Pathophysiology and management of Akathisia 70 years after the introduction of the chlorpromazine, the first antipsychotic.

OBJECTIVE: Akathisia is among the most troubling effects of psychiatric drugs as it is associated with significant distress on behalf of the patients, and it limits treatment adherence. Though it most commonly presents during treatment with antipsychotic drugs which block dopamine D2 receptors, Akathisia has also been reported during treatment with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), stimulants, mirtazapine, tetrabenazine and other drugs. MATERIALS AND METHODS: This article was designed as a narrative review on akathisia with a focus on its clinical presentation, pathophysiology and management. A PubMed search for akathisia was conducted which returned 8481 articles. RESULTS: Akathisia is experienced as severe restlessness commonly accompanied by dysphoria and purposeless movement which relieves subjective tension. It has been attributed to an imbalance between dopaminergic and noradrenergic neurotransmission in the basal ganglia. Acute akathisia commonly resolves upon treatment discontinuation but tardive and chronic akathisia may persist after the causative agent is withdrawn and prove resistant to pharmacological treatment. Even drugs which induce no other extrapyramidal side effects (such as clozapine, quetiapine, aripiprazole and cariprazine) may induce akathisia. A high index of suspicion should be maintained in patients with motor disabilities, drug-induced parkinsonism and those under mechanical restraint. Propranolol and low-dose mirtazapine are the most thoroughly studied pharmacological interventions for akathisia, though benzodiazepines, voltage-gated calcium channel blockers (gabapentin, pregabalin) and opioids may be effective. CONCLUSIONS: Pharmacological management may pose a challenge in chronic akathisia. Rotation between different pharmacological management strategies may be optimal in resistant cases. Discontinuation of the causative drug and use of b-blockers, mirtazapine, benzodiazepines or gabapentinoids for symptomatic relief is the basis of management.

Adult Emergence Agitation: A Veteran-Focused Narrative Review.

Emergence agitation (EA) is a self-limited state of psychomotor excitement during awakening from general anesthesia. EA is confined to the emergence period as consciousness is restored, which sharply distinguishes it from other postoperative delirium states. Sporadic episodes of EA may become violent with the potential for harm to both patients and caregivers, but the long-term consequences of such events are not fully understood. Current literature on EA in adults is limited to small-scale studies with inconsistent nomenclature, variable time periods that define emergence, a host of different surgical populations, and conflicting diagnostic criteria. Therefore, true incidence rates and risk factors are unknown. In adult noncardiac surgery, the incidence of EA is approximately 19%. Limited data suggest that young adults undergoing otolaryngology operations with volatile anesthetic maintenance may be at the highest risk for EA. Currently suggested EA mechanisms are theoretical but might reflect underblunted sympathetic activation in response to various internal (eg, flashbacks or anxiety) or external (eg, surgical pain) stimuli as consciousness returns. Supplemental dexmedetomidine and ketamine may be utilized for EA prevention. Compared to the civilian population, military veterans may be more vulnerable to EA due to high rates of posttraumatic stress disorder (PTSD) manifesting as violent flashbacks; however, confirmatory data are limited. Nonetheless, expert military medical providers suggest that use of patient-centered rapport tactics, PTSD trigger identification and avoidance, and grounding measures may alleviate hyperactive emergence phenomena. Future research is needed to better characterize EA in veterans and validate prophylactic measures to optimize care for these patients. This narrative review provides readers with an important framework to distinguish EA from delirium. Furthermore, we summarize current knowledge of EA risk factors, mechanisms, and adult management strategies and specifically revisit them in the context of veteran perioperative health. The anesthesiology care team is ideally positioned to further explore EA and develop effective prevention and treatment protocols.

Trazodone as an Alternative Treatment for Neuroleptic-Associated Akathisia: A Placebo-Controlled, Double-Blind, Clinical Trial.

