Faculty Bibliography

Central retinal artery occlusion (CRAO) is a form of acute ischemic stroke which affects the retina. Intravenous thrombolysis is emerging as a compelling therapeutic approach. However, it is not known which patients may benefit from this therapy because there are no imaging modalities that adequately distinguish viable retina from irreversibly infarcted retina. The inner retina receives arterial supply from the central retinal artery and there is robust collateralization between this circulation and the outer retinal circulation, provided by the posterior ciliary circulation. Fundus photography can show canonical changes associated with CRAO including a cherry-red spot, arteriolar boxcarring and retinal pallor. Fluorescein angiography provides 2-dimensional imaging of the retinal circulation and can distinguish a complete from a partial CRAO as well as central versus peripheral retinal non-perfusion. Transorbital ultrasonography may assay flow through the central retinal artery and is useful in the exclusion of other orbital pathology that can mimic CRAO. Optical coherence tomography provides structural information on the different layers of the retina and exploratory work has described its utility in determining the time since onset of ischemia. Two experimental techniques are discussed. 1) Retinal functional imaging permits generation of capillary perfusion maps and can assay retinal oxygenation and blood flow velocity. 2) Photoacoustic imaging combines the principles of optical excitation and ultrasonic detection and - in animal studies - has been used to determine the retinal oxygen metabolic rate. Future techniques to determine retinal viability in clinical practice will require rapid, easily used, and reproducible methods that can be deployed in the emergency setting.

BACKGROUND:Little is known regarding long-term outcomes of patients hospitalized with COVID-19. METHODS:We conducted a prospective study of 6-month outcomes of hospitalized COVID-19 patients. Patients with new neurological complications during hospitalization who survived were propensity score-matched to COVID-19 survivors without neurological complications hospitalized during the same period. The primary 6-month outcome was multivariable ordinal analysis of the modified Rankin Scale(mRS) comparing patients with or without neurological complications. Secondary outcomes included: activities of daily living (ADLs;Barthel Index), telephone Montreal Cognitive Assessment and Neuro-QoL batteries for anxiety, depression, fatigue and sleep. RESULTS:Of 606 COVID-19 patients with neurological complications, 395 survived hospitalization and were matched to 395 controls; N = 196 neurological patients and N = 186 controls completed follow-up. Overall, 346/382 (91%) patients had at least one abnormal outcome: 56% had limited ADLs, 50% impaired cognition, 47% could not return to work and 62% scored worse than average on ≥1 Neuro-QoL scale (worse anxiety 46%, sleep 38%, fatigue 36%, and depression 25%). In multivariable analysis, patients with neurological complications had worse 6-month mRS (median 4 vs. 3 among controls, adjusted OR 1.98, 95%CI 1.23-3.48, P = 0.02), worse ADLs (aOR 0.38, 95%CI 0.29-0.74, P = 0.01) and were less likely to return to work than controls (41% versus 64%, P = 0.04). Cognitive and Neuro-QOL metrics were similar between groups. CONCLUSIONS:Abnormalities in functional outcomes, ADLs, anxiety, depression and sleep occurred in over 90% of patients 6-months after hospitalization for COVID-19. In multivariable analysis, patients with neurological complications during index hospitalization had significantly worse 6-month functional outcomes than those without.

OBJECTIVE:To determine the long-term safety and tolerability profile of M207 in the acute treatment of migraine. BACKGROUND:M207 is an investigational microneedle-based system for intracutaneous delivery of zolmitriptan for the treatment of migraine attacks. Following on the positive results of a Phase 2/3 placebo-controlled efficacy study (ZOTRIP), this study was designed to evaluate the safety of this novel product during repeated use for the treatment of migraine attacks. METHODS:In this 6-12 month open-label, multicenter observational study, participants used an eDiary to record headache symptoms and adverse events at specified intervals up to 48 h following treatment of a qualifying attack with M207 3.8 mg (intracutaneous zolmitriptan). Participants underwent clinical evaluations at specified intervals up to 12 months. RESULTS:Among 335 participants who treated ≥1 migraine attack, 257 completed 6 months and 127 completed 1 year of treatment. The most common reason for withdrawal from the study was a low frequency of reported attacks post randomization. Overall, 5963 migraine attacks were treated. Most participants (96%) experienced at least 1 adverse event, the vast majority of which concerned the application site, and > 95% of which were mild. Fifteen participants (4%) withdrew due to adverse events; 4 withdrew due to 7 application site reactions, 6 of which were mild. Participants achieved pain freedom in 2477/5617 (44%) of attacks, most bothersome symptom freedom in 3315/5330 (62%) of attacks, and pain relief 2 h post-dose in 4552/5617 (81%) of attacks. Sustained pain freedom 2-24 h was seen in 1761/4698 (38%) of attacks, and 2-48 h in 1534/4429 (35%) of attacks. CONCLUSIONS:The majority of participants experienced cutaneous adverse reactions such as application site erythema, swelling, and bleeding, and most reactions were scored as mild. These results are consistent with what was observed in the single migraine attack treatment ZOTRIP trial indicating that M207 is well tolerated in the setting of longer-term repeated use. Efficacy findings were also similar to those in the ZOTRIP trial. TRIAL REGISTRATION/BACKGROUND:Clinicaltrials.gov on September 13, 2017 ( NCT03282227 ).

