
consumption of alcohol often resolve with abstinence.
► Addressing the alcohol addiction is an essential
first intervention when commencing treatment for
depression.
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Chronic trauma
Chronic alcohol use is often noted to be associated
with cortical atrophy and it has been suggested that
alcohol potentiates and exacerbates the atrophic
effects of brain injury.70 The exact mechanism of this
is unknown, but studies have shown that in an older
population, the consumption of alcohol at higher levels
in both men and women is associated with subjective
and objective measures of atrophy particularly in the
frontal and temporal lobes.71 Poor nutrition is also
associated with temporal atrophy.
TREATMENT OF ALCOHOL-RELATED CNS DISEASE
The diagnosis of alcohol-­related CNS disease is often
a challenging part of the management process. Treat-
ment of specific complications has been referred
to above, but the long-­term need is for prevention
of further harm using a combination of education,
a good therapeutic relationship and holistic care.
Current NICE guidelines on alcohol use disorders
advocate an empathic and non-­judgemental approach
that preserves the patient’s dignity and involves
carers.17 Initial evaluation should include assessment
of alcohol-­related harms to physical, mental and social
well-­being and consideration of onward referral to
specialist addiction services. As previously discussed,
structured clinical tools should be used for screening
and for assessment of the nature and severity of
alcohol-­related problems.
11
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Box 2  Practical considerations when reviewing
a patient with a history of alcohol use disorder
presenting with agitation and psychotic-­ like
symptoms
► Although ‘common things are common’, do not
automatically assume that the presentation relates to
alcohol.
► A collateral history from a relevant other is crucial.
► Is there ongoing intoxication?
► Is it due to withdrawal?
► Have they ingested other substances? (this is
common).
► Have they sustained a head injury which is
contributing to the confusion?
► Consider previous history of mental illness including
psychosis.
► Consider capacity to consent to treatment.
The principles of management of alcohol-­related
CNS disease should address the direct and indirect
toxicity of alcohol.
1. Avoid—or at least minimise—further exposure to alco-
hol and its attendant lifestyle risks.
2. Replace nutrients: prophylactic thiamine should be of-
fered to those at risk of Wernicke’s due to malnutrition,
alcohol dependence or risk of withdrawal. For those with
Wernicke’s, parenteral thiamine should continue for at
least 5 days, although as described above, in some situa-
tions, patients require treatment for much longer.
3. Treat acute paroxysmal symptoms, such as seizures.
4. Manage and prevent withdrawal using benzodiazepines
(usually chlordiazepoxide or diazepam unless there is liv-
er impairment, in which case an alternative should be
Box 3  Prolonged confusion in someone with alcohol
dependence in the general hospital—practical
considerations
► Consider other common comorbid pathologies that
might prolong delirium, for example, cerebrovascular
disease, previous brain injury.
► It is very unusual to see a clear-­cut case of Korsakoff’s
or Wernicke’s: mixed presentations are much more
likely and tend to take longer to resolve.
► Find out about/establish premorbid cognitive baseline
(often the person’s cognitive function was already
impaired).
► Review the medication regimen; for example,
benzodiazepines withdrawn too quickly or medication
contributing to confusion (eg, opioids).
► Be aware that recovery with reasonable cognitive
function can still occur after weeks of confusion/
delirium.
► Consider the need for incapacity or mental health act
legislation.
12
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chosen, which does not rely as heavily on liver metabo-
lism, such as lorazepam).
5. Manage long-­term psychiatric comorbidities and neuro-
logical problems, such as epilepsy
6. Plan follow-­up with addiction services and promote self-­
management strategies to increase the chances of long-­
term abstinence or prevention of excessive consumption.
7. Attend to the social context and to the carer’s needs.
Collateral history from carers can be extremely valuable
and should be sought.
There are many practical considerations for clini-
cians managing patients presenting with disturbances
of cognition, mood and behaviour in the context of
problematic alcohol use (see boxes 1–3). It is essential
to have an holistic approach to history-­taking, exam-
ination and risk assessment.
However, the long-­term case management of people
with alcohol use disorders relies on understanding
the relationship between alcohol and the individual,
as people use alcohol for various purposes, including
managing mental distress and psychological trauma.
It is important to develop a therapeutic alliance to
encourage engagement with appropriate services,
particularly as those with alcohol use disorders are hesi-
tant to engage in supports due to stigma and discrim-
ination. Alcohol brief interventions are an important
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tool to encourage and promote behavioural changes
in alcohol consumption, with significant outcomes.72
Case 1 – Alcohol-­related brain damage and traumatic
brain injury
A 55-­ year-­old man was admitted to hospital after a
witnessed seizure and was later referred to liaison psychi-
atry due to 4 weeks of protracted delirium. He had a
history of alcohol dependence with previous inpatient
alcohol detoxification when abroad and a right subdural
haematoma 3 months before. He initially required low-­
dose antipsychotic medication for agitation.
After the delirium had resolved, he still had cognitive
deficits. During this time, he drank alcohol when not on
the ward, and staff reported a regression of skills in activi-
ties of daily living, declining mood, and expressing suicidal
ideation. He underwent inpatient functional occupational
therapy. Cognitive assessment identified persistent diffi-
culties with executive dysfunction and safety awareness
and he was transferred to the neurorehabilitation unit
under detention. One week later, he was participating well
in activities on the unit but still had very poor insight and
felt he was suitable for rapid discharge.