BACKGROUND: Akathisia is a distressing extrapyramidal complication that follows the use of antipsychotic medications. Early treatment of neuroleptic-associated akathisia (NAA) is of great importance because it may lead to poor therapeutic response and ultimately treatment noncompliance. Considering the lack of adequate response of some patients to conventional treatments and the assumption that serotonin might be involved in the pathophysiology of the disease in addition to dopaminergic mechanisms, we aimed to evaluate the effectiveness of trazodone as an antidepressant agent with strong antagonistic effects on serotonin receptors in the treatment of akathisia. METHODS: In a double-blind clinical trial, 52 patients receiving antipsychotic medications who were diagnosed to have mild to severe NAA using Barnes Akathisia Rating Scale were treated with trazodone 50 mg daily for 5 days and compared with the placebo control group. RESULTS: Patients receiving trazodone did not show a significant difference compared with the control group in terms of the severity of akathisia symptoms until the third day of the study. In contrast, at the end of the fifth day, there was a significant improvement in objective (P = 0.01) and subjective (P = 0.001) symptoms of akathisia and the global clinical assessment of akathisia scale (P = 0.001). Moreover, there was no clear difference between trazodone and placebo group in terms of adverse effects. CONCLUSIONS: Considering the antagonistic effect of trazodone on postsynaptic 5-hydroxytryptamine2A receptors as a possible mechanism of efficacy of this agent in the treatment of NAA, this study suggests that trazodone might be an effective and relatively safe drug.

Validation of the Serbian version of the Liverpool Adverse Events Profile of antiseizure therapy in patients with epilepsy.

The Liverpool Adverse Event Profile (LAEP) is a useful instrument in assessing the consequences of adverse events in patients using antiseizure medication. The LAEP scale has been validated in several languages to date. The aim of our study was to validate the LAEP scale in the Serbian language (SVLAEP). Validation of the SVLAEP scale was conducted by translating the original English version into the Serbian language and backtranslated into the English language. The translation was accepted when the two versions of the text were compatible. The questionnaire is then given to a group of patients with epilepsy treated with a stable dose of antiseizure medication. For the assessment of the quality of life and depression, we used the Serbian version of the Quality of Life in Epilepsy Inventory-31 (SVQOLIE-31) and the Serbian version of the Neurological Disorders Depression Inventory for Epilepsy (SVNDDI-E). From a total of 166 patients, 118 patients were included, and the remaining 48 were excluded because of other comorbidities and using other psychotropic drugs. Internal consistency (Cronbach's α = 0.87) and test-retest reliability (intraclass correlation coefficient (ICC) = 0.80) were satisfactory. The SVLAEP and SVQOLIE-31 had a strong negative statistical correlation (rs = -0.73; p < 0.001). The SVLAEP and SVNDDI-E final scores had a positive moderate correlation (rs = 0.52; p < 0.001). A moderate negative statistical correlation was found between SVNDDI-E and SVQOLIE-31 (rs = -0.56; p < 0.001). Our study showed that the LAEP scale is a useful indicator for the frequency of the adverse events in antiepileptic drug (AED) usage, despite a minor overlap with the symptoms of depression.

Ertapenem-induced encephalopathy.

Neurotoxicity is an unusual side effect of carbapenems, and it has been reported most commonly presenting as seizures, encephalopathy and hallucinations. Ertapenem neurotoxicity most classically presents as seizures in patients with end-stage renal disease (estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2). We present a patient with a baseline eGFR of 30-59 mL/min/1.73 m2 with acute kidney injury who developed non-seizure neurotoxicity after ertapenem exposure. This patient is a middle-aged Caucasian man who received intravenous ertapenem for treatment of empyema. Although the empyema improved, he developed delirium beginning on day 7 of ertapenem. The delirium progressed to constant agitation and visual hallucinations requiring transfer to the intensive care unit with eventual intubation for airway protection. No improvement in mental status was observed with cessation of other medications. Ertapenem was discontinued and within 24 hours, he was extubated, and his mental status returned to baseline. He was discharged from the hospital the following day. The timely resolution after ertapenem discontinuation makes ertapenem-induced encephalopathy the most likely explanation for this patient's course.

Iron homeostasis alterations and risk for akathisia in patients treated with antipsychotics: A systematic review and meta-analysis of cross-sectional studies.

