Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Alcohol withdrawal seizures are frequently encountered in the emergency room as a severe manifestation of alcohol withdrawal syndrome. Such seizures comprise acute and serious complications to chronic alcohol abuse that need immediate attention. However, alcohol withdrawal is often neglected as a possible cause of seizures, and the consequences of misdiagnosis include significant morbidity and mortality as well as missing other potentially catastrophic neurologic complications of chronic alcohol dependence such as Wernicke encephalopathy and Korsakoff psychosis. Thus, in addition to benzodiazepines as the first choice in the pharmacological management of such seizures, all such patients should be given thiamine during hospitalization, regardless of nutritional state. In this article, the authors explain the clinical presentation, pathophysiology, diagnostic work-up, and management of alcohol withdrawal seizures and provide clues to the differentiation of withdrawal seizures from seizures due to epilepsy.
• Alcohol withdrawal is a major seizure-precipitating factor. All adult patients arriving to the emergency room with a seizure should be questioned about alcohol intake history.
• Drinking history is essential; biomarkers such as GGT and CDT may be useful ancillary aids to diagnosis.
• A history of epilepsy prior to alcohol abuse is suggestive of seizures triggered by alcohol abuse instead of alcohol withdrawal seizures and management may vary accordingly.
• Existing alcohol-related liver damage is an important consideration in choice of antiepileptic drug treatment.
• Benzodiazepines are safe and effective in alleviating both seizures and general withdrawal symptoms as well as preventing further seizures. High initial doses may be necessary, but treatment should be discontinued within a week. Barbiturates have been shown to be effective in acute severe withdrawal syndrome.
• Parenteral thiamine should be given before any carbohydrate-containing fluids or food.
• The recommended initial preventive thiamine dose is 200 mg; if Wernicke encephalopathy is suspected, give 200 mg 3 times daily for at least 2 days.
• Investigation of first seizures must include neuroimaging.
The relationship between alcohol and seizures was first mentioned by Hippocrates (30), as well as by the Romans, who even put a name to it, morbus convivialis, or “disorder related to partying” (27). Centuries later, Magnus Huss introduced the term “alcoholismus chronicus” in 1851 and showed that after prolonged intoxication, alcoholics may have seizures (21). He also established that patients with epilepsy who drink must be differentiated from alcohol abusing patients having epileptic seizures during withdrawal (22). In 1953 the first systematic article describing alcohol withdrawal syndrome appeared (59), and later an article exploring the nature of alcohol withdrawal seizures (60). These have remained landmark articles, forming a basis for our current knowledge.
“Alcohol-related seizures” describes all types of interrelationships between seizures and chronic alcohol abuse in adults (39). Acute intoxication with alcohol is not a proven cause of seizures (26). On the other hand, situations that are consequent to alcohol abuse and acute withdrawal are where seizures are most often encountered. Alcohol withdrawal seizures are caused by abrupt cessation of heavy alcohol consumption (39). For a comprehensive discussion of seizure types related to alcohol, see McMicken and Liss (33). This article deals only with seizures occurring during alcohol withdrawal in adults.
• Alcohol withdrawal seizures occur 6 to 48 hours after alcohol cessation.
• It is characterized by being generalized tonic-clonic, and patients have a nonfocal neurologic examination.
Alcohol withdrawal seizures are a symptom of early and severe alcohol withdrawal syndrome, usually occurring within 6 to 48 hours of cessation of drinking (59; 60; 23), during which period seizure threshold is reduced (55). Alcohol withdrawal seizures typically occur as blood alcohol reaches zero, up to 24 hours after alcohol cessation or with abrupt reduction in intake (33). Although seizures occur in the context of alcohol withdrawal, frequently other signs of alcohol withdrawal syndrome are not present because they develop gradually (23). The seizure type is predominantly the generalized tonic-clonic, occurring singly in about 50% of cases or occurring as a series of seizures within a 6-hour period (60). In principle, patients have a nonfocal neurologic examination and alcohol blood levels must be close to zero g/dL. Other causes of acute symptomatic seizures must be ruled out (see Differential diagnosis), especially if seizures are focal or if status epilepticus develops (40).