Background/UNASSIGNED:Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with a prevalence of 1:3000 births and a wide variety of clinical manifestations. Cutaneous neurofibromas (cNF) are among the most common visible manifestations of NF1 and present a major clinical burden for patients. NF1 patients with cNF often report decreased quality of life, emotional well-being and physical comfort. Developing effective medical therapies for cNF has been identified as a priority for the majority of adults with NF1. Methods/UNASSIGNED:The study was an open, controlled and prospective proof-of-concept clinical trial. The topical treatment consisted of two steps: cNF microporation using a laser device followed by topical application of one drop of diclofenac 25 mg/mL on the surface of the cNF (T neurofibroma = treatment) or physiological saline (C neurofibroma = control) and reapplied twice daily for 3 days. Neurofibroma assessments included visual and dermatoscopy observations noting color and presence of necrosis, presence of flaccidity, measurements in two dimensions, photographs, and histopathology after excision. The primary efficacy variable was the presence of tissue necrosis. The primary safety variable was the occurrence of treatment-related adverse events. Results/UNASSIGNED:Six patients were included in the study. The treatment resulted in transitory topical changes (healing of the microporation grid with formation of scintillating tissue layer, hyperemia and desquamation), with no statistically significant variation in the dimensions of the T and C neurofibromas in relation to pretreatment measurements. There was no necrosis in the T or C neurofibromas. In the histopathological analysis, there was no significant difference in the distribution of chronic (lymphocytic) inflammatory infiltrate in the papillary reticular dermis (subepithelial), type of infiltrate (diffuse, perivascular, or both), presence of fibrosis, and presence of atrophy among the T and C neurofibromas. No adverse events attributable to the use of diclofenac were reported during the treatment period. Conclusions/UNASSIGNED:Treatment did not result in significant alterations in terms of presence of tissue necrosis, size, or histopathological features in the T neurofibromas or in comparison to the C neurofibromas. Topical diclofenac with laser microporation was well-tolerated, with no adverse events attributable to diclofenac reported. Whether these observations are due to minimal systemic and neurofibroma exposure remain to be explored in dosage studies with larger patient groups. Trial registration/UNASSIGNED:ClinicalTrials.gov (NCT03090971) retrospectively registered March 27, 2017.

Peripheral neuropathy is one of the most prevalent neurologic conditions encountered by neurologists and nonneurologists. Geriatricians and primary care physicians often face the task of screening patients for early neuropathy when they have underlying conditions such as diabetes mellitus and evaluating patients who report new symptoms that suggest neuropathy. An understanding about different forms of neuropathies based on anatomic pattern and type of nerve fiber involvement and ability to perform basic neurologic examination reliably can help determine how to pursue further investigations and identify those patients who are likely to benefit from early specialist referral.

BACKGROUND:Neurologists need to be adept at disclosing prognosis and breaking bad news. Objective structured clinical examinations (OSCE) allow trainees to practice these skills. METHODS:In 2017, in conjunction with the NYU School of Medicine Simulation Center, neurology faculty designed an OSCE case in which a resident had to inform a standardized patient (SP) her father had severe global hypoxic ischemic injury. The residents were surveyed on the experience using a Likert scale from 1 (worst) to 5 (best). The SP completed a behavioral anchored checklist and marked items as "not done," "partly done," or "well done". RESULTS:57 third and fourth year neurology residents completed the case from 2018 to 2020, 54 (95%) of whom completed the post-OSCE survey. Residents reported feeling moderately prepared for the simulation (mean Likert score 3.7/5), and thought their performance was average (3.4/5). Overall, they found the case to be very helpful (4.6/5). The residents performed well in the realms of maintaining professionalism (64% rated "well done"), developing a relationship (62% rated "well done"), and information gathering (61% rated "well done"). There was room for improvement in the realms of providing education and presenting the bad news (39% and 37% rated "partly/not done," respectively). CONCLUSIONS:OSCE cases can be used to teach neurology trainees how to discuss prognosis and break bad news. Feedback about this simulation was positive, though its efficacy has yet to be evaluated and could be a future direction of study.

