Descriptive assessment of adverse events associated with midazolam-etomidate versus saline-etomidate in healthy hydromorphone premedicated dogs.

OBJECTIVES: To determine the frequency, severity and duration of adverse events including myoclonus, pain on injection, hypersalivation, regurgitation and apnoea after administration of midazolam or saline followed by etomidate in hydromorphone premedicated dogs. MATERIALS AND METHODS: Dogs undergoing elective dental prophylaxis or soft tissue surgeries were enrolled in this randomised trial. Dogs were premedicated with hydromorphone 0.1 mg/kg IV. Sixty seconds later, midazolam 0.3 mg/kg or saline at an equivalent volume was administered IV. Sixty seconds after that, etomidate 1.5 mg/kg IV was administered over 60 seconds. Additional doses of 0.5 mg/kg etomidate were administered until endotracheal intubation was successful. Observers were blinded to the treatment. Frequency, duration and a severity score of 0 to 3 were recorded for myoclonus, pain on injection, hypersalivation and regurgitation. Duration of apnoea and frequency of any additional complications was recorded. RESULTS: Forty variable breed healthy dogs were enrolled in the study. Myoclonus, pain on injection, regurgitation, hypersalivation, gagging, tachypnoea and pigmenturia occurred, respectively, in 10%, 40%, 0%, 15%, 35%, 25% and 5% of dogs in the saline group and 0%, 65%, 0%, 10%, 45%, 15% and 5% of dogs in the midazolam group. Apnoea occurred for 115 seconds (range 0 to 660 seconds) and 160 seconds (range 0 to 600 seconds) in the saline and midazolam groups, respectively. Two dogs developed pigmenturia. The trial was stopped early due to the occurrence of pigmenturia. CLINICAL SIGNIFICANCE: Due to early stopping of the trial, the predefined sample size was not reached. Further investigation is needed to determine if midazolam reduced the incidence of adverse events or improved the induction quality when combined with hydromorphone and etomidate.

Assessment of a Targeted Gene Panel for Identification of Genes Associated With Movement Disorders.

Importance: Movement disorders are characterized by a marked genotypic and phenotypic heterogeneity, complicating diagnostic work in clinical practice and molecular diagnosis. Objective: To develop and evaluate a targeted sequencing approach using a customized panel of genes involved in movement disorders. Design, Setting and Participants: We selected 127 genes associated with movement disorders to create a customized enrichment in solution capture array. Targeted high-coverage sequencing was applied to DNA samples taken from 378 eligible patients at 1 Luxembourgian, 1 Algerian, and 25 French tertiary movement disorder centers between September 2014 and July 2016. Patients were suspected of having inherited movement disorders because of early onset, family history, and/or complex phenotypes. They were divided in 5 main movement disorder groups: parkinsonism, dystonia, chorea, paroxysmal movement disorder, and myoclonus. To compare approaches, 23 additional patients suspected of having inherited cerebellar ataxia were included, on whom whole-exome sequencing (WES) was done. Data analysis occurred from November 2015 to October 2016. Main Outcomes and Measures: Percentages of individuals with positive diagnosis, variants of unknown significance, and negative cases; mutational frequencies and clinical phenotyping of genes associated with movement disorders. Results: Of the 378 patients (of whom 208 were male [55.0%]), and with a median (range) age at disease onset of 31 (0-84) years, probable pathogenic variants were identified in 83 cases (22.0%): 46 patients with parkinsonism (55% of 83 patients), 21 patients (25.3%) with dystonia, 7 patients (8.4%) with chorea, 7 patients (8.4%) with paroxysmal movement disorders, and 2 patients (2.4%) with myoclonus as the predominant phenotype. Some genes were mutated in several cases in the cohort. Patients with pathogenic variants were significantly younger (median age, 27 years; interquartile range [IQR], 5-36 years]) than the patients without diagnosis (median age, 35 years; IQR, 15-46 years; P = .04). Diagnostic yield was significantly lower in patients with dystonia (21 of 135; 15.6%; P = .03) than in the overall cohort. Unexpected genotype-phenotype correlations in patients with pathogenic variants deviating from the classic phenotype were highlighted, and 49 novel probable pathogenic variants were identified. The WES analysis of the cohort of 23 patients with cerebellar ataxia led to an overall diagnostic yield of 26%, similar to panel analysis but at a cost 6 to 7 times greater. Conclusions and Relevance: High-coverage sequencing panel for the delineation of genes associated with movement disorders was efficient and provided a cost-effective diagnostic alternative to whole-exome and whole-genome sequencing.

