Benzodiazepine Treatment Research Articles

A series of 8 cases of sleep-related psychogenic dissociative disorders and proposed updated diagnostic criteria.

To identify the most relevant clinical and video-polysomnographic characteristics of patients with sleep-related dissociative disorders (SRDDs) and to propose a framework for new diagnostic criteria. We searched potential SRDD cases from the scientific literature and from a database of patients referred for clinical and video-polysomnographic assessment in a single sleep disorders center for disruptive nocturnal behaviors (n = 731). The most relevant clinical and neurophysiological characteristics of the cases were extracted and a descriptive analysis was performed. Twenty-six SRDD cases (8 new and 18 previously published cases) were reviewed. Almost all cases of SRDDs occurred in a context of past traumatic events or abuse and were associated with at least 1 comorbid psychiatric disorder. We highlighted 4 relevant clinical characteristics of SRDD useful for the differential diagnosis with parasomnias: episodes of long duration of more than 1 hour (90.9%), self-inflicted injuries (83.3%), occurrence while awake close to bedtime (35.7%), and the presence of daytime dissociative symptoms (72.7%). The video-polysomnography documented typical episodes of SRDD with prolonged wakefulness before, during, and after the event in 11/26 cases. New diagnostic criteria for SRDD were proposed, with 3 levels of certainty for the diagnosis based on clinical, video-polysomnographic, and homemade video findings. More than 30 years after its formal identification, SRDD is not currently recognized as an official diagnostic entity. We better delineate the clinical and neurophysiological features of SRDD and propose a framework for its reinstatement in the next revisions of the sleep and psychiatric disorders classifications. Lopez R, Lefevre L, Barateau L, Micoulaud-Franchi J-A, Dauvilliers Y, Schenck CH. A series of 8 cases of sleep-related psychogenic dissociative disorders and proposed updated diagnostic criteria. J Clin Sleep Med. 2022;18(2):563-573.

Inhibiting with-no-lysine kinases enhances K+/Cl- cotransporter 2 activity and limits status epilepticus.

First-in-line benzodiazepine treatment fails to terminate seizures in about 30% of epilepsy patients, highlighting a need for novel anti-seizure strategies. It is emerging that impaired K+/Cl- cotransporter 2 (KCC2) activity leads to deficits in GABAergic inhibition and increased seizure vulnerability in patients. In neurons, the with-no-lysine (WNK) kinase-STE20/SPS1-related proline/alanine-rich (SPAK) kinase signalling pathway inhibits KCC2 activity via T1007 phosphorylation. Here, we exploit the selective WNK kinase inhibitor WNK463 to test the effects of pharmacological WNK inhibition on KCC2 function, GABAergic inhibition, and epileptiform activity. Immunoprecipitation and western blotting analysis revealed that WNK463 reduces KCC2-T1007 phosphorylation in vitro and in vivo. Using patch-clamp recordings in primary rat neurons, we further observed that WNK463 hyperpolarized the Cl- reversal potential, and enhanced KCC2-mediated Cl- extrusion. In the 4-aminopyridine slice model of acute seizures, WNK463 administration reduced the frequency and number of seizure-like events. In vivo, C57BL/6 mice that received intrahippocampal WNK463 experienced delayed onset of kainic acid-induced status epilepticus, less epileptiform EEG activity, and did not develop pharmaco-resistance to diazepam. Our findings demonstrate that acute WNK463 treatment potentiates KCC2 activity in neurons and limits seizure burden in two well-established models of seizures and epilepsy. In summary, our work suggests that agents which act to increase KCC2 activity may be useful adjunct therapeutics to alleviate diazepam-resistant status epilepticus.

Association between Term Equivalent Brain Magnetic Resonance Imaging and 2-Year Outcomes in Extremely Preterm Infants: A Report from the Preterm Erythropoietin Neuroprotection Trial Cohort

