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Alcohol withdrawal syndrome (AWS) is a medical emergency, rare in the general population, but very common among alcoholic individuals, which can lead to severe complications when unrecognized or late treated. It represents a clinical condition which can evolve in few hours or days following an abrupt cessation or reduction of alcohol intake and is characterized by hyperactivity of the autonomic nervous system resulting in the development of typical symptoms. According to DSM-5 criteria, the alcohol withdrawal syndrome is defined as such: if patients present at least two of typical signs and symptoms. The Clinical Institute Withdrawal Assessment of Alcohol Scale, revised version (CIWA-Ar), is the tool for assessing the severity of AWS. The support to patient with AWS includes pharmacological intervention as well as general support, restoration of biochemical imbalances and specific therapy. Regarding the pharmacological treatment, benzodiazepines represent the gold standard, in particular long-acting benzodiazepines, administered with a gradual reduction up to cessation.

Noninvasive assessment of disease activity in patients with nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) is still unsettled, but essential for the evaluation of disease progression. We here studied the association of total (M65) and caspase-cleaved (M30) serum keratin-18 fragments (n = 204) with histological parameters (n = 106) in heavy drinkers primarily admitted for alcohol withdrawal before and after alcohol detoxification. An age-, sex-, and fibrosis-stage matched NAFLD cohort (n = 30) was used for comparison. The prognostic value of M30 and M65 levels were assessed in an additional prospectively followed-up cohort of 230 patients with alcoholic cirrhosis (AC) using competing risk analyses. Among the histological parameters, both M30/65 correlated significantly and better than any other serum marker with apoptosis and liver damage, such as ballooning (r = 0.65; P < 0.001), followed by lobular inflammation (0.48; P < 0.001), steatosis (0.46; P < 0.001), but less with fibrosis (0.24; P < 0.001). Area under the receiver operating characteristics curves to detect ballooning, steatosis, or steatohepatitis (SH) were slightly better for M30 (P < 0.005). Optimal M30 cut-off values for mild and severe ballooning were 330 and 420 U/L, and 290 and 330 U/L for SH grades 1 and 2. No significant differences of M30/65 were found between the matched NAFLD and ALD cohort. In contrast to aspartate-amino-transferase and M65, M30 levels increased significantly from 391 to 518 U/L during alcohol detoxification. Moreover, levels of M30 and M65 predicted non-hepatocellular carcinoma liver-related mortality in patients with AC during a mean observation interval of 67.2 months., Conclusion: Our data suggest M30 as highly specific marker of liver apoptosis both in ALD and NAFLD. In addition, hepatocellular apoptosis, as determined by M30 levels, occurs during alcohol withdrawal, and survival data point toward a novel underestimated role of apoptosis in patients with ALD. (Hepatology 2017;66:96-107)., (© 2017 by the American Association for the Study of Liver Diseases.)

Objectives: We sought to determine occurrence, predictors, and prognosis of alcohol withdrawal syndrome and delirium tremens in patients with traumatic injury., Design: Retrospective multicenter cohort study., Setting: Three U.S. trauma centers., Patients: Twenty-eight thousand one hundred one trauma patients admitted from 2010-2014., Interventions: None., Measurements and Main Results: Measures included occurrence of alcohol withdrawal syndrome and delirium tremens, injury characteristics, risk factors for alcohol withdrawal syndrome, clinical outcomes, pharmacologic treatment for alcohol withdrawal syndrome, and Clinical Institute Withdrawal Assessment for Alcohol, Revised (CIWA-Ar) scores. Alcohol withdrawal syndrome severity was defined by CIWA-Ar score as minimal (< 10), moderate (10-20), and severe (> 20). Alcohol withdrawal syndrome developed in 0.88% (n = 246), including 12% minimal, 36% moderate, and 53% severe. Alcohol withdrawal syndrome progressed to delirium tremens in 11%. Before adjustment, alcohol withdrawal syndrome severity was associated with injury severity, hypokalemia, baseline CIWA-Ar score, and established alcohol withdrawal syndrome risk factors. Logistic regression identified the following predictors of delirium tremens: baseline CIWA-Ar score greater than or equal to 10 (odds ratio, 6.05; p = 0.02) and age greater than or equal to 55 (odds ratio, 3.24; p = 0.03). In patients with severe alcohol withdrawal syndrome, severe head injury also predicted progression to delirium tremens (odds ratio, 6.08; p = 0.01), and hypokalemia was borderline significant (odds ratio, 3.23; p = 0.07). Clinical outcomes of hospital length of stay, ICU length of stay, and alcohol withdrawal syndrome complications differed significantly by alcohol withdrawal syndrome severity and were worse with more severe manifestations of alcohol withdrawal syndrome. Mortality also significantly differed by alcohol withdrawal syndrome severity but was only greater in patients who progressed to delirium tremens (11.1%; p = 0.02); otherwise, there were no differences in mortality by severity (4%, 4%, and 0% by minimal, moderate, and severe alcohol withdrawal syndrome)., Conclusions: Trauma patients with alcohol withdrawal syndrome experience a high occurrence of delirium tremens that is associated with significant mortality. These data demonstrate the predictive ability of baseline CIWA-Ar score, age, and severe head injury for developing delirium tremens.

