Bottom-up PBPK modeling of phenytoin brain disposition in postpartum newborns after intrauterine dosing.

OBJECTIVES: The antiepileptic phenytoin has a narrow therapeutic window, nonlinear pharmacokinetics, and can cross the placenta causing apathy and jitteriness in postpartum newborns. Further, the sudden decay of phenytoin concentration can cause withdrawal seizures. This work aimed to assess the brain toxic exposure to phenytoin in newborns after transplacental transfer using neonatal saliva-brain correlations. METHODS: The phenytoin dose that the newborn receives transplacentally at birth was estimated using verified physiologically based pharmacokinetic (PBPK) model simulations in third-trimester pregnancy (pregnancy T3). Such doses were used as an input to the newborn PBPK model to estimate the neonatal levels of phenytoin and their correlations in brain extracellular fluid (bECF), plasma, and saliva. RESULTS: The PBPK model-estimated neonatal plasma and bECF concentrations of phenytoin were below the necessary thresholds for anticonvulsant and toxic effects. The neonatal salivary thresholds for phenytoin anticonvulsant and toxic effects were estimated to be 1.3 and 2.5 mg/L, respectively using the plasma-saliva-bECF correlations established herein. CONCLUSIONS: The salivary TDM of phenytoin can be a more convenient option for avoiding phenytoin brain toxicity in newborns of epileptic mothers. Still, the appropriateness of using the same adult values of phenytoin anticonvulsant and toxic effects for infants needs investigation.

Long-term observation and mortality of children with nodding syndrome in western Uganda, 1994 - 2018.

PURPOSE: To assess long-term mortality and causes of death in children with nodding syndrome, an epileptic disorder of sub-Sahara Africa. METHODS: Ten children with nodding syndrome were followed over 24 years. The mortality rate was determined as the number of deaths per 1000 person-years of observation. The standard mortality ratio (SMR) was calculated as the number of observed deaths divided by the number of expected deaths in the general population. Patients were started on phenobarbital and treatment response was monitored during the first 20 months of follow-up. RESULTS: During an observation period of 89.8 person-years, eight patients had died, one patient was found alive, and one patient had been lost to follow-up. This corresponded to a mortality rate of 89.1 deaths per 1000 person-years and a SMR of 21.4 (95 % CI 6.6-36.2). Five deaths were related to status epilepticus, in two cases occurring after inadvertent drug withdrawal. All patients responded on phenobarbital with a reduction of seizure frequency but only four reached a seizure-free period of at least 6 months. CONCLUSIONS: This long-term follow-up demonstrated high mortality in patients with nodding syndrome. Anti-seizure treatment with phenobarbital was of moderate efficacy. Abrupt interruption of phenobarbital was found leading to seizure aggravation, status epilepticus, and death. Our findings point out the importance of securing continuity of treatment access once anti-seizure therapy is included in health services in resource-poor settings. More rigorous observations and controlled studies are needed to improve the therapeutic options for nodding syndrome.

Long-term outcome of alcohol withdrawal seizures.

BACKGROUND AND PURPOSE: Alcohol withdrawal seizures (AWS) are a well-known complication of chronic alcohol abuse, but there is currently little knowledge of their long-term relapse rate and prognosis. The aims of this study were to identify risk factors for AWS recurrence and to study the overall outcome of patients after AWS. METHODS: In this retrospective single-center study, we included patients who were admitted to the Emergency Department after an AWS between January 1, 2013 and August 10, 2021 and for whom an electroencephalogram (EEG) was requested. AWS relapses up until April 29, 2022 were researched. We compared history, treatment with benzodiazepines or antiseizure medications (ASMs), laboratory, EEG and computed tomography findings between patients with AWS relapse (r-AWS) and patients with no AWS relapse (nr-AWS). RESULTS: A total of 199 patients were enrolled (mean age 53 ± 12 years; 78.9% men). AWS relapses occurred in 11% of patients, after a median time of 470.5 days. Brain computed tomography (n = 182) showed pathological findings in 35.7%. Risk factors for relapses were history of previous AWS (p = 0.013), skull fractures (p = 0.004) at the index AWS, and possibly epileptiform EEG abnormalities (p = 0.07). Benzodiazepines or other ASMs, taken before or after the index event, did not differ between the r-AWS and the nr-AWS group. The mortality rate was 2.9%/year of follow-up, which was 13 times higher compared to the general population. Risk factors for death were history of AWS (p < 0.001) and encephalopathic EEG (p = 0.043). CONCLUSIONS: Delayed AWS relapses occur in 11% of patients and are associated with risk factors (previous AWS >24 h apart, skull fractures, and pathological EEG findings) that also increase the epilepsy risk, that is, predisposition for seizures, if not treated. Future prospective studies are mandatory to determine appropriate long-term diagnostic and therapeutic strategies, in order to reduce the risk of relapse and mortality associated with AWS.