Assessment of the Anticonvulsant Potency of Ursolic Acid in Seizure Threshold Tests in Mice.

Ursolic acid (UA) is a plant derived compound which is also a component of the standard human diet. It possesses a wide range of pharmacological properties, i.e., antioxidant, anti-inflammatory, antimicrobial and antitumor, which have been used in folk medicine for centuries. Moreover, influence of UA on central nervous system-related processes, i.e., pain, anxiety and depression, was proved in experimental studies. UA also revealed anticonvulsant properties in animal models of epilepsy and seizures. The aim of the present study was to investigate the influence of UA on seizure thresholds in three acute seizure models in mice, i.e., the 6 Hz-induced psychomotor seizure threshold test, the maximal electroshock threshold (MEST) test and the timed intravenous pentylenetetrazole (iv PTZ) infusion test. We also examined its effect on the muscular strength (assessed in the grip strength test) and motor coordination (estimated in the chimney test) in mice. UA at doses of 50 and 100 mg/kg significantly increased the seizure thresholds in the 6 Hz and MEST tests. The studied compound did not influence the seizure thresholds in the iv PTZ test. Moreover, UA did not affect the motor coordination and muscular strength in mice. UA displays only a weak anticonvulsant potential which is dependent on the used seizure model.

The Inter-rater Variability of Clinical Assessment in Post-anoxic Myoclonus.

BACKGROUND: Acute post-anoxic myoclonus (PAM) can be divided into an unfavorable (generalized/subcortical) and more favorable ((multi)focal/cortical) outcome group that could support prognostication in post-anoxic encephalopathy; however, the inter-rater variability of clinically assessing these PAM subtypes is unknown. METHODS: We prospectively examined PAM patients using a standardized video protocol. Videos were rated by three neurologists who classified PAM phenotype (generalized/(multi)focal), stimulus sensitivity, localization (proximal/distal/both), and severity (Clinical Global Impression-Severity Scale (CGI-S) and Unified Myoclonus Rating Scale (UMRS)). RESULTS: Poor inter-rater agreement was found for phenotype and stimulus sensitivity (κ=-0.05), moderate agreement for localization (κ=0.46). Substantial agreement was obtained for the CGI-S (intraclass correlation coefficient (ICC)=0.64) and almost perfect agreement for the UMRS (ICC=0.82). DISCUSSION: Clinical assessment of PAM is not reproducible between physicians, and should therefore not be used for prognostication. PAM severity measured by the UMRS appears to be reliable; however, the relation between PAM severity and outcome is unknown.

Treatment of Gabapentin Toxicity With Peritoneal Dialysis: Assessment of Gabapentin Clearance.

Gabapentin is almost exclusively cleared by the kidney and thus presents challenges in patients with kidney failure. Gabapentin is known to be effectively cleared by hemodialysis, but the efficiency of clearance by peritoneal dialysis (PD) has not been previously described. We report a case of gabapentin toxicity in a patient on long-term PD who was treated with continuous automated cycling PD. We find that continuous PD provides significant clearance of gabapentin. With 2-L exchanges every 2 hours, we document an apparent elimination half-life of 41.33 hours, which is substantially shorter than the reported elimination half-life of 132 hours in the absence of kidney function. Further, our patient's symptoms of gabapentin toxicity gradually improved and had fully resolved after about 36 hours of dialysis. Gabapentin clearance by PD was estimated at 94% of urea clearance. We conclude that intensive PD provides gabapentin clearance that approximates that of urea and is an effective but slow method to treat gabapentin overdose and toxicity.