Alcohol withdrawal syndrome has a high clinical prevalence. Severe cases must be treated in an intensive care unit and are associated with a high mortality rate, depending on patient comorbidities. Clinical requirements include sedation, control of vegetative symptoms, treatment of hallucinations and, when necessary, anticonvulsive therapy. Currently, there is no single substance that fulfills these requirements. National and international guidelines recommend a combination of various substances. The central α2-adrenergic receptor agonist clonidine is used as a therapeutic adjuvant. In consideration of its pharmacological characteristics, dexmedetomidine is assumed to be more advantageous compared to clondine. Case studies with dexmedetomidine in alcohol withdrawal syndrome show the safety of its application and a benzodiazepine-sparing effect. Its incorporation in escalating intensive care therapy of severe cases could be appropriate.

Alcohol-related hospital attendances and admissions continue to escalate despite a fall in alcohol consumption levels in the UK population overall. People with alcohol-related problems pose a significant and often disproportionate burden on acute medical services as their management is often complex and challenging. This article focuses on the management of alcohol intoxication, with particular emphasis on aggressive and possibly violent behaviour; alcohol withdrawal; fitting; and the prevention and treatment of Wernicke's encephalopathy., (© Royal College of Physicians 2015. All rights reserved.)

The efficacy and safety of sedation on 44 patients in alcohol withdrawal state (AWS) for use of intravenous dexmedetomidine infusion. Dexmedetomidine increased the duration of target sedation level to 20%, decreased the duration of excessive/insufficient sedation to 10%, it was associated with AWS symptoms regression, better communication with the patient, reduced consumption of benzodiazepines (BZD) from 40 to 30 mg per day and antypsihotics for control AWS symptoms. The common complications of dexmedetomidine infusion were bradycardia and hypotension. Dexmedetomidine could be an alternative drug for sedation patients with mild or moderate AWS and applied in addition to BZD and antipsyhotics in patients with severe AWS.

We experienced a case showing various psychotic symptoms following cessation of alcohol consumption. The symptoms included depressive state, delusion, confusion, psychomotor excitement and delirium, all of which disappeared in about two months. At first, we regarded all the symptoms as alcoholic hallucinosis, by a clinical standpoint, in spite of no auditory hallucination in this case. However, taking the overall clinical course into consideration, withdrawal syndrome could have been affected by some factors. One of the possibilities is that delusion might have been induced by aripiprazole. There still may be some other unknown influential factors on withdrawal, which are indicated by previous papers.

Symptoms of alcohol withdrawal syndrome (AWS) may develop within 6-24 h after the abrupt discontinuation or decrease of alcohol consumption. Symptoms can vary from autonomic hyperactivity and agitation to delirium tremens. The gold-standard treatment for AWS is with benzodiazepines (BZDs). Among the BZDs, different agents (i.e., long-acting or short-acting) and different regimens (front-loading, fixed-dose or symptom-triggered) may be chosen on the basis of patient characteristics. Severe withdrawal could require ICU admission and the use of barbiturates or propofol. Other drugs, such as α2-agonists (clonidine and dexmetedomidine) and β-blockers can be used as adjunctive treatments to control neuroautonomic hyperactivity. Furthermore, neuroleptic agents can help control hallucinations. Finally, other medications for the treatment for AWS have been investigated with promising results. These include carbamazepine, valproate, sodium oxybate, baclofen, gabapentin and topiramate. The usefulness of these agents are discussed.

Delirium associated with excessive alcohol consumption has been known since antiquity. This condition became more common as the supply of distilled fermented liquors increased. Delirium, including delirium associated with excessive alcohol consumption, was for many centuries regarded as a form of brain inflammation - "phrenitis" - and was treated with depletion. At the end of the eighteenth century treatment by depletion of alcohol-related delirium began to be replaced by sedation and led to significantly better outcomes. Thomas Sutton established that alcohol-related delirium was a disease sui generis, distinct from phrenitis, and he named it delirium tremens. Because historical accounts of this disease are rare, brief, and not easily accessible, we offer this account of events that culminated in the discovery of the molecular basis of delirium tremens.

Background: Chronic and excessive alcohol consumption increases oxidative stress. We previously found that levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, are elevated in alcohol-dependent patients without delirium tremens (DTs). The aim of this study was to compare serum 8-OHdG levels between alcohol-dependent patients with and without DTs., Methods: We recruited 16 alcohol-dependent patients with DTs (DTs group) and 58 patients without DTs (non-DTs group). Alcohol withdrawal severity was evaluated using the Chinese version of the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar-C) every 8 hours. Serum levels of 8-OHdG and other biological indices were assayed at baseline and after 1 week of detoxification., Results: The mean 8-OHdG level in the DTs group was significantly higher than that in the non-DTs group (0.50 vs. 0.34 ng/ml, p < 0.001). A significant correlation was found between the highest CIWA-Ar-C scores and serum 8-OHdG levels (β = 0.43, p = 0.001) in the non-DTs group, but not in the DTs group (β = 0.34, p = 0.19). An area under receiver operating characteristic curve of 0.83 suggests that 8-OHdG levels potentially differentiate patients with DTs from those without DTs. After dividing the patients into quartiles by 8-OHdG level, we found that compared to the patients in the third and fourth quartiles, the patients in the highest quartile had an odds ratio of 24.1 (p < 0.001) to have DTs, while those in the second highest quartile had an odds ratio of 3.5 (p = 0.19). Serum 8-OHdG levels did not significantly change after 1 week of detoxification in either group., Conclusions: Alcohol-dependent patients with DTs have higher serum 8-OHdG levels than those without DTs, suggesting that higher oxidative stress carries a greater risk of the occurrence of DTs., (Copyright © 2014 by the Research Society on Alcoholism.)