Sex difference in alcohol withdrawal syndrome: a scoping review of clinical studies.

Background: We conducted a review of all studies comparing clinical aspects of alcohol withdrawal syndrome (AWS) between men and women. Methods: Five databases (PubMed, Cochrane, EMBASE, Scopus and Clinical Trials) were searched for clinical studies using the keywords "alcohol withdrawal syndrome" or "delirium tremens" limited to "sex" or "gender" or "sex difference" or "gender difference." The search was conducted on May 19, 2023. Two reviewers selected studies including both male and female patients with AWS, and they compared males and females in type of AWS symptoms, clinical course, complications, and treatment outcome. Results: Thirty-five observational studies were included with a total of 318,730 participants of which 75,346 had AWS. In twenty of the studies, the number of patients presenting with or developing AWS was separated by sex, resulting in a total of 8,159 (12.5%) female patients and a total of 56,928 (87.5%) male patients. Despite inconsistent results, males were more likely than females to develop complicated AWS [delirium tremens (DT) and AW seizures, collective DT in Males vs. females: 1,792 (85.4%) vs. 307 (14.6%), and collective seizures in males vs. females: 294 (78%) vs. 82 (22%)]. The rates of ICU admissions and hospital length of stay did not show sex differences. Although variable across studies, compared to females, males received benzodiazepine treatment at higher frequency and dose. One study reported that the time from first hospitalization for AWS to death was approximately 1.5 years shorter for males and males had higher mortality rate [19.5% (197/1,016)] compared to females [16% (26/163)]. Conclusion: Despite the significant heterogeneity of the studies selected and the lack of a focus on investigating potential sex differences, this review of clinical studies on AWS suggests that men and women exhibit different AWS manifestations. Large-scale studies focusing specifically on investigating sex difference in AWS are needed.

Blood Alcohol Level as a Predictor of Withdrawal Severity.

Few studies have explored the correlation between the severity of alcohol withdrawal and blood alcohol level at the time of admission. Specifying prognostic factors for life-threatening withdrawal necessitating inpatient pharmacologic management over the course of days would be useful to identify at-risk patients at the time of admission. Hence, we present the case of a 34-year-old Caucasian male with a past medical history of poly-substance abuse who has presented to our emergency department 11 times over the past four years with a mean blood alcohol level (BAL) of 287 mg/dL upon withdrawal. BAL at the time of withdrawal is highly variable depending on the chronicity of abuse; however, a BAL this elevated is highly unusual and indicative of severe and long-term use. While in the unit at this admission, the patient's BAL was 437 and his withdrawal symptoms were severe, necessitating ICU admission and strong sedating medications to control his symptoms. Even after these interventions, he still demonstrated severe withdrawal symptoms including full body tremors, vital sign instability, and continuous visual, auditory, and tactile hallucinations. This patient presents an interesting case of severe alcohol withdrawal at an abnormally elevated blood alcohol level progressing to a prolonged withdrawal course in the ICU. Alcohol level at the time of withdrawal could be a helpful predictor of the course of severity of alcohol withdrawal; however, more studies are required to prove this relationship.

Adult hemiconvulsive hemiatrophy syndrome: a novel clinicoradiologic disorder in adults.

The association of focal motor seizures with cerebral hemiatrophy is a recognised rare paediatric syndrome known as 'hemiconvulsion, hemiatrophy and epilepsy' (HHE). To date, HHE has not been reported in adults. We present four adult patients with striking similarities to HHE, following alcohol withdrawal in chronic alcoholics. We document the imaging findings in the acute and subacute phases, discuss the underlying mechanisms and present a hypothesis regarding the pathophysiology.

Evaluation of Acute Symptomatic Seizures and Etiological Factors in a Tertiary Care Hospital From a Developing Country.

