Multiple assessment scales have been devised for evaluation of withdrawal symptoms [3, 5, 12]. The most commonly utilized scale to quantify the severity of alcohol withdrawal is the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar). The CIWA-Ar is a ten item questionnaire, which scores withdrawal severity in a range of 0–67. Scores 0–8 indicate absent to minimal withdrawal, 9–15 moderate withdrawal, and scores greater than 16 demonstrate severe withdrawal [8].

Most patients require ICU care for symptomatic treatment for scores greater than 15–20 [12, 13]. Use of the CIWA-Ar scale for symptomatic guidance of therapy in the critical care setting may be difficult in mechanically ventilated patients not able to verbalize responses appropriately. This may potentially lead to falsely inflated scores and subsequent medication over-administration, as symptoms of comorbid critical illness may be erroneously misinterpreted as withdrawal symptoms; or to delay in appropriate critical care, as symptoms and signs are attributed to alcohol withdrawal [5].

The Prediction of Alcohol Withdrawal Severity Scale (PAWSS ) has also been developed and utilized in conjunction with the CIWA-Ar scale as a clinical prediction scale to define patients which are more likely to suffer from complicated alcohol withdrawal syndrome. The questionnaire has threshold criteria of alcohol use within 30 days; if patients meet this requirement they are screened into receiving the questionnaire; and are given points for previous episodes of severe intoxication, blackouts, delirium tremens, seizures, comorbid substance use, and previous alcohol rehabilitation treatment. Points are also given for meeting clinical criteria of BAL>200 mg ethanol/deciliter, or evidence of autonomic hyperactivity.

Patients with PAWSS< 4 are considered at low risk for complicated alcohol withdrawal syndrome; scores of PAWSS ≥4 are considered at high risk for complicated alcohol withdrawal syndrome. The study by Maldonado et al. suggested that using a PAWSS cutoff score of 4 led the scale to have a sensitivity for identifying complicated alcohol withdrawal syndrome of 93.1%, specificity of 99.5%, positive predictive value of 93.1%, and negative predictive value of 99.5% [12].

Alcohol-related seizures (ARS) are a frequent occurrence in the critical care setting, and appropriate recognition and management may help decrease length of stay and improve morbidity and mortality outcomes in that patient population. Seizures are found to occur predominately in the setting of alcohol withdrawal due to the neurochemical adaptive changes, which manifest secondary to chronic alcohol usage [5, 6, 8, 14, 15]. Seizures related to alcohol withdrawal usually occur prior to the onset of delirium tremens, (i.e., at onset of admission up to 72 h, and usually within a 5 day period of admission). In previous literature reviews, questions have been raised as to whether there is an actual association between alcohol withdrawal seizures and delirium tremens; or if these are of overlapping, but independent pathologies [5, 11].

Seizures may also occur during episodes of severe intoxication. While this may be less commonly encountered, this must remain in the differential diagnosis of the severely intoxicated patient who remains unarousable, or has focality in their neurologic exam. Patients with history of previous head trauma or previous intracranial pathology, toxometabolic abnormalities, renal or hepatic dysfunction, increased age (>60), or history of epilepsy may be more prone to seizures during acute alcohol intoxication. Cerebral atrophy combined with coagulopathy secondary to bone marrow suppression and hepatic dysfunction occurring with severe, prolonged alcohol use may lead to predisposition to development of subdural or epidural hematomas, leaving one vulnerable to alcohol-related seizures. Acute hepatic failure due to severe alcohol intoxication may also result in seizures, cerebral edema, coma, and death. Profound hyponatremia associated with chronic alcohol use may also lead to seizures during severe intoxication. Thorough laboratory workup including biochemical profile, blood counts, coagulation profile, liver profile, ammonia level, blood glucose levels, along with blood alcohol level, and arterial blood gases may be key in directing and predicting risk of seizures .