Delirium is a common acute neuropsychiatric syndrome. It is characterized by concurrent disturbances of consciousness and attention, perception, reasoning, memory, emotionality, the sleep-wake cycle as well as psychomotor symptoms. Delirium caused by alcohol or medication withdrawal is not the subject of the current review. Specific predisposing and precipitating factors have been identified in delirium which converge in a common final pathway of global brain dysfunction. The major predisposing factors are older age, cognitive impairment or dementia, sensory deficits, multimorbidity and polypharmacy. Delirium is always caused by one or more underlying pathologies which need to be identified. In neurology both primary triggers of delirium, such as stroke or epileptic seizures and also secondary triggers, such as metabolic factors or medication side effects play a major role. Nonpharmacological interventions are important in the prevention of delirium and lead to an improvement in prognosis. Delirium is associated with increased mortality and in the long term the development of cognitive deficits and functional impairment.

Aim: To study the profile of delirium associated with alcohol withdrawal syndrome (AWS) in a developing country in terms of symptomatology, associated risk factors/physical complications, and outcome., Methodology: Using a prospective design, 112 patients in whom delirium could be attributed to AWS as either the sole or a contributory cause were assessed by Delirium Rating Scale-Revised-98 and the associated etiological factors were assessed by using delirium etiology checklist., Findings: In all patients, delirium was acute in onset and all patients had disturbance of sleep-wake cycle and inattention. Other common symptoms were: disorientation (99.1%), fluctuation in symptoms (97.3%), motor agitation (94.6%), and short-term memory disturbance (92.9%). In terms of delirium etiology checklist etiological categories, besides alcohol withdrawal, the most common factors were metabolic/endocrine abnormalities (76%), followed by organ insufficiency and infection (37% and 35%, respectively). Most patients (67%) improved or recovered completely from delirium during the short stay of 4 days. During the short stay of mean duration of 4 days 13.4% of the patients died during the hospital stay., Conclusion: Delirium associated with alcohol withdrawal is characterized by an acute onset of symptoms with high prevalence of disturbance of sleep-wake cycle, inattention, disorientation, fluctuation in symptoms, motor agitation, and disturbance in short-term memory. There are certain differences in the symptom profile of delirium associated with alcohol withdrawal and that associated with medical-surgical causes. About one-sixth of the patients developing delirium due to alcohol withdrawal die during the short hospital stay of 4 days., (Copyright © American Academy of Addiction Psychiatry.)

Agrypnia (from the Greek: to chase sleep) excitata (AE) is a syndrome characterized by loss of sleep and permanent motor and autonomic hyperactivation (excitata). Disruption of the sleep-wake rhythm consists in the disappearance of spindle-delta activities, and the persistence of stage 1 non-rapid eye movement (NREM) sleep. Rapid eye movement (REM) sleep persists but fails to stabilize, appearing in short recurrent episodes, isolated, or mixed with stage 1 NREM sleep. Diurnal and nocturnal motor, autonomic and hormonal overactivity is the second hallmark of AE. Of particular interest is the finding that norepinephrine secretion is extremely elevated at all hours of the day and night whereas the nocturnal melatonin peak is lacking. Oneiric stupor is probably an exclusive sign of AE and consists in the recurrence of stereotyped gestures mimicking simple daily life activities. Agrypnia excitata aptly defines 3 different clinical conditions, fatal familial insomnia (FFI), an autosomal dominant prion disease, Morvan syndrome (MS), an autoimmune encephalitis, and delirium tremens (DT), the alcohol withdrawal syndrome. Agrypnia excitata is due to an intralimbic disconnection releasing the hypothalamus and brainstem reticular formation from cortico-limbic inhibitory control. This pathogenetic mechanism is visceral thalamus degeneration in FI, whereas it may depend on autoantibodies blocking voltage-gated potassium (VGK) channels within the limbic system in MS, and in the sudden changes in gabaergic synapses down-regulated by chronic alcohol abuse within the limbic system in DT.