INTRODUCTION: The etiologies of acute symptomatic seizures (ASS) differ across the globe. We aimed to evaluate the etiological spectrum of acute seizures and to observe the pattern of seizure types among study participants. METHODOLOGY: We conducted this prospective study from 2016 to 18. We included all patients aged 20 years or older, presenting with ASS. We excluded those with pseudoseizures. We performed appropriate descriptive analyses to describe the demographic details, etiology of ASS, and pattern of ASS. RESULTS: One hundred and thirty-eight patients were enrolled, constituting about 0.8% of total hospital admissions. The mean age at presentation was 44.33 ± 17.73 years. The most common etiologies for ASS were cerebrovascular accidents (CVA - 32.6%), neuroinfections (26.8%), metabolic derangements (13%), alcohol withdrawal (10.9%), and intracranial tumors (4.3%). 71% of the patients presented with only a single episode of ASS. The predominant type of seizure was generalized tonic-clonic seizures, seen in 70.2% of all patients, followed by focal with the bilateral tonic-clonic type (15.9%) and focal seizures (10.1%). New-onset seizures presenting as status epilepticus were observed in 3.6%. DISCUSSION: CVA and neuroinfections were the most common causes of ASS in our study, highlighting the need for community awareness of these conditions and the need to seek rapid care. The majority of our patients had only a single episode of seizures, with generalized seizures being the most common type, followed by focal onset seizures.

The hemodynamic effects of diazepam versus dexmedetomidine in the treatment of alcohol withdrawal syndrome: A randomized clinical trial / Efectos hemodinámicos del diazepam versus la dexmedetomidina en el tratamiento del síndrome de abstinencia del alcohol: ensayo clínico aleatorizado

Background: Dexmedetomidine (DEX) is an alpha-2 adrenergic drug used for short sedation and as an alternative to diazepam (DZP) in the treatment of alcohol withdrawal syndrome (AWS).PurposeThis study aims to compare the hemodynamic effect of DZP versus DEX on heart rate (HR) and blood pressure in patients with AWS.MethodsProspective randomized clinical trial that includes 40 patients with AWS from Mérida, Yucatán, México.ResultsForty patients were randomly divided into two groups: one group DZP (n=20) patients received diazepam (doses 5–20mg IV) and the other group (n=20) received DEX (dexmedetomidine infusion .2–.7mcg/kg/min). We obtained statistical significance in sedation with the DEX group in the degree of traumatic brain injury I/II (p=.003). The DEX group remained haemodynamically stable in the first 24h, the mean HR (73.85±8.39) was significant comparing both groups (p=.002). In the comparison of the figures for the DEX group with the DZP (143.85±2.30–137.95±5.62) the SBP was significant with a (p=.0001). Furthermore, DEX treatment was shorter.ConclusionAlthough DEX is not indicated for the routine treatment of AWS, this study proposes a positive effect on HR, SBP and fewer days of treatment compared to the standard DZP treatment for AWS. (AU)

Antecedentes: La dexmedetomidina (DEX) es un fármaco alfa-2 adrenérgico, utilizado para la sedación corta y como alternativa al diazepam (DZP) en el tratamiento por síndrome de abstinencia por alcohol.ObjetivosComparar el efecto hemodinámico del DZP versus la DEX en la frecuencia cardíaca (FC) y la presión arterial en pacientes con síndrome de abstinencia del alcohol.MétodosEnsayo clínico aleatorizado prospectivo en 40 pacientes con síndrome de abstinencia de alcohol, del Hospital General Agustín O’Horán Mérida, Yucatán, México.ResultadosCuarenta pacientes fueron divididos aleatoriamente en 2 grupos: grupo DZP (n=20) recibió DZP n=20 (dosis: 5-20mg IV) y el otro grupo (n=20) recibió DEX (infusión de DEX: 0,2-0,7μg/kg/min). Obtuvimos significancia estadística en la sedación con el grupo de DEX en el grado de trauma craneoencefálico I/II (p=0,003). El grupo de DEX se mantuvo hemodinámicamente estable en las primeras 24h, la media FC (73; 85±8,39) fue significativa comparando ambos grupos (p=0,002). Las cifras de PAS para el grupo DEX comparada con DZP (143; 85±2; 30-137, 95±5,62) fue significativa con a (p=0,0001). Además, el tratamiento con DEX fue de menor duración.ConclusiónAunque DEX no está indicado para el tratamiento de rutina de AWS, este estudio propone un efecto positivo hemodinámicamente sobre la FC, la PAS y menos días de tratamiento en comparación con el tratamiento estándar de DZP para el tratamiento del síndrome de abstinencia del alcohol. (AU)

The hemodynamic effects of diazepam versus dexmedetomidine in the treatment of alcohol withdrawal syndrome: A randomized clinical trial.