In the normal brain, there exists a carefully orchestrated balance between excitatory and inhibitory neurotransmission. Alcohol withdrawal produces not only changes in the autonomic system (which may result in hypertension, tachycardia, or psychomotor agitation), but also changes which may lead to seizures and coma. Alcohol acts as a central nervous system depressant. Acute alcohol ingestion causes up regulation and potentiation of the inhibitory γ-aminobutyric acid (GABA) pathway on efferent neurons and inhibition of the excitatory N-methyl-D-aspartate (NMDA) receptors, resulting in significant CNS sedation [3]. As an adaptive mechanism, chronic use of alcohol results in down regulation of the GABA pathway, causing a decrease in the number and sensitivity of GABA receptors as well as reduction in endogenous levels of GABA [16].

Over time, in order to produce the same levels of CNS sedation, an increased concentration of alcohol is needed (usually resulting in increased amounts of alcohol ingestion). This phenomenon is known as tolerance [8, 11]. In parallel, compensatory increases in the activation of the excitatory glutamate pathways also occur, resulting in up regulation of NMDA receptors and increased levels of glutamate [3, 5, 8, 16, 17].

Abrupt cessation or reduction in chronic alcohol intake in a patient who has become physiologically dependent on alcohol creates an imbalance in the CNS, with unopposed excitation resulting in hyperactivity of the autonomic system, leading to withdrawal symptoms, and potentially to alcohol withdrawal seizures [8]. All of these changes over time lead to neuroplastic changes in the mesocorticolimbic system and the extended amygdala, which result in the strengthening of the compulsivity and relapse behaviors present during withdrawal phases in order to avoid manifestation of withdrawal symptoms [16].

Alcohol withdrawal in itself can also potentiate hippocampal neuronal loss and can lead to a kindling effect which may lead to increased severity of future episodes of alcohol withdrawal, ultimately negative impacting memory and cognitive functioning [12].

In individuals where there is a suspected history of chronic alcohol use and impending withdrawal is predicted to occur, coverage with oral or IV benzodiazepines should be utilized to prevent withdrawal symptoms and ultimately seizures for at least a 7 day course. Patients may be considered for therapy, if daily consumption reaches ten beverages in a female or 15 beverages in a male (with each beverage containing ~8 g of ethanol), history of recent withdrawal symptoms or history of withdrawal seizures, recent heavy binge drinking (greater than 20 drinks or 160 g of ethanol daily for longer than 7 days) [15].

Genetic predisposition to alcohol intolerance may self-select some individuals from engaging in ingestion of excessive amounts of alcohol or vice versa.

Genetic polymorphisms of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), two enzymes involved in alcohol metabolism may contribute to the variability in tolerance and abuse of alcohol in different patient populations across the world [15]. Most often seen in Asian populations, individuals with these variants (specifically in ALDH2*2 allele (Glu504Lys)) often have low alcohol tolerance and experience a flushing syndrome and palpitations [18]. This may affect up to 40% of Chinese, Korean, and Japanese populations, and may result in lower levels of alcohol abuse, withdrawal, and presence of alcohol-related seizures, which, if they occur, may be secondary to comparatively lower consumption amounts.

Polymorphisms in ALDH1A1 and ALDH1B1 enzymes have been associated with alcohol consumption in Finnish and Danish populations, respectively [18]. There have been a significant number of genes, and gene polymorphisms which have been implicated in the development of alcohol dependence, predisposition for withdrawal symptoms and alcohol-related seizures.

A specific cluster of 58 genes has been identified by Morozova et al. in networks that were significantly enriched for alcohol metabolism and biotransformation . Some of these genes include GRIA1 and GRIA4, which encode ionotropic AMPA 1 and 4 glutamate receptors, and GRIN1, GRIN2B, and GRIN2C, which encode NMDA ionotropic glutamate receptor subunits 1, 2B, and 2C, indicating the importance of glutamatergic transmission as a central role in alcohol abuse, dependence, and withdrawal. Further studies need to be conducted in order to develop genetically tailored therapies, or at least genetic mapping to identify individuals likely to engage in alcohol abuse behaviors [18].

