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206 Practical Neurology

REVIEW
REVIEW

Pract Neurol 2011; 11: 206219

Neurological complications of
alcohol and misuse of drugs
Killian A Welch
The nature of many of the symptoms associated with substance and alcohol use
means that patients often present to neurologists. The frequently catastrophic
consequences of overlooking these patients makes this an important cause
to identify. Here I will discuss various acute and non-acute substance misuse
associated presentations, with particular emphasis on the neurology. As
neurological sequelae are particularly common in alcohol use, there will be
an emphasis on this drug while other substances are included when relevant,
extending to the recently notorious legal highs. I hope this review will increase
vigilance to the possibility of substance use disorder, and persuade neurologists
that they have a role in the detection and treatment of these conditions.

INTRODUCTION
When asked what happened to all the money
he made in the 1960s, George Best (figure 1)
famously replied: I spent a lot on booze, birds
and fast cars. The rest I just squandered.
A significant proportion of the population of

Correspondence to
Dr Killian Welch, Consultant
Neuropsychiatrist, Robert
Fergusson Unit, Astley Ainslie
Hospital, 133 Grange Loan,
Midlothian EH9 2HL, UK;
killian.welch@nhslothian.scot.
nhs.uk
10.1136/practneurol-2011-000062

the UK appear to share his priorities. Despite


a slight, possibly recession related, fall in use,
alcohol consumption in the UK has doubled
from the time of Bests football playing career.
Recent estimates suggest 31% of men and 21%
of women exceed the widely publicised weekly

Welch 207
low risk drinking limits of 21 units for men and
14 for women. Unsurprisingly, the number of
people for whom alcohol use is causing health
problems has also increased; the most obvious
manifestation being the explosion in UK cirrhosis rates (figure 2). Inevitably there will also
be more neurological presentations.
However, alcohol is only one of many drugs
of abuse and the diversity of substances
used for their psychoactive properties has
expanded unimaginably in only a generation.
Consideration of drug and/or alcohol use as
a possible cause of a patients presentation is
more relevant than ever and requires consideration of this ever expanding variety of substances. This review aspires to cover the most
common and/or important not to miss substance misuse related presentations a neurologist may encounter, and the basic principles
of their management.

WHAT IS SUBSTANCE
DEPENDENCE?
Although there are many pharmacological
effects of abused drugs, the features of dependence are remarkably similar, regardless of the
specific substance used; the diagnostic criteria are identical for all addictive drugs (box 1).
Psychological craving is the key feature of the
dependence syndrome which can exist without physiological withdrawal symptoms; this
is psychological dependence. Dependence
forming drugs activate the mesolimbic dopamine system; dysregulation of this reward
pathway is believed to mediate the compulsive and pathological drug use central to the
dependence state.
Although some drugs have a greater dependence liability than others, clearly not everyone who uses a particular substance becomes
dependent. Risk arises from a combination of
genetic, personality and social factors. Alcohol
dependence has been the most studied with
estimates that 5060% of the liability results
from genetic factors.1 Susceptibility to complications of alcohol dependence, such as
withdrawal seizures and cirrhosis, is also substantially genetically determined.2 3
A lesser state of harmful use is defined in
ICD-10 (International Statistical Classification
of Diseases and Related Health Problems
10th Revision) as a pattern of psychoactive
substance [mis]use that is causing damage to

Figure 1
George Best was described by Pele as the greatest footballer ever. His affable nature led to many
memorable quotes. However, his career was cut tragically short through alcohol addiction. He retired
from Manchester United aged only 27 years. Less well known, his mother also died from alcoholism
having never drunk until in her forties. The family tragedy emphasises both the human cost and also
genetic risks of addiction. Photograph: PA.

Box 1 ICD-10 diagnostic criteria for harmful use and


dependence
Harmful use
A pattern of psychoactive substance use that is causing damage to
health, physical or mental:
Physicaleg, liver cirrhosis with alcohol, phlebitis with heroin
injection
Mentaleg, psychosis with amphetamine use
Dependence syndrome
Patients must meet at least 3 of the following criteria:
Loss of control, when and where, for how long and how much
Compulsion or desire and craving
Tolerance, requiring increasing doses
Withdrawal state, and use to avoid this state
Neglect alternative pleasures or interests
Persistence despite harm to relationships, work, crime, health and
finance
ICD-10, International Statistical Classification of Diseases and Related Health
Problems, 10th Revision.
health, physical or mental (box 1). In other
words, maladaptive patterns of substance use
that impair health in a broad sense. Contrary
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208 Practical Neurology


with many more meeting diagnostic criteria for
alcohol misuse. Maybe this reflects the admission policy of neurologists rather than the
prevalence of neurological complications.

DETECTION

Figure 2
Time trends in age standardised mortality for liver cirrhosis per 100 000 by country between 1950 and
2002 (with permission from Leon and McCambridge39).

to popular opinion, the natural history of substance misuse is not an inevitable slide in to
worsening dependence; in an American study
of problem drinkers, in 45% of cases alcohol was no longer causing difficulties at the
20 year follow-up.4

EPIDEMIOLOGY

There is no
substitute for
routinely asking
patients about
alcohol and drug
intake
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The prevalence of active substance misuse disorder in neurology outpatients was 13% in a
Danish study5 but there are no comparable UK
data. In neurology wards, the limited data available suggest the prevalence of substance misuse problems may be as low as 3%, a fraction
of the 20% in acute general medical admissions.6 This low figure is particularly interesting
given that 4% of the UK population are alcohol dependent (6% of men and 2% of women),