Conclusion
This case demonstrates the complexity of treating
comorbid alcohol-­ related brain damage and traumatic
brain injury, which requires a multidisciplinary approach,
thoughtful and holistic assessment, and in this case, use of
incapacity and mental health legislation to allow inpatient
assessment and rehabilitation.
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Case 2 – Wernicke’s encephalopathy
A 62-­year-­old man with a history of alcohol dependence
and alcoholic cirrhosis was admitted to hospital from
his own home. He had phoned emergency services in a
panicked state to say that he was locked in a house he
didn’t know.
His family knew that he had been drinking around two
bottles of vodka per day for at least 2 years. His walking was
very poor, and he had several falls at home, and eventually
had been restricted to sleeping downstairs and unable to
leave the house. He had stopped drinking suddenly without
explanation around 6 weeks before admission. Two weeks
before admission, he had developed problems with daily
functioning, for example, confusing the microwave for the
cooker, and could not work out how to use the TV remote
control. He also started having problems with his memory,
commenting to family that his children looked too old, and
at times believing that he still lived with his parents.
On initial presentation, he was irritable, easily distracted,
and disorientated. His speech was tangential, with confab-
ulation. He was treated with Pabrinex and low doses of
haloperidol for agitation. Initial bloods were unremarkable.
CT scan of brain showed bilateral periventricular hypoat-
tenuation and low attenuation foci in the basal ganglia.
After a few weeks, his disorientation and agitation
improved, but with some persisting cognitive problems.
A kitchen assessment reported problems with sequencing
tasks, poor safety awareness, and requirement for frequent
prompting. An Addenbrookes Cognitive Examination iden-
tified poor memory and fluency. The patient was keen to
engage with a programme of rehabilitation for alcohol-­
related brain injury and to remain abstinent from alcohol,
and after several months, was transferred to an supported
accommodation rehabiliation facility.
Simply encouraging individuals to reduce and stop
drinking in isolation may expose underlying difficul-
ties and lead to relapse, without further support in
place.
With appropriate support, individuals may engage in
specialist addiction services, where other interventions
may be available, including regular case management,
access to alcohol protective medications including
acamprosate, disulfiram and naltrexone, mental health
supports, occupational therapy, dietetics, physio-
therapy, access to recovery communities and support
groups and residential rehabilitation.
CONCLUSION
The increasing incidence of harm related to alcohol
across society should prompt us to remain vigilant
to its possibility in a range of patients. The potential
for reversibility of CNS effects makes this especially
worthwhile. Modifying alcohol intake may help the
management of other neuropsychiatric conditions that
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Further reading
► WHO (2018) Alcohol. Available at: https://www.who.
int/news-room/fact-sheets/detail/alcohol (Accessed: 11
February 2022).
► Billingham, R., Collins, M. and Germain, J. (1996) ‘Ray’s
a laugh’. (Out of print but viewable at https://www.
youtube.com/watch?v=3_T_AKPfVdI)
► SIGN (2019) SIGN 156: Children and young people
exposed prenatally to alcohol. Available at: https://
www.sign.ac.uk/our-guidelines/children-and-young-
people-exposed-prenatally-to-alcohol/ (Accessed: 10
December 2021).
► Nutt, D. et al. (2021) ‘Alcohol and the Brain’, Nutrients
2021, Vol. 13, Page 3938, 13(11), p. 3938. doi:
10.3390/NU13113938
Key points
► Alcohol misuse appears to be increasing, with
increasing rates of its neurological sequelae.
► Identifying specific alcohol-­related neurological
syndromes can help to target treatments and
prevention.
► The clinical assessment of alcohol use and its
Protected by copyright.
complications is an important clinical skill.
► Imaging is important in assessing the degree of
complications of acute and chronic alcohol use.
► Treatment can reverse the acute and chronic effects of
alcohol ingestion.
► A multidisciplinary and holistic approach can help
in managing alcohol-­related harms to the central
nervous system.
may be exacerbated or triggered by alcohol’s direct
and indirect effects. An holistic approach to an indi-
vidual’s relationship with alcohol is most likely to
produce meaningful outcomes.
Twitter Arun Menon @drarunmenon and John-­Paul Leach @
jpleach246
Collaborators  Not applicable.
Contributors  J-­PL and MW wrote first draft. MW provided
composite case histories MO and AM helped edit subsequent
drafts NEF sourced imaging and provided expert commentary.
Funding  The authors have not declared a specific grant for this
research from any funding agency in the public, commercial or
not-­for-­profit sectors.
Competing interests  None declared.
Patient consent for publication  Not applicable.
Ethics approval  Not applicable.
Provenance and peer review  Commissioned. Externally peer
reviewed by Joanna Lovett, Southampton, UK and Martin
Sadler, Plymouth, UK.
Data availability statement  No data are available.
Supplemental material  This content has been supplied by the
author(s). It has not been vetted by BMJ Publishing Group
13
 Review
Limited (BMJ) and may not have been peer-­reviewed. Any
opinions or recommendations discussed are solely those of
the author(s) and are not endorsed by BMJ. BMJ disclaims
all liability and responsibility arising from any reliance placed
on the content. Where the content includes any translated
material, BMJ does not warrant the accuracy and reliability of
the translations (including but not limited to local regulations,
clinical guidelines, terminology, drug names and drug dosages),
and is not responsible for any error and/or omissions arising
from translation and adaptation or otherwise.
ORCID iD
John-­Paul  Leach http://orcid.org/0000-0003-2086-9937
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