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Alcohol Withdrawal Syndrome (AWS)

Discuss the pathogenesis of alcohol withdrawal?
Chronic alcohol intake down regulates the inhibitory GABA pathway as well as the excitatory pathways (glutamate neurotransmission). Alcohol withdrawal reverses the excitatory pathway inhibition while the GABA inhibition persist leading to the symptoms of alcohol withdrawal.
What are the symptoms of alcohol withdrawal?
The alcohol withdrawal syndrome may be a continuum from simple tremulousness through hallucinosis in a clear sensorium to seizures and most severe delirium tremens. The AWS can therefore be grouped into four sets of symptoms:

Uncomplicated Alcohol withdrawal Alcoholic Hallucinosis Withdrawal seizures Delirium Tremens
Onset 6-36 hours 12-48 hours 6-48 hours 48-96 hours
Symptoms • Tremulousness • Sweating • Fever, with or without infection • Nausea, vomiting, retching • Anxiety • Agitation • Irritability • Anorexia • Insomnia • Tachycardia • Mild systolic hypertension Visual, auditory or tactile hallucinations with intact sensorium (Unlike DT where sensorium is impaired) Grand mal seizures usually single or as a brief flurry over a short period.
Untreated can progress to DT in 1/3 rd of cases
• Auditory and visual hallucinations • Clouding of consciousness • Confusion and disorientation • Delusions • Severe tremor • Tachycardia • Agitation • Fever > 38.3°C • Profound symptoms of autonomic over activity (as in uncomplicated alcohol withdrawal)
Other Symptoms that occur within a few hours, even if severe, are not manifestations of DT.
It may resolve within 72 hours or go on to progressive stages of withdrawal
DT and Alcoholic hallucinosis are not synonymous Recurrent or prolonged seizures are unusual and should prompt investigations (CT scan/LP) Symptoms of DT last 1-5 days.
Untreated, DT is fatal in 15-20% cases, mostly from arrhythmias or cardiovascular or respiratory failure.

Who would you consider for treatment?

  • Patients having symptoms of AWS as listed above.
  • Patients should also be considered for treatment, if they do not have symptoms of AWS but are at risk of developing severe AWS. The risk factors are:
    • High alcohol intake ( > 15 units/day)
    • Previous history of severe withdrawal, seizures and/or DTs
    • Concomitant use of other psychotropic drugs
    • Poor physical health
    • High levels of anxiety
    • Other psychiatric disorders
    • Hypoglycaemia
    • Hypokalaemia
    • Hypocalcaemia
    • Fever
    • Sweating
    • Insomnia
    • Tachycardia.

Discuss the role of benzodiazepine in the treatment of AWS?

  • Benzodiazepines are used to control psychomotor agitation and prevent progression to more severe withdrawal.
  • The oral long-acting benzodiazepines, chlordiazepoxide and diazepam, are preferred as they have both a long half-life and a smoother more protracted effect.
  • Oral chlordiazepoxide is the drug of choice as it has a lower potential for abuse than diazepam.
  • Chlordiazepoxide 5mg is approximately equivalent to diazepam 2mg.
  • Oxazepam and lorazepam are benzodiazepines with shorter half life that are not significantly metabolised by the liver so are preferred for patients with liver failure as there is a lower risk of accumulation.
  • 0.5 mg of lorazepam is roughly equivalent to 5 mg of diazepam

Discuss the management of AWS?

  • Baseline tests- All patients should have FBC, U&E, LFT, Magnesium, phosphate, Blood glucose, clotting, B12 and folate.
  • Chlordiazepoxide- The aim of treatment is that the patient is calm and sedated but easily aroused. The dose should be tailored to each patient dependent upon symptoms. A total daily dose of 120mg chlordiazepoxide (given at 6-hourly intervals) on day one is usually appropriate, with additional prn (5mg to 10mg) doses available for breakthrough symptoms. The total daily dose is then steadily reduced to zero over a number of days (5-10 days). Use the regime applicable to your trust. Some patients may need massive doses of benzodiazepines while other agitated patients may need intravenous benzodiazepines. A few patients with refractory DTs may need intubation and ventilation. Diazepam can also be administered rectally.
  • Thiamine- All patients undergoing alcohol withdrawal or treatment for AWS should be treated prophylactically for WE. If any signs of WE is present, treatment doses of thiamine should be administered (see WE below). Multivitamin tablet should also be started.
  • Seizures- use IV benzodiazepines. There is little evidence to support the use of conventional anti-epileptics in the prophylaxis or treatment of seizures arising as a result of acute alcohol withdrawal.
  • Supportive care
    • Hydration- most patients are hypovolemic as a result of sweating, hyperthermia, vomiting, and tachypnea. Patients with DTs may lose up to 6 litres of fluid in a day.
    • Electrolytes-Low K, Mg and PO4 is common and should be corrected
    • Alcoholic Ketoacidosis- may occur in a non-diabetic alcohol abuser who is malnourished. Restoration of fluid balance with glucose-containing saline solution is usually effective
    • Patients should be placed in a quiet environment. Mechanical restraint may be temporarily needed to protect the patients and staff.