In susceptible patients, alcohol withdrawal syndrome (AWS) is often precipitated by other medical or surgical disorders, and AWS can adversely affect the course of these underlying conditions. Although the mortality rate of AWS has decreased over the past few decades, significant risk for morbidity and death remain if management is complicated by a variety of conditions. This review of AWS focuses on the scope of the clinical problem, historical features, pathophysiology, clinical presentation, and approaches to therapy, with particular emphasis on severe AWS that requires management in the intensive care unit., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Delirium tremens is the severe form of alcohol withdrawal. It carries a certain degree of mortality and there has been and advancement in the understanding of pathophysiology and risk factors for the development of the condition. This prospective study is carried out to study the characteristic of the patient of delirium tremens in our setting using ICD-10 diagnostic criteria. Thirty seven cases of delirium tremens with majority of males and of all hill origin people were identified. Patients with delirium tremens has been using alcohol for average of 24.8 years with an average intake of around 2.2 litres per day. Most of the patient has seizure and similar episodes in past and using alcohol from morning time.

We present a descriptive, retrospective study of initial symptoms, comorbidity, and alcohol withdrawal in 73 alcoholic patients with subsequent Korsakoff syndrome. In 25/73 (35%) of the patients the classic triad of Wernicke's encephalopathy with ocular symptoms, ataxia and confusion, was found. In at least 6/35 (17%) of the initial deliria (95% confidence interval: 10-25%) we observed no other underlying causes, thus excluding other somatic causes, medication, (recent) alcohol withdrawal, or intoxication. We suggest that these deliria may have been representing Wernicke's encephalopathy. A high frequency (15%) of diabetics may reflect a contributing factor of diabetes mellitus in the evolution of the Wernicke-Korsakoff syndrome., (Copyright © American Academy of Addiction Psychiatry.)

The concept of Agrypnia excitata (AE) was originally proposed as a concept deriving from the clinical and anatomo-pathological observations obtained in three different diseases, Fatal familial insomnia (FFI), Delirium tremens (DT), and Morvan syndrome (MS). Agrypnia refers to a condition of severely reduced or absent sleep due to organic disorders. Excitata refers to the association of agrypnia with generalized motor and autonomic hyperactivation. AE is a syndrome that has been claimed to relate to a dysfunction in the thalamo-limbic circuits that govern sleep-wake cycles and autonomic activities., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: To determine the incidence, prescribing risk factors of alcohol withdrawal delirium (AWD), and factors complicating AWD, in alcohol dependent patients hospitalized for alcohol detoxification., Material and Method: Patients attending the detoxification program at Chiang Mai University Hospital and the Northern drug dependence treatment center between May and September 2005 were assessed. Patients with signs of AWD at baseline were excluded. Incidence, risk factors, and dosage of benzodiazepines of patients with and without subsequent AWD were compared Risk factors that prolonged the course of AWD were analyzed., Results: Nineteen male patients were assessed. Ten patients (52.6%) developed AWD despite receiving benzodiazepine detoxification. Risk factors of age, previous history of AWD and epilepsy, alcohol use history, frequency and quantity of drinking, signs of simple withdrawal at first admission, and dosage of benzodiazepines were not significantly different between the groups. However, patients with systolic blood pressure at first admission (> 120 mmHg) had longer duration of AWD than those without abnormal blood pressure (72.0 +/- 53.7 hr versus 168.0 +/- 24.0 hr, respectively, p = 0.038)., Conclusion: The incidence of AWD was relatively high despite treatment. Although the present study did not find any risk factor predicting AWD. AWD patients hypertensive at the first admission had significantly longer duration of delirium. Physicians should be aware of monitor and treat hypertensive state and give early treatment of alcohol withdrawal with adequate doses of benzodiazepines to decrease morbidity and mortality of AWD.

In the summer, alcohol consumption increases and the number of those requiring rehabilitation peaks at the end of the holiday season. Treatment of alcohol withdrawal symptoms early enough helps the patient to break the drinking cycle. Treatment of alcohol withdrawal symptoms will also prevent complications, such as convulsions and alcoholic delirium. Untreated alcoholic delirium is a life-threatening condition. Treatment aims to calm down the hyperactivity state of the autonomous nervous system, and correct electrolyte and fluid balance disturbances. Initiation of rehabilitation is determined by the severity of the patient's withdrawal symptoms. Benzodiazepines are the first-line drugs.