To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 240/7-276/7weeks of gestational age and to assess the associations between MRI findings and neurodevelopmental outcomes at 2years corrected age. The association between brain abnormality scores and Bayley Scales of Infant Development, Third Edition at 2years corrected age was explored in a subset of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial. Potential risk factors for neurodevelopmental outcomes such as treatment assignment, recruitment site, gestational age, inpatient complications, and treatments were examined using generalized estimating equation models. One hundred ten infants were assigned to Epo and 110 to placebo groups. 27% of MRI scans were rated as normal, and 60%, 10%, and 2% were rated as having mild, moderate, or severe abnormality. Brain abnormality scores did not significantly differ between the treatment groups. Factors that increased the risk of higher brain injury scores included intubation; bronchopulmonary dysplasia; retinopathy of prematurity; opioid, benzodiazepine, or antibiotic treatment >7days; and periventricular leukomalacia or severe intraventricular hemorrhage diagnosed on cranial ultrasound. Increased global brain abnormality and white matter injury scores at term equivalent were associated with reductions in cognitive, motor, and language abilities at 2years of corrected age. Evidence of brain injury on brain MRIs obtained at term equivalent correlated with adverse neurodevelopmental outcomes as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition at 2years corrected age. Early Epo treatment had no effect on the MRI brain injury scores compared with the placebo group.

Improving time for administration of second-line antiseizure medications for children with generalized convulsive status epilepticus using quality improvement methodology.

Status epilepticus is a life-threatening neurological emergency. However, delay in median time to administration of second-line antiseizure medication exists. The aim of this quality improvement initiative was to decrease the average delay before fosphenytoin is administered for pediatric patients with generalized convulsive status epilepticus from 30min (baseline data collected in 2013) to 15min (50% reduction) by December 2015 and sustain this for 1year. Our team conducted an analysis of baseline data for patients with continuous generalized convulsive status epilepticus who received fosphenytoin after receiving first-line benzodiazepine treatment. Using quality improvement methodology, areas for improvement were identified and specific interventions developed and implemented. A timeline of 15min to initiate fosphenytoin administration after failure of first-line treatment was considered reasonable and achievable as a project aim. A total of 199 patients were included in the dataset for the project. The database included patients aged 1month and older. Ninety-eight percent of patients were between 1month and 19years of age. The gender distribution was even, with 54% of patients being White or Caucasian, 30% African American or Black, and 16% classified as "other." From January 2014 through December 2019, the average time before initiating fosphenytoin administration after failure of benzodiazepine therapy, for patients with generalized convulsive status epilepticus, decreased from 30min (SD=45.7) to 11.4min (SD=8.2, p=.043), thus reducing time to administration by 62%. Quality improvement methodology can be successfully applied to decrease administration time between first- and second-line antiseizure medications for status epilepticus.

Different Attitudes of Patients and Psychiatrists Toward Benzodiazepine Treatment.

BackgroundConcern regarding the benefit/risk ratio of the long-term use of benzodiazepines (BDZs) and Z-drugs is increasing. To prevent the risk of dependence in BDZ long-term use, it is essential to understand the attitudes of patients and psychiatrists toward BDZ treatment. The aims of this investigation were to 1) obtain information on patients’ attitudes with long-term BDZ use and their referring psychiatrists’ attitudes toward BDZ treatment, including their perception of the difficulty of reducing the dose of BDZs, and 2) identify discrepancies between patients’ and psychiatrists’ perceptions.MethodsA brief questionnaire was constructed to investigate the attitudes of patients receiving BDZ treatment and their referring psychiatrists. Our sample comprised 155 patients who received BDZ treatment for more than one year and their referring eight psychiatrists. Both the patients and their psychiatrists completed our questionnaire between August 2017 and December 2017.ResultsOf the patients, 13% felt that it was more difficult to reduce the dose of BDZs than their referring psychiatrists (type A discrepancy), while 25% felt that it was less difficult (type B discrepancy). In the multivariate logistic regression analysis, the female sex and both the patients’ (“psychotherapy plus BDZs was necessary” and “it was necessary to increase the dose of BDZs”) and psychiatrists’ beliefs (“short-term prescription was justified”) were associated with type A discrepancies. Type B discrepancies were associated with psychiatrists’ beliefs that the patient’s wishes justified the use of BDZs and that the cessation of treatment with BDZs would lead to the deterioration of their rapport with their patients.ConclusionTo overcome the discrepancies in the attitudes of patients and psychiatrists toward the cessation of BDZ treatment, it is necessary to promote patient-centered care involving patient psychoeducation and practice guidelines for the decision-making process. Further studies investigating the promotion of patient-centered care to reduce BDZ use are needed.