Wernicke’s encephalopathy (WE)
Discuss WE?
WE is a reversible biochemical lesion of the CNS caused by overwhelming metabolic demands being made upon depleted B-vitamin reserves, in particular thiamine (B1). Although, usually associated with chronic alcoholism, WE can occur in the setting of poor nutrition caused by any other condition. It has been shown to occur in 12.5% of alcohol misusers. It is fatal in 17% of inappropriately managed patients. Permanent brain damage (Korsakoff’s psychosis) occurs in 85% of inappropriately managed survivors, 25% of whom require long-term institutionalisation.

Discuss the pathogenesis of WE?

  • Caused by acute and severe CNS deficiency of thiamine (chronic def lead to Beri beri)
  • Thiamine is a cofactor for several key enzymes important in energy metabolism and production of ATP
  • Alcohol withdrawal causes CNS over activity leading to increased need for thiamine.
  • Thiamine deficiency cause brain cell death by inhibiting metabolism in brain regions with high metabolic requirements and high thiamine turnover.
  • WE may be precipitated in susceptible patients by administration of intravenous glucose before thiamine supplementation (glucose lead to utilisation of thiamine)
  • Thiamine deficiency in alcohol abusers results from inadequate intake and reduced GI absorption. Thiamine absorption is significantly reduced in malnourished alcoholic abusers. Thus parenteral treatment is needed.

Discuss the clinical features of WE?

  • Mental changes- confusion, disorientation, inattentiveness, drowsiness, obtundation, semi coma, coma. Mental changes are most common and may be the only sign of WE. These changes are however non specific and may be caused by alcohol intoxication or withdrawal.
  • Oculomotor- nystagmus, lateral rectus palsy, conjugate gaze palsy
  • Gait- wide based gait with small steps. When severe- walking may not be possible
  • Hypotension and hypothermia

Discuss the diagnosis of WE?

  • The classic triad of WE includes acute confusion, ataxia and ophthalmoplegia. However the triad is present in only 10% of patients with WE. Thus if the classic triad is used for diagnosis, WE will be missed or the diagnosis will be delayed till the classic triad becomes obvious.
  • A high index of suspicion is therefore needed and the presence of only one sign should be sufficient to assign a diagnosis and commence treatment.
  • Untreated WE- most patients progress to coma and death. IV thiamine is safe and effective. Thus treatment takes priority over diagnosis. Response to thiamine may be diagnostic.
  • The diagnosis should be based on the presence of any one or more of the following signs:
    • Acute confusion
    • Decreased consciousness level including unconsciousness or coma
    • Memory disturbance
    • Ataxia/unsteadiness
    • Ophthalmoplegia
    • Nystagmus
    • Unexplained hypotension with hypothermia.

Discuss treatment?
Treatment is required where WE is suspected or as prophylaxis in patients at high risk. All patients undergoing alcohol withdrawal or treatment for AWS should be treated prophylactically.

  • Treatment of WE
    • Oral B-vitamin replacement is both inadequate and ineffective owing to limited gastrointestinal absorption in alcohol misusers. Parenteral B-vitamin replacement is therefore required
    • Dosage Pabrinex (2 ampoule pairs) tds for 2 – 3 days followed by:
      • Pabrinex OD for 3 to 5 days
      • Then Thiamine Oral 100mg TDS for 1 week then thiamine 100mg OD
      • Multivitamin (One a day) OD
  • Prophylaxis against WE
    • Dosage Pabrinex OD for 3 to 5 days (each paired ampoule of pabrinex contains 250 mg of thiamine beside other vitamins)
    • Then Thiamine Oral 100mg TDS for one week , then thiamine 100mg OD
    • Multivitamin (One a day) OD
  • There are no RCT to support any particular dosing regimen. However high doses are justified based on reports of failed clinical improvement in WE with low doses.
  • 100mg OD of thiamine should be continued after discharge until patients are no longer considered at risk. (NB- dietary requirement of thiamine is only 1-2 mg daily)
  • There is a small risk (1 in 1 million IV doses) of anaphylaxis with parenteral thiamine.

Discuss laboratory abnormalities in WE?

Atrophy of the mamillary bodies on MRI is a highly specific finding in WE and Korsakoff syndrome and is present in most cases and can be detected within a week of onset of WE.


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