Iron homeostasis may be implicated in the pathophysiology of antipsychotic-related akathisia. We performed a systematic review in six databases from database inception until 03/2020, conducting a meta-analysis of studies investigating iron metabolism in antipsychotic-treated patients with versus without akathisia. Using a fixed- and a random-effects model, standardized mean difference (SMD) was estimated for levels of iron, ferritin, transferrin and total iron-binding capacity. Meta-regression analyses included sex, age, illness duration and antipsychotic treatment and dose. Subgroup analyses included chronic vs. acute akathisia and different diagnoses. Study quality was assessed using the Newcastle-Ottawa scale. In 10 studies (n = 395), compared to non-akathisia patients (n = 213), iron levels were lower in patients with akathisia (n = 182; fixed-effect model: SMD=-0.49, 95%CI=-0.28,-0.70, p<0.001; random-effects model: SMD=-0.55, 95%CI=-0.14,-0.96, p = 0.008). For secondary outcomes, differences were significant regarding lower ferritin levels in patients with akathisia in the fixed-effect model (SMD=-0.32, 95%CI=-0.08,-0.55, p = 0.007), but not in the random-effects model (SMD=-0.29, 95%CI=0.20,-0.79, p = 0.24). None of the moderators/mediators had a significant effect on the group difference of iron levels. Subgroup analyses reported lower iron levels in both patients with chronic and acute akathisia vs. patients without. Iron levels for schizophrenia patients were lower in the fixed-effect model (SMD=-0.55, 95%CI=-0.23, -0.86, p<0.001), while a trend was observed in the random-effects model (SMD=-0.52, 95%CI=-0.07, -1.12, p = 0.08). The studies' quality was overall poor, with one exception. This meta-analysis suggests lower iron levels in akathisia patients, while ferritin differences were significant only in the fixed-effect model. Further data are required to promote the understanding of related pathways.

Aripiprazole vs. brexpiprazole for acute schizophrenia: a systematic review and network meta-analysis.

RATIONALE: What is the difference between aripiprazole and brexpiprazole? OBJECTIVES: This systematic review, network meta-analysis of randomized trials evaluated the efficacy and safety/tolerability of aripiprazole and brexpiprazole for treating acute schizophrenia. METHODS: We searched Scopus, MEDLINE, and Cochrane Library from inception until May 22, 2019. The response rate was set as the primary outcome. Other outcomes were discontinuation rate and incidence of individual adverse events. The risk ratio (RR) and 95% credible interval (95%CrI) were calculated. RESULTS: Fourteen studies were identified (n = 3925). Response rates of both aripiprazole and brexpiprazole were superior to that of the placebo (RR [95%CrI]: aripiprazole = 0.84 [0.78, 0.92], brexpiprazole = 0.84 [0.77, 0.92]). Aripiprazole and brexpiprazole were associated with a lower incidence of all-cause discontinuation (0.80 [0.71, 0.89], 0.83 [0.72, 0.95]), adverse events (0.67 [0.47, 0.97], 0.64 [0.46, 0.94]), and inefficacy (0.56 [0.40, 0.77], 0.68 [0.48, 0.99]) compared with the placebo. Although brexpiprazole was associated with a lower incidence of schizophrenia as an adverse event compared with the placebo (0.57 [0.37, 0.85]), aripiprazole and brexpiprazole were associated with a higher incidence of weight gain compared with the placebo (2.12 [1.28, 3.68], 2.14 [1.35, 3.42]). No significant differences were found in other individual adverse events, such as somnolence, akathisia, extrapyramidal symptoms, and dizziness between aripiprazole or brexpiprazole and placebo. Any outcome between aripiprazole and brexpiprazole were not different. CONCLUSIONS: Differences in short-term efficacy and safety for acute schizophrenia were not apparent between aripiprazole and brexpiprazole. Future studies are warranted to evaluate whether there are differences in the long-term outcome between treatments.

Neurological soft signs in schizophrenia spectrum disorders are not confounded by current antipsychotic dosage.

Neurological soft signs (NSS) have garnered increasing attention in psychiatric research on motor abnormalities in schizophrenia spectrum disorders (SSD). However, it remains unclear whether the assessment of NSS severity could have been confounded by current antipsychotic dosage. In this study, we recruited 105 patients with SSD that underwent a comprehensive motor assessment evaluating NSS and extrapyramidal motor symptoms (EPMS) by means of standardized instruments. Current antipsychotic dosage equivalence estimates were determined by the classical mean dose method (doses equivalent to 1 mg/d olanzapine). We used multiple regression analyses to describe the relationship between NSS, EPMS and antipsychotic medication. In line with our expectations, current antipsychotic dosage had no significant effects on NSS total score (p = 0.27), abnormal involuntary movements (p = 0.17), akathisia (p = 0.32) and parkinsonism (p = 0.26). Further, NSS total score had a significant effect on akathisia (p = 0.003) and parkinsonism (p = 0.0001, Bonferroni corr.), but only marginal effect on abnormal involuntary movements (p = 0.08). Our results support the notion that NSS are not significantly modulated by current antipsychotic dosage in SSD. The associations between NSS, akathisia and parkinsonism, as revealed by this study, support the genuine rather than medication-dependent origin of particular motor abnormalities in SSD.