Delirium Tremens is quite rare in children and it is usually caused by withdrawal or abstinence from alcohol, barbiturates and other major tranquilizers. The usual symptoms of Delirium Tremens include severe altered mental status with confusion, delusions, hallucinations, and severe agitation. Although psychosis is a recognized manifestation of Phenytoin toxicity, visual hallucinations are not. This study reports the case of a 4-year-old male with febrile seizures plus syndrome who developed acute complex visual hallucinations and psychomotor agitation early after therapy with intravenous Phenytoin was administered. These visual hallucinations mimicked those linked to Delirium Tremens and were not associated with an encephalopathy or other known neuropsychiatric side effects of this drug. Moreover, the hallucinations occurred while serum Phenytoin concentrations were below therapeutic range. We made an extensive investigation in order to exclude a non-convulsive Status Epilepticus, a Central Nervous System infection, a metabolic disorder, an underlying psychiatric disease and a possible drug toxicity. The temporal relationship between initiation of Phenytoin and onset of visual hallucinations and resolution of symptoms with withdrawal of Phenytoin suggests that the visual disturbances were probably due to that antiepileptic drug., (Copyright (c) 2010 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Several genetic polymorphisms have been reported to be associated with alcohol withdrawal seizures (AWS) and delirium tremens (DT). To replicate and further explore these findings, we investigated the effects of 12 previously reported candidate genetic variations in two groups of alcohol-dependent European Americans with a history of withdrawal, which differed according to the presence (n = 112) or absence (n = 92) of AWS and/or DT. Associations of AWS and/or DT with the genomic and clinical characteristics and gene-gene interaction effects were investigated using logistic regression models. None of the polymorphisms were significantly associated with AWS/DT after correction for multiple testing. However, we found a significant interaction effect of the SLC6A4 promoter polymorphism (5-HTTLPR) and DRD2 exon 8 single nucleotide polymorphism rs6276 on AWS and/or DT history (P = 0.009), which became more significant after adjustment for lifetime maximum number of drinks consumed per 24 hours (P < 0.001). Subsequent analysis revealed an even stronger association of the SLC6A4-DRD2 interaction with DT (P < 0.0001), which remained significant after Bonferroni correction. Results reveal decreased likelihood of DT in alcoholics that carry the DRD2 rs6276 G allele and SLC6A4 LL genotype. This study provides the first evidence to implicate the interaction between serotonin and dopamine neurotransmission in the etiology of DT. Replication is necessary to verify this potentially important finding.

Aims: Neuropeptide Y (NPY) is widely distributed throughout the brain and has been implicated in some of the actions of ethanol. The aim of the present study was to characterize the subtypes of NPY receptors in ethanol induced sedation, tolerance and withdrawal hyper-excitability., Main Methods: The loss of righting reflex paradigm was used to record the sleep duration in mice., Key Findings: The acute administration of ethanol (3-4g per kg, i.p., 20%v/v) resulted in marked sedation. While prolonged ethanol consumption led to the development of tolerance, the mice showed hyper-excitability following ethanol withdrawal. Prior acute intracerebroventricular (i.c.v.) injection of NPY (5-20 ng per mouse) or NPY Y1 and Y5 receptors agonist [Leu(31), Pro(34)]-NPY (0.02-0.2 ng per mouse) potentiated ethanol induced sedation. On the other hand, administration of selective NPY Y1 receptor antagonist BIBP3226 (5 ng per mouse, i.c.v.) inhibited ethanol induced sedation. Chronic concomitant treatment of NPY (20 ng per mouse, i.c.v.) or [Leu(31), Pro(34)]-NPY (0.2 ng per mouse, i.c.v.) to ethanol-fed groups prevented the development of tolerance and attenuated withdrawal hyper-excitability. Moreover, acute treatment of NPY (5 ng per mouse, i.c.v.) or [Leu(31), Pro(34)]-NPY (0.02 ng per mouse, i.c.v.) reversed the peak ethanol withdrawal hyper-excitability., Significance: The results underscore a role for NPY Y1 and Y5 receptors in the ethanol induced sedation, tolerance and withdrawal hyper-excitability. We suggest that modulation of NPY Y1 and Y5 receptors may be a strategy to address the ethanol withdrawal conditions.

Alcohol dependence and alcohol abuse or harmful use cause substantial morbidity and mortality. Alcohol-use disorders are associated with depressive episodes, severe anxiety, insomnia, suicide, and abuse of other drugs. Continued heavy alcohol use also shortens the onset of heart disease, stroke, cancers, and liver cirrhosis, by affecting the cardiovascular, gastrointestinal, and immune systems. Heavy drinking can also cause mild anterograde amnesias, temporary cognitive deficits, sleep problems, and peripheral neuropathy; cause gastrointestinal problems; decrease bone density and production of blood cells; and cause fetal alcohol syndrome. Alcohol-use disorders complicate assessment and treatment of other medical and psychiatric problems. Standard criteria for alcohol dependence-the more severe disorder-can be used to reliably identify people for whom drinking causes major physiological consequences and persistent impairment of quality of life and ability to function. Clinicians should routinely screen for alcohol disorders, using clinical interviews, questionnaires, blood tests, or a combination of these methods. Causes include environmental factors and specific genes that affect the risk of alcohol-use disorders, including genes for enzymes that metabolise alcohol, such as alcohol dehydrogenase and aldehyde dehydrogenase; those associated with disinhibition; and those that confer a low sensitivity to alcohol. Treatment can include motivational interviewing to help people to evaluate their situations, brief interventions to facilitate more healthy behaviours, detoxification to address withdrawal symptoms, cognitive-behavioural therapies to avoid relapses, and judicious use of drugs to diminish cravings or discourage relapses.

Adolescents are at heightened risk for the development of both depressive and substance-related disorders. These two disorders frequently co-occur in adolescents and are associated with significant morbidity and mortality. Given the substantial economic and psychosocial burden associated with the comorbid condition, the identification of causal mechanisms associated with their co-occurrence is of great public health importance. Although there is significant understanding of the environmental and neurobiological factors involved in depression and addictive disorders considered separately, the mechanisms underlying the comorbid illness have not been investigated carefully. The purpose of this review is to summarize the extant literature on genetic, environmental and neurobiological processes involved in the etiology of depressive and substance-related disorders in adolescents and adults. It is important to note that the data on common neurobiological systems that link addictive and depressive disorders are primarily from research with adult animals and humans. Given the ongoing maturation of these systems throughout adolescence and early adult life, it is not clear how these neurobiological processes influence the development and progression of both disorders. A better understanding of the pathophysiological mechanisms leading to the onset and course of these disorders during adolescence will be helpful in developing more effective preventive and treatment strategies not only for this population but also for adult patients with early-onset illness.