Considering substance abuse as a possibility is


the first step to detection. There is no typical
patient. Whereas certain signs and symptoms
do raise suspicion, there is no substitute for
routinely asking patients about alcohol and
drug intake. For alcohol, it only takes seconds
to pose the single question How often would
you have eight (for a man) or six (for a woman)
or more drinks on a single occasion? (you may
need to check that the patient knows what a
unit is (see box 2, the Fast Alcohol Screening
Tool (FAST) questionnaire).7 If the answer
is weekly or daily or almost daily they are
drinking at a hazardous, harmful or dependent
level and consumption should be quantified
and symptoms of dependence sought. If the
answer is monthly or less than monthly,
three further questions are indicated (box 2).
Without screening, some patients who
may respond to brief interventions will be
missed. Furthermore, attempts to elucidate
the cause of presentations which are in fact
due to substance use may entail unnecessary
and potentially damaging investigations and
treatments.
Although the FAST test has good sensitivity,
it will not detect all hazardous drinkers or those
abusing other substances. One must be alert
to signs and symptoms which raise suspicion
(figure 3). Specific presentations suggesting
alcohol or drug use are outlined below, artificially divided into acute and chronic. Given its
dominance, the focus is on alcohol but other
drugs are included where relevant.

ACUTE PRESENTATIONS
Intoxication
Alcohol intoxication is generally obvious.
The individual smells of alcohol and may
have nystagmus, dysarthria, skin flushing,
hypotension and ataxia. Presentations depend
on the blood alcohol concentration (table 1)
but are individual dependent. This variation
can be informative. For example, the ability
to maintain conversation with a blood alcohol of 300 ml/dl indicates severe dependence;
such individuals will exhibit withdrawal at
alcohol levels associated with intoxication in

Welch 209

Figure 3
Signs and symptoms suggesting an alcohol problem.

non-tolerant individuals (ie, around 100 mg/


dl). In practice, treatment should be initiated
when withdrawal symptoms occur, rather
than waiting for the alcohol level to fall to
near zero.
A common emergency department scenario is a patient with reduced consciousness
smelling of alcohol. While this could be simple
drunkenness, exclusion of metabolic causes,
poisoning/concomitant use of other drugs or
an underlying structural brain lesion all need
to be considered. Alcoholics may have cerebral
atrophy predisposing them to subdural haematomas, and disordered coagulation rendering them liable to intracerebral haemorrhage.
Such patients need a full examination, blood
alcohol testing and often a CT brain scan.
Focal neurological signs are not expected in
alcohol intoxication, and a blood alcohol level
of <200 mg/dl should not cause coma.
Blood alcohol level can easily be quantified
with a breathalyser. Quantifying the levels of
other substances is much more difficult (or
impossible), although recent use of commonly
used drugs can be ascertained by bedside and/
or laboratory drug urine (or salivary) testing.

TABLE 1 Acute intoxication with alcohol


Units of
alcohol

Blood alcohol
(mg/100 ml)

30

50

5
10

80
150

12
25
30
38

200
400
500
600

Effects
Impairment in some tasks requiring skill, more
accidents
Loss of inhibitions, relaxation, increased
talkativeness
Driving limit in the UK
Loss of self-control, lack of coordination,
slurred speech
Memory loss, hypothermia, nausea, vomiting
Coma, respiratory depression
Possible death
Death

However, the half-life of many drugs is so


short that they will only be detected if used in
the previous few days (table 2). Concomitant
intoxication with different substances confuses the clinical picture. Recently, legal highs
have become popular. There are generally no
tests for these ever changing substances, the
most current being listed in table 3.
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210 Practical Neurology

Treatment
Box 2 The Fast Alcohol Screening Tool (FAST) for
alcohol problems
For the following questions please circle the answer which best applies.
1 drink = 1 unit = 0.5 pint of beer or 1 glass of wine or 1 single spirits
1. MEN : How often do you have EIGHT or more drinks on one occasion?
WOMEN: How often do you have SIX or more drinks on one occasion?
NeverLess than monthlyMonthlyWeeklyDaily or almost daily
Only ask questions 2, 3 and 4 if the response to question 1 is less than
monthly or monthly. If the patient has given other answers they have
already been classified (see below).
2. How often during the last year have you been unable to remember what
happened the night before because you had been drinking?
Never Less than monthlyMonthlyWeekly Daily or almost daily
3. How often during the last year have you failed to do what was normally
expected of you because of drink?
Never Less than monthlyMonthlyWeekly Daily or almost daily
4. In the last year has a relative or friend, or a doctor or other health worker,
been concerned about your drinking or suggested you cut down?
NoYes, on one occasionYes, on more than one occasion
Scoring is quick and can be completed with just a glance at the pattern
of responses as follows:
Stage 1
The first stage only involves question 1. If the response
is never then the patient is not misusing alcohol. If the
response is weekly/daily or almost daily then the patient is
a hazardous, harmful or dependent drinker. Over 50% of
people will be classified using just this one question. Only
consider questions 2, 3 and 4 if the response to question 1 is
less than monthly or monthly.
Stage 2
If the response to question 1 is less than monthly or
monthly, then each of the four questions is scored 04
which when added result in a total score between 0
and 16. The person is misusing alcohol if the total score is 3
or more:
Score questions 1, 2 and 3 as follows:
Never = 0
Less than monthly = 1
Monthly = 2
Weekly = 3
Daily or almost daily = 4
Score question 4 as follows:
No = 0
Yes, on one occasion = 2
Yes, on more than one occasion = 4

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Treatment of extreme alcohol intoxication


is essentially supportive. Opiate intoxication is treated with naloxone (lifesaving, but
patients can be aggressive when revived), and
dysphoric reactions to hallucinogens with
benzodiazepines.