Assessment of Blink Reflex in Genetic Generalized Epilepsy Patients With Eyelid Myoclonia.

Eyelid myoclonia (EM) with or without absences are a rare type of generalized seizures associated with a variety of epilepsy syndromes with an unknown pathophysiology. The aim of this study was to investigate the possible contribution of the brainstem structures in this underrecognized special type of seizures. Sixteen consecutive patients with EM, diagnosed with genetic generalized epilepsy (GGE) according to International League Against Epilepsy 2010 criteria were included. Brainstem excitabilities were examined by blink reflex (BR) studies. The results of BR studies in GGE patients with EM were statistically compared with 2 control groups; namely age- and gender-matched healthy volunteers and juvenile myoclonic epilepsy (JME) patients without any absences and using similar antiepileptic drugs. There were no statistical differences between the thresholds of the BR studies and the BR recovery curves in terms of amplitudes and areas of healthy subjects, JME patients and GGE patients with EM. Our findings do not support a profound interictal hyperexcitability in the BR-related brainstem structures of the GGE patients with EM. It can be considered that EM may be associated with excitability changes of the occipital cortex and other cortical areas.

An update on the epidemiology and key issues associated with the diagnosis and management of Creutzfeldt-Jakob disease cases in NSW.

Creutzfeldt-Jakob disease (CJD) is a fatal disease caused by the accumulation of abnormal prion proteins in neurological tissues. Routine notification data reveal that NSW has similar rates of CJD to other states and territories in Australia; however, it is likely that there is significant under-ascertainment of cases. It is important that clinicians and public health staff remain vigilant for the clinical signs of CJD and understand the limitations of the different diagnostic tests available. This paper provides a brief overview of the epidemiology of CJD in NSW, as well as current issues in the diagnosis and public health investigation of CJD.

Manual quantitative assessment of amplitude and sleep stage distribution of excessive fragmentary myoclonus.

INTRODUCTION: Excessive fragmentary myoclonus (EFM) consists of brief, asynchronous, twitch-like movements appearing asymmetrically in sleep. The new AASM Manual for the Scoring of Sleep and Associated Events identifies some EFM scoring criteria but does not provide amplitude criteria for scoring EFM. Older observational series have used 50 µVs. We report data from various amplitude criteria using blinded comparisons. METHODS: EFMs were analyzed on the polysomnograms of 8 patients (7 men and 1 woman, mean age 57 years, range: 47-79) using a standardized protocol for sensitivity, tonus threshold, impedance, amplitude measurements, and sleep stage. The first 20 minutes each of wake, Stage 1-2, SWS, and REM were analyzed. EFMs ≥ 25, ≥ 40, and ≥ 50 microvolts (µVs) in negative deflection above the baseline were counted in tibialis anterior muscle electromyography (EMG) channels bilaterally. RESULTS: The mean EFM index per minute for wake, regardless of impedance, was: 7.19 ± 5.90 for ≥ 25 µV amplitude; 2.43 ± 2.02 for ≥ 40 µVs; and 2.08 ± 2.23 for ≥ 50 µVs. For sleep stages, the EFM index by stage and amplitude criteria used for measurements were: Stage 1-2: 7.38 ± 5.79 for ≥ 25 µVs; 3.13 ± 3.33 for ≥ 40 µVs; and 2.36 ± 2.66 for ≥ 50 µVs; SWS: 10.05 ± 8.04 for ≥ 25 µVs; 2.71 ± 3.13 for ≥ 40 µVs; and 1.38 ± 1.92 for ≥ 50 µVs; Total REM: 15.96 ± 11.32 for ≥ 25 µVs; 6.32 ± 4.25 for ≥ 40 µVs; and 3.94 ± 3.73 for ≥ 50 µVs; Phasic REM: 19.69 ± 15.45 for ≥ 25 µVs; 8.63 ± 7.06 for ≥ 40 µVs; and 5.52 ± 6.44 for ≥ 50 µVs; Non-phasic REM: 13.93 ± 11.31 for ≥ 25 µVs; 5.16 ± 3.57 for ≥ 40 µVs; and 3.20 ± 2.92 for ≥ 50 µVs. CONCLUSION: EFM rates increase with SWS and total REM with the highest EFM rates occurring during phasic REM. EFM rates were increased across all sleep stages when impedance was > 30 KΩ.