Are anxiety disorders a prelude to delusional disorder? A systematic review

IntroductionPrevalence rates of panic attacks have been reported to be around 24-63% in psychotic patients. Common underlying biological substrates for panic and paranoia have been proposed, suggesting that delusional disorder (DD) may be preceded by the development of anxiety disorders.ObjectivesThe main objective of this study was to investigate anxiety comorbidity in DD. As a second objective, we set ourselves to know prescription rates for the use of antidepressants and benzodiazepines in anxiety disorders in the context of DD.MethodsA systematic literature search was performed using PubMed (1980- September 2020) according to the PRISMA guidelines. The following search terms were used: (delusional disorder) AND (anxiety OR anxiety disorder OR anxi*). Research studies and case reports were included if they met the following criteria: DD diagnosis (DSM, ICD), publication in peer-review journal and investigations containing information on anxiety comorbidity in DD.ResultsFour studies fulfilled our criteria, including 155 patients: 65 (42%) women, mean age 42.7 years (SD:14.96). Thirty-three of the 155 patients (21.29%) presented at least one comorbid anxiety disorder: 14 specific phobias, 9 panic attacks, 5 social phobias and 2 agoraphobias. Treatment was not reported for many patients (n= 28). Four patients received fluoxetine and 1 patient benzodiazepines. All of them showed partial improvement of symptoms.ConclusionsLess than a third of DD patients showed an anxiety disorder. The effectiveness of antidepressant and benzodiazepine treatment has been poorly described. Future studies may be focused on the investigation of preceding comorbid anxiety disorders in patients with DD.

Association between benzodiazepine outpatient treatment and risk of early seizure recurrence in emergency patients with seizure: A multicenter retrospective study.

Seizures are one of the most common neurological reasons for emergency department (ED) visits. The benefit of ED-initiated, short-course outpatient benzodiazepine (BZD) treatment to prevent early recurrent seizure is unknown. This study assesses the risk of early seizure recurrence in patients who were or were not started with outpatient BZD in the ED. This was a multicenter retrospective study conducted in eight French EDs between January 1 and December 31, 2019. All patients admitted for seizure were retrospectively screened and those discharged home from the ED were included. Patients with a history of chronic alcohol intoxication or chronic BZD therapy were excluded. Baseline characteristics, type of seizure, and 30-day outcome were retrospectively collected from the electronic health records. The primary endpoint was a return visit for seizure recurrence within 30days. Independent factors associated with a seizure recurrence were identified using a multivariable binary logistic regression. A total of 2,218 patients were included and 1,820 were analyzed. The median age was 39years and 60% were men. Among them 82% of patients had a generalized tonic-clonic seizure and 47% of seizures were idiopathic. BZD treatment was started in 773 (42%) patients. A total of 154 (8%) patients had an early recurrence at 30days: 68 (9%) in patients who were treated with BZD versus 86 (8%) in patients who were not (odds ratio [OR]= 1.07, 95% confidence interval [CI]= 0.71 to 1.43). In multivariable analysis, two factors were independently associated with the primary endpoint: chronic epileptic treatment (adjusted OR= 2.58, 95% CI= 1.55 to 4.37) and having had a focal seizure (adjusted OR= 2.16, 95% CI= 1.56 to 4.37). BZD therapy was started in 42% of patients who were discharged home after ED visit for a seizure. This treatment was not an independent factor associated with the risk of return visit for seizure recurrence at 30days.

Association Between Benzodiazepine or Z-Drug Prescriptions and Drug-Related Poisonings Among Patients Receiving Buprenorphine Maintenance: A Case-Crossover Analysis.