This review summarizes the pioneering steps culminating in the identification of a novel disease, fatal familial insomnia (FFI), a hereditary prion disease. Together with Morvan's chorea and delirium tremens, FFI is characterized by an inability to sleep associated with motor and autonomic overactivation. We named this pattern agrypnia excitata, a syndrome caused by a dysfunction in thalamolimbic circuits. This review highlights the strategic role of the limbic thalamus in the central autonomic network running from the limbic cortex to the lower brainstem and regulating sleep and wakefulness.

Background: Delirium tremens (DT) is one of the more severe complications of alcohol withdrawal (AW), with a 5 to 10% lifetime risk for alcohol-dependent patients. The 2 most important neurosystems involved in AW are gamma-aminobutyric acid and glutamate. It is unknown whether these neurosystems are involved in the pathophysiology of DT as well. The candidate gene approach in DT could contribute to this knowledge and demonstrate a possible genetic predisposition for DT. The purpose of this study is to give an overview of all studied genetic polymorphisms in the diverse candidate genes related to DT and to summarize what these studies contribute to insights into the pathophysiology of DT., Methods: The inclusion criteria for this literature study were articles in English analyzing the association between a genetic polymorphism and DT without other AW syndromes. Studies were identified until February 2006 in MEDLINE and EMBASE databases., Results: We found 25 studies dealing with 30 polymorphisms, located in 19 different genes. Positive associations were found in 3 different candidate genes involved in the dopamine transmission, 1 gene involved in the glutamate pathway, 1 neuropeptide gene, and 1 cannabinoid gene. Two candidate genes involved in the dopamine transmission, dopamine receptor D3, and solute carrier family 6, were each associated with DT in 2 different study populations. The other 4 positive associations were not replicated in other studies., Conclusions: A total of 8 positive associations out of 30 polymorphisms makes a genetic base for DT plausible. Understanding the pathophysiological process of the development of DT has, indeed, been augmented by the reviewed genetic association studies. These studies suggest that the regulation of dopaminergic neurotransmission may play an important role.

Background: Many symptoms of alcohol withdrawal (AW) such as tachycardia or elevated blood pressure might be explained by increased peripheral and central adrenergic activity. In contrast to many neurochemical studies of sympathetic activation during AW, only very few studies investigated autonomic balance using neurophysiological methods., Methods: We investigated heart rate variability (HRV) and sympathetic skin response (SSR) in male patients suffering from mild AW syndrome (n = 20, no treatment required) and in patients with moderate to severe AW syndrome (n = 20, clomethiazole treatment) in the acute stage. Sympathovagal influence was quantified using measures of time and frequency domain of HRV as well as modern nonlinear parameters (compression entropy). Furthermore, we obtained latencies and amplitudes of SSR to quantify isolated sympathetic influence. Measures were obtained during the climax of withdrawal symptomatology before treatment, 1 day after climax, and shortly before discharge from hospital. Alcohol withdrawal scores were obtained and correlated to autonomic measures., Results: Ambulatory blood pressure and AW scores revealed characteristic withdrawal symptoms in both patient groups. Apart from the nonlinear parameter compression entropy, Hc, measures of HRV revealed no sign of autonomic dysfunction in contrast to the significantly increased heart rates at the time of admission. Latencies and amplitudes of SSR did not indicate any increase of sympathetic activity. A negative correlation was found between Hc and mental withdrawal symptoms., Conclusions: We show here that classical measures for autonomic nervous system activity such as HRV and SSR are not suitable for describing the autonomic changes seen in acute AW, although a major role for the sympathetic nervous system has been proposed. This might be due to multiple dysregulation of metabolites in AWS or to subtle alcohol-induced damage to neuronal structures, issues that should be addressed in future studies.

As the enzyme dopamine-beta-hydroxylase (DbetaH) converts dopamine to norepinephrine and both transmitters seem to be involved in the pathology of alcoholism and severe alcohol withdrawal symptoms, the gene encoding DbetaH (DBH) was applied to explore the genetic background of alcoholism and severe withdrawal symptoms. 102 healthy control subjects and 208 alcoholics, including 97 patients with a history of mild withdrawal symptoms, 57 with a history of alcohol withdrawal seizure (AWS) and 82 with a history of delirium tremens (DT) were genotyped for the DBH*444G/A polymorphism revealing a significantly elevated frequency of genotypes carrying the A-allele (p = 0.02; after Bonferroni adjustment for multiple tests) in alcoholics compared to healthy controls. Frequencies of alleles and genotypes of individuals with mild withdrawal symptoms did not differ significantly from those of patients with DT or AWS.