Myoclonus in Creutzfeldt-Jakob disease: polygraphic and video-electroencephalography assessment of 109 patients.

We used electroencephalography (EEG)-polygraphic recordings to classify myoclonus in 109 patients with Creutzfeldt-Jakob disease (CJD) on the basis of its electromyography (EMG) pattern, time course, distribution, and EEG correlates. We recorded myoclonic jerks in 55 patients (50.4%), and we classified them as periodic myoclonus in 28, rhythmic in 13, and irregular in 20 (6 patients showed two types of myoclonus). Myoclonus occurred as a prominently negative event (interrupting the EMG discharge) in 10. Periodic sharp-wave complexes (PSWCs) were present in all but one patient with myoclonic jerks but were time-locked with EMG-bursts only in case of periodic myoclonus. Jerk-locked back averaging revealed a variable EEG-EMG transfer-time commonly exceeding that characterizing cortical myoclonus. Myoclonus was frequently associated with Met/Met polymorphism at codon 129 of the prion protein gene, but it was also observed in association with Met/Val or Val/Val polymorphisms provided that the EEG showed the presence of the PSWC pattern. The presence of enlarged somatosensory evoked potentials significantly correlated with the myoclonic presentation, as did MR signal hyperintensity involving the cortical mantle. Our observations on the basis of standard polygraphic criteria suggest that CJD associates with a remarkable variety of myoclonic jerks, and therefore different brain structures are probably involved as generators. The significant association between the presence of all myoclonus types with PSWCs suggests that hyperexcitable corticosubcortical loops are always required to generate (or allow) both myoclonus and the EEG complexes, either they are time locked or not.

Idiopathic spinal myoclonus: a clinical and neurophysiological assessment of a movement disorder of uncertain origin.

Spinal Myoclonus (SM) is characterized by brief and sudden movements caused by the activation of muscles belonging to adjacent spinal myotomes. Recent reports have indicated that "typical" clinical and electrophysiological features of SM can be mimicked voluntarily. A useful tool that can distinguish between organic and psychogenic jerks is the detection of a Bereitschaftspotential (BP). In this study, we looked for evidence of a BP in a cohort of patients with idiopathic SM. A clinical and neurophysiological assessment of 20 patients affected by idiopathic SM was performed. A video EEG-EMG multichannel recording was performed in each patient to detect BP. An expert neurophysiologist (PB) reviewed the BP recordings and divided them into those showing a definite, possible, and no BP. A clinical assessment of the videoed movements was performed by two neurologists expert in movement disorders (KB and MJE) who indicated if the movements were compatible with organic or psychogenic myoclonus. A definite or possible BP was recorded in 15 out of 20 patients. Clinical raters agreed in their clinical opinion on 15 patients (75%). All patients where both raters agreed the movements appeared to be organic had definite or possible BP. BP are commonly seen in patients with idiopathic SM. There is discordance between clinicians in their clinical rating of SM as organic or psychogenic, but even in those patients where movements appear clinically to be organic, a BP is commonly detected, indicating that the aetiology is psychogenic. This suggests that BP recordings are a useful adjunct to clinical assessment in the accurate diagnosis of patients with idiopathic SM.

Effect of cold application and tizanidine on clonus: clinical and electrophysiological assessment.