Persons with opioid use disorder who take benzodiazepines are at high risk for overdose. The objective of this study was to evaluate the association of benzodiazepine and Z-drug use with drug-related poisonings among patients receiving buprenorphine maintenance treatment. A case-crossover study design was used to analyze prescription claims among persons ages 12-64 with opioid use disorder who had buprenorphine prescriptions and had claims data in the IBM MarketScan databases (2006-2016), encompassing 14,213,075 person-days of observation time for 23,036 individuals who experienced drug-related poisoning. The exposures were buprenorphine prescriptions and benzodiazepine or Z-drug prescriptions, standardized as daily diazepam-equivalent milligram doses and separated by pharmacologic properties (short-acting or long-acting benzodiazepines, Z-drugs). The outcome of interest was nonfatal drug-related poisoning. Conditional logistic regression was used to evaluate variation in benzodiazepine or Z-drug and buprenorphine use between poisoning and nonpoisoning days. Buprenorphine treatment days were associated with a nearly 40% reduction in the risk of poisoning events (odds ratio=0.63, 95% CI=0.60, 0.66) compared with nontreatment days, whereas benzodiazepine or Z-drug treatment days were associated with an 88% increase in the risk of such events (95% CI=1.78, 1.98). In stratified analyses by dose, we observed a 78% (95% CI=1.67, 1.88) and 122% (95% CI=2.03, 2.43) increase in poisonings associated with low-dose and high-dose benzodiazepine or Z-drug treatment days, respectively. High-dose, but not low-dose, benzodiazepine or Z-drug treatment was associated with increased poisonings in combination with buprenorphine cotreatment (odds ratio=1.64, 95% CI=1.39, 1.93), but this was lower than the odds risk associated with benzodiazepine or Z-drug treatment in the absence of buprenorphine (low-dose: odds ratio=1.69, 95% CI=1.60, 1.79; high-dose: odds ratio=2.23, 95% CI=2.04, 2.45). Increased risk of nonfatal drug-related poisoning is associated with benzodiazepine or Z-drug treatment in patients with opioid use disorder, but this risk is partially mitigated by buprenorphine treatment. Dose reduction of benzodiazepines or Z-drugs while maintaining buprenorphine treatment may provide the advantage of lowering drug-related poisoning risk.

Evaluation of the course and treatment of Alcohol Withdrawal Syndrome with the Clinical Institute Withdrawal Assessment for Alcohol – Revised: A systematic review-based meta-analysis

BackgroundAlthough the Clinical Institute Withdrawal Assessment for Alcohol – Revised (CIWA-Ar) is a gold standard tool for the clinical evaluation of alcohol withdrawal syndrome (AWS), a systematic analysis using the total scores of the CIWA-Ar as a means of an objective follow-up of the course and treatment of AWS is missing. The aims of the present study were to systematically evaluate scientific data using the CIWA-Ar, to reveal whether the aggregated CIWA-Ar total scores follow the course of AWS and to compare benzodiazepine (BZD) and non-benzodiazepine (nBZD) therapies in AWS. Methods1054 findings were identified with the keyword “ciwa” from four databases (PubMed, ScienceDirect, Web of Science, Cochrane Registry). Articles using CIWA-Ar in patients treated with AWS were incorporated and two measurement intervals (cumulative mean data of day 1−3 and day 4−9) of the CIWA-Ar total scores were compared. Subgroup analysis based on pharmacotherapy regimen was conducted to compare the effectiveness of BZD and nBZD treatments. ResultsThe random effects analysis of 423 patients showed decreased CIWA-Ar scores between the two measurement intervals (BZD: d = –1.361; CI: –1.829 < δ < –0.893; nBZD: d = –0.858; CI: –1.073 < δ < –0.643). Sampling variances were calculated for the BZD (v1 = 0.215) and the nBZD (v2 = 0.106) groups, which indicated no significant group difference (z = −1.532). ConclusionsOur findings support that the CIWA-Ar follows the course of AWS. Furthermore, nBZD therapy has a similar effectiveness compared to BZD treatment based on the CIWA-Ar total scores.

Determinants of Post-Operative Cognitive Decline in Elderly People

Surgery and anesthesia can result in temporary or permanent deterioration of the cognitive functions, for which causes remain unclear. In this pilot study, we analyzed the determinants of cognitive decline following a non-emergency elective prosthesis implantation surgery for hip or knee. Prospective single-center study investigating psychomotor response time and changes in MoCA scores between the day before (D-1) and 2 days after (D+2) following surgery at the Lariboisière Hospital (Paris, France). 60 patients (71.9±7.1-year-old, 72% women) were included. Collected data consisted in sociodemographic data, treatments, comorbidities and the type of anesthesia (local, general or both). Furthermore, we evaluated pain and well-being before as well as after the surgery using point scales. Post-operative (D+2) MoCA scores were significantly lower than pre-operative ones (D-1) with a median difference of 2 pts [IQR]=4pts, (p<0.001), we found no significant difference between locoregional and general anesthesia. Pre-operative benzodiazepine or anticholinergic treatments were also associated to a drop in MoCA scores (p=0.006). Finally, the use of ketamine during anesthesia (p=0.043) and the well-being (p=0.006) evaluated before intervention, were both linked to a reduced cognitive impact. In this pilot study, we observed a post-operative short-term cognitive decline following a lower limb surgery. We also identified pre and perioperative independent factors linked to cognitive decline following surgery. In a next stage, a larger cohort should be used to confirm the impact of these factors on cognitive decline.