Multiple additional genetic factors regarding predisposition to dependence and withdrawal have been studied in rats and other small animals. In rats, low levels or pharmacological blockade of mGluR2 mRNA were found to increase alcohol intake, and alcohol seeking behavior. In post-mortem evaluation of frontal cortex samples of alcohol-dependent patients, presence of decreased expression of metabotropic glutamate receptor mGluR2 mRNA was found to be prevalent, which may act as a marker of alcohol dependence [16]. In the complex environment of the ICU, how much these and additional genes, interacting with each other and with the medications administered, lead to seizure development, is unknown.

Based on the aforementioned, seizures in the alcoholic patient may be multifactorial. As noted previously, patients admitted and found to have severe alcohol withdrawal symptoms may suffer from alcohol withdrawal seizures at a rate of 5–17%. Alcohol abusers may ultimately also suffer from a significant number of medical comorbidities which may leave them prone to having seizures for other reasons. Often times, these individuals may concurrently suffer from anxiety, depression, or other psychiatric disorders . They may be prescribed anxiolytics, opioids, and antipsychotics, and may additionally be abusing other substances. An emergency toxicology screen and STAT CT head as well as EKG, and lab work including complete blood count, biochemical profile, electrolytes, ammonia, troponin, lipase, amylase, blood glucose, and infectious workup should always be obtained. Consideration should additionally be made for lumbar puncture , if the clinical picture and patient history indicate a diagnosis of meningitis, which should be treated without delay.

Acute systemic comorbidities , such as electrolyte disturbances (hypomagnesemia, hyponatremia, hypoglycemia), diabetic ketoacidosis, uncontrolled hypertension, myocardial infarction, immunosuppression leading to infectious processes (bacteremia, urinary tract infections, pneumonia), and respiratory depression or insufficiency or central nervous system comorbidities, such as infections (including meningitis, encephalitis, brain abscess), previous or concurrent ischemic or hemorrhagic strokes, traumatic brain injury, tumors and other intracranial pathologies, may all lead to decrease the threshold for seizures in the context of alcohol withdrawal.

Chronic alcohol abuse may lead to a host of systemic medical issues. Neurologic manifestations of major concern may include Wernicke’s encephalopathy (triad of ataxia, confusion, and ophthalmoplegia), secondary to thiamine deficiency, which may progress to Wernicke-Korsakoff syndrome, a later manifestation which further includes confabulation and memory loss. Prophylactic treatment with IV thiamine and folic acid should be administered on admission, and prior to administration of any dextrose containing solution, as glucose oxidation is dependent on thiamine, and in case of thiamine deficiency may lead to worsening of neurologic injury. Treatment of hypomagnesemia which usually accompanies low thiamine levels is necessary, as low magnesium levels may hinder thiamine absorption.

Additional neurologic manifestations may include profound neuropathy, burning mouth syndrome (from thiamine deficiency), myopathy, severe memory impairment, difficulty with executive decision processes, insomnia, tremors, and profound ataxia from cerebellar degeneration.

Cardiac abnormalities include development of alcohol-related cardiomyopathy, electrolyte disturbances resulting in arrhythmias (from profound hypokalemia and hypomagnesemia), or elevated risk for cardiovascular disease including hypertension, hypertriglyceridemia, and myocardial infarction.

Gastrointestinal disturbances may include gastric or duodenal ulcers, alcoholic hepatitis, cirrhosis, fulminant liver failure leading to death, coagulopathies, pancreatitis, esophagitis, esophageal varices, as well as esophageal, pancreatic, and liver cancers. Risk of re-feeding syndrome due to malnutrition (which may also be suggested by hypomagnesemia, hypokalemia, and hypophosphatemia) must be considered.