Analytically Confirmed Intoxication by 4-Fluoromethylphenidate, an Analog of Methylphenidate.

4-Fluoromethylphenidate (4F-MPH) is an halogenated derivative of methylphenidate (MPH), a re-uptake inhibitor for dopamine and norepinephrine used for the treatment of attention deficit hyperactivity disorders. In the last few years, several compounds structurally related to MPH have been marked as new psychoactive substances (NPS) with stimulating and euphoric effects similar to the parent drug, but with more dopaminergic activity. This report represents the first case of an analytically confirmed non-fatal intoxication by 4F-MPH. A 26-year-old female was admitted to the emergency department with neuropsychiatric and cardiologic symptoms that lasted for a week, during which she sniffed a powder named 4F-MPH acquired as entactogen on the Internet. The patient required sedation with intravenous diazepam and was discharged two days later with a prescription of promazine and quetiapine. The seized product was analytically characterized by gas chromatography-mass spectrometry, liquid chromatography high-resolution mass spectrometry and nuclear magnetic resonance. These analyses confirmed the composition of the product as a 4F-MPH diastereomeric (±)-threo and (±)-erythro mixture, with a large preponderance of the active (±)-threo isomer. A minimal validation, intended for rare analytes, was performed for the quantification of 4F-MPH in the biological samples by liquid chromatography-tandem mass spectrometry. Accuracy (bias) and precision were within ±15% for both blood and urine. The blood and urine concentration of (±)-threo 4F-MPH were 32 ng/mL and 827 ng/mL, respectively. Analyses for classic drugs (opiates, methadone, cocaine, cannabis metabolites, amphetamines, ecstasy and LSD), ethanol, qualitative full screen by gas chromatography-mass spectrometry and targeted analysis for 50 NPS by liquid chromatography-tandem mass spectrometry tested negative; comorbidities were excluded, too. Based on these data, it can be assumed that the clinical manifestations were due to 4F-MPH only.

Setting the record straight: The nosology of tardive syndromes.

We propose the use of the term tardive dyskinesia to refer to the original description of repetitive and complex oral-buccal-lingual (OBL) movements and the analogous repetitive movements of the limbs, trunk, or pelvis. The term tardive syndrome is an umbrella term to be used to refer to the spectrum of all persistent hyperkinetic, hypokinetic, and sensory phenomenologies resulting from chronic dopamine receptor blocking agent (DRBA) exposure. TD is a type of TS. The term tardive dystonia (TDyst) should be used when dystonia is the main feature of TS. Retrocollis and oromandibular dystonia appear to be the most common form of Tdyst. Tardive akathisia refers to the inability to remain still with an urge to move, giving the appearance of restlessness. In tardive tourettism, the patient has complex motor and phonic tics associated with premonitory urge and relief of tension after performing the tic behavior, thus resembling Tourette's syndrome. Tardive tremor is composed of mainly postural and kinetic tremors. It differs from the resting tremor seen in drug-induced parkinsonism. Tardive pain occurs in association with chronic use of DRBAs and involves the mouth, tongue, and genital region with no physical findings. In tardive parkinsonism, the patient has persistent parkinsonism even after discontinuation of the DRBA although this diagnosis is in question and may represent DRBA-uncovered idiopathic Parkinson's disease or coincident development of Parkinson's disease while taking DRBAs.

Acute phenibut withdrawal: A comprehensive literature review and illustrative case report.