The Effectiveness of Non-Benzodiazepine, Non-Barbiturate Medications for Alcohol Withdrawal Syndrome: A Rapid Systematic Review.

There are potential clinical, ethical and legal concerns with overdosing benzodiazepines (or barbiturates) for the treatment of moderate to severe alcohol withdrawal symptoms (AWS) through telemedicine or ambulatory outpatients. A rapid systematic review to (a) qualitatively summarize the non-benzodiazepine treatment alternatives, (b) evaluate the quality of evidence for the same to effectively manage moderate to severe AWS. We conducted searches on PubMed (January 1990 to 31 March 2020), Cochrane Central Register of Controlled Trials, and Google Scholar. We selected the English language randomized controlled trials (RCTs) assessing the efficacy and adverse effects of non-benzodiazepine and non-barbiturate medications among adults with a diagnosis of AWS. Data extraction was done in a predefined format. Risk of bias (RoB) assessment and qualitative synthesis of evidence was done with the RoB2 tool and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) proGDT. Thirty-four RCTs were included. Gabapentin (n=6), carbamazepine (n=5), baclofen (n=5), valproate (n=3), clonidine/lofexidine (n=3) and acamprosate (n=2) had more than one trial with a particular comparison group. Four studies were found to have a low ROB. The GRADE evidence summary showed gabapentin had a 'moderate' level of evidence against standard benzodiazepine treatments for reducing the severity of AWS. The level of certainty was 'low' for carbamazepine, baclofen and valproate and 'very low' for acamprosate and clonidine/lofexidine. Reported adverse events between these alternative medications and benzodiazepines or placebo were generally unremarkable. Although benzodiazepines remain the treatment of choice for AWS, during particular circumstances, gabapentin could be an alternative although like benzodiazepines is not without risk when used in the community. Future RCTs must aim to improve upon the quality of evidence.

Ramelteon modulates gamma oscillations in the rat primary motor cortex during non-REM sleep

Sleep disorders adversely affect daily activities and cause physiological and psychiatric problems. The shortcomings of benzodiazepine hypnotics have led to the development of ramelteon, a melatonin MT1 and MT2 agonist. Although the sleep-promoting effects of ramelteon have been documented, few studies have precisely investigated the structure of sleep and neural oscillatory activities. In this study, we recorded electrocorticograms in the primary motor cortex, the primary somatosensory cortex and the olfactory bulb as well as electromyograms in unrestrained rats treated with either ramelteon or vehicle. A neural-oscillation-based algorithm was used to classify the behavior of the rats into three vigilance states (e.g., awake, rapid eye movement (REM) sleep, and non-REM (NREM) sleep). Moreover, we investigated the region-, frequency- and state-specific modulation of extracellular oscillations in the ramelteon-treated rats. We demonstrated that in contrast to benzodiazepine treatment, ramelteon treatment promoted NREM sleep and enhanced fast gamma power in the primary motor cortex during NREM sleep, while REM sleep was unaffected. Gamma oscillations locally coordinate neuronal firing, and thus, ramelteon modulates neural oscillations in sleep states in a unique manner and may contribute to off-line information processing during sleep.

The effect of concomitant benzodiazepine use on neurocognition in stable, long-term patients with bipolar disorder.

