IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials. OBJECTIVE To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS. DESIGN, SETTING, AND PARTICIPANTSThis double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements. INTERVENTIONS Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks. MAIN OUTCOMES AND MEASURESThe primary outcome was change in short-interval intracortical inhibition (SICI; SICI −1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies.RESULTS A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI −1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI −1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, −2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001).CONCLUSIONS AND RELEVANCE Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials.
Background Ischemic stroke is a time-sensitive disease, with improved outcomes associated with decreased time from onset to treatment. It was hypothesised that ambulance-based assessment of the National Institutes of Health Stroke Scale (NIHSS) using a Health Insurance Portability and Accountability Act (HIPAA)-compliant mobile platform immediately prior to arrival is feasible. Methods This is a proof-of-concept feasibility pilot study in two phases. The first phase consisted of an ambulance-equipped HIPAA-compliant video platform for remote NIHSS assessment of a simulated stroke patient. The second phase consisted of remote NIHSS assessment by a hospital-based neurologist of acute stroke patients en route to our facility. Five ambulances were equipped with a 4G/LTE-enabled tablet preloaded with a secure HIPAA-compliant telemedicine application. Secondary outcomes assessed satisfaction of staff with the remote platform. Results Phase one was successful in the assessment of three out of three simulated patients. Phase two was successful in the assessment of 10 out of 11 (91%) cases. One video attempt was unsuccessful because local LTE was turned off on the device. The video signal was dropped transiently due to weather, which delayed NIHSS assessment in one case. Average NIHSS assessment time was 7.6 minutes (range 3-9.8 minutes). Neurologists rated 83% of encounters as 'satisfied' to 'very satisfied', and the emergency medical service (EMS) rated 90% of encounters as 'satisfied' to 'very satisfied'. The one failed video attempt was associated with 'poor' EMS satisfaction. Conclusion This proof-of-concept pilot demonstrates that remote ambulance-based NIHSS assessment is feasible. This model could reduce door-to-needle times by conducting prehospital data collection.
Background Hereditary transthyretin (ATTRv) amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We aimed to assess the efficacy and safety of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with ATTRv amyloidosis with polyneuropathy. MethodsThis multi-country, multi-centre, open-label extension (OLE) trial enrolled patients at 43 sites in 19 countries as of 24 September 2018. Patients were eligible if they had completed the phase 3 APOLLO (randomised, double-blind, placebo-controlled [2:1], 18-month study) or phase 2 OLE (single-arm, 24-month study) parent studies and tolerated the study drug. Eligible patients from APOLLO (APOLLO-patisiran [received patisiran during APOLLO] and APOLLO-placebo [received placebo during APOLLO] groups) and the phase 2 OLE (phase 2 OLE patisiran group) studies enrolled in this Global OLE trial and receive patisiran 0•3 mg/kg by intravenous infusion every 3 weeks for up to 5 years. Efficacy assessments include measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress. Patients included in the current efficacy analyses are those who had completed 12-month efficacy assessments as of the data cut-off. Safety analyses included all patients who received ≥1 dose of patisiran up to the data cut-off. The Global OLE is ongoing with no new enrolment, and current findings are based on the 12-month interim analysis. The study is registered with ClinicalTrials.gov, NCT02510261.
Introduction We assessed patients’ perceptions of physician empathy during telemedicine consultations as compared to in-person consultations during clinical encounters for acute stroke. Methods This prospective cohort study was undertaken at a comprehensive stroke centre hub in collaboration with a distant community hospital spoke site. Eligible participants presented to hub or spoke emergency departments with suspected acute stroke within three hours of symptom onset. Participants were evaluated at the hub site in person or at the remote site via telemedicine by the same group of neurologists. Following acute care decisions, single-visit data including participant-reported assessments of physician empathy were collected within 24 h. The primary outcome was the Consultation and Relational Empathy score. The secondary outcome for the telemedicine cohort was the Telemedicine Patient Satisfaction Measure score. Results Between 31 May 2013–13 March 2019, 70 patients completed the study. Fifty patients were seen by telemedicine and 20 patients were seen in person. Median Consultation and Relational Empathy scores (with a possible score of 10–50) were 49 (range 27–50) for telemedicine and 45 (range 26–50) for in-person consultations (Wilcoxon rank sum p = 0.18). Each item of the Consultation and Relational Empathy questionnaire was rated very good or excellent by at least 87% of participants in the telemedicine group. The median Telemedicine Patient Satisfaction Measure score was 54 (range 12–60), with each item rated agree or strongly agree by at least 84% of participants. Discussion We found no difference between telemedicine and in-person visits in patient perception of physician empathy in acute stroke care. Therefore, we conclude that empathy can be conveyed by facial expression, voice and attentiveness in a telemedicine encounter and, in the setting of acute stroke care, does not require physical touch or proximity.