Drug induced psychosis


Psychotic phenomena which are neither
explained by acute intoxication alone nor by a
withdrawal state can arise during or following
psychoactive substance use. Symptoms last at
least 48 h and include delusions, hallucinations
(potentially visual or tactile as well as auditory) and psychomotor agitation. Distinction
between intoxication, withdrawal and drug
use precipitating a chronic psychosis can be
difficult, but very sudden onset and transiency
(in the absence of further drug use) generally distinguish drug use from schizophrenia.
In contrast with the delirium associated with
intoxication or withdrawal, chronic psychotic
patients are usually orientated. Drug testing
is essential, and medical causes of psychotic
symptoms (delirium, encephalopathies, epilepsy, etc) must be excluded. Those experiencing a drug induced psychosis pose substantial
risks to themselves and others; although one
cannot be detained under Mental Health legislation (in either England or Scotland) for
intoxication alone, a person experiencing a
drug induced psychosis can be.

Withdrawal
Alcohol withdrawal occurs in those physiologically dependent on alcohol. It is the result of
unmasking of the compensatory changes that
occur during prolonged exposure to its depressant effects. These changes underpin tolerance
and include downregulation of -aminobutyric
acid type A receptors and upregulation of
N-methyl-D-aspartate receptors.8 If a dependent individual abruptly stops drinking, the
inhibitory effects of alcohol are lost whereas
the adaptive changes persist. The resulting
overstimulation generates withdrawal symptoms, with a wide range of severity (table 4).

Treatment
Withdrawal in moderate to severe alcohol
dependence is treated with benzodiazepines
which prevent seizures and delirium tremens.

Welch 211
There are arguments for both fixed dose and
symptom triggered prescribing, the latter
being associated with reduced total dose of
medication and duration of detoxification. In
busy neurology wards, withdrawal symptoms
can be missed however, so fixed interval prescribing with vigilance for the need for top
ups seems optimal. A typical detoxification
protocol is chlordiazepoxide 2030 mg four
times a day reducing over 5 days, but some
patients may require much higher doses.
Various factors predict severe withdrawal and
its likelihood (box 3).
If there is severe withdrawal, dietary neglect
or other risk factors/features of Wernickes
encephalopathy (box 4), then it is essential
that intravenous Pabrinex (or its equivalent),
which contains nicotinamide, riboflavin, pyridoxine and ascorbic acid as well as thiamine,
is given. Although there is no evidence, some
believe that intravenous thiamine alone may
not be adequate for prevention. Thiamine is a
cofactor for the enzymes required in glucose
metabolism, which is why Wernickes may be
precipitated by administering glucose prior
to thiamine; consequently, Pabrinex should
always be administered before parenteral
glucose.9 Uncomplicated patients discharged
before completion of alcohol detoxification must be given the remaining doses and
instructions of how to take them.
The unmasking of compensatory changes
that have occurred during prolonged exposure to the drug also gives rise to the
withdrawal syndromes associated with benzodiazepines, GBL (-butyrolactone), GHB
(-hydroxybutyrate) and opiates. Withdrawal
from the first three is associated with serious
complications comparable with alcohol (ie, seizures, delirium and psychosis). Reducing doses
of benzodiazepines (long acting, generally
diazepam) are the mainstay of treatment, and
in GBL/GHB withdrawal, heroic doses may be
required. Baclofen is an essential adjunct for
GBL/GHB withdrawal, and on occasion general
anaesthesia may be required.
Opiate withdrawal by contrast is not life
threatening, and not associated with delirium.
It is thoroughly unpleasant however, and if of
any severity requires treatment:
If already receiving substitute treatment
(such as methadone), which has been confirmed with the prescriber, and fewer than
3 days prescription has been missed, the

normal dose of substitute treatment is


given.
If not on a substitute treatment and
dependence is relatively mild, then symptomatic treatment (eg, lofexidine for
autonomic overactivity, loperamide for

Box 3 Clinical features


predicting severe withdrawal
(modified from Raistrick40)
Recent high levels of alcohol intake
Previous history of severe withdrawal
Previous history of seizures or delirium
Concomitant use of psychoactive drugs
Poor physical health
High levels of anxiety or other psychiatric
disorder

Box 4 Clinical features, risk factors and treatment of


Wernickes encephalopathy
Clinical features
Acute confusion
Ophthalmoplegia
Decreased conscious level
Nystagmus
Memory disturbance
Unexplained hypotension with hypothermia
Ataxia/unsteadiness
When clinical symptoms present, treat with 2 pairs (4 Pabrinex ampoules)
intravenously three times a day for 3 days, then daily 23 days, then oral
thiamine 100 mg three times a day
Risk factors
Intercurrent illness
Peripheral neuropathy
Delirium tremens/treatment for delirium tremens
Drinking >20 units daily
Alcohol related seizures
Recent diarrhoea/vomiting
Intravenous glucose infusion
Signs of malnutrition
Significant weight loss
Poor diet/nil by mouth
When only risk factors present, treat with 1 pair (2 Pabrinex ampoules)
intravenously daily for 3 days, then oral thiamine 100 mg three times a day
NB: Concern is often raised about Pabrinex associated anaphylaxis. In the
UK there have been four reports per 1 million intravenous ampoules sold
and one report per 5 million ampoules sold of the intramuscular preparation.
Thus although facilities for the treatment of anaphylactic reactions should be
available where parenteral preparations are given, the actual risk is very low.
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212 Practical Neurology

TABLE 2 Clinical presentation of intoxication together with duration of detectability in urine of commonly
encountered drugs of abuse (window of detectability for blood or salivary testing will be similar although slightly
shorter)
Drug