BACKGROUND: Dexmedetomidine (DEX) is an alpha-2 adrenergic drug used for short sedation and as an alternative to diazepam (DZP) in the treatment of alcohol withdrawal syndrome (AWS). PURPOSE: This study aims to compare the hemodynamic effect of DZP versus DEX on heart rate (HR) and blood pressure in patients with AWS. METHODS: Prospective randomized clinical trial that includes 40 patients with AWS from Mérida, Yucatán, México. RESULTS: Forty patients were randomly divided into two groups: one group DZP (n=20) patients received diazepam (doses 5-20mg IV) and the other group (n=20) received DEX (dexmedetomidine infusion .2-.7mcg/kg/min). We obtained statistical significance in sedation with the DEX group in the degree of traumatic brain injury I/II (p=.003). The DEX group remained haemodynamically stable in the first 24h, the mean HR (73.85±8.39) was significant comparing both groups (p=.002). In the comparison of the figures for the DEX group with the DZP (143.85±2.30-137.95±5.62) the SBP was significant with a (p=.0001). Furthermore, DEX treatment was shorter. CONCLUSION: Although DEX is not indicated for the routine treatment of AWS, this study proposes a positive effect on HR, SBP and fewer days of treatment compared to the standard DZP treatment for AWS. Clinical Trials.gov ID: NCT03877120-https://clinicaltrials.gov/ct2/show/NCT03877120.

A machine learning approach to risk assessment for alcohol withdrawal syndrome.

At present, risk assessment for alcohol withdrawal syndrome relies on clinical judgment. Our aim was to develop accurate machine learning tools to predict alcohol withdrawal outcomes at the individual subject level using information easily attainable at patients' admission. An observational machine learning analysis using nested cross-validation and out-of-sample validation was applied to alcohol-dependent patients at two major detoxification wards (LMU, n = 389; TU, n = 805). 121 retrospectively derived clinical, blood-derived, and sociodemographic measures were used to predict 1) moderate to severe withdrawal defined by the alcohol withdrawal scale, 2) delirium tremens, and 3) withdrawal seizures. Mild and more severe withdrawal cases could be separated with significant, although highly variable accuracy in both samples (LMU, balanced accuracy [BAC] = 69.4%; TU, BAC = 55.9%). Poor outcome predictions were associated with higher cumulative clomethiazole doses during the withdrawal course. Delirium tremens was predicted in the TU cohort with BAC of 75%. No significant model predicting withdrawal seizures could be found. Our models were unique to each treatment site and thus did not generalize. For both treatment sites and withdrawal outcome different variable sets informed our models' decisions. Besides previously described variables (most notably, thrombocytopenia), we identified new predictors (history of blood pressure abnormalities, urine screening for benzodiazepines and educational attainment). In conclusion, machine learning approaches may facilitate generalizable, individualized predictions for alcohol withdrawal severity. Since predictive patterns highly vary for different outcomes of withdrawal severity and across treatment sites, prediction tools should not be recommended for clinical practice unless adequately validated in specific cohorts.

Derivation and validation of a multivariable model, the alcohol withdrawal triage tool (AWTT), for predicting severe alcohol withdrawal syndrome.

BACKGROUND: Alcohol withdrawal and its consequences are a common concern for the large numbers of patients who present to emergency departments (EDs) with alcohol use disorders. While the majority of patients who go on to develop alcohol withdrawal experience only mild symptoms, a small proportion will experience seizures or delirium tremens. The aim of this study was to develop a tool to predict the need for hospital admission in patients at risk for alcohol withdrawal using only objective criteria that are typically available during the course of an ED visit. METHODS: We conducted a retrospective study at an academic medical center. Our primary outcome was severe alcohol withdrawal syndrome (SAWS), which we defined as a composite of delirium tremens, seizure, or use of high benzodiazepine doses. All candidate predictors were abstracted from the electronic health record. A logistic regression model was constructed using the derivation dataset to create the alcohol withdrawal triage tool (AWTT). RESULTS: Of the 2038 study patients, 408 20.0 %) developed SAWS. We identified eight independent predictors of SAWS. Each of the predictors in the regression model was assigned one point. Summing the points for each predictor generated the AWTT score. An AWTT score of 3 or greater was defined as high risk based on sensitivity of 90 % and specificity of 47 % for predicting SAWS. CONCLUSIONS: We were able to identify a set of objective, timely, independent predictors of SAWS. The predictors were used to create a novel clinical prediction rule, the AWTT.