Phenibut is a glutamic acid derivative with activity on the γ-aminobutyric acid (GABA)B, A, and B-phenethylamine receptors. It is prescribed in former Communist Bloc countries for anxiolysis and related psychiatric disorders. It can be easily obtained in Western countries and is thought to have abuse potential. Abrupt discontinuation has been reported to precipitate an abstinence syndrome. A review of the literature identified 22 reported cases, many of which were notable for severe psychomotor agitation and requirements for aggressive pharmacologic treatment. Neurologic and autonomic signs and symptoms may mimic serotonin or neuroleptic malignant syndrome. Patients were typically younger and had coexisting substance abuse disorders to other drugs. Also presented is a case of a 23-year-old male with an acute phenibut abstinence syndrome. This patient exhibited severe psychomotor agitation requiring physical restraints, dexmedetomidine, lorazepam, haloperidol, diphenhydramine, cyproheptadine, melatonin, olanzapine, and baclofen for symptom control.

Incidence and predictors of acute akathisia in severely ill patients with first-episode schizophrenia treated with aripiprazole or risperidone: secondary analysis of an observational study.

RATIONALE: In the antipsychotic treatment of schizophrenia with little medication history, especially in drug-naïve cases, predictors of side effects are important. However, predictors of antipsychotic-induced akathisia remain unclear. OBJECTIVES: This study aimed to investigate the incidence and predictors of acute akathisia in severely ill patients with first-episode schizophrenia spectrum disorders (FES). METHODS: This is a secondary analysis of our retrospective observational study. Data were obtained from 129 consecutive patients with FES involuntarily hospitalized in a tertiary psychiatric public hospital and treated with aripiprazole or risperidone. The primary outcome was the presence of acute akathisia during the first 1 month. A Cox proportional hazard model was used to examine significant predictors of the onset of akathisia. RESULTS: Acute akathisia was diagnosed in 54 patients (42%). Neither antipsychotics (aripiprazole or risperidone), duration of untreated psychosis, iron deficiency, sex, age nor baseline symptomatic severity was identified as an independent predictor of akathisia. Rapid risperidone initiation significantly increased the onset of akathisia (adjusted hazard ratio [HR], 6.47; 95%; 95% confidence interval [CI], 1.94-21.65; p = 0.002), but rapid aripiprazole initiation did not (adjusted HR, 1.08; 95% CI, 0.50-2.31; p = 0.84). A significant interaction was found between rapid antipsychotic initiation and the risk of akathisia with aripiprazole versus risperidone (p = 0.027). CONCLUSIONS: Severely ill patients with FES initiating aripiprazole or risperidone could have a high risk for akathisia. Rapid risperidone initiation should be avoided because of the risk for akathisia, and careful monitoring of akathisia may be necessary for all patients initiating aripiprazole.

Novel Adverse Events of Iloperidone: A Disproportionality Analysis in US Food and Drug Administration Adverse Event Reporting System (FAERS) Database.

BACKGROUND: The signal is defined as "reported information on a possible causal relationship between an adverse event and a drug, of which the relationship is unknown or incompletely documented previously". OBJECTIVE: To detect novel adverse events of iloperidone by disproportionality analysis in FDA database of Adverse Event Reporting System (FAERS) using Data Mining Algorithms (DMAs). METHODOLOGY: The US FAERS database consists of 1028 iloperidone associated Drug Event Combinations (DECs) which were reported from 2010 Q1 to 2016 Q3. We consider DECs for disproportionality analysis only if a minimum of ten reports are present in database for the given adverse event and which were not detected earlier (in clinical trials). Two data mining algorithms, namely, Reporting Odds Ratio (ROR) and Information Component (IC) were applied retrospectively in the aforementioned time period. A value of ROR-1.96SE>1 and IC- 2SD>0 were considered as the threshold for positive signal. RESULTS: The mean age of the patients of iloperidone associated events was found to be 44years [95% CI: 36-51], nevertheless age was not mentioned in twenty-one reports. The data mining algorithms exhibited positive signal for akathisia (ROR-1.96SE=43.15, IC-2SD=2.99), dyskinesia (21.24, 3.06), peripheral oedema (6.67,1.08), priapism (425.7,9.09) and sexual dysfunction (26.6-1.5) upon analysis as those were well above the pre-set threshold. CONCLUSION: Iloperidone associated five potential signals were generated by data mining in the FDA AERS database. The result requires an integration of further clinical surveillance for the quantification and validation of possible risks for the adverse events reported of iloperidone.

Incidence of akathisia after postoperative nausea and vomiting prophylaxis with droperidol and ondansetron in outpatient surgery: A multicentre controlled randomised trial.