BACKGROUND/OBJECTIVES: Clonus is an involuntary rhythmic muscle contraction after sudden muscle stretch that occurs as a result of a lesion in the upper motor neurons. The real mechanism behind clonus remains obscure. The objective of this study was to investigate the effects of central-acting tizanidine treatment and peripheral extremity cooling on clonus. PARTICIPANTS: Thirty-eight patients with upper motor neuron involvement and sustained clonus. METHODS: The 38 patients were divided into 3 groups: cold group (n=19), tizanidine group (n=13), and patient control group (n=6). A separate group of 21 able-bodied volunteers served as controls for the cold group. The physiologic effects of cold application were measured in the able-bodied group and compared with the effects in the patients in the cold group. All participants were evaluated by clinical and electrophysiologic measurements. RESULTS: Changes in clinical and electrophysiologic measurements in the cold group were statistically significant compared with those of the tizanidine and patient control groups. CONCLUSIONS: Subsequent and long-term cold application induced prolonged inhibitory effects on clonus. Tizanidine had no significant effect on clonus. Suppression of clonus by cold highlights the importance of peripheral input in relation to central mechanisms.

Complaints of heroin-maintained patients: A survey of symptoms ascribed to diacetylmorphine.

Prescribing of injectable diacetylmorphine (DAM) for heroin dependence has raised concerns about its safety. In light of various reports by heroin-maintained patients of DAM-related adverse events, and previously established unwanted effects of opioids in pain management, we undertook a survey in February 2001 of a random sample of 132 (127 participated) of 1061 patients prescribed DAM in Switzerland at that time. The purpose was to document the prevalence rates of a list of unintended symptoms experienced and attributed to DAM by patients. To assess symptom complaints and other data, staff administered a six-page self-report questionnaire. The patients ascribed numerous symptoms to DAM, with the best-known being the most frequently reported (e.g. skin itching, sweating, constipation). Among potentially more problematic complaints ranged irregular menses, cognitive deficits, muscle twitches, labored breathing, pains in the cardiac region, and temporary paralysis of limbs. In the absence of a control group, however, these may also be due to other factors, such as expectation, co-medication, concomitant substance use or co-morbidity. This pilot study emphasizes the necessity of rigorous assessment of the true rates, types, severity and preventability of such complications, especially given the current efforts to establish heroin maintenance as an optional treatment for heroin dependence.

Assessment of the seizure susceptibility of Wistar Audiogenic rat to electroshock, pentyleneterazole and pilocarpine.

This work evaluates the seizure susceptibility of nai;ve female Wistar Audiogenic rats (WARs), a genetic model of reflex epilepsy in which seizures are induced by high-intensity sound stimulation (120 dB SPL), to other pro-convulsive stimuli: transauricular electroshock (ES), pentylenetetrazole (PTZ) and pilocarpine (PILO). Normal Wistar rats from the main breeding stock of the Institute of Biological Sciences, UFMG were taken as controls. Electroshock seizures were induced through a pair of ear-clip electrodes (10 mA, at a frequency of 60 Hz, applied for 1 s). In order to test WAR susceptibility to chemically induced seizures, animals were treated either with PTZ (37.5 mg/kg i.p.) or PILO (200, 270 and 300 mg/kg i.p.). Seizure severity was evaluated by appropriate behavioral severity index scales (SI) specific to each epilepsy model and tested for statistical significance using the non-parametric Mann-Whitney Rank Sum test. Results show a significantly greater susceptibility of WARs for ES (SI(WAR)=3+/-3/3, SI(Wistar)=1+/-1/1; median+/-interquartile range 25%/75%, P<0.01) and PTZ (SI(WAR)=4+/-4/4, SI(Wistar)=1+/-1/4; median+/-interquartile range 25%/75%, P<0.02), as indicated by significantly higher SI scores and shorter latencies for seizure onset (T(WAR)=71+/-7 s, T(Wistar)=94+/-8 s; P<0.05 Student t-test, mean+/-S.E.M.). Although PILO also caused higher SI scores in WARs (WAR(200 mg)=1+/-1/1, Wistar(200 mg)=1+/-1/1; WAR(270 mg)=1.5+/-1/2, Wistar(270 mg)=1+/-1/1.25; WAR(300 mg)=9+/-1/9, Wistar(300 mg)=4+/-1.5/7.5; median+/-interquartile range 25%/75%), statistically significant differences were not observed. In conclusion, our results show that WARs have an inherited broader predisposition for seizures.