Role of Hippocampal Neurogenesis in Alcohol Withdrawal Seizures.

Chronic alcohol consumption results in alcohol use disorder (AUD). Interestingly, however, sudden alcohol withdrawal (AW) after chronic alcohol exposure also leads to a devastating series of symptoms, referred to as alcohol withdrawal syndromes. One key feature of AW syndromes is to produce phenotypes that are opposite to AUD. For example, while the brain is characterized by a hypoactive state in the presence of alcohol, AW induces a hyperactive state, which is manifested as seizure expression. In this review, we discuss the idea that hippocampal neurogenesis and neural circuits play a key role in neuroadaptation and establishment of allostatic states in response to alcohol exposure and AW. The intrinsic properties of dentate granule cells (DGCs), and their contribution to the formation of a potent feedback inhibitory loop, endow the dentate gyrus with a "gate" function, which can limit the entry of excessive excitatory signals from the cortex into the hippocampus. We discuss the possibility that alcohol exposure and withdrawal disrupts structural development and circuitry integration of hippocampal newborn neurons, and that this altered neurogenesis impairs the gate function of the hippocampus. Failure of this gate function is expected to alter the ratio of excitatory to inhibitory (E/I) signals in the hippocampus and to induce seizure expression during AW. Recent functional studies have shown that specific activation and inhibition of hippocampal newborn DGCs are both necessary and sufficient for the expression of AW-associated seizures, further supporting the concept that neurogenesis-induced neuroadaptation is a critical target to understand and treat AUD and AW-associated seizures.

Voltage-Sensitive Calcium Channels in the Brain: Relevance to Alcohol Intoxication and Withdrawal.

Voltage-sensitive Ca2+ (CaV) channels are the primary route of depolarization-induced Ca2+ entry in neurons and other excitable cells, leading to an increase in intracellular Ca2+ concentration ([Ca2+]i). The resulting increase in [Ca2+]i activates a wide range of Ca2+-dependent processes in neurons, including neurotransmitter release, gene transcription, activation of Ca2+-dependent enzymes, and activation of certain K+ channels and chloride channels. In addition to their key roles under physiological conditions, CaV channels are also an important target of alcohol, and alcohol-induced changes in Ca2+ signaling can disturb neuronal homeostasis, Ca2+-mediated gene transcription, and the function of neuronal circuits, leading to various neurological and/or neuropsychiatric symptoms and disorders, including alcohol withdrawal induced-seizures and alcoholism.

Alcohol Withdrawal-Induced Seizure Susceptibility is Associated with an Upregulation of CaV1.3 Channels in the Rat Inferior Colliculus.

BACKGROUND: We previously reported increased current density through L-type voltage-gated Ca(2+) (CaV1) channels in inferior colliculus (IC) neurons during alcohol withdrawal. However, the molecular correlate of this increased CaV1 current is currently unknown. METHODS: Rats received three daily doses of ethanol every 8 hours for 4 consecutive days; control rats received vehicle. The IC was dissected at various time intervals following alcohol withdrawal, and the mRNA and protein levels of the CaV1.3 and CaV1.2 α1 subunits were measured. In separate experiments, rats were tested for their susceptibility to alcohol withdrawal-induced seizures (AWS) 3, 24, and 48 hours after alcohol withdrawal. RESULTS: In the alcohol-treated group, AWS were observed 24 hours after withdrawal; no seizures were observed at 3 or 48 hours. No seizures were observed at any time in the control-treated rats. Compared to control-treated rats, the mRNA level of the CaV1.3 α1 subunit was increased 1.4-fold, 1.9-fold, and 1.3-fold at 3, 24, and 48 hours, respectively. In contrast, the mRNA level of the CaV1.2 α1 subunit increased 1.5-fold and 1.4-fold at 24 and 48 hours, respectively. At 24 hours, Western blot analyses revealed that the levels of the CaV1.3 and CaV1.2 α1 subunits increased by 52% and 32%, respectively, 24 hours after alcohol withdrawal. In contrast, the CaV1.2 and CaV1.3 α1 subunits were not altered at either 3 or 48 hours during alcohol withdrawal. CONCLUSIONS: Expression of the CaV1.3 α1 subunit increased in parallel with AWS development, suggesting that altered L-type CaV1.3 channel expression is an important feature of AWS pathogenesis.