Features of intoxication

Duration of detection in urine

Cocaine

23 days

Methadone

Euphoria, increased energy, reduced sleep,


hypertension, tachycardia, diaphoresis,
mydriasis, hyperthermia, hyperreflexia, tremor,
dysrhythmias, cardiac ischaemia/infarction,
agitation, psychosis, seizures, intracerebral
haemorrhage
Clinical manifestations similar to cocaine,
although duration of effect tends to be longer
and psychosis more likely, but seizures and
dysrhythmias less likely
Intoxication similar to amphetamines but with
the experience of empathy as well as euphoria.
Intoxication also similar to amphetamines
but with superimposed serotonin syndrome
caused by serotonergic effects of the drug
(hyperthermia, diaphoresis, hyperreflexia,
myoclonus, seizures)
Euphoria, relaxation, increased appetite,
tachycardia, tremor, conjunctival injection,
perceptual alterations, psychosis
Altered visual perception, synaesthesia (a
sensory stimulus in one modality resulting in
sensory experience in another), rapid mood
alterations (euphoria to suicidality), mydriasis,
tremor, hyperreflexia, diaphoresis, ataxia,
hallucinations, terror
Intoxication: slurred speech, incoordination,
unsteady gait, impaired attention, memory and
judgement, disinhibition and lability of mood
Overdose: respiratory depression, especially if
other respiratory depressing drugs used
Analgesia, euphoria, miosis, hypotension,
bradycardia and respiratory depression
Overdose: pinpoint pupils, pallor, severe
respiratory depression, pulmonary oedema,
coma
Similar to heroin but little euphoric effect

Dihydrocodeine

Similar to heroin but less euphoric effect

Amphetamines

3,4-Methylenedioxymethamphetamine

Cannabis

Lysergic acid diethylamide (LSD)

Benzodiazepines

Heroin (morphine)

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diarrhoea, metoclopramide for nausea)


may be adequate.
Opiate substitution should only be started
if there is objective evidence of withdrawal
and, ideally, a confirmed history of dependence (self-report must be supported by
urine/oral swab testing, track marks, etc).

2 days

13 days

Single use: 3 days


Daily use: 10 days or longer
Not routinely tested for

13 days

Up to 2 days

Single dose: 12 days


Maintenance dose: up to 1
week
12 days

Opioid dependent patients need more


opioid analgesia for pain relief compared
with a non-user. Non-opioid analgesics
should be used in preference where appropriate, but if opioid analgesia is prescribed
the baseline methadone dose should
remain constant.

Welch 213

TABLE 3 Legal highs (many of which are no longer legal in the UK) which have come to prominence by
November 2010

Drug

Legal status
(November 2010)

-Hydroxybutyrate (GHB,
liquid ecstasy)

Illegal (since
2003)

Acute effects
Recreational doses:
euphoria, increased
libido

Illegal (since
December 2009)
Illegal (from April
2010)

Higher doses:
agitation, visual
disturbance, seizures
(especially if taken
with amphetamines),
respiratory depression,
death
Precursor of GHB.
Effects as above
Euphoria, heightened
awareness, empathy

Naphyrone (NRG-1)

Illegal (from July


2010)

Euphoria, heightened
awareness, empathy

Methylenedioxypyrovalerone
(MDPV, ivory wave)

Illegal (from April


2010)

6-(2-Aminopropyl)
benzofuran (6-ABP,
benzofury)

Currently legal

Stimulant with little


euphoric effect, sexual
arousal
Euphoria, heightened
awareness, empathy

-Butyrolactone (GBL)
Mephedrone (MCAT, miaowmiaow, plant food)

Potential
neurological
presentations

Long term effects

Withdrawal
with delirium,
convulsions and
hallucinations

Dependence
with associated
withdrawal
syndrome

As above

As above

Hallucinations,
seizures

Craving,
dependence
forming
Craving,
dependence
forming

Hallucinations,
delusions, seizures.
Greater risk of
adverse effects
than mephedrone
Hallucinations,
delusions, seizures

Craving,
dependence
forming
Unknown

Hallucinations,
seizures

A legal high is pragmatically defined as a substance sold by virtue of the similarity of its effects to an illegal drug but which is
not covered by the UK Misuse of Drugs Act (1971, or later amendments) at the time of marketing.

Seizures
The most common substance related cause
of seizures is alcohol withdrawal. Typically
they occur 648 h after last alcohol use
and are generalised tonicclonic seizures
although partial seizures also occur. They
are usually self-limiting but can give rise to
status epilepticus where alcohol dependence
accounts for 925% of cases.10 The severity
of alcohol withdrawal symptoms progressively increases, and repeated detoxifications
increase the likelihood of alcohol withdrawal
seizures.11

TABLE 4 Clinical presentation of alcohol withdrawal


Major
(delirium tremens)
2472 h

Minor
072 h

Intermediate
2472 h

Apprehension, anxiety,
restlessness
Tachycardia
Insomnia
Weakness
Irritability
Sweating
Anorexia

Minor features plus:


Hypertension
Illusions
Confusion
Agitation
Disorientation
Fear

Intermediate features
plus:
Hallucinations (may
provoke self-harm)
Delusions
Seizures
Cardiac arrhythmias
Circulatory collapse

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214 Practical Neurology


intracranial lesions, most commonly subdural
haematoma, and metabolic causes for seizures
(such as hypoglycaemia). Brain imaging should
normally be performed in those with their first
alcohol related seizure, and when there are
focal signs or other reasons for concern.

Delirium tremens
Delirium tremens occurs in about 5% of
patients hospitalised for alcohol withdrawal,13
generally developing 2472 h after the last
drink. Worsening agitation, distractibility and
illusions/misinterpretations generally precede
the onset which is characterised by fluctuating
disturbance of consciousness, changes in cognition, exacerbation of autonomic symptoms
(sweating, nausea, palpitations and tremor),
fear or terror.