Introduction: While most patients with alcohol withdrawal (AW) respond to standard treatment that includes doses of benzodiazepines, nutrition and good supportive care (non resistant alcohol withdrawal-NRAW), a subgroup may resist therapy (resistant alcohol withdrawal-RAW). This study describes a distinct group of AW patients, their sedative requirements, and hospital courses., Methods: Over a period of 6 months, AW patients requiring 50 mg diazepam IV in the first hour were followed. We recorded admission indices and diazepam doses with vital signs at 1, 2, 3, 6, 12, and 24 hours. Patients were considered to have RAW if they required additional sedatives for control of symptoms and/or were having persistent abnormal vital signs despite the physicians' choices of therapy., Results: Nineteen patients were enrolled; all had similar admission indices. While the 4 NRAW had normal vital signs within 3 hours, all 15 RAW patients had abnormal vital signs; 15 RAW patients required escalating diazepam doses--14 required barbiturates, 7 were intubated, and 5 had hypotension. Comparing groups: interval and total diazepam doses were not different at 1,2, and 3 hours; interval doses at 6 and 12 hours, and total doses at 6, 12, and 24 hours were significantly different., Conclusions: RAW patients require large doses of benzodiazepine administration, additional sedatives, and undergo complicated hospitalizations.

A retrospective chart review was performed within an inpatient VA hospital setting in an attempt to identify risk factors for delirium tremens (DTs). Cases of delirium tremens were compared to cases where patients' alcohol withdrawal during hospitalization did not progress to DTs. Significant differences were found in regard to prior histories of DTs and laboratory values at admission. The amount and duration of benzodiazepine use during hospitalization, antipsychotic use during hospitalization, and length of hospitalization were also statistically different between the groups. While not reaching statistical significance, there were differences in reason for admission and relapse rate upon follow-up between the groups.

Introduction: Alcohol withdrawal seizures and delirium tremens (DT) are serious complications of alcohol dependence. The prevalence of arrhythmias and other electrocardiographic (ECG) changes occurring in these clinical situations is not well studied., Methods: We performed a retrospective analysis of clinical data and ECG's from patients discharged between 1995 and 2005 with the diagnosis of DT (ICD-Code F10.4) or alcohol withdrawal seizures (F10.3). Measurement of the ECG intervals was done in lead II. The corrected QT interval (QTc) was obtained using Bazett's formula., Results: 49 patients (38 males; 11 females) with a mean age of 48 years were included in the study. 23 patients with DT and 16 with convulsions were admitted to the hospitals. Ten patients developed DT while being hospitalised for other reasons. The QTc interval was prolonged (>440 ms and >460 ms in males and females, respectively) in 31 patients (63%). Five patients (10%) developed tachyarrhythmias (two torsade de pointes, one sustained ventricular tachycardia, two supraventricular tachycardia, one atrial fibrillation). All returned to sinus rhythm after appropriate treatment., Conclusions: Tachyarrhythmias are common amongst patients with severe alcohol withdrawal syndromes. The majority of the patients had an acquired long QT syndrome which led to a torsade de pointes in two cases. No patient died in the hospital and all were discharged in sinus rhythm. Clinicians should possibly avoid QT prolonging drugs and carefully monitor the rhythm in patients with severe alcohol withdrawal syndromes.

Male mice (Mus musculus) from 15 standard inbred strains were exposed to a nearly constant concentration of ethanol (EtOH) vapor for 72 hr, averaging 1.59 +/- 0.03 mg EtOH/mL blood at withdrawal. EtOH- and air-exposed groups were tested hourly for handling-induced convulsions for 10 hr and at Hours 24 and 25. Strains differed markedly in the severity of withdrawal (after subtraction of control values), and by design these differences were independent of strain differences in EtOH metabolism. Correlation of strain mean withdrawal severity with other responses to EtOH supported previously reported genetic relationships of high EtOH withdrawal with low drinking, high conditioned taste aversion, low tolerance to EtOH-induced hypothermia, and high stimulated activity after low-dose EtOH. Also supported were the positive genetic correlations among EtOH, barbiturate, and benzodiazepine withdrawal. Sensitivity of naive mice to several chemical convulsant-induced seizures was also correlated with EtOH withdrawal., ((c) 2005 APA)

This article presents the proceedings of the symposium "Endogenous Opioids and Voluntary Ethanol Consumption: What Have We Learnt From Knock-out Mice?" presented at the meeting of the International Society for Biomedical Research on Alcoholism held in Heidelberg/Mannheim, Germany, in September/October 2004. The organizers and chairpersons were Michael S. Cowen and Carles Sanchis-Segura. The presentations were as follows: (1) Regulation of the Opioid System by Alcohol: Comparison of Alcohol-Preferring and -Nonpreferring Strains by Michael S. Cowen; (2) Endogenous Opioids and Alcohol: Lessons From Microdialysis and Knock-out Mice by M. Foster Olive; (3) From Neurochemistry to Neuroanatomy: The Hypothalamic Arcuate Nucleus as a Main Site for Ethanol-Opioids Interaction by Carles Sanchis-Segura; (4) Sensitivity to Ethanol Is Modulated by beta-Endorphin in Transgenic Mice by Judy E. Grisel, Amanda J. Roberts, and George F. Koob; and () The mu-Opioid Receptor Modulates Acute Ethanol Sensitivity and Ethanol Withdrawal Severity by Sandra Ghozland.