Evaluation of adjunctive ketamine to benzodiazepines for management of alcohol withdrawal syndrome.

BACKGROUND: Adjunctive medications to manage alcohol withdrawal syndrome (AWS) in patients not adequately responding to escalating doses of benzodiazepines (BZDs) are limited. The use of the N-methyl-d-aspartate antagonist ketamine, may serve as an effective adjunct agent; however, no published data currently exist for this practice. OBJECTIVE: To determine the safety and efficacy of adjunct ketamine for management of AWS. METHODS: The study was a retrospective review of adult patients from April 2011 to March 2014 who were administered ketamine specifically for management of AWS. Outcomes included changes in BZD requirements and ketamine-related adverse reactions. RESULTS: Of 235 patients screened, 23 patients met study eligibility. Ketamine was initiated primarily with toxicology consultation for significant BZD requirements or delirium tremens. The mean time to initiation of ketamine from first treatment of AWS, and total duration of therapy were 33.6 and 55.8 hours, respectively. Mean initial infusion dose and median total infusion rate during therapy were 0.21 and 0.20 mg/kg/h, respectively. There was no change in sedation or alcohol withdrawal scores in patients within 6 hours of ketamine initiation. The median change in BZD requirements at 12 and 24 hours post-ketamine initiation were -40.0 and -13.3 mg, respectively. The mean time to AWS resolution was 5.6 days. There was one documented adverse reaction of oversedation, requiring dose reduction. CONCLUSIONS: Ketamine appears to reduce BZD requirements and is well tolerated at low doses. Prospective dose range evaluations in the management of AWS would be helpful in determining its place as an adjunctive agent.

Multicenter evaluation of pharmacologic management and outcomes associated with severe resistant alcohol withdrawal.

INTRODUCTION: A subset of patients with alcohol withdrawal syndrome does not respond to benzodiazepine treatment despite escalating doses. Resistant alcohol withdrawal (RAW) is associated with higher incidences of mechanical ventilation and nosocomial pneumonia and longer intensive care unit (ICU) stay. The objective of this study is to characterize pharmacologic management of RAW and outcomes. METHODS: Adult patients were identified retrospectively via International Classification of Diseases, Ninth Revision codes for severe alcohol withdrawal from 2009 to 2012 at 3 hospitals. Data collected included pharmacologic management and clinical outcomes. RESULTS: A total of 184 patients met inclusion criteria. Sixteen medications and 74 combinations of medications were used for management. Propofol was the most common adjunct agent, with dexmedetomidine and antipsychotics also used. One hundred seventy-five patients (96.2%) were admitted to the ICU, with 149 patients (81.9%) requiring ventilator support. Median time to resolution of alcohol withdrawal syndrome from RAW designation was 6.0 days. Median ICU and hospital length of stay were 9.0 and 12.7 days, respectively. CONCLUSION: Diverse patterns exist in the management of patients meeting RAW criteria, indicating lack of refined approach to treatment. High doses of sedatives used for these patients may result in a high level of care, illustrating a need for evidence-based clinical guidelines to optimize outcomes.

BKCa channel dysfunction in neurological diseases.

The large conductance, Ca(2+)-activated K(+) channels (BKCa, KCa1.1) are expressed in various brain neurons where they play important roles in regulating action potential duration, firing frequency and neurotransmitter release. Membrane potential depolarization and rising levels of intracellular Ca(2+) gated BKCa channels, which in turn results in an outward K(+) flux that re/hyperpolarizes the membrane. The sensitivity of BKCa channels to Ca(2+) provides an important negative-feedback system for Ca(2+) entry into brain neurons and suppresses repetitive firing. Thus, BKCa channel loss-of-function gives rise to neuronal hyperexcitability, which can lead to seizures. Evidence also indicates that BKCa channels can facilitate high-frequency firing (gain-of-function) in some brain neurons. Interestingly, both gain-of-function and loss-of-function mutations of genes encoding for various BKCa channel subunits have been associated with the development of neuronal excitability disorders, such as seizure disorders. The role of BKCa channels in the etiology of some neurological diseases raises the possibility that these channels can be used as molecular targets to prevent and suppress disease phenotypes.