Treatment

Figure 4
FLAIR image of Central pontine myelinolysis (arrowed), (courtesy of Dr Susan Kealey).

Treatment

Brain imaging
should normally
be performed in
those with their
first alcohol related
seizure,
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Benzodiazepines are the mainstay of treatment. In the acute context other antiepileptic
drugs add little,12 not least because time to
reach therapeutic levels exceeds the highest
risk period for seizures. If seizures have previously occurred despite adequate benzodiazepine treatment, then carbamezapine prior to
detoxification may have added benefit. Because
withdrawal seizures do not recur if the patient
remains abstinent, long term antiepileptic drugs
are unnecessary in abstinent patients.
Benzodiazepine and GHB/GBL withdrawal
are also associated with seizures. Indeed, if
withdrawal seizures occur after the first few
days of alcohol detoxification, concurrent benzodiazepine dependence should be considered.
Other causes of substance related seizures
include intoxication with cocaine and amphetamines, and 3,4-methylenedioxymethamphetamine overdose (table 2). It should be
remembered that substance misusing individuals are at increased risk of significant

Adequate benzodiazepine is central to treatment but is usefully augmented with haloperidol (510 mg intramuscularly or 5 mg twice
daily). Indeed, low dose haloperidol (15 mg
twice daily) should be added if hallucinations
are a feature of withdrawal, even outwith
frank delirium tremens. Affected patients may
need to be prevented from leaving hospital,
potentially necessitating use of mental health
legislation. Owing to high associated mortality (most case series report 515%), management in a medical rather than a psychiatric
bed is generally recommended.

WernickeKorsakoff syndrome
Alcohol withdrawal can precipitate Wernickes
encephalopathy, delayed or otherwise inadequate treatment of which can result in
Korsakoffs syndrome. The risk factors and
early manifestations of Wernickes must be recognised and treated promptly and adequately
with parenteral vitamins (box 4). Improvement
in confusion usually occurs in 12 days, ocular
abnormalities in days to weeks, while ataxia
usually responds within the first week but can
take months or much longer to resolve.14
Korsakoffs is an amnestic syndrome with
impaired recent memory and relatively intact
intellectual function probably caused by interruption of diencephalichippocampal circuitry,
including between thalamic nuclei and mamillary bodies.15 Patients rarely have truly discrete
deficits in forming new memories, generally
exhibiting more global deficits along a spectrum

Welch 215
of severity. It is often perceived as untreatable
but in fact only 25% show no recovery, 25%
experiencing slight, 25% significant and 25%
complete recovery of memory.16
Korsakoffs can arise without a clear episode
of Wernickes, developing insidiously or following undiagnosed subacute episodes.17 This has
led to prescribing oral thiamine supplements
to chronic alcoholics. Magnesium is a cofactor for many thiamine dependent enzymes, and
deficiency may induce clinical signs of thiamine
deficiency.18 This may explain occasional thiamine refractory cases of Wernickes encephalopathy; clinical signs in these cases tend to
resolve after magnesium correction.

Pellagra
Niacin (vitamin B3, nicotinic acid) and/or tryptophan deficiency results in skin, gastrointestinal
and mental abnormalities which can progress
to memory impairment, delusions, hallucinations, dementia or delirium. Hypertonus and
startle myoclonus may be present.19 Symptoms
usually improve with nicotinic acid or nicotinamide (amide of vitamin B3) replacement.

Blackouts
These are periods of dense amnesia during and
after episodes of heavy alcohol consumption.
They are not accompanied by drowsiness, inattentiveness or impairment of consciousness,
and speech and behaviour may appear normal.
They are similar to episodes of transient global
amnesia (which occur in the absence of alcohol consumption) and are attributed to ethanol
inhibiting the N-methyl-D-aspartate receptor
and impairing long term potentiation. They
can arise in social drinkers, but are indicative
of heavy consumption and risk of developing
alcohol dependence.

Central pontine and extrapontine


myelinolysis
Hyponatraemia is common in chronic alcoholics, particularly beer drinkers, due to the
intake of large volumes of fluid. It is generally
chronic and best treated by restoring normal
hydration and diet while abstaining from alcohol. Attempts to correct the electrolyte disturbance with saline (particularly hypertonic
saline) may result in demyelination, thought
to be triggered by rapid osmotic shifts in the
brain causing complement mediated oligodendrocyte toxicity.9 This most commonly

Figure 5
T2 weighted MR axial image in MarchiafavaBignami disease, showing hyperintense signal in the genu
of the corpus callosum (arrowed) (courtesy of Dr Susan Kealey).

occurs in the pons (central pontine myelinolysis) (figure 4) but it can also occur elsewhere
(extrapontine myelinolysis), the basal ganglia
and thalamus being vulnerable.20
If the pons is primarily affected, symptoms
include dysarthria, dysphagia and spastic quadriparesis. Lesions outside the pons have a much
more variable presentation which can include
mutism, parkinsonism, dystonia and catatonia.21
Outcome is variable but often poor, so prevention is critical.