Neurocognitive dysfunction is a common feature of bipolar disorder even in euthymia, and psychopharmacological treatment could have an effect on cognition. Long-term prescription of benzodiazepines in bipolar disorder is a common practice, and their effect on neurocognition has not been well studied in this population. The aim of this study was to evaluate the impact of concomitant benzodiazepine long-term use on neurocognitive function in stable euthymic bipolar disorder patients. Seventy-three euthymic bipolar disorder outpatients and 40 healthy individuals were assessed using a neurocognitive battery. Patients were classified in two groups according to the presence of benzodiazepines in their treatment: the benzodiazepine group (n = 34) and the non- benzodiazepine group (n = 39). Neurocognitive performance was compared between the groups using a multivariate analysis of covariance, considering age, number of depressive episodes, adjuvant antipsychotic drugs, Young Mania Rating Scale score and Hamilton Depression Rating Scale score as covariates. Both bipolar disorder groups (benzodiazepine and non-benzodiazepine) showed an impairment in memory domains (Immediate Visual Memory [p = 0.013], Working Memory [p < 0.001], and Letter-Number Sequence [p < 0.001] from the Wechsler Memory Scale-Revised-III) and slower processing speed functions (Stroop Colour [p < 0.001]) relative to the control group. Nevertheless, the benzodiazepine group showed a greater impairment in executive functions (Conceptual Level Responses [p = 0.024] from the Wisconsin Card Sorting Test and Frontal Assessment Battery [p = 0.042]). Although memory and processing speed impairments were found in bipolar disorder, regardless of their benzodiazepine treatment, benzodiazepine users presented additional neurocognitive impairments in terms of executive functioning. These findings support restricted prescription of benzodiazepines in individuals with bipolar disorder.

Add-on benzodiazepine treatment in patients with major depressive disorder – results from a European cross-sectional multicenter study

Since many patients with major depressive disorder (MDD) do not satisfactorily respond to initial antidepressant monotherapy, add-on treatment strategies with other psychiatric compounds are often established. The present European multicenter cross-sectional study comprising 1410 MDD in- and outpatients investigated the prescription pattern of benzodiazepines as add-on treatment in the psychopharmacotherapy of MDD. Analyses of variance, chi-squared tests, and logistic regression analyses were conducted to examine differences in socio-demographic, clinical, and treatment characteristics between benzodiazepine users and non-users. The prescription rate for adjunctive benzodiazepine treatment amounted to 31.35%. The most often administered benzodiazepines were lorazepam (11.13%), clonazepam (6.74%), and alprazolam (6.60%). Benzodiazepine users exhibited more severe depressive symptoms expressed by a higher mean Montgomery and Åsberg Depression Rating Scale total score at study entry (26.92 ± 11.07 vs 23.55 ± 11.23, p<.0001) and at the beginning of the current major depressive episode (35.74 ± 8.08 vs 33.31 ± 7.40, p<.0001). Furthermore, they were characterized by a higher proportion of patients receiving additional augmentation/combination medications with antidepressants (40.95% vs 24.28%, p<.0001), antipsychotics (41.63% vs 18.39%, p<.0001), and low-potency antipsychotics (10.18% vs 4.75%, p<.0001). Moreover, benzodiazepine prescription was associated with older age, unemployment, inpatient treatment, suicide risk, psychotic and melancholic features, comorbid panic disorder, agoraphobia, social phobia, and obsessive-compulsive disorder. Taken together, our findings indicate that benzodiazepine augmentation in MDD is first of all established in severe/difficult-to-treat conditions and serves as predictor for the use of additional augmentation/combination treatment strategies.

How predictable is cognitive performance in Brazilian patients with pharmacoresistant mesial temporal lobe epilepsy?

ObjectiveThe objective of the study was to investigate the independent association between clinical, demographic, psychiatric, radiologic, electrophysiological, and pharmacologic variables and cognitive performance of Brazilian patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE). MethodsNinety-three patients with pharmacoresistant MTLE related to hippocampal sclerosis (HS) were included in the study. Multiple linear regressions were done to identify predictor variables for 24 cognitive tests. Independent variables analyzed were sex, hand dominance, age, years of education, marital status, work activity, history for an initial precipitant injury (IPI), family history of epilepsy, lesion side, antiseizure medication (ASM) treatment type, ASM serum levels, benzodiazepine (BDZ) treatment, age at epilepsy onset, disease duration, monthly frequency of seizures, and Hospital Anxiety and Depression Scale (HADS) scores. ResultsYears of education was an independent and positive predictor in 22 of the 24 cognitive tests evaluated. Male sex was also a positive predictor of one cognitive test. Variables negatively associated with cognitive performance were left side lesion (10 tests), disease duration (5 tests), polytherapy (3 tests), ASM serum levels (3 tests), and BDZ treatment or not working (1 test each). The regression model explained between 6% and 44% of the cognitive test scores variation. SignificanceIn Brazilian patients with pharmacoresistant MTLE-HS, up to 44% of cognitive test scores variation is predictable by clinical, demographic, psychiatric, radiologic, electrophysiology, and pharmacological variables. The identification of predictors of cognitive performance may be helpful for better planning of patient care.

