Benzodiazepine Use During Hospitalization: Automated Identification of Potential Medication Errors and Systematic Assessment of Preventable Adverse Events.

OBJECTIVE: Benzodiazepines and "Z-drug" GABA-receptor modulators (BDZ) are among the most frequently used drugs in hospitals. Adverse drug events (ADE) associated with BDZ can be the result of preventable medication errors (ME) related to dosing, drug interactions and comorbidities. The present study evaluated inpatient use of BDZ and related ME and ADE. METHODS: We conducted an observational study within a pharmacoepidemiological database derived from the clinical information system of a tertiary care hospital. We developed algorithms that identified dosing errors and interacting comedication for all administered BDZ. Associated ADE and risk factors were validated in medical records. RESULTS: Among 53,081 patients contributing 495,813 patient-days BDZ were administered to 25,626 patients (48.3%) on 115,150 patient-days (23.2%). We identified 3,372 patient-days (2.9%) with comedication that inhibits BDZ metabolism, and 1,197 (1.0%) with lorazepam administration in severe renal impairment. After validation we classified 134, 56, 12, and 3 cases involving lorazepam, zolpidem, midazolam and triazolam, respectively, as clinically relevant ME. Among those there were 23 cases with associated adverse drug events, including severe CNS-depression, falls with subsequent injuries and severe dyspnea. Causality for BDZ was formally assessed as 'possible' or 'probable' in 20 of those cases. Four cases with ME and associated severe ADE required administration of the BDZ antagonist flumazenil. CONCLUSIONS: BDZ use was remarkably high in the studied setting, frequently involved potential ME related to dosing, co-medication and comorbidities, and rarely cases with associated ADE. We propose the implementation of automated ME screening and validation for the prevention of BDZ-related ADE.

Plasticity of cortical inhibition in dystonia is impaired after motor learning and paired-associative stimulation.

Artificial induction of plasticity by paired associative stimulation (PAS) in healthy volunteers (HV) demonstrates Hebbian-like plasticity in selected inhibitory networks as well as excitatory networks. In a group of 17 patients with focal hand dystonia and a group of 19 HV, we evaluated how PAS and the learning of a simple motor task influence the circuits supporting long-interval intracortical inhibition (LICI, reflecting activity of GABA(B) interneurons) and long-latency afferent inhibition (LAI, reflecting activity of somatosensory inputs to the motor cortex). In HV, PAS and motor learning induced long-term potentiation (LTP)-like plasticity of excitatory networks and a lasting decrease of LAI and LICI in the motor representation of the targeted or trained muscle. The better the motor performance, the larger was the decrease of LAI. Although motor performance in the patient group was similar to that of the control group, LAI did not decrease during the motor learning as it did in the control group. In contrast, LICI was normally modulated. In patients the results after PAS did not match those obtained after motor learning: LAI was paradoxically increased and LICI did not exhibit any change. In the normal situation, decreased excitability in inhibitory circuits after induction of LTP-like plasticity may help to shape the cortical maps according to the new sensorimotor task. In patients, the abnormal or absent modulation of afferent and intracortical long-interval inhibition might indicate maladaptive plasticity that possibly contributes to the difficulty that they have to learn a new sensorimotor task.

Agomelatine for Depression in Schizophrenia: A Case-Series.

OBJECTIVES: Agomelatine, a melatonin (MT1/MT2) receptor agonist and 5-HT2C receptor antagonist, is a new antidepressant and a potential therapeutic option for major depressive episodes and negative symptoms in persons with schizophrenia. We investigated such treatment outcomes with respect to antidepressant efficacy, safety, and tolerability. METHODS: We report a consecutive case series of seven patients with schizophrenia and comorbid major depressive symptoms who received agomelatine for a period of at least six weeks in addition to stable doses of antipsychotic agents. General psychopathology, positive, negative and depressive symptoms were assessed with standardized interviews. Relevant blood parameters were assessed. RESULTS: Depressive symptoms improved significantly. Positive symptoms remained stable, while negative symptoms and global psychopathology improved significantly. Agomelatine was well tolerated in most patients. CONCLUSIONS: Our findings provide initial evidence that agomelatine is safe and efficacious in treating depressive symptoms in patients with schizophrenia. Furthermore, agomelatine seems to be effective for the treatment of negative symptoms. Randomized controlled trials are necessary to confirm these first observations.

Mutism and amnesia following high-voltage electrical injury: psychogenic symptomatology triggered by organic dysfunction?