The "Prediction of Alcohol Withdrawal Severity Scale" (PAWSS): systematic literature review and pilot study of a new scale for the prediction of complicated alcohol withdrawal syndrome.

BACKGROUND: To date, no screening tools for alcohol withdrawal syndromes (AWS) have been validated in the medically ill. Although several tools quantify the severity of AWS (e.g., Clinical Institute Withdrawal Assessment for Alcohol [CIWA]), none identify subjects at risk of AWS, thus missing the opportunity for timely prophylaxis. Moreover, there are no validated tools for the prediction of complicated (i.e., moderate to severe) AWS in the medically ill. OBJECTIVES: Our goals were (1) to conduct a systematic review of the published literature on AWS to identify clinical factors associated with the development of AWS, (2) to use the identified factors to develop a tool for the prediction of alcohol withdrawal among patients at risk, and (3) to conduct a pilot study to assess the validity of the tool. METHODS: For the creation of the Prediction of Alcohol Withdrawal Severity Scale (PAWSS), we conducted a systematic literature search using PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines for clinical factors associated with the development of AWS, using PubMed, PsychInfo, MEDLINE, and Cochrane Databases. Eligibility criteria included: (i) manuscripts dealing with human subjects, age 18 years or older, (ii) manuscripts directly addressing descriptions of AWS or its predisposing factors, including case reports, naturalistic case descriptions, and all types of clinical trials (e.g., randomized, single-blind, or open label studies), (iii) manuscripts describing characteristics of alcohol use disorder (AUD), and (iv) manuscripts dealing with animal data (which were considered only if they directly dealt with variables described in humans). Obtained data were used to develop the Prediction of Alcohol Withdrawal Severity Scale, in order to assist in the identification of patients at risk for complicated AWS. A pilot study was conducted to assess the new tool's psychometric qualities on patients admitted to a general inpatient medicine unit over a 2-week period, who agreed to participate in the study. Blind to PAWSS results, a separate group of researchers retrospectively examined the medical records for evidence of AWS. RESULTS: The search produced 2802 articles describing factors potentially associated with increased risk for AWS, increased severity of withdrawal symptoms, and potential characteristics differentiating subjects with various forms of AWS. Of these, 446 articles met inclusion criteria and underwent further scrutiny, yielding a total of 233 unique articles describing factors predictive of AWS. A total of 10 items were identified as correlated with complicated AWS (i.e., withdrawal hallucinosis, withdrawal-related seizures, and delirium tremens) and used to construct the PAWSS. During the pilot study, a total of 68 subjects underwent evaluation with PAWSS. In this pilot sample the sensitivity, specificity, and positive and negative predictive values of PAWSS were 100%, using the threshold score of 4. DISCUSSION: The results of the literature search identified 10 items which may be correlated with risk for complicated AWS. These items were assembled into a tool to assist in the identification of patients at risk: PAWSS. The results of this pilot study suggest that PAWSS may be useful in identifying risk of complicated AWS in medically ill, hospitalized individuals. PAWSS is the first validated tool for the prediction of severe AWS in the medically ill and its use may aid in the early identification of patients at risk for complicated AWS, allowing for prophylaxis against AWS before severe alcohol withdrawal syndromes develop.

Clinical management of alcohol withdrawal: A systematic review.

Alcohol withdrawal is commonly encountered in general hospital settings. It forms a major part of referrals received by a consultation-liaison psychiatrist. This article aims to review the evidence base for appropriate clinical management of the alcohol withdrawal syndrome. We searched Pubmed for articles published in English on pharmacological management of alcohol withdrawal in humans with no limit on the date of publication. Articles not relevant to clinical management were excluded based on the titles and abstract available. Full-text articles were obtained from this list and the cross-references. There were four meta-analyses, 9 systematic reviews, 26 review articles and other type of publications like textbooks. Alcohol withdrawal syndrome is a clinical diagnosis. It may vary in severity. Complicated alcohol withdrawal presents with hallucinations, seizures or delirium tremens. Benzodiazepines have the best evidence base in the treatment of alcohol withdrawal, followed by anticonvulsants. Clinical institutes withdrawal assessment-alcohol revised is useful with pitfalls in patients with medical comorbidities. Evidence favors an approach of symptom-monitored loading for severe withdrawals where an initial dose is guided by risk factors for complicated withdrawals and further dosing may be guided by withdrawal severity. Supportive care and use of vitamins is also discussed.