Alcohol-related status epilepticus. Status epilepticus is a relatively rare manifestation of alcohol withdrawal seizures, occurring in 4% of these patients (60). Although status epilepticus probably has a better prognosis when alcohol-related compared to many other etiologies (01), it possibly increases the risk for subsequent epilepsy (15). The presence of both status epilepticus and partial seizures should prompt a careful evaluation for structural brain lesions and underlying epilepsy (06).
Delirium tremens. Alcohol withdrawal seizures are a strong risk factor for progression into a severe withdrawal state, with subsequent development of delirium tremens in up to 30% of cases if untreated (60). This is the most severe manifestation of alcohol withdrawal syndrome and progresses 48 to 72 hours after consumption cessation, lasting up to 14 days, with a mortality of 1% (35; 23).
A 62-year-old male with a past medical history of hypertension and alcoholism was brought to the emergency department on a Monday morning with a suspicion of epilepsy. The patient was seen to have a tonic-clonic seizure lasting 3 minutes with lateral tongue trauma after which he was confused and sleepy. According to the patient’s wife, he did not have a known seizure disorder. The patient gradually became responsive in the ER with disorientation in time and place and but had no other focal neurologic abnormalities. Brain CT showed no acute or chronic intracranial lesions, biochemistry panel showed a mild hyponatremia, and toxicological panel was negative, including alcohol levels that were undetectable. The patient was discharged but returned 6 hours later because of 2 further tonic-clonic seizures that occurred 20 minutes apart. The patient was now tremulous and agitated. The treating physician inquired further into his alcoholism in order to clarify the origin of his seizures, as severe head trauma and metabolic derangements were ruled out and there was no known past medical history of epilepsy. The wife clarified that that he was a heavy drinker and that during the weekend the patient had been drinking continuously for 3 days. He had stopped drinking the night before the seizure occurred. The patient’s Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar [see below]) scale was 14 (54). A diagnosis of alcohol withdrawal seizures was suspected and treated with lorazepam 4 mg as needed, according to the CIWA-Ar. An EEG was performed and interpreted as normal. He was later admitted to a rehabilitation clinic for detoxification. No subsequent seizures were reported at 6-month follow-up appointment.
Alcohol withdrawal seizures develop after chronic alcohol abuse. Case-control studies convincingly demonstrate the association of first seizures to alcohol use in a dose-dependent manner. For example, the risk was 3-fold for people drinking 51 to 100 g alcohol/day and steadily increased to 8-fold and more than 16-fold for people drinking 101 to 200 g/day and more than 200 g/day (38; 28).
Occasionally, seizures are observed after short binges or even single drinking episodes. In such cases, underlying seizure susceptibility is often present, ie, cortical brain damage from trauma, tumors, or epilepsy, and it may be concluded that the alcohol withdrawal state lowered seizure threshold.
Potential mechanisms of alcohol withdrawal seizures have been researched in animals and humans (20). Four mechanisms summarized by Tan and Weaver have been proposed (56):
(1) Chronic intake of ethanol alters fluidity of lipid cell membranes in the brain, affecting interactions between proteins and membrane phospholipids. These changes perturb physiologic function and signal transduction of NMDA, GABA-A, and L-type calcium receptors. It is hypothesized that these changes explain tolerance to alcohol and predispose to a hyperexcitable state when alcohol is withdrawn.
(2) Acute alcohol intake inhibits N-methyl-D-aspartate (NMDA) receptors in a tonic fashion, reducing excitatory glutamatergic synaptic transmission and inhibiting calcium flux through the ion-gated NMDA receptor in a concentration-dependent manner (31; 20). Chronic exposure to alcohol leads to upregulation of NMDA receptor function, increasing NR1, NR2A, and NR2B subunits in hippocampus, cortex, and cerebellum in mice (56). The signs and symptoms of alcohol withdrawal syndrome are thought to reflect this upregulation (12; 20).
(3) Ethanol potentiates GABA-A receptor transmission, increasing chloride influx, similar to benzodiazepines. However, chronic use decreases the number and affinity of GABA-A receptors, altering alpha and delta subunits leading to tolerance (20).
(4) Chronic ethanol intake increases the number of L-type calcium channels in different brain regions. Upregulation of these receptors may explain alcohol dependence and hyperexcitability.