Prehospital midazolam use and outcomes among patients with out-of-hospital status epilepticus.

To examine the use of benzodiazepines and the association between low benzodiazepine dose, breakthrough seizures, and respiratory support in patients with status epilepticus. In this cross-sectional analysis of adult patients with status epilepticus treated by an emergency medical services agency from 2013 to 2018, the primary outcome was treatment with a second benzodiazepine dose, an indicator for breakthrough seizure. The secondary outcome was receiving respiratory support. Midazolam was the only benzodiazepine administered. Among 2,494 patients with status epilepticus, mean age was 54.0 years and 1,146 (46%) were female. There were 1,537 patients given midazolam at any dose, yielding an administration rate of 62%. No patients received a dose and route consistent with national guidelines. Rescue therapy with a second midazolam dose was required in 282 (18%) patients. Higher midazolam doses were associated with lower odds of rescue therapy (odds ratio [OR], 0.8; 95% confidence interval [CI], 0.7-0.9) and were not associated with increased respiratory support. If anything, higher doses of midazolam were associated with decreased need for respiratory support after adjustment (OR, 0.9; 95% CI, 0.8-1.0). An overwhelming majority of patients with status epilepticus did not receive evidence-based benzodiazepine treatment. Higher midazolam doses were associated with reduced use of rescue therapy and there was no evidence of respiratory harm, suggesting that benzodiazepines are withheld without clinical benefit. This study provides Class III evidence that for patients with status epilepticus, higher doses of midazolam led to a reduced use of rescue therapy without an increased need for ventilatory support.

First-line medication dosing in pediatric refractory status epilepticus.

To identify factors associated with low benzodiazepine (BZD) dosing in patients with refractory status epilepticus (RSE) and to assess the impact of BZD treatment variability on seizure cessation. This was a retrospective study with prospectively collected data of children with convulsive RSE admitted between June 2011 and January 2019. We analyzed the initial and total BZD dose within 10 minutes of treatment initiation. We used logistic regression modeling to evaluate predictors of low BZD dosing and multivariate Cox regression analysis to assess the impact of low BZD dosing on time to seizure cessation. We included 289 patients (55.7% male) with a median age of 4.3 (1.3-9.5) years. BZDs were the initial medication in 278 (96.2%). Of those, 161 patients (57.9%) received a low initial dose. Low initial BZD doses occurred in both out-of-hospital (57 of 106; 53.8%) and in-hospital (104 of 172; 60.5%) settings. One hundred three patients (37.1%) received low total BZD dose. Male sex (odds ratio [OR] 2, 95% confidence interval [CI] 1.18-3.49; p = 0.012), older age (OR 1.1, 95% CI 1.05-1.17; p < 0.001), no prior diagnosis of epilepsy (OR 2.1, 95% CI 1.23-3.69; p = 0.008), and delayed BZD treatment (OR 2.2, 95% CI 1.24-3.94; p = 0.007) were associated with low total BZD dose. Patients who received low total BZD dosing were less likely to achieve seizure cessation (hazard ratio 0.7, 95% CI 0.57-0.95). BZD doses were lower than recommended in both out-of-hospital and in-hospital settings. Factors associated with low total BZD dose included male sex, older age, no prior epilepsy diagnosis, and delayed BZD treatment. Low total BZD dosing was associated with decreased likelihood of Seizure cessation. This study provides Class III evidence that patients with RSE who present with male sex, older age, no prior diagnosis of epilepsy, and delayed BZD treatment are more likely to receive low total BZD doses. This study provides Class III evidence that in pediatric RSE low total BZD dose decreases the likelihood of seizure cessation.

The Antidepressant Effect of Ketamine Is Dampened by Concomitant Benzodiazepine Medication