BACKGROUND: Akathisia, a distressing movement disorder induced by butyrophenones, has been described with low doses of droperidol used for postoperative nausea and vomiting (PONV) prophylaxis, but the incidence remains unclear. OBJECTIVES: To determine the incidence of akathisia after PONV prophylaxis with two doses of droperidol in comparison with ondansetron, in patients undergoing ambulatory surgery. We hypothesised that the incidence of akathisia is higher with droperidol than that with ondansetron. DESIGN: Randomised controlled double blind trial. SETTING: Two University Hospital Centres and two private Clinics from January to September 2014. PATIENTS: Patients (n=297) undergoing general anaesthesia for ambulatory surgery were randomly allocated to receive PONV prophylaxis with droperidol (0.625 or 1.25 mg) or ondansetron 4 mg; patients of the three groups also received 4 mg of dexamethasone. Exclusion criteria were contraindication to droperidol and ondansetron, use of psychotropic medications or benzodiazepines or history of psychotic illness. INTERVENTIONS: Participants received droperidol (0.625 or 1.25 mg) or ondansetron 4 mg during general anaesthesia. After discharge from the postanaesthesia care unit presence and severity of akathisia were assessed using the Barnes Akathisia Rating Scale at 4 h postoperatively. MAIN OUTCOME MEASURES: Score of the Global Clinical Assessment of Akathisia of Barnes Akathisia Rating Scale. RESULTS: The number of akathisia observed was 1/118 (0.8%) in the ondansetron group, 1/84 (1.2%) in droperidol 0.625 mg group, and 3/87 (3.4%) in droperidol 1.25 mg group. The akathisia rate difference among the three groups was not significant (P = 0.52). We could not demonstrate significant differences in the incidence of akathisia between the two doses of droperidol. The only case of marked akathisia treated with benzodiazepines was observed after droperidol 1.25 mg. CONCLUSION: The use of droperidol or ondansetron for PONV prophylaxis is associated to a low incidence of akathisia (0.8 to 3.4%) after general anaesthesia for ambulatory surgery. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01942343.

Tardive syndromes.

Tardive syndromes are a group of hyperkinetic and hypokinetic movement disorders that occur after some delay following exposure to dopamine receptor blocking agents such as antipsychotic and anti-emetic drugs. The severity of these disorders ranges from mild to disabling or even life-threatening. There is a wide range of recognized tardive phenomenologies that may occur in isolation or in combination with each other. These phenomenologies include stereotypy, dystonia, chorea, akathisia, myoclonus, tremor, tics, gait disorders, parkinsonism, ocular deviations, respiratory dyskinesia, and a variety of sensory symptoms. Recognition of the various tardive phenomenologies may not only lead to early diagnosis but also to appropriate therapeutic intervention. This review focuses on the diagnosis and clinical course of tardive syndromes and how to distinguish between the various phenomenologies as well as how to differentiate them from other, similar but etiologically different, movement disorders.

The nosology of tardive syndromes.

Since the original description of side effects of neuroleptics, different terminologies and definitions for tardive dyskinesia (TD) and tardive syndrome (TS) have been used by different authors, and often these two terms have been used interchangeably. This paper proposes a nosology designed to define and clarify various terms and phenomenologies within the TS spectrum. We propose to use the term tardive dyskinesia to refer to the original description of repetitive and complex oral-buccal-lingual (OBL) movements, as well as to the analogous repetitive movements that can appear in the limbs, trunk, or pelvis. The repetitive, relatively rhythmic nature of the movements is the common denominator of this phenomenologic category. The term tardive syndrome refers to the spectrum of all persistent hyperkinetic, hypokinetic and sensory phenomenologies resulting from chronic dopamine receptor blocking agents (DRBA) exposure. Thus, TS is an umbrella term. When dystonia is the main feature of TS it is considered to be tardive dystonia (TDyst). Retrocollis appears to be the predominant form of cervical dystonia in this condition. Cranial dystonias, particularly oromandibular dystonia, are also common forms of TDyst. Tardive akathisia refers to the inability to remain still with an urge to move, giving the appearance of restlessness. It is a sensory phenomenon and a common and disabling form of TS. Unlike acute akathisia, tardive akathisia tends to occur late and persists after the drug is withdrawn. In tardive tourettism, the patient exhibits the features of Tourette syndrome with complex motor and phonic tics associated with premonitory urge and relief of tension after performing the tic behavior. Tardive tremor differs from the resting tremor seen in drug-induced parkinsonism in that it is mainly a postural and kinetic greater than resting tremor. Tardive pain has been reported in association with chronic use of DRBA's. The pain involved the mouth, tongue and the genital region. The patients tended to obsess over the pain and usually had some other form of motor tardive syndrome, either tardive dyskinesia, tardive akathisia or tardive dystonia. The term tardive parkinsonism has been proposed for those drug induced parkinsonism patients who have persistent symptoms following discontinuation of the DRBA. However, there is a strong possibility that the DRBA may have simply unmasked subclinical parkinsonism or that there is coincident Parkinson disease developing during the period the patient is taking the DRBA.