Among patients with aSAH, RBC transfusion was independently associated with an increased mortality after adjustment for the most common clinical indications for transfusion.
Ezogabine, clobazam, and perampanel are among the newest antiseizure drugs approved by the Food and Drug Administration between 2011 and 2012. Ezogabine and perampanel are approved for adjunctive treatment of partial epilepsy. Perampanel is also approved for adjunctive treatment of primary generalized tonic-clonic seizures. Ezogabine and perampanel have novel mechanisms of action. Ezogabine binds to voltage-gated potassium channels and increases the M-current thereby causing membrane hyperpolarization. Perampanel is a selective, non-competitive 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid receptor antagonist, which reduces neuronal excitation. Clobazam has been used worldwide since the 1970s and is approved for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. Clobazam is the only 1,5-benzodiazepine currently in clinical use, which is less sedating than the commonly used 1,4-benzodiazepines. Phase III multicenter, randomized, double-blind, placebo-controlled trials demonstrated efficacy and good tolerability of these 3 new antiepileptic drugs. These drugs represent a welcome addition to the armamentarium of practitioners, but it remains to be seen how they will affect the landscape of pharmacoresistant epilepsy.
Introduction/Aims Cortical hyperexcitability is a feature of amyotrophic lateral sclerosis (ALS) and cortical excitability can be measured using transcranial magnetic stimulation (TMS). Resting motor threshold (MT) is a measure of cortical excitability, largely driven by glutamate. Perampanel, a glutamate α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor blocker, is predicted to increase the cortical excitability threshold. This study aimed to evaluate TMS to functionally assess target engagement in a study of perampanel in ALS. Method We studied the MT of ALS patients randomized to a single dose of perampanel or placebo 5:1 hourly for 4 h. Twelve patients participated at 4 mg and 7 returned for dosing and retesting at 8 mg. The study was terminated in April 2020 due to coronavirus disease 2019‐related restrictions, after 7 out of 12 planned patients had received the 8 mg dose. Serum concentrations were also measured. Results Ten patients received the 4 mg dose (2 received placebo) and 5 received the 8 mg dose (2 received placebo). Motor Threshold increased at 2 h after dosing in the combined treatment group +7% of maximal stimulator output (P < .01). Change could be detected in the larger 4 mg group (P = .02), but not in the smaller 8 mg dose group (P = .1). No side effects were reported after single dose exposure. Discussion This study shows that perampanel effects the physiology of upper motor neurons. Studies aiming at gauging the effect of perampanel on ALS disease progression are already ongoing. Motor threshold may serve as a marker of biological target engagement.
Electromyographic (EMG) reporting of radiculopathies is not standardized, and the terminology used in reports can be misinterpreted by referring physicians. Physicians who refer patients for EMG studies at the Mayo Clinic were surveyed about their understanding of 6 different EMG interpretations of an S1 radiculopathy. Of 45 responders, the terms “acute, active,” “chronic, inactive,” and “old” were interpreted consistently by 95%, 98%, and 84% of responders, respectively. Physicians had the most difficulty understanding the meaning of “chronic” in isolation, “chronic, active,” or “old with uncompensated denervation.” These findings suggest a need to educate referring physicians on the meaning of the terms used in EMG reports and to develop standard guidelines for qualifying radiculopathies. Based on our observations, guidelines for the reporting of radiculopathies have been adopted in the Mayo Clinic Florida EMG laboratory.
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