BACKGROUND: Mutism and dense retrograde amnesia are found both in organic and dissociative contexts. Moreover, dissociative symptoms may be modulated by right prefrontal activity. A single case, M.R., developed left hemiparesis, mutism and retrograde amnesia after a high-voltage electric shock without evidence of lasting brain lesions. M.R. suddenly recovered from his mutism following a mild brain trauma 2 years later. METHODS: M.R.'s neuropsychological pattern and anatomoclinical correlations were studied through (i) language and memory assessment to characterize his deficits, (ii) functional neuroimaging during a standard language paradigm, and (iii) assessment of frontal and left insular connectivity through diffusion tractography imaging and transcranial magnetic stimulation. A control evaluation was repeated after recovery. FINDINGS: M.R. recovered from the left hemiparesis within 90 days of the accident, which indicated a transient right brain impairment. One year later, neurobehavioral, language and memory evaluations strongly suggested a dissociative component in the mutism and retrograde amnesia. Investigations (including MRI, fMRI, diffusion tensor imaging, EEG and r-TMS) were normal. Twenty-seven months after the electrical injury, M.R. had a very mild head injury which was followed by a rapid recovery of speech. However, the retrograde amnesia persisted. DISCUSSION: This case indicates an interaction of both organic and dissociative mechanisms in order to explain the patient's symptoms. The study also illustrates dissociation in the time course of the two different dissociative symptoms in the same patient.

Paired associative stimulation induces change in presynaptic inhibition of Ia terminals in wrist flexors in humans.

Enhancements in the strength of corticospinal projections to muscles are induced in conscious humans by paired associative stimulation (PAS) to the motor cortex. Although most of the previous studies support the hypothesis that the increase of the amplitude of motor evoked potentials (MEPs) by PAS involves long-term potentiation (LTP)-like mechanism in cortical synapses, changes in spinal excitability after PAS have been reported, suggestive of parallel modifications in both cortical and spinal excitability. In a first series of experiments (experiment 1), we confirmed that both flexor carpi radialis (FCR) MEPs and FCR H reflex recruitment curves are enhanced by PAS. To elucidate the mechanism responsible for this change in the H reflex amplitude, we tested, using the same subjects, the hypothesis that enhanced H reflexes are caused by a down-regulation of the efficacy of mechanisms controlling Ia afferent discharge, including presynaptic Ia inhibition and postactivation depression. To address this question, amounts of both presynaptic Ia inhibition of FCR Ia terminals (D1 and D2 inhibitions methods; experiment 2) and postactivation depression (experiment 3) were determined before and after PAS. Results showed that PAS induces a significant decrease of presynaptic Ia inhibition of FCR terminals, which was concomitant with the facilitation of the H reflex. Postactivation depression was unaffected by PAS. It is argued that enhancement of segmental excitation by PAS relies on a selective effect of PAS on the interneurons controlling presynaptic inhibition of Ia terminals.

Associative plasticity in intracortical inhibitory circuits in human motor cortex.

OBJECTIVE: Paired associative stimulation (PAS) is a transcranial magnetic stimulation technique inducing Hebbian-like synaptic plasticity in the human motor cortex (M1). PAS is produced by repetitive pairing of a peripheral nerve shock and a transcranial magnetic stimulus (TMS). Its effect is assessed by a change in size of a motor evoked response (MEP). MEP size results from excitatory and inhibitory influences exerted on cortical pyramidal cells, but no robust effects on inhibitory networks have been demonstrated so far. METHOD: In 38 healthy volunteers, we assessed whether a PAS intervention influences three intracortical inhibitory circuits: short (SICI) and long (LICI) intracortical inhibitions reflecting activity of GABA(A) and GABA(B) interneurons, respectively, and long afferent inhibition (LAI) reflecting activity of somatosensory inputs. RESULTS: After PAS, MEP sizes, LICI and LAI levels were significantly changed while changes of SICI were inconsistent. The changes in LICI and LAI lasted 45 min after PAS. Their direction depended on the delay between the arrival time of the afferent volley at the cortex and the TMS-induced cortical activation during the PAS. CONCLUSIONS: PAS influences inhibitory circuits in M1. SIGNIFICANCE: PAS paradigms can demonstrate Hebbian-like plasticity at selected inhibitory networks as well as excitatory networks.

Ambulatory monitoring of physical activities in patients with Parkinson's disease.