Clinical assessment of tics.

Comprehensive clinical evaluation of tics includes (1) assessments to diagnose (a) akathisia, myoclonus, stereotypies, and other dyskinesias and (b) their frequent behavioral concomitants, including attention deficits, compulsions, obsessions, and other psychopathologic manifestations, (2) descriptions of movement parameters from the patients, their parents, teachers, and important others, and (3) precise topographical localization of tics.

Phase relationships between cortical and muscle oscillations in cortical myoclonus: electrocorticographic assessment in a single case.

AIM: To compare voluntary- and sensory-induced myoclonic jerks using spectral analysis in a subject with cortical myoclonus. METHODS: The coherence, phase and cumulant density estimates were calculated between right electrocorticographic (ECoG) signals and distal left leg muscles in a patient with subdural electrodes inserted over the right sensorimotor cortex. RESULTS: Significant coherence between sensorimotor cortex and muscle was found up to 60 Hz during voluntary induced myoclonic jerks. Additional higher frequency coherence ( approximately 140 and 190 Hz) was found during sensory-induced myoclonic jerks. The cortical signals phase led muscle signals at frequencies >15 Hz by delays consistent with transmission along corticospinal pathways. Below 15 Hz the cortex phase lagged the muscle signals. Polarity reversal of the cumulant density estimate and the ECoG site demonstrating the highest coherence helped to localize the site of the abnormal oscillatory activity to the leg area of the motor cortex. CONCLUSIONS: Oscillations of different frequencies can co-exist at a given location and can both phase lead and lag contralateral muscle. This has implications for cortex-muscle latency measures calculated by back-averaging techniques.

Alfentanil decreases the excitatory phenomena of sodium methohexital.

STUDY OBJECTIVE: To evaluate the effects of alfentanil or lidocaine on the excitatory phenomena (myoclonus, cough, hiccough) caused by methohexital anesthesia and on the hemodynamic changes induced by retrobulbar block. DESIGN: Prospective, randomized, placebo-controlled, double-blind study. SETTING: University-affiliated, tertiary-care hospital. PATIENTS: 60 ASA physical status II and III patients who were admitted for elective cataract extractions and intraocular lens implantations. INTERVENTIONS: Patients were randomly assigned to one of three groups. After adequate preoxygenation in the holding area, Group 1 received alfentanil 5 micrograms/kg intravenously (i.v.), Group 2 received lidocaine 1 mg/kg i.v. and Group 3 received the placebo (saline) i.v. Immediately after the bolus injection of the study solution, sodium methohexital 1.5 mg/kg was injected i.v. over 30 seconds. As soon as the eyelid reflex was lost, the retrobulbar block was placed over 5 seconds. MEASUREMENTS AND MAIN RESULTS: Occurrences of excitatory phenomena were recorded by an independent observer who was blinded as to treatment allocation. Other side effects such as oculocardiac reflex, nausea, vomiting, itching, or chest wall rigidity were recorded. Vital signs were recorded at baseline and 1, 3, and 5 minutes after placement of the block. In the alfentanil group, the incidence of myoclonus or cough was significantly less than in the lidocaine or placebo groups. Alfentanil also decreased systolic and diastolic blood pressure significantly at 1, 3, and 5 minutes after retrobulbar block. Changes in heart rate were not significantly different from baseline. CONCLUSION: A small dose of alfentanil (5 micrograms/kg i.v.) decreases myoclonus and cough induced by sodium methohexital anesthesia i.v., resulting in improved quality of induction of anesthesia. Alfentanil also attenuates the cardiovascular responses caused by placement of a retrobulbar block.