Bone marrow suppression or hypersplenism from cirrhosis may be prominent in these patients, and caution should be taken to evaluate for thrombocytopenia prior to performing any procedures. By the same token, if there is concern for infectious process, consideration should be made to provide broad spectrum coverage with antibiotics.

Changes in hormonal balance may also occur, and males may suffer from low testosterone, gynecomastia, and erectile dysfunction. Females may suffer from irregular menses, spontaneous abortions, and births of infants with risk of fetal alcohol syndrome, if alcohol use is continued during pregnancy.

Some studies have proposed that ARS are more common in patients that have been repeatedly detoxified from alcohol, as opposed to chronic abusers with abrupt cessation . Postulation of increased rate of withdrawal seizures in repeatedly detoxified patient relies on the kindling model of seizure activity in alcoholic individuals [19]. Individuals who imbibe greater than 50 g of ethanol daily are at higher risk of developing alcohol withdrawal seizures [15]. Patients with history of repeated binge drinking are at less of a risk of developing ARS than the above two groups, unless they have a history of previous post-traumatic epilepsy or idiopathic epilepsy, which may make even moderate amounts of alcohol intoxication lower the seizure threshold, and may increase the ability for these patients to seize.

Previous reviews have identified clinical predictors of those more likely to suffer from severe alcohol withdrawal syndrome and ARS. These include having had previous documented episodes of delirium tremens; previous documented ARS; higher ALT on admission (clinical predictor of severe alcohol withdrawal), higher γ-GT (clinical predictor for ARS), hypokalemia, and or thrombocytopenia on admission [11]. ARS usually precede delirium tremens. Seizures after the 5–7 day post-withdrawal period should be investigated for alternative comorbidities, including intracranial pathology, infection, hypoxemia, metabolic disturbance (electrolyte or blood glucose), or drugs which may decrease the threshold for seizures.

Most ARS are of generalized onset (80%), and manifest as generalized tonic-clonic seizures, with some studies reporting partial onset seizures in 8.3–22%. Some of these patients may have overlapping underlying localization related epilepsy, idiopathic generalized epilepsy, or post-traumatic epilepsy. MRI brain with and without gadolinium and with epilepsy protocol should be obtained on patients with any focality found on the clinical examination or the EEG to help differentiate whether there is an underlying organic pathology, which may have been exacerbated by alcohol withdrawal [20–27].

Rarely, ARS progresses into status epilepticus . Patients should be placed on continuous EEG monitoring, and consideration should be made for airway protection with intubation if seizures persist. Evaluation for underlying pathology (infectious or intracranial pathology) via imaging and CSF analysis should be obtained. Rare cases of non-convulsive status epilepticus (NCSE) have also been reported. If obtundation persists despite normalization of BAL and correction of toxometabolic abnormalities, consideration for NCSE should be made. Continuous EEG should be initiated and AED treatment administered if findings are indicative of seizure activity.

A proposed condition of subacute encephalopathy with seizures in alcoholics (SESA ) has been recognized in rare cases, and has been proposed as a new subset of NCSE. Less than ten cases have been reported. First described in the 1980s, case reports describe chronic alcoholics presenting with confusion, persistent encephalopathy despite toxometabolic workup, intermittent unilateral weakness or jerking (in some cases) and presence of persistent ictal activity on EEG, or presence of periodic lateralized epileptiform discharges (PLEDS ). SESA has been postulated as a variant of NSCE which has gone unrecognized in the alcohol population thought of to have had a single seizure with prolonged post-ictal state (which may have been NCSE, just not recorded on EEG). MRI findings may demonstrate T2 hyperintensities on FLAIR , and DWI changes which may resolve. It has been postulated that the pathophysiology of SESA is similar to that of PRES, as FLAIR and DWI changes have been shown to resolve in some case reports, with resolution of ictal activity. While only a few cases have been reported; if this indeed is responsible for the suspected “prolonged post ictal state” found in many alcoholics with seizures, SESA NCSE may responsible for a larger number of cases of unexplained prolonged encephalopathy than previously thought.