A new ambulatory method of monitoring physical activities in Parkinson's disease (PD) patients is proposed based on a portable data-logger with three body-fixed inertial sensors. A group of ten PD patients treated with subthalamic nucleus deep brain stimulation (STN-DBS) and ten normal control subjects followed a protocol of typical daily activities and the whole period of the measurement was recorded by video. Walking periods were recognized using two sensors on shanks and lying periods were detected using a sensor on trunk. By calculating kinematics features of the trunk movements during the transitions between sitting and standing postures and using a statistical classifier, sit-to-stand (SiSt) and stand-to-sit (StSi) transitions were detected and separated from other body movements. Finally, a fuzzy classifier used this information to detect periods of sitting and standing. The proposed method showed a high sensitivity and specificity for the detection of basic body postures allocations: sitting, standing, lying, and walking periods, both in PD patients and healthy subjects. We found significant differences in parameters related to SiSt and StSi transitions between PD patients and controls and also between PD patients with and without STN-DBS turned on. We concluded that our method provides a simple, accurate, and effective means to objectively quantify physical activities in both normal and PD patients and may prove useful to assess the level of motor functions in the latter.

Quantification of tremor and bradykinesia in Parkinson's disease using a novel ambulatory monitoring system.

An ambulatory system for quantification of tremor and bradykinesia in patients with Parkinson's disease (PD) is presented. To record movements of the upper extremities, a sensing units which included miniature gyroscopes, has been fixed to each of the forearms. An algorithm to detect and quantify tremor and another algorithm to quantify bradykinesia have been proposed and validated. Two clinical studies have been performed. In the first study, 10 PD patients and 10 control subjects participated in a 45-min protocol of 17 typical daily activities. The algorithm for tremor detection showed an overall sensitivity of 99.5% and a specificity of 94.2% in comparison to a video reference. The estimated tremor amplitude showed a high correlation to the Unified Parkinson's Disease Rating Scale (UPDRS) tremor subscore (e.g., r = 0.87, p < 0.001 for the roll axis). There was a high and significant correlation between the estimated bradykinesia related parameters estimated for the whole period of measurement and respective UPDRS subscore (e.g., r = -0.83, p < 0.001 for the roll axis). In the second study, movements of upper extremities of 11 PD patients were recorded for periods of 3-5 hr. The patients were moving freely during the measurements. The effects of selection of window size used to calculate tremor and bradykinesia related parameters on the correlation between UPDRS and these parameters were studied. By selecting a window similar to the period of the first study, similar correlations were obtained. Moreover, one of the bradykinesia related parameters showed significant correlation (r = -0.74, p < 0.01) to UPDRS with window sizes as short as 5 min. Our study provides evidence that objective, accurate and simultaneous assessment of tremor and bradykinesia can be achieved in free moving PD patients during their daily activities.

Changes in spinal excitability after PAS.

Repetitive pairing of a peripheral stimulation with a magnetic transcortical stimulation (PAS) is widely used to induce plastic changes in the human motor cortex noninvasively. Based on the contrast between PAS-induced increase of corticospinal excitability and absence of PAS-induced increase of the spinal F wave size, it has been generally accepted that PAS-induced plasticity is cortical in origin. Here, instead of F waves, we used H reflex recruitment curves to assess spinal excitability, and we demonstrate that PAS induces parallel changes in cortical and spinal excitability.

Spinal use-dependent plasticity of synaptic transmission in humans after a single cycling session.

The spinal cord is able to express use-dependent plasticity, as demonstrated in spinalized cats following treadmill training. In humans, spinal use-dependent plasticity is inferred from modifications in the size of H reflex, which are often more prominent after skilled motor training. Plasticity can develop at synaptic connections between afferent fibres and/or descending tracts and motoneurones or interneurones interposed in the spinal pathways. Here we explore whether skilled training induces a change in synaptic efficacy at the synapse between Ia afferents and soleus (Sol) motoneurones. Synaptic efficacy can be modulated presynaptically through changes of the probability of transmitter release (homosynaptic depression, HD). The frequency-related depression of the Sol H reflex, thought to reflect HD, was tested at rest, before and after one single skilled (14 subjects) or non-skilled (9 subjects) cycling training session. Performance improved in both groups but to a larger extent with skilled training, while HD increased immediately after and the day following skilled training in the absence of changes with non-skilled training. These results support the view that spinal cord function is able to encode a local motor memory.

Long-duration response to levodopa in patients with advanced Parkinson disease treated with subthalamic deep brain stimulation.

BACKGROUND: Long-duration response (LDR) to levodopa is supposed to decrease with Parkinson disease (PD) progression, but direct observation of this response in advanced PD has never been performed. OBJECTIVE: To study the LDR to levodopa in patients with advanced PD treated with subthalamic deep brain stimulation (DBS). DESIGN AND SETTING: We studied 30 consecutive patients with PD who underwent subthalamic DBS. One group had no antiparkinsonian treatment since surgery (no-levodopa group), whereas medical treatment had to be reinitiated in the other group (levodopa group). MAIN OUTCOME MEASURE: Motor subscale score of the Unified Parkinson's Disease Rating Scale. RESULTS: Compared with preoperative assessment, evaluation 6 months postoperatively with DBS turned off for 3 hours found a worsening of the motor subscale score of the Unified Parkinson's Disease Rating Scale in the no-levodopa group. This worsening being absent in the levodopa group, it probably reflected the loss of the LDR to levodopa in the no-levodopa group. When DBS was turned on, postoperative motor subscale scores of the Unifid Parkinson's Disease Rating Scale in both groups were similar to preoperative scores while receiving medication, suggesting that subthalamic DBS compensated for the short-duration response and LDR to levodopa. CONCLUSIONS: Our results suggest that the LDR to levodopa remains significant even in advanced PD, and that subthalamic DBS compensates for the short-duration response and LDR to levodopa.