Suspected Synthetic Cannabinomimetic Intoxication: Case Series and Review.

PURPOSE: The purpose of this work was to retrospectively review patient cases presenting to the University of Kentucky Chandler Medical Center (UKCMC) emergency department (ED) with symptoms of suspected synthetic cannabinomimetic (SC) intoxication. These drugs, currently undetected by standard urine drug screen tests, comprise a structurally diverse group of compounds designed to mimic the psychoactive effects of Δ9-tetrahydrocannabinol (Δ9-THC), the primary psychoactive cannabinoid in marijuana. SUMMARY: Fourteen cases of suspected SC intoxication were identified between July 1, 2015, through September 30, 2015. The median patient age was 25.5 years (range: 13-45 years), and most (64%) patients were males. The most common psychoactive symptom was agitation (n = 6, 42.9%), while the most common physical symptoms were altered level of consciousness (n = 9, 64.3%) and mydriasis (n = 3, 21.4%). Most cases resolved without complication in 24 hours; 2 patients required hospitalization. CONCLUSION: Recent legislation has failed to curb the public health concerns emanating from SC misuse. Education about the risks of SC use along with additional regulation may be required to remove the false sense of safety that some individuals, especially adolescents and young adults, may associate with these compounds, which are often misconstrued as "herbal marijuana." Clinicians need to be prepared to identify and treat symptoms of SC intoxication as incidents of toxicity continue to rise.

The correlation among the Ramsay sedation scale, Richmond agitation sedation scale and Riker sedation agitation scale during midazolam-remifentanil sedation / Correlação entre a escala de sedação de Ramsay, escala de sedação-agitação de Richmond e escala de sedação-agitação de Riker durante sedação com midazolam-remifentanil

Abstract Background and objectives: Sedative and analgesic treatment administered to critically ill patients need to be regularly assessed to ensure that previously stated goals are well achieved as the risk of complications of oversedation is minimized. We revised and prospectively tested the Ramsay Sedation scale (RSS) for interrater reliability and compared it with the Sedation-Agitation Scale (SAS) and the Richmond Agitation Sedation Scale (RASS) to test construct validity during midazolam-remifentanil sedation. Methods: A convenience sample of ICU patients was simultaneously and independently examined by pairs of trained evaluators by using the revised SAS, RSS, and RASS. Ninety-two ICU patients were examined a total of 276 times by evaluator pairs. Results: The mean patient age was 61.32 ± 18.68 years, 45,7% were female (n = 42), 54.3% male (n = 50). Their APACHE values varied between 3 and 39 with an average of 13.27 ± 7.86 and 75% of the cases were under mechanical ventilation. When classified by using RSS (2.70 ± 1.28), 10.9% were anxious or agitated (RSS1), 68.5% were calm (RSS 2-3), and 20.6% were sedated (RSS 4-6). When classified by using RASS (-0.64 ± 1.58), 20.7% were anxious or agitated (RASS+1 to +4), 63.0% were calm (RASS 0 to -2), and 16.3% were sedated (RASS -3 to -5). When classified by using SAS (2.63 ± 1.00), 12% were anxious or agitated (SAS 5-7), 57.6% were calm (SAS 4), and 30.4% were sedated (SAS 1-3). RSS was correlated with the SAS (r = -0.656, p < 0.001) and RASS was correlated with the SAS (r = 0.565, p < 0.001). RSS was highly correlated with the RASS (r = -0.664, p < 0.001). Conclusions: Ramsay is both reliable and valid (high correlation with the RASS and SAS scales) in assessing agitation and sedation in adult ICU patients.