MarchiafavaBignami disease
This is characterised by demyelination and
necrosis of the corpus callosum (figure 5). It
generally occurs in chronic alcoholism with
poor nutrition. It may present acutely with
stupor, coma or seizures, or chronically with
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216 Practical Neurology


dementia, gait problems, apraxia and ataxia.
It is reliably diagnosed with MRI. Treatment
is generally as for Wernickes encephalopathy
although this is pragmatic rather than evidence based. High dose steroids have also been
suggested.22

Hepatic encephalopathy
Acute presentations of frank hepatic encephalopathy are unlikely to be missed. A more
subtle presentation known as minimal hepatic
encephalopathy may however affect 60% of
patients with cirrhosis and impact significantly
on daily functioning.23 Manifestations include
psychomotor slowing with deficits in attention
and visual perception, possibly only detectable
by neuropsychological testing. In recurrent

Box 5 The serotonin syndrome


Symptoms are on a spectrum and can include:
Mental status change (confusion, hypomania)
Agitation
Myoclonus
Hyperreflexia
Diaphoresis
Shivering
Tremor
Diarrhoea
Incoordination
Fever
Rise in plasma creatine kinase generally relatively modest (in comparison
to neuroleptic malignant syndrome)

Box 6 When to refer to specialist substance misuse


services
All opiate misusers should be referred for triage assessment. In other cases
the patient should be referred if:
The patient requests a referral
Physical dependence
Evidence of marked problems secondary to substance use (biological,
psychological, social)
Presentation complicated by one or more of:
Age under 17
Pregnancy
Chaotic behaviour
Poly-substance misuse
Injecting
Dual diagnosis (concurrent psychiatric disorder)
Severe risk of suicide, violence or neglect
Possible risk to children posed by patient
10.1136/practneurol-2011-000062

or chronic forms, cognitive impairment can


develop into dementia. Various movement
disorders including asterixis, extrapyramidal
rigidity and choreoathetosis may occur.24

Serotonin syndrome
Serotonin syndrome is caused by excessive
serotonergic agonism in the CNS (box 5). It
can be precipitated by ecstasy, with the illicit
nature of use meaning the patients exposure
can be missed. This underlines the importance
of drug screens in young people presenting
with acute confusion.

CHRONIC, OUTPATIENT,
CLINIC-TYPE PRESENTATIONS
Vague, unexplained symptoms
A typical presentation can be merely unexplained fatigue accompanied by anxiety and/
or depression and possibly sleep disturbance.
Furthermore, alcohol dependence can produce
any of the symptoms of depression. A fifth of
chronic cannabis users report tiredness. These
symptoms are usually secondary to substance use and will resolve with abstinence.25
However, insomnia can persist in recovering
alcoholics and is associated with increased
risk of relapse.26 Sleep hygiene is preferred to
pharmacological approaches. Benzodiazepines
or z drugs, such as zopiclone or zolpidem,
should be avoided given their potential for
dependence.

Neuropathy
Alcohol misuse is classically associated with
Saturday night palsy due to compression
of the radial nerve when sleeping heavily, or stuperose. Chronic alcohol misusers
may develop a symmetrical, bilateral mixed
sensory and motor peripheral neuropathy, usually of the lower limbs. Individuals
may be asymptomatic or present with pain,
numbness, burning feet and hyperaesthesia. There may also be muscle weakness and
depressed tendon reflexes.27 This neuropathy
is generally attributed to thiamine deficiency
although direct alcohol toxicity may contribute. Indeed, it has been suggested that if
thiamine deficiency is the predominant cause
the symptoms are motor, whereas direct
alcohol toxicity produces a sensory dominant picture.28 Some recovery is expected
with abstinence from alcohol accompanied
by thiamine supplementation.

Welch 217
Antabuse, a drug commonly used to assist
abstinence in patients with alcohol dependency, can sometimes be associated with a
peripheral neuropathy.

Ataxia
As well as presenting acutely in intoxication or
Wernickes encephalopathy, chronic cerebellar
ataxia affects approximately one-third of the
chronically alcohol dependent.29 It is believed
to be due to a combination of malnutrition
and the direct toxic effects of alcohol.30 The
ataxia consists of instability of gait and stance
with severe incoordination of the kneeshin
test, but relatively little involvement of the
arms. There is degeneration of neurons in the
anterior and superior portions of the cerebellar
vermis with extension into the anterior lobes
and flocculi in severe cases.31

Cognitive impairment
There is no single cause for alcohol related
brain damage. At one end of the spectrum
is classical thiamine deficiency attributable Korsakoffs syndrome, discussed above.
However, the alcohol dependent are also subject to repeated episodes of intoxication and
withdrawal, dietary neglect, other vitamin
deficiencies, traumatic brain injury, cerebrovascular events and alcoholic liver disease, all
of which can contribute to impairment in brain
structure and function. These direct and indirect effects interact with individual (including genetic) vulnerabilities so no two people
develop exactly the same patterns of damage.
There is much debate as to whether alcohol has a direct neurotoxic effect on the brain
or if (in the absence of other causes) evident
cognitive impairment is more attributable to
subtle and undetected past or present thiamine deficiency. In reality, it is likely that these
processes are inter-related and it is increasingly believed that the glutamate induced
excitotoxicity associated with repeated binges
and withdrawals is exacerbated by increases in
glutamate availability consequent on thiamine
deficiency.17 The interaction may be synergistic so the argument whether there are pure
thiamine deficiency effects and pure alcohol
related effects is essentially academic.
That said, brain scanning of alcoholics with
no obvious history of nutritional deficiency
shows ventricular and sulcal enlargement

accompanied by white and grey matter loss,


particularly for white matter and in the prefrontal cortex.32 In keeping with these structural abnormalities, the patients commonly
show frontal-type deficits such as difficulties
with planning, organisation, problem solving,
lack of insight, disinhibition, and perseveration,
with visuospatial impairments also particularly common. Significant executive function
deficits may be missed if only a very basic
screening tool such as the Mini-Mental State
Examination is used whereas simple bedside
tests such as verbal fluency have reasonable
sensitivity.
Whatever the mechanism of damage the
effects can be profound. Alcohol is the primary
cause in 10% of dementia cases and likely to
contribute to many more.33 In an Irish acute
general hospital, 25% of delayed discharges
were attributable to alcohol related brain disorders.34 Anecdotal evidence suggests a similar picture in many other countries.
Whether classical Korsakoffs or not, abstinence and adequate nutrition are central to
management. Cognitive deficits (as well as the
aforementioned frontal lobe imaging abnormalities) generally improve with abstinence.32 35
Early recovery of cognition can be substantial,
meaning formal psychometric evaluation is
ideally not undertaken until after 3 weeks of
abstinence. These patients require multidisciplinary input, involving social work, occupational therapy and liaison psychiatry. Discharge
from hospital without adequate ongoing input
can have catastrophic consequences.