OBJECTIVE:To evaluate the safety, tolerability, and pharmacokinetics of soticlestat, a first-in-class cholesterol 24-hydroxylase inhibitor, in adults with developmental and/or epileptic encephalopathies (DEE). METHODS:The study comprised a 30-day, randomized, double-blind, placebo-controlled phase (Part A), followed by a 55-day open-label phase (Part B) (ClinicalTrials.gov ID: NCT03166215) . In Part A, patients with DEE and at least one bilateral motor seizure during the 4-week prospective baseline period were randomized 4:1 to receive soticlestat or placebo, in addition to their usual antiseizure medication. In Part B, all patients received open-label soticlestat. Soticlestat doses were titrated according to tolerability to a maximum of 300 mg twice daily (BID). Safety evaluations included the incidence of treatment-emergent adverse events (TEAEs). Plasma soticlestat concentrations were measured at various times for determination of multiple-dose pharmacokinetics and 24S-hydroxycholesterol (24HC). Efficacy was assessed by evaluation of changes in seizure frequency from baseline. RESULTS:Eighteen patients (median age, 28.5 years) were enrolled and randomized, and 14 (78 %) completed the study. In Part A, TEAEs occurred in 71.4 % of soticlestat-treated patients and 100 % of placebo-treated patients. In Part B, the overall incidence of TEAEs was 68.8 %. In Part A, TEAEs that occurred in more than one patient in the soticlestat group were dysarthria (n = 3, 21.4 %), lethargy (n = 2, 14.3 %), upper respiratory tract infection (n = 2, 14.3 %), fatigue (n = 2, 14.3 %), and headache (n = 2, 14.3 %). Four patients discontinued treatment because of TEAEs, of whom two reported drug-related seizure clusters as serious TEAEs. There were no deaths. Pharmacokinetic analysis showed dose-dependent increases in systemic exposure and peak plasma soticlestat concentrations. At the end of Part B, the overall mean percent change from baseline in plasma 24HC was -80.97 %. Changes from baseline in median seizure frequency were +16.71 % and +22.16 % in the soticlestat and placebo groups, respectively, in Part A, and -36.38 % in all participants in Part B. CONCLUSION/CONCLUSIONS:Soticlestat was well tolerated at doses of up to 300 mg BID and was associated with a reduction in median seizure frequency over the study duration. Further studies are warranted to assess the possible efficacy of soticlestat as adjunctive therapy in patients with DEEs such as Dravet syndrome and Lennox-Gastaut syndrome.

Individual differences in perception are widespread. Considering inter-individual variability, synesthetes experience stable additional sensations; schizophrenia patients suffer perceptual deficits in, eg, perceptual organization (alongside hallucinations and delusions). Is there a unifying principle explaining inter-individual variability in perception? There is good reason to believe perceptual experience results from inferential processes whereby sensory evidence is weighted by prior knowledge about the world. Perceptual variability may result from different precision weighting of sensory evidence and prior knowledge. We tested this hypothesis by comparing visibility thresholds in a perceptual hysteresis task across medicated schizophrenia patients (N = 20), synesthetes (N = 20), and controls (N = 26). Participants rated the subjective visibility of stimuli embedded in noise while we parametrically manipulated the availability of sensory evidence. Additionally, precise long-term priors in synesthetes were leveraged by presenting either synesthesia-inducing or neutral stimuli. Schizophrenia patients showed increased visibility thresholds, consistent with overreliance on sensory evidence. In contrast, synesthetes exhibited lowered thresholds exclusively for synesthesia-inducing stimuli suggesting high-precision long-term priors. Additionally, in both synesthetes and schizophrenia patients explicit, short-term priors-introduced during the hysteresis experiment-lowered thresholds but did not normalize perception. Our results imply that perceptual variability might result from differences in the precision afforded to prior beliefs and sensory evidence, respectively.

OBJECTIVE:Vinpocetine has been shown to enhance memory in animal models, with possible cognitive benefit in humans. The present study sought to demonstrate if vinpocetine can enhance cognition in healthy volunteers or patients with epilepsy. In addition, we compare blood levels of vinpocetine and its active metabolite (apovincaminic acid; AVA) in humans and animals to further characterize factors related to possible therapeutic benefit. METHODS:The cognitive effects of vinpocetine were assessed in healthy adult volunteers (n = 8) using a double-blind, randomized, crossover design at single doses (placebo, 10, 20, and 60 mg oral). Cognitive effects of vinpocetine in patients with focal epilepsy (n = 8) were tested using a double-blind, randomized, crossover design at single doses (placebo, 20 mg oral) followed by one-month open label at 20 mg oral three times a day. The neuropsychological battery included both computerized and non-computerized tests. Levels of vinpocetine and AVA in the human studies were compared to levels in 45 mice across time dosed at 5-20 mg/kg intraperitoneal of vinpocetine. RESULTS:No significant cognitive benefits were seen in healthy volunteers or patients with epilepsy. No appreciable side effects occurred. Vinpocetine and AVA levels were lower in humans than animals. CONCLUSIONS:Vinpocetine was well tolerated, but was not associated with positive cognitive effects. However, blood levels obtained in humans were substantially less than levels in animals obtained from dosages known to be effective in one model. This suggests that higher dosages are needed in humans to assess vinpocetine's cognitive efficacy.