Resumo Justificativa e objetivos: O tratamento de pacientes em estado crítico com sedativos e analgésicos deve ser regularmente avaliado para garantir que as metas pré-definidas sejam atingidas, bem como minimizar o risco de complicações resultantes de sedação em excesso. Conduzimos uma revisão e testamos prospectivamente a Escala de Sedação de Ramsay (Ramsay Sedation Scale [RSS]) para a confiabilidade interavaliador e a comparamos com a Escala de Sedação e Agitação de Riker (Riker Sedation-Agitation Scale [RRSAS]) e a Escala de Sedação e Agitação de Richmond (Richmond Agitation Sedation Scale [RASS]) para testar a validade de construto durante a sedação com midazolam-remifentanil. Métodos: Uma amostra de conveniência de pacientes de UTI foi simultânea e independentemente examinada por pares de avaliadores treinados com o uso das escalas revisadas RRSAS, RSS e RASS. Foram examinados 92 pacientes de UTI por pares de avaliadores em 276 momentos. Resultados: A média dos pacientes foi de 61,32 ± 18,68 anos; 45,7% eram do sexo feminino (n = 42) e 54,3% do masculino (n = 50). Seus escores APACHE variaram entre 3-39, com média de 13,27 ± 7,86, e 75% dos casos receberam ventilação mecânica. Quando RSS foi usada para a classificação (2,70 ± 1,28), 10,9% dos pacientes estavam ansiosos ou agitados (RSS1), 68,5% estavam calmos (RSS 2 a 3) e 20,6% estavam sedados (RSS 4 a 6). Quando RASS foi usada para a classificação (-0,64 ± 1,58), 20,7% dos pacientes estavam ansiosos ou agitados (RASS +1 a +4), 63,0% estavam calmos (RASS 0 a -2) e 16,3% estavam sedados (RASS -3 a -5). Quando RSAS foi usada para a classificação (2,63 ± 1,00), 12% dos pacientes estavam ansiosos ou agitados (RSAS 5 a 7), 57,6% estavam calmos (RSAS 4) e 30,4% estavam sedados (RSAS 1 a 3). Houve correlação de RSS com RSAS (r = -0,656, p < 0,001) e de RASS com RSAS (r = 0,565, p < 0,001). Houve forte correlação de RSS com RASS (r = -0,664, p < 0,001). Conclusões: A RSS é confiável e válida (forte correlação com RASS e RSAS) para avaliar a sedação e agitação em pacientes adultos internados em UTI.

Pramipexole Overdose Associated with Visual Hallucinations, Agitation and Myoclonus.

INTRODUCTION: Pramipexole is a dopamine D2 receptor agonist used to treat idiopathic Parkinson's disease and primary restless legs syndrome. There is limited information on pramipexole overdose. CASE REPORT: A 59-year-old male ingested 3 mg pramipexole, 2250 mg venlafaxine, 360 mg mirtazapine, with suicidal intent. He presented alert, had normal vital observations and normal pupillary reflexes. He was mildly agitated, reported visual hallucinations and was given 5 mg diazepam. He had a mildly elevated lactate of 1.7 mmol/L, but otherwise normal laboratory investigations. Overnight, he remained agitated with visual hallucinations and developed myoclonus while awake. He had increasing difficulty passing urine on a background of mild chronic urinary retention. On review, 14 h post-ingestion, he was hypervigilant, jittery and mildly agitated. He had pressured speech and difficulty focusing on questioning. He had a heart rate of 110 bpm, but had an otherwise normal examination, with no clonus or extrapyramidal effects. He was unable to mobilize due to dizziness and ataxia. Over the next few hours, he improved, the visual hallucinations and agitation resolved and he mobilized independently. Pramipexole was measured with liquid chromatography mass spectrometry. The initial plasma pramipexole concentration was 34.2 ng/mL (therapeutic range 0.2 to 7 ng/mL), 9 h post-overdose. Concentration time data fitted a one-compartment model with an estimated elimination half-life of 18 h. DISCUSSION: Pramipexole overdose with hallucination, agitation, and myoclonus is consistent with adverse effects reported with therapeutic toxicity, but mirtazapine and venlafaxine may have contributed. Pramipexole concentrations exceeded the therapeutic range for over 24 h. With the increasing use of pramipexole in restless legs syndrome, adult overdoses may become more common.