Acute

Chronic

Intoxication

The acute CNS effects of alcohol are familiar across the globe and include emotional instability impaired judgement, 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 depression 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).

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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).

Blackouts

The term ‘blackouts’ refers to episodic amnesia experienced after acute intoxication and usually indicates that serum alcohol concentrations have been significantly high. Although historically, blackouts have indicated ‘alcoholism’, it is now clear that they happen in 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 probably 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 significant 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 hippocampus.24 Studies measuring blood alcohol concentrations 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 downregulated GABA receptors and upregulated NMDA receptors in the absence of alcohol. The relative deficiency of GABAergic effects and excessive glutamatergic stimulation 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 guidelines recommend giving symptom-triggered benzodiazepines 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 characterised by the acute onset of hallucinations, agitation, autonomic hyperactivity, hand tremulousness and nausea. Visual hallucinations are most common, classically in the form of Lilliputian hallucinations of 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 electrolyte 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 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. Escalation to use of antiseizure medications and, if necessary, 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 medication 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 antiseizure 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 concentrations of long-term antiseizure medication may help to ensure adherence; ready access to laboratory facilities may influence the choice of antiseizure medication 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-induced 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-induced psychotic disorder, prominent psychotic symptoms occur during or shortly after intoxication or withdrawal from alcohol, and symptoms should be more than those usually found in alcohol intoxication 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-disorder typically seen in other forms of psychosis, but around 10% may have features of delirium in the acute stage of the disorder. Alcohol-induced psychotic disorder tends to occur later in life and has a better prognosis than other psychoses. Among 61 inpatients, the mean 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-related psychosis, highlighting risk of recurrence. There is no clear consensus on the nature of alcohol-induced psychotic disorder; some highlight similarities with delirium tremens, for example, a tendency towards physical symptoms and slight clouding of consciousness, and others favour a conceptualisation 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 standard treatment, but improvement usually requires abstinence from alcohol and use of antipsychotic drugs to treat psychotic symptoms. Some have suggested that initial treatment with benzodiazepines helps in only some cases.35

Alcohol-related brain damage

Alcohol-related brain damage is the unofficial, but widely-used term encompassing a wide spectrum of pathology and cognitive impairment related to 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 definition can sometimes create difficulties. DSM-V classifies alcohol-related cognitive disorders as mild and severe alcohol-related neurocognitive disorder, amnestic and non-amnestic38 (see online supplemental case 1). This diagnosis is supported by other signs of long-term systemic effects of alcohol, for example, cirrhosis, ataxia or peripheral sensory 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 exposure to alcohol.39

Pathophysiology

In alcohol-related brain damage, the frontal lobes appear particularly vulnerable to glutamate excitotoxicity, oxidative stress and disruption of neurogenesis.40 Cycles of bingeing and withdrawal probably predispose to upregulation of NMDA receptors and effects on cholinergic transmission in the basal forebrain. 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)

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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.

Wernicke/Korsakoff’s

Wernicke’s syndrome classically represents the acute effects of CNS nutritional deficiency whereas Korsakoff’s represents the chronic effects. However, 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 susceptible 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.

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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 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.

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 nutritional deficiency due to pyloric stenosis. This highlights 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 malabsorption from any cause, including hyperemesis gravidarum and malignancy. People with alcohol dependence are at particular risk of Wernicke’s due to poor nutrition, decreased capacity for hepatic nutrient storage and decreased vitamin absorption. A diagnosis of Wernicke’s is based on Caine’s classification requiring two of four features of dietary deficiency, eye signs (ranging from subtle nystagmus to complete ophthalmoplegia), cerebellar dysfunction 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-specific, it is a good practice to treat prophylactically if alcohol dependence 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 to thiamine deficiency. The most important contributory 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 confabulation. 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 mechanisms for the effects of alcohol on the cerebellum.55 They lead to neuropathological effects more prominent in the cerebellar vermis, and clinical effects more prominent in assessment of gait and the lower limbs. The clinical features of a cerebellar ataxia may be exacerbated by a coincident peripheral neuropathy.

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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).

Marchiafava–Bignami disease

This is a rare and poorly understood clinical constellation first described in the early 20th century. The most common features include personality change, encephalopathy, 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 interhemispheric transference of unilateral somatosensory stimulation of both hands.57 Other features of the damage wrought by alcohol can include longstanding cognitive decline, gait problems and incontinence. Focal neurological 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 ultimately 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 similar lesions may also develop in the corticospinal tracts, cerebellar peduncles and the hemispheric white matter. Treatment involves avoiding alcohol and nutritional replacement with thiamine alongside B12 and folate. Some have suggested that prognosis is better in those with unimpaired level of consciousness.58

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Figure 5

(A,B) MR scan of brain (sagittal and coronal) showing corpus callosal changes of Marchiafava-Bignami disease. Images courtesy of Radiopedia.

Osmotic demyelination

Patients with chronic excessive alcohol consumption 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 demyelination in some white matter tracts, most evident in the pons. A recent review of clinical and neurological features listed signs including most commonly encephalopathy and dysphonia (50%), less so with extrapyramidal symptoms and seizures. Neuroimaging results (figure 6) showed central pontine myelinolysis 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 incidentally during later imaging.61

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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.

Fetal alcohol spectrum disorder

The frequency and severity of this condition merits further consideration. Given the range of neurochemical effects exerted by alcohol, it is not surprising that prenatal exposure to alcohol affects the developing brain. Fetal alcohol spectrum disorder describes a spectrum 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 underestimate, 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.

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 there is persisting disorientation or encephalopathy, 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.

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 encephalopathy.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 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).

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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).

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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.

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.