Sporadic Creutzfeldt-Jakob disease: a comparison of pathological findings and diffusion weighted imaging.

To investigate a possible relationship between the severity of pathological and radiological lesions in diffusion-weighted MRI (DWI) we compared DWI findings from 6 sequential brain MRI scans with pathological features of numerous tissue blocks of different cortical and subcortical regions in a case of autopsy-proven sporadic CJD. Whereas DWI and pathological examination revealed multifocal, cortical and deep hyperintensities at corresponding localizations, no correlation between the degree of severity of radiologically visible and pathological damage was found. The characteristic focal involvement and extension of lesions of the cortex and the basal ganglia bilaterally shown by DWI may be an argument for the spreading of the disease per contiguitatem.

Gait assessment in Parkinson's disease: toward an ambulatory system for long-term monitoring.

An ambulatory gait analysis method using body-attached gyroscopes to estimate spatio-temporal parameters of gait has been proposed and validated against a reference system for normal and pathologic gait. Later, ten Parkinson's disease (PD) patients with subthalamic nucleus deep brain stimulation (STN-DBS) implantation participated in gait measurements using our device. They walked one to three times on a 20-m walkway. Patients did the test twice: once STN-DBS was ON and once 180 min after turning it OFF. A group of ten age-matched normal subjects were also measured as controls. For each gait cycle, spatio-temporal parameters such as stride length (SL), stride velocity (SV), stance (ST), double support (DS), and gait cycle time (GC) were calculated. We found that PD patients had significantly different gait parameters comparing to controls. They had 52% less SV, 60% less SL, and 40% longer GC. Also they had significantly longer ST and DS (11% and 59% more, respectively) than controls. STN-DBS significantly improved gait parameters. During the stim ON period, PD patients had 31% faster SV, 26% longer SL, 6% shorter ST, and 26% shorter DS. GC, however, was not significantly different. Some of the gait parameters had high correlation with Unified Parkinson's Disease Rating Scale (UPDRS) subscores including SL with a significant correlation (r = -0.90) with UPDRS gait subscore. We concluded that our method provides a simple yet effective way of ambulatory gait analysis in PD patients with results confirming those obtained from much more complex and expensive methods used in gait labs.

Acute infarction limited to the lenticular nucleus: clinical, etiologic, and topographic features.

BACKGROUND: Chronic diseases involving the putamen and globus pallidus induce parkinsonism and other movement disorders. Sensory and motor dysfunction from deep middle cerebral artery infarction is usually due to an involvement of the internal capsule. The clinical picture associated with isolated infarction of the lenticular nucleus is less well established. OBJECTIVE: To analyze clinical features, topographic correlations, and cause of purely lenticular ischemic infarction. PATIENTS AND METHODS: We reviewed 820 consecutive patients with deep hemispheral infarct included in the Lausanne Stroke Registry between 1986 and 1998 and selected those with isolated lenticular involvement on computed tomography or magnetic resonance imaging. RESULTS: Thirteen patients had pure lenticular infarction. All had faciobrachiocrural hemisyndrome, while none showed acute or delayed parkinsonism or abnormal movement. Nine patients had a lesion restricted to the putamen. Two of them had ataxic motor hemisyndrome and 7 had sensorimotor hemisyndrome (with ataxia in 4, left hemineglect in 1, and deep pain in the arm and leg in 1). Four patients had a lesion of putamen and globus pallidus externus. Three of them had motor hemisyndrome (with nonfluent aphasia in 2 and ataxia in 1) and 1 had ataxic sensorimotor hemisyndrome. All infarcts were in the territory of the medial perforating branches of the medial cerebral artery. Presumed cause of stroke was small-artery disease in 5, artery-to-artery embolism in 4, cardioembolism in 3 and undetermined in 1. CONCLUSIONS: Acute lenticular infarction induces mainly hemiparesis but no movement disorder. Associated sensory deficits, aphasia, and hemineglect underline clinically the function of the lenticular nucleus in connection with the prefrontal, temporal, and parietal cortices.