This review summarizes new findings on the bidirectional interactions between alcohol and the clock genes, underlying the generation of circadian rhythmicity. At the behavioral level, both adult and perinatal ethanol treatments after the free-running period and light response of the circadian clock in rodents; genetic ethanol preference in alcohol-preferring rat lines is also associated with alterations in circadian pacemaker function. At the neuronal level, it has been shown that ethanol consumption alters the circadian expression patterns of period (per) genes in various brain regions, including the suprachiasmatic nucleus. Notably, circadian functions of beta-endorphin-containing neurons that participate in the control of alcohol reinforcement become disturbed after chronic alcohol intake. In turn, per2 gene activity regulates alcohol intake through its effects on the glutamatergic system through glutamate reuptake mechanisms and thereby may affect a variety of physiological processes that are governed by our internal clock. In summary, a new pathologic chain has been identified that contributes to the negative health consequences of chronic alcohol intake. Thus, chronic alcohol intake alters the expression of per genes, and as a consequence, a variety of neurochemical and neuroendocrine functions become disturbed. Further steps in this pathologic chain are alterations in physiological and immune functions that are under circadian control, and, as a final consequence, addictive behavior might be triggered or sustained by this cascade.

Delirium tremens is recognized as a potentially fatal and debilitating complication of ethanol withdrawal. Research thus far has primarily focused on the prevention of delirium tremens.

The authors reviewed MEDLINE and references of major articles in the published literature over the last 30 years regarding the complications of alcohol abuse and discuss the critical care aspects of alcohol abuse. This article discusses the severe medical conditions associated with alcohol abuse that lead to admission to the medical intensive care unit. The clinical manifestations, pathophysiology, diagnostic studies, and management of these conditions are discussed in detail.

Critically ill patients with alcoholism are at greater risk of morbidity and mortality from alcohol withdrawal syndrome than are patients without alcoholism. Benzodiazepines are considered the drugs of choice for the prevention and treatment of alcohol withdrawal syndrome, but some studies have suggested that intravenous ethanol may be as effective as those agents, as well as being less sedating. We evaluated the evidence regarding the use of intravenous ethanol for the prevention and treatment of alcohol withdrawal syndrome in critically ill patients in order to determine its role in this patient population. Because of the paucity of well-designed clinical trials, and because of intravenous ethanol's questionable efficacy, inconsistent pharmacokinetic profile, and relatively narrow therapeutic index, routine use of this drug is not recommended in critically ill patients who have alcohol withdrawal syndrome or are at risk for it.

Previous studies have found an association between the A9 allele (nine-copy repeat) of the dopamine transporter (DAT) gene and two complications of alcohol withdrawal, namely delirium tremens (DT) and alcohol withdrawal seizures (AWS). Most of these studies only included male alcohol-dependent patients. Even those that included a small proportion of women did not look at the effect of gender. We compared the frequency of the A9 allele in 64 French Caucasian alcohol-dependent women with a history of alcohol withdrawal complications. Women carrying the A9 allele had more visual hallucinations during withdrawal than those without this allele (P = 0.03). However, women with the A9 allele were not more susceptible to DT or AWS than those without (P = 0.48 and P = 1.00, respectively). Our results suggest that the A9 allele of the DAT gene is involved in vulnerability to alcohol withdrawal complications in women, but that these complications differ from those associated with this polymorphism in alcohol-dependent men., (Copyright 2004 Elsevier Ireland Ltd.)

The objective of this paper is to review and describe the main neuropharmacological changes caused by the chronic use of alcohol and those observed during its withdrawal period. The results show international data referring to the involvement of monoamine systems, neurotransmitters and calcium channels in both neuroadaptation and tolerance to alcohol effects and withdrawal. Relevant studies showing the participation of other systems in those mechanisms, as opioids and other substances, are also shown. The article reinforces the importance, for both physicians and researchers, of an always growing understanding of alcohol central mechanisms of action. This understanding is necessary to new pharmacological options to alcohol harm reduction as well as to alcohol withdrawal treatment.

The spectrum of alcohol withdrawal symptoms ranges from such minor symptoms as insomnia and tremulousness to severe complications such as withdrawal seizures and delirium tremens. Although the history and physical examination usually are sufficient to diagnose alcohol withdrawal syndrome, other conditions may present with similar symptoms. Most patients undergoing alcohol withdrawal can be treated safely and effectively as outpatients. Pharmacologic treatment involves the use of medications that are cross-tolerant with alcohol. Benzodiazepines, the agents of choice, may be administered on a fixed or symptom-triggered schedule. Carbamazepine is an appropriate alternative to a benzodiazepine in the outpatient treatment of patients with mild to moderate alcohol withdrawal symptoms. Medications such as haloperidol, beta blockers, clonidine, and phenytoin may be used as adjuncts to a benzodiazepine in the treatment of complications of withdrawal. Treatment of alcohol withdrawal should be followed by treatment for alcohol dependence.