The rapid antidepressant effect of ketamine has become a breakthrough in the research and treatment of depression. Although predictive and modulating factors of the response to ketamine are broadly studied, little is known about optimal concurrent medication protocols. Concerning gamma-aminobutyric acid neurotransmission being a shared target for both ketamine and benzodiazepines (BZD), we evaluated the influence of BZD on the antidepressant effect of a single ketamine infusion in depressed patients. Data from 47 patients (27 females) with major depression (MADRS ≥ 20, ≥ 1 prior nonresponse to antidepressant treatment in current episode) who participated in two previous studies (EudraCT Number: 2009-010625-39 and 2013-000952-17) entered the analysis. All of the subjects were given an infusion of a subanesthetic dose of racemic ketamine (0.54 mg per kg) as an add-on medication to ongoing antidepressant treatment. Thirteen patients (28%) reached ≥ 50% reduction in MADRS within one week after ketamine administration. Nineteen (40%) patients took concomitant benzodiazepines on a daily basis. The doses of BZDs were significantly higher in nonresponders (p=0.007). ROC analysis distinguished responders from nonresponders by a criterion of >8mg of diazepam equivalent dose (DZ equivalent) with a sensitivity of 80% and a specificity of 85% (p<0.001). RM-ANOVA revealed a different time pattern of response to ketamine between the BZD+ (>8mg of DZ equivalent) and BZD− (≤8mg of DZ equivalent) groups, with a significantly worse outcome in BZD+ on day 3 (p=0.04) and day 7 (p=0.02). The results of the study indicate that concomitant benzodiazepine treatment in higher doses may attenuate ketamine’s antidepressant effect. The pathophysiological, clinical and methodological implications of this finding should be considered in future research and ketamine treatment.

Retrospective Analysis of Gabapentin for Alcohol Withdrawal in the Hospital Setting: The Mayo Clinic Experience

ObjectiveTo evaluate the efficacy and safety of a fixed-dose gabapentin taper protocol for alcohol withdrawal in hospitalized patients.Patients and MethodsWe retrospectively identified patients admitted to the hospital from January 1, 2016, to April 30, 2018, for alcohol withdrawal syndrome. Based on the treatment that patients received, they were divided into the gabapentin, benzodiazepine, and combination treatment groups. The primary outcome was length of stay, defined as time from admission to either discharge or 36 hours with Clinical Institute Withdrawal Assessment (CIWA) score less than 10. Inverse probability of treatment weight was used to account for differences in baseline characteristics between groups.ResultsA total of 443 patients met criteria for inclusion (128, 253, and 62 patients in the gabapentin, benzodiazepine, and combination groups, respectively). Baseline characteristics were similar among all groups. The median gabapentin group length of stay was 4.0 hours shorter than the benzodiazepine group (P=.012). Maximum CIWA score was 2.2 points lower in the gabapentin group (P=.003). No statistical differences were noted among safety outcomes, including incidence of seizure, intensive care unit transfer, or delirium tremens. Results were not statistically altered by inverse probability of treatment weight analysis.ConclusionA fixed-dose gabapentin taper protocol appears to be an effective and safe alternative to CIWA-driven benzodiazepines in patients hospitalized with alcohol withdrawal syndrome, though further research is necessary to define the potential subpopulations that benefit most.

The adenosine A1 receptor agonist WAG 994 suppresses acute kainic acid-induced status epilepticus in vivo

Status epilepticus (SE) is a neurological emergency characterized by continuous seizure activity lasting longer than 5 min, often with no recovery between seizures (Trinka et al., 2015). SE is refractory to benzodiazepine and second-line treatments in about 30% cases. Novel treatment approaches are urgently needed as refractory SE is associated with mortality rates of up to 70%. Robust adenosinergic anticonvulsant effects have been known for decades, but translation into seizure treatments was hampered by cardiovascular side effects. However, the selective adenosine A1 receptor agonist SDZ WAG 994 (WAG) displays diminished cardiovascular side effects compared to classic A1R agonists and was safely administered systemically in human clinical trials.Here, we investigate the anticonvulsant efficacy of WAG in vitro and in vivo. WAG robustly inhibited high-K+-induced continuous epileptiform activity in rat hippocampal slices (IC50 = 52.5 nM). Importantly, WAG acutely suppressed SE in vivo induced by kainic acid (20 mg/kg i.p.) in mice. After SE was established, mice received three i.p. injections of WAG or diazepam (DIA, 5 mg/kg). Interestingly, DIA did not attenuate SE while the majority of WAG-treated mice (1 mg/kg) were seizure-free after three injections. Anticonvulsant effects were retained when a lower dose of WAG (0.3 mg/kg) was used. Importantly, all WAG-treated mice survived kainic acid induced SE.In summary, we report for the first time that an A1R agonist with an acceptable human side-effect profile can acutely suppress established SE in vivo. Our results suggest that WAG stops or vastly attenuates SE while DIA fails to mitigate SE in this model.