Chronic adaptations in these receptors induce tolerance and dependence during active ethanol abuse. The combination of these mechanisms leads to a hyperexcitable neuronal state during withdrawal episodes because upregulation of NMDA receptors and L-type Ca++ receptors increases influx of calcium in neurons, concurrently leading to membrane depolarization and excitotoxicity. As GABA-A receptors are downregulated, a hyperexcitable state develops, leading to lowered seizure threshold and to acute withdrawal seizures when the patient abruptly ceases alcohol intake. Of note, repeated episodes of alcohol withdrawal seizures may lead to a kindling-like phenomenon (26). Other mechanisms proposed include: homocysteine increase (through stimulation of NMDA receptors), acting as an excitatory neurotransmitter and possible biomarker in active drinking patients; polymorphisms in dopamine transporter gene, with changes in these gene related to greater susceptibility to severe alcohol withdrawal syndrome and seizures; and apolipoprotein E allele 3 possibly associated with a history of alcohol withdrawal seizures (20).
It has been estimated that up to 15% of alcoholics at some stage will suffer a seizure (09) and that alcohol withdrawal is a common cause of adult-onset seizures (33). Of all alcohol-related seizures, 30% to 39.3% are related to alcohol withdrawal (40). Severe alcohol withdrawal syndrome accounts for 8% of inpatients with alcohol abuse disorders, with seizures and delirium tremens doubling inpatient stay and frequently requiring admission to the ICU (23).
Primary seizure prevention. When a patient is hospitalized for symptoms of alcohol withdrawal, the question arises as to whether treatment aims should include prevention of seizures. Patients with mild-to-moderate alcohol withdrawal symptoms (CIWA scale < 10) and no history of alcohol withdrawal seizures can successfully be detoxified with supportive care only (61). Supportive treatment includes a calm, reassuring atmosphere, coffee restriction, daylight views, and hydration.
Patients with severe alcohol withdrawal symptoms and all those with seizures during previous alcohol withdrawal episodes have higher risk for alcohol withdrawal seizures and may benefit from seizure preventive treatment (17). When pharmacological treatment is necessary, benzodiazepines should be chosen for the primary prevention of seizures in a person with alcohol withdrawal. The drugs of choice are lorazepam and diazepam.
Secondary seizure prevention. Following an alcohol withdrawal seizure, the recurrence risk within the same withdrawal episode is 13% to 24% (17). In addition, history of an alcohol withdrawal seizure and a seizure during the concurrent withdrawal episode are associated with increased risk of complications and progression to alcohol withdrawal delirium and should be treated as an inpatient (62). Consequently, there is good rationale for treating these patients as soon as possible in order to prevent subsequent seizures. It is a common mistake to attribute repeated withdrawal seizures to epilepsy and start treatment with antiepileptic drugs. In fact, a Cochrane review of 56 studies (n= 4076) found no convincing evidence in favor of using antiseizure medications in patients with alcohol withdrawal (34). Additionally, poor compliance, no treatment effect, and risk of drug interaction problems can be expected in such cases (16).
Differential diagnosis. Potential alternative diagnoses should be ruled out in an adult with a first episode of alcohol-related seizures (40; 33):
• Withdrawal seizures from chronic drug abuse (benzodiazepines, barbiturates)
• Uncontrolled epilepsy, including noncompliance to antiseizure medication and pharmaco-resistance
• Acute intoxication with drugs such as amphetamines, anticholinergics, cocaine, isoniazid, organophosphates, tricyclic antidepressants, or salicylates
• Life-threatening metabolic disorders (hypoglycemia, hyponatremia, hypernatremia, hypocalcemia, hypomagnesemia)
• Infections (meningitis, encephalitis, systemic)
• Significant head trauma, past or current
• Intracranial hemorrhage (subarachnoid, intraparenchymal, subdural hematoma, epidural hematoma)
• Acute ischemic stroke
• Nontraumatic intracranial lesions (tumors, gliosis)
• Convulsive syncope
• Psychogenic nonepileptic events
The first consideration in a patient with possible alcohol withdrawal seizures is the exclusion of life-threatening causes of seizures, as described in the differential diagnoses above (33). At the same time, a history of chronic alcohol abuse must be sought and the patient should be classified as having one of the categories of alcohol-related seizures (33). As more than 90% of alcohol withdrawal seizures occur soon after the cessation of sustained drinking, whereas other withdrawal symptoms develop gradually, withdrawal may not be readily evident in the beginning (23).
