**5. Alcohol withdrawal syndrome**

AWS can be considered a spectral illness, ranging from early/mild to late/severe, with additional complications, including delirium tremens (DT) and possibly Wernicke's Encephalopathy (WE) and Wernicke-Korsakoff Syndrome (WKS) which are generally considered to be secondary to thiamine (vitamin B1) deficiency. WE is often reversible with prompt recognition and treatment but can progress to the less reversible WKS if inadequately treated. It is important to realize that for patients with mild AUD, symptoms may never progress beyond mild, while for patients with severe AUD, early withdrawal may start with severe symptoms and rapidly progress. Additionally, DT is an entirely avoidable phenomenon and results from either late presentation or suboptimal treatment.

#### **5.1 Mild: moderate AWS**

In classic AWS, patients typically become symptomatic 6-hours after their last drink (or if they have significantly decreased their ethanol intake) but can take up to 24-hours before they become apparent [16]. Symptoms may begin mildly or can abruptly start as more severe grades of AWS [17]. Nausea, vomiting, and diaphoresis are common, as well as tremors, headaches, anxiety, and insomnia. Autonomic dysfunction may develop as well, including hypertension, tachycardia, and hyperthermia. It is important to recognize that patient's taking certain medication classes, such as beta-blockers or alpha-2 agonists, may mask their autonomic dysfunction [17]. Tactile, auditory, and visual hallucinations may be present in up to 25% of AWS patient's, however patient's sensorium often remains intact (as opposed to in alcoholic hallucinosis or organic psychosis) [17]. Mild to moderate AWS usually dissipates between 2 and 7 days and often without treatment [17]. These patients may not even present to healthcare facilities for evaluation or treatment and it is likely an underdiagnosed phenomenon.

#### **5.2 Moderate: severe AWS**

Moderate-severe AWS includes many of the symptoms described in mild-moderate AWS; however, symptoms are severe and may be refractory to treatment. Classic symptom (tachycardia, hypertension, tremor, nausea, vomiting, diaphoresis, anxiety) are notably worse and will likely require more aggressive treatment regimens. Hallucinations may become persistent, progressing into alcoholic hallucinosis (AH). AH occurs in up to 8% of patients and typically 12- to 24-hours after a patient's last drink [18, 19]. Neuroleptic medication has been shown to worsen hallucinations in AH and should be avoided [19].

Wernicke's Encephalopathy, the triad of confusion, ophthalmoplegia, and cerebellar symptoms (such as ataxia), may also become apparent in moderate-severe AWS. Seizures can occur in up to 10% of patients with AWS [17]. AWS seizures generally occur 24- to 48- hours after alcohol cessation. Seizure activity includes generalized tonic-clonic jerks and can lack a post-ictal period [17, 18]. AWS seizures are notoriously difficult to treat with traditional antiepileptic agents and may portend a worse prognosis, including progression into delirium tremens, a form of agitated delirium, the most severe manifestation of AWS [17]. Often escalating doses of BZD and other adjunct therapy is needed in these cases, and intensive care management may be warranted.

#### **5.3 Delirium tremens**

Delirium Tremens (DT), a form of agitated delirium, is the most severe form of AWS and occurs in up to 5% of patients [19–21]. Symptoms generally occur in the 2–4-day time range from a patient's last known ingestion. DT as a syndrome includes severe, rapid changes in cognition, memory, consciousness, and perception in addition to extreme autonomic distress including malignant hypertension and hyperthermia [17, 20]. Hallucinations, disorientation, psychosis, and coma are hallmarks of DT. Symptoms are generally refractory to treatment, may last up to one week or longer, and may be lethal. The mortality rate for DT is between 1% and 5%, generally secondary to medical complications such as aspiration or myocardial infarction [17]. Treatment for DT requires the maximum therapeutic options available to treating clinicians. Aggressive BZD dosing (often defined as >20-40 mg diazepam or equivalent per hour for severe CIWA or SEWS), phenobarbital, and adjunct therapies such as dexmedetomidine, propofol, or ketamine may be necessary. Endotracheal intubation and intensive care management are sometimes needed for patients with DT. Ultimately, DT is the most severe form of AWS and causes substantial morbidity and mortality. From a patient safety perspective, it is important to realize that DT is not a routine outcome of the spectrum of alcohol withdrawal and can be completely prevented with early, adequate treatment of AWS [22].