alcohol dependence
can produce any of
the symptoms of
depression

There is no single
cause for alcohol
related brain
damage.

PRACTICE POINTS

Neurological complications are a common result of substance misuse, in


particular alcohol. Clinical vigilance is essential.
Effective treatments are available, and even brief interventions and encouragement delivered by non-specialists can have a significant impact on subsequent substance use.
If there is any risk of Wernickes encephalopathy the consequences of not
administering parenteral thiamine are catastrophic whereas the risks associated with its use are very low.
Delirium tremens is associated with high mortality. The mainstay of treatment is benzodiazepines but haloperidol can be an important adjunct and
concerns about lowered seizure threshold should not preclude its use.
Alcohol is primarily responsible for at least 10% of dementia cases. The
aetiology is complex but improvement will often occur with abstinence.

www.practical-neurology.com

218 Practical Neurology

10.1136/practneurol-2011-000062

GENERAL MANAGEMENT

SUMMARY

Alcohol based brief interventions are useful and cost effective.36 This is likely true for
abuse of other substances as well. Brief interventions involve screening (eg, the FAST tool),
identification of a problem and discussion of
the benefits of change. While abstinence will
be the goal in those with a history of alcohol
dependence or who have developed physical
complications, clearly any reduction in use is
beneficial. Meta-analysis has demonstrated
that brief interventions result in a mean
reduction of 45 units of alcohol/week after
follow-up of 1 year or longer.37
Brief interventions are primarily aimed at
hazardous, but not yet dependent users. The
latter require more sophisticated treatment. In
alcohol dependence the need for detoxification must always be considered, but maintaining abstinence poses much greater challenges.
Alcoholics Anonymous, Narcotics Anonymous
and related organisations should always be
suggested, meeting times being available from
websites (eg, http://www.alcoholics-anonymous.org.uk).
Referral to specialist addiction services
should also be considered (box 6). As well as
psychological treatment, medically led addiction services will consider the use of pharmacological interventions. For alcohol problems
the most common are antabuse, acamprosate
and naltrexone. Baclofen, a -aminobutyric
acid receptor agonist, may reduce craving and
intake of alcohol, although this requires further research.
Opiate dependence is often treated with
substitute prescribing (most commonly with
methadone) within a programme also delivering psychosocial interventions. Contrary
to popular belief there is robust evidence
for substitute prescribing; it reduces criminal activity, lowers risk of blood borne virus
acquisition, and improves re-socialisation.38
Maintenance opiate prescribing should only
be initiated by or in association with substance misuse services. In detoxified individuals, naltrexone, an opiate antagonist, can
promote abstinence.
Substitute prescribing is not commonly
employed for other illicit drugs (eg, stimulants,
cannabis); harm reduction and psychologically
based abstinence orientated interventions are
the cornerstones of treatment.

Substance misuse is a major problem, and one


which all doctors will encounter. It is also where
misconceptions abound, and robust evidence
for treatment efficacy is under appreciated or
just ignored. When this is combined with the
embarrassment, avoidance and denial associated with these conditions, the frequency with
which doctors ignore clear signs or symptoms
and overlook opportunities to intervene is all
too understandable. I hope this article helps
busy clinicians recognise substance misuse
problems and appreciate that there is good
reason for therapeutic optimism.
Acknowledgements Alan Carson, Edinburgh, and
Phil Smith, Cardiff, for reviewing the manuscript.
Competing interests None.
Provenance and peer review Not commissioned;
externally peer reviewed.

REFERENCES
1. Dick DM, Agrawal A. The genetics of alcohol and other
drug dependence. Alcohol Res Health 2008;31:11118.
2. Schaumann BA, Annegers JF, Johnson SB, et al. Family
history of seizures in posttraumatic and alcoholassociated seizure disorders. Epilepsia 1994;35:4852.
3. Day CP, Bassendine MF. Genetic predisposition to
alcoholic liver disease. Gut 1992;33:14447.
4. Vaillant GE. The natural history of alcoholism
revisited. Cambridge, MA: Harvard University Press,
1995.
5. Fink P, Hansen MS, Sndergaard L, et al. Mental illness
in new neurological patients. J Neurol Neurosurg
Psychiatry 2003;74:81719.
6. Jefferies K, Owino A, Rickards H, et al. Psychiatric
disorders in inpatients on a neurology ward:
estimate of prevalence and usefulness of screening
questionnaires. J Neurol Neurosurg Psychiatry
2007;78:41416.
7. Hodgson R, Alwyn T, John B, et al. The FAST Alcohol
Screening Test. Alcohol Alcohol 2002;37:616.
8. Hughes JR. Alcohol withdrawal seizures.
Epilepsy Behav 2009;15:927.
9. McKeon A, Frye MA, Delanty N. The alcohol
withdrawal syndrome. J Neurol Neurosurg Psychiatry
2008;79:85462.
10. Hillbom M, Pieninkeroinen I, Leone M. Seizures
in alcohol-dependent patients: epidemiology,
pathophysiology and management. CNS Drugs
2003;17:101330.
11. Brown ME, Anton RF, Malcolm R, et al. Alcohol
detoxification and withdrawal seizures: clinical
support for a kindling hypothesis. Biol Psychiatry
1988;23:50714.
12. Minozzi S, Amato L, Vecchi S, et al. Anticonvulsants
for alcohol withdrawal. Cochrane Database Syst Rev
2010;3:CD005064.
13. Mayo-Smith MF, Beecher LH, Fischer TL, et al.;
Working Group on the Management of Alcohol
Withdrawal Delirium, Practice Guidelines Committee,
American Society of Addiction Medicine. Management
of alcohol withdrawal delirium. An evidence-based
practice guideline. Arch Intern Med 2004;164:140512.
14. Lishman WA. Organic psychiatry, 3rd Edn. Oxford:
Blackwell, 1998.