Physical examination. The patient should be checked for other signs of alcohol withdrawal such as tachycardia, tachypnea, mydriasis, elevated blood pressure, hyperthermia, diaphoresis, and tremor, among others (23). In addition, perform a neurologic examination to determine possible etiology (62). Clinical features distinctive of either epilepsy or alcohol withdrawal seizures should be delimited (04). In case of epilepsy, postictal symptoms may prevail. Most patients with epilepsy will be drowsy or in postictal coma. In contrast, patients in a withdrawal state frequently manifest other symptoms like tremor, anxiety, irritability, delirium, and agitation. In most cases, clinical signs and symptoms distinctive of alcohol withdrawal syndrome will develop shortly and evolve gradually (within 24 hours) after the seizure and the patient should be observed for such symptoms. The length of time required for observation is not recommended in the current literature and should be determined on an individual basis.
Electrocardiogram. Alcohol withdrawal may increase risk of sudden death because it may prolong QT interval, the reason why EKG should be performed in patients presenting with alcohol withdrawal seizures or alcohol-related seizures (26).
Biomarkers. For detection of alcohol overuse, questionnaire-based interviews are reported to be more sensitive than any biomarker (03). However, in cases where information on recent alcohol consumption is unavailable or considered unreliable, markers of alcohol consumption can increase accuracy of clinical diagnosis (05; 07). Carbohydrate-deficient transferrin (CDT) and gammaglutamyl transferase (GGT) are sensitive markers for alcohol overuse; systematic literature reviews have been inconclusive as to which marker is better (46; 52). No biomarker can be recommended for screening of unselected seizure populations (05; 07).
As the current intoxication level is important information with potential treatment consequences, blood alcohol concentration should be measured in patients with suspected alcohol-related seizures (50). Urinary ethyl glucuronide and ethyl sulfate have been reported to have high sensitivity and specificity for recent drinking (10; 53).
Neuroimaging. It is recommended to rule out structural causes of seizures in patients with a first seizure, status epilepticus, or in patients where head trauma is suspected (23). A CT scan of the brain suffices in the acute setting, although an MRI is preferable if there is a question of an underlying epilepsy. Seizures that occur later than 48 hours after intake of the last drink may indicate other potential etiologies than simple alcohol withdrawal, such as subdural hematoma, brain contusion, or mixed drug and alcohol overuse (16). When patients present repeatedly with typical alcohol withdrawal seizures, imaging is not necessary unless changes in seizure type and frequency, seizure occurrence more than 48 hours after cessation of drinking, or other unusual features are present.
Electroencephalography (EEG). Inpatient EEG should be recorded after a first seizure, if status epilepticus is suspected, or if a new seizure pattern emerges (23). Yet the value of EEG in the setting of alcohol withdrawal seizures is limited and findings such as epileptiform activity should prompt the evaluation of an underlying epilepsy (20). In addition, where repeated withdrawal seizures are a pattern, EEG is considered necessary only if an alternative etiology is suspected. The incidence of EEG abnormalities (focal slowing or epileptiform activity) is lower among patients with alcohol withdrawal seizures than in those with seizures of other etiologies. Therefore, an abnormal EEG suggests that the seizure may not have been caused exclusively by alcohol withdrawal (47).
Acute drug treatment. Because alcohol withdrawal seizures are a symptom of severe acute withdrawal syndrome, they should be treated as such. Patients should be admitted and close monitoring should be available, assessing the patient every 1 to 2 hours for up to 6 to 24 hours (62). As mentioned above, the revised CIWA-Ar scale can be applied to grade the severity of alcohol withdrawal (54). It has prognostic value, as patients with scores less than 10 generally do not need pharmacological treatment. However, symptom-triggered therapy based on the CIWA-Ar protocol depends on correct application of the inventory (14).
