Cortical excitability threshold can be increased by the AMPA blocker Perampanel in amyotrophic lateral sclerosis.

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.

Patient perception of physician empathy in stroke telemedicine.

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.

Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

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 Participants: This 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 Measures: The 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. Trial Registration: ClinicalTrials.gov Identifier: NCT02450552.

Incorporation of Telestroke into Neurology Residency Training: "Time Is Brain and Education".

Background: With increasing demand for neurologists, nontraditional health care delivery mechanisms have been developed to leverage this limited resource. Introduction: Telemedicine has emerged as an effective digital solution. Over the past three decades, telemedicine use has steadily grown; however, neurologists often learn on the job, rather than as part of their medical training. The current literature regarding telestroke training during neurology training is sparse, focusing on cerebrovascular fellowship curricula. We sought to enhance telestroke training in our neurology residency by incorporating real-life application. Materials and Methods: We implemented a formal educational model for neurology residents to use telemedicine for remote acquisition of the National Institutes of Health Stroke Scale (NIHSS) for patients with suspected acute ischemic stroke (AIS) before arrival at our comprehensive stroke center. This three-phase educational model involved multidisciplinary classroom didactics, simulation exercises, and real-world experience. Training and feedback were provided by neurologists experienced in telemedicine. Results: All residents completed formal training in telemedicine prehospital NIHSS acquisition and had the opportunity to participate in additional simulation exercises. Currently, residents are gaining additional experience by performing prehospital NIHSS acquisition for patients in whom AIS is suspected. Our preliminary data indicate that resident video encounters average 10.6 min in duration, thus saving time once patients arrive at our hospital. Discussion: To our knowledge, this is the first report of a telestroke-integrated neurology residency program in a comprehensive stroke center resulting in shortened time to treatment in patients with suspected AIS. Conclusions: We present a model that can be adopted by other neurology residency programs as it provides real-world telemedicine training critical to future neurologists.

Burnout and attrition: Expanding the gender gap in neurology?

Neurology faces an increasing shortage of neurologists in the United States due to a growing demand for neurologic services. A 7% increase in the supply of neurologists is predicted from 2012 to 2025, whereas the demand will rise by 16%. An increase in the neurology workforce is critical to meet the demands, and a significant gender gap remains within the workforce that must be addressed to further ease the discrepancy between supply and demand. Individual, institutional, and societal factors contribute to this gender discrepancy and potentially result in the burnout or soft attrition of women from neurology. These factors, including earning disparity between male and female neurologists, one of the largest gaps in pay for any medical specialty, and the lack of representation at higher academic levels with only 12% (14 of 113) of neurology department chairs at academic medical centers being women, could lead to increased attrition of women from neurology. Identifying and mitigating these factors may help narrow the gender gap and increase the supply of neurologists to better meet future demand.

Inclusion Body Myositis Mimicking Bilateral Anterior Interosseous Neuropathies.

Anterior interosseous neuropathy is a rare cause of weakness of flexion of the thumb interphalangeal and index and middle finger distal interphalangeal joints, most commonly caused by trauma, compression, or inflammation. Bilateral anterior interosseous nerve palsies are rare, and other neuromuscular disorders may present with a similar pattern of weakness. We describe 2 patients who initially presented for orthopedic evaluation for suspected anterior interosseous neuropathy and were subsequently diagnosed with inclusion body myositis, an uncommon inflammatory myopathy affecting adults, with a predilection for finger and thumb flexor muscles. Electromyography, serologic and radiographic studies, and muscle biopsy can aid in diagnosis and help to distinguish inclusion body myositis from an anterior interosseous neuropathy.

Ambulance-based assessment of NIH Stroke Scale with telemedicine: A feasibility pilot study.

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.

New antiepileptic drugs: focus on ezogabine, clobazam, and perampanel.

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.

Utility of minimum F-wave latencies compared with F-estimates and absolute reference values in S1 radiculopathies: are they still needed?

INTRODUCTION: The utility of F-waves in assessing radiculopathies is debated. The aim of this study is to determine the frequency of abnormal minimum tibial F-wave latencies compared to an F-estimate and an absolute reference value in patients with electromyography (EMG) confirmed S1 radiculopathies. METHODS: A retrospective review of F-waves in patients with an EMG-confirmed isolated S1 radiculopathy was performed. The minimum and mean latencies of 8 tibial F-waves were compared with the calculated F-estimate and to an absolute reference value, and the frequencies of abnormal responses were determined. RESULTS: Of the 50 patients with an S1 radiculopathy, 4% had prolongation of the minimum reproducible F-wave latency, and 8% had prolongation of the mean latency relative to the calculated F-estimate. CONCLUSIONS: The minimum and mean F-wave latencies are infrequently abnormal when compared with an estimated F-wave latency in S1 radiculopathies and are insensitive in the assessment of S1 nerve root injury.

Improving referring physicians' understanding of electromyography reports when qualifying radiculopathies: a need for standardized terminology.

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.

Blood transfusion is an important predictor of hospital mortality among patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND: Red blood cell (RBC) transfusion after aneurysmal subarachnoid hemorrhage (aSAH) has been associated with increased mortality but prior studies have not adequately adjusted for transfusion-indication bias. METHODS: This is a retrospective study of consecutive aSAH patients admitted to the intensive care units of two academic medical centers over a 7-year period. Data collection included demographics, World Federation of Neurosurgical Surgeons score (WFNS), modified Fisher score (mFisher), admission and nadir hemoglobin (Hb) level, vasospasm, cerebral infarction, acute lung injury, and hospital mortality. The association between RBC transfusion and mortality was evaluated using a multivariate logistic regression analysis using the propensity for RBC transfusion as a covariate. RESULTS: We identified 318 patients. The median age was 54 years (46, 65), and 204 (64 %) were females. Hospital mortality was 13 % (42/318). Seventy-two (23 %) patients were transfused. Predictors of transfusion were admit and nadir Hb levels (p < 0.001), age (p = 0.02), gender (0.008), WFNS score (p < 0.001), mFisher score (p = 0.009), surgical versus endovascular treatment (p < 0.001) and moderate to severe vasospasm (p = 0.025) were predictors of transfusion. After adjustment for probability of receiving RBC transfusion, APACHE IV and nadir Hb, transfusion remained independently associated with hospital mortality (OR 3.16, 95 % CI = 1.02-9.69, p = 0.047). CONCLUSIONS: Among patients with aSAH, RBC transfusion was independently associated with an increased mortality after adjustment for the most common clinical indications for transfusion.