Welch 219
15. Sullivan EV, Marsh L. Hippocampal volume deficits
in alcoholic Korsakoffs syndrome. Neurology
2003;61:171619.
16. Victor M, Adams RD, Collins GH. The Wernicke
Korsakoff syndrome and related neurologic disorders
due to alcoholism and malnutrition, 2nd Edn.
Philadelphia, PA: FA Davis, 1989.
17. Thomson AD, Cook CC, Guerrini I, et al. Wernickes
encephalopathy: Plus a change, plus cest la mme
chose. Alcohol Alcohol 2008;43:1806.
18. Traviesa DC. Magnesium deficiency: a possible cause
of thiamine refractoriness in WernickeKorsakoff
encephalopathy. J Neurol Neurosurg Psychiatry
1974;37:95962.
19. Serdaru M, Hausser-Hauw C, Laplane D, et al. The
clinical spectrum of alcoholic pellagra encephalopathy.
A retrospective analysis of 22 cases studied
pathologically. Brain 1988;111:82942.
20. Uchino A, Yuzuriha T, Murakami M, et al. Magnetic
resonance imaging of sequelae of central
pontine myelinolysis in chronic alcohol abusers.
Neuroradiology 2003;45:87780.
21. Martin RJ. Central pontine and extrapontine
myelinolysis: the osmotic demyelination syndromes.
J Neurol Neurosurg Psychiatry 2004;75(Suppl 3):228.
22. Gerlach A, Oehm E, Wattchow J, et al. Use of highdose cortisone in a patient with MarchiafavaBignami
disease. J Neurol 2003;250:75860.
23. Riordan SM, Williams R. Gut flora and hepatic
encephalopathy in patients with cirrhosis.
N Engl J Med 2010;362:11402.
24. Jover R, Compay L, Gutirrez A, et al. Minimal hepatic
encephalopathy and extrapyramidal signs in patients
with cirrhosis. Am J Gastroenterol 2003;98:1599604.
25. Brown SA, Schuckit MA. Changes in depression
among abstinent alcoholics. J Stud Alcohol
1988;49:41217.
26. Brower KJ, Aldrich MS, Robinson EA, et al. Insomnia,
self-medication, and relapse to alcoholism.
Am J Psychiatry 2001;158:399404.
27. McIntosh C, Chick J. Alcohol and the nervous system.
J Neurol Neurosurg Psychiatry 2004;75(Suppl 3):1621.

28. Koike H, Iijima M, Sugiura M, et al. Alcoholic


neuropathy is clinicopathologically distinct from
thiamine-deficiency neuropathy. Ann Neurol
2003;54:1929.
29. Scholz E, Diener HC, Dichgans J, et al. Incidence of
peripheral neuropathy and cerebellar ataxia in chronic
alcoholics. J Neurol 1986;233:21217.
30. Harper C. The neuropathology of alcohol-related brain
damage. Alcohol Alcohol 2009;44:13640.
31. Gilman S, Adams K, Koeppe RA, et al. Cerebellar
and frontal hypometabolism in alcoholic cerebellar
degeneration studied with positron emission
tomography. Ann Neurol 1990;28:77585.
32. Sullivan EV, Pfefferbaum A. Neurocircuitry in
alcoholism: a substrate of disruption and repair.
Psychopharmacology (Berl) 2005;180:58394.
33. Gupta S, Warner J. Alcohol-related dementia:
a 21st-century silent epidemic? Br J Psychiatry
2008;193:3513.
34. Popoola A, Keating A, Cassidy E. Alcohol, cognitive
impairment and the hard to discharge acute hospital
inpatients. Ir J Med Sci 2008;177:1415.
35. Fein G, Torres J, Price LJ, et al. Cognitive performance
in long-term abstinent alcoholic individuals.
Alcohol Clin Exp Res 2006;30:153844.
36. Crawford MJ, Patton R, Touquet R, et al. Screening
and referral for brief intervention of alcohol-misusing
patients in an emergency department: a pragmatic
randomised controlled trial. Lancet 2004;364:13349.
37. Kaner EF, Beyer F, Dickinson HO, et al. Effectiveness
of brief alcohol interventions in primary care
populations. Cochrane Database Syst Rev
2007;2:CD004148.
38. Mattick RP, Kimber J, Breen C, et al. Buprenorphine
maintenance versus placebo or methadone
maintenance for opioid dependence.
Cochrane Database Syst Rev 2008;2:CD002207.
39. Leon DA, McCambridge J. Liver cirrhosis mortality
rates in Britain from 1950 to 2002: an analysis of
routine data. Lancet 2006;367:526.
40. Raistrick D. Management of alcohol detoxification.
Adv Psychiatr Treat 2000;6:34855.

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