Benzodiazepines. Benzodiazepines should be chosen as the preferred drug class and are standard of care (02; 37). They should be given parenterally following a withdrawal seizure to prevent another seizure and the occurrence of delirium (62). In comparison to other medications, this group of GABA-ergic medications has been shown to reduce severity of withdrawal symptoms, prevent appearance of delirium tremens, status epilepticus, and recurrent seizures, and at the same time provide safety and low abuse potential (11; 17; 02). In fact, an overview of systematic reviews in Cochrane provides moderate evidence that benzodiazepines perform better than any other treatment, compared to placebo, in preventing alcohol withdrawal seizures (RR 0.16 [95%CI 0.004-0.69]) (02).
In a meta-analysis of controlled trials for prevention of alcohol withdrawal seizures, a highly significant risk reduction for seizures with benzodiazepines compared to placebo was demonstrated (17). For the purpose of reducing risk of seizures and rebound withdrawal symptoms after discontinuation, long-acting drugs should be preferred to short-acting ones (32; 17). However, short-acting benzodiazepines may have advantages for patients with respiratory insufficiency. Symptom-triggered treatment has been reported to be as effective as fixed-dose or loading therapy, resulting in lower doses and shorter treatment time (45). Yet, treatment strategies and doses vary from center to center and consensus is lacking (37).
Lorazepam has some advantages over diazepam. Despite a shorter half-life it has longer duration of action because it is distribution is slower and less extensive (11). However, its onset of action is slightly slower than that of diazepam. In a study that compared lorazepam versus diazepam, no differences were seen in seizure recurrence and other parameters such as readmission, CIWA-Ar score, or length of stay (51).
When loading with a benzodiazepine, it is important to monitor the patient for signs of over-sedation and respiratory depression (62).
Barbiturates. Studies have assessed use of barbiturates in the treatment of alcohol withdrawal syndrome. A systematic review of clinical trials considered 7 studies using barbiturates versus benzodiazepines for the treatment of acute withdrawal syndrome (35). In their analysis, the authors concluded that for patients with severe alcohol withdrawal syndrome, benzodiazepines with barbiturates may control symptoms in an additive fashion. They also indicated that barbiturates have the potential of treating patients who become refractory to benzodiazepines. The combination of benzodiazepines with phenobarbital (single intravenous dose of 10 mg/kg) may also prevent ICU admission and ventilation, with a similar safety profile in comparison to benzodiazepines alone (43). Similar to benzodiazepines, dose regimens vary from study to study with phenobarbital (35). Parenteral phenobarbital should be used with caution and in a setting with frequent supervision due to the risk of sedation and respiratory depression (62).
Antiseizure medication and other drugs. Phenytoin is ineffective in preventing recurrent seizures within a withdrawal episode (17). Many other drugs and drug combinations are used, including carbamazepine, gabapentin, chlormethiazole, sodium valproate, gamma-hydroxybutyrate, and clonidine, for all of which evidence is generally poor (42; 45; 18; 17; 34). A Cochrane review of studies using baclofen for acute withdrawal syndrome found very low-quality evidence and no greater efficacy when compared to placebo, diazepam, and chlordiazepoxide (29). Risk of seizures and delirium were not assessed as outcomes, and the reviewers concluded that there was insufficient and very low quality evidence to draw any conclusions (29). In addition, alpha 2-adrenergic agonists (clonidine), beta-blockers, or dexmedetomidine should not be used in the prevention or treatment of alcohol-withdrawal seizures (62).
Seizures. Acute seizure treatment should follow standard protocol, ie, repeated doses of a benzodiazepine (preferably lorazepam or diazepam) until seizures stop. If ineffective (alcohol-related status epilepticus), sodium valproate should be considered before fosphenytoin/phenytoin, as phenytoin has been shown to be ineffective in preventing recurrent seizures in 3 controlled studies (17).
Thiamine therapy. Due to risk of developing Wernicke-Korsakoff syndrome, which is often underdiagnosed and may lead to permanent brain damage, patients presenting with known or suspected alcohol overuse should be given thiamine parenterally in the emergency room, before starting any carbohydrate-containing fluids or food. The optimal dose is not settled, but because parenteral thiamine administration is generally safe, diagnosis of thiamine deficiency is difficult, and potential consequences of not treating are devastating; erring on the side of caution with liberal dosing is to be recommended. Prophylactic therapy is recommended in all patients with known or suspected alcoholism, malnutrition, or frequent vomiting. Parenteral administration of 200 mg thiamine should be given in the emergency room before any carbohydrates are started. Oral administration is insufficient as the intestinal thiamine absorption is too low and may be severely impaired in alcohol abuse (19).
When Wernicke encephalopathy is suspected or manifest, parenteral administration of 200 mg thiamine 3 times daily should be started with no delay. Intravenous infusion of thiamine diluted with 100 ml saline or 5% glucose, given over 30 minutes is recommended (13). The treatment should continue for at least 2 to 3 days. Patients with manifest Wernicke-Korsakoff syndrome may benefit from a treatment period of up to 2 weeks. It has been speculated that patients who are in a catabolic state or under the influence of alcohol have reduced ability to store thiamine because enzymes depending on thiamine are downregulated or protein binding is altered by the influence of alcohol (13). In such cases, early re-institution of a normal diet may be important.
Electrolyte disturbances. Hyponatremia in alcohol abusers generally shows a benign clinical course, and usually corrects with cessation of alcohol intake and re-institution of a normal diet (24). The serious disorder of central pontine myelinolysis is thought to be triggered by osmotic gradients in the pons, a situation that might result from attempts to correct electrolyte disturbances too rapidly (25). If parenteral treatment is considered necessary, according to a retrospective study, the rate of serum sodium correction should not exceed 10 mmol/l per day (44).
Hypomagnesemia and respiratory alkalosis seem to be associated with alcohol withdrawal, and correction of hypomagnesemia may raise the seizure threshold in the initial phase of alcohol withdrawal (58). It has been speculated that unresponsiveness to parenteral thiamine therapy may result from hypomagnesemia (57). Despite the theoretical benefit, there is not sufficient evidence to recommend magnesium supplement, as demonstrated by a Cochrane systematic review (49).
Alcohol withdrawal syndrome is associated with poor clinical outcomes and with an in-hospital mortality that ranges from 2% to 7% (36; 08). Severe alcohol withdrawal syndrome (including seizures) increases 12 times the risk of long-term mortality when compared to a control population (adjusted hazard ratio of 12.7; 95% CI 8.9-17.5) (08).
Alcohol is teratogenic. Fetal alcohol spectrum disorders are more prevalent than previously recognized and cause a wide range of birth defects and neurodevelopmental disorders (41). There is no current evidence that alcohol-related seizures confer additional maternal or fetal risk, over and above those of alcohol abuse and seizures independently.
Newborns whose mothers are intoxicated prior to or during delivery can experience withdrawal symptoms, such as tremors and even seizures. It is likely that withdrawal also can occur during fetal development. Thus, repeated withdrawals during pregnancy may pose an additional risk to the fetus from that of alcohol exposure in itself. Pregnant women should refrain from drinking alcohol.
During alcohol withdrawal, patients may require higher than normal doses of GABAergic substances (benzodiazepines).
Samden D Lhatoo MD FRCP
Dr. Lhatoo of the University of Texas Health Science Center at Houston has no relevant financial relationships to disclose.See Profile
Manuela Ochoa-Urrea MD
Dr. Ochoa-Urrea of the University of Texas Health Science Center at Houston has no relevant financial relationships to disclose.See Profile
Solomon L Moshé MD
Dr. Moshé of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Childhood Degenerative & Metabolic Disorders
Jun. 10, 2021
Epilepsy & Seizures
Jun. 01, 2021
Epilepsy & Seizures
May. 04, 2021
Epilepsy & Seizures
Apr. 26, 2021
Epilepsy & Seizures
Inhibitory motor seizures are ictal motor epileptic events of central paresis usually unilateral mono- or hemiparesis while consciousness is intact.
Apr. 26, 2021
Epilepsy & Seizures
Although absences are considered a paradigm of primarily generalized seizures, they may occasionally be of focal onset (focal onset generalized absence
Apr. 26, 2021
Epilepsy & Seizures
Initial evaluation The initial diagnosis of seizure is based on the history. If first-line treatment fails, the diagnosis is (or should be) questioned
Apr. 23, 2021
Epilepsy & Seizures
Apr. 12, 2021