Faculty Bibliography

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) not only differ for the time of onset of cognitive deficits but also present variability in affected functions which are relevant in understanding underlying pathology. Cognitive performance of two global cognitive screening scales, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), as well as of a neuropsychological test battery, was evaluated in 18 DLB and 21 PDD patients. Feasibility for each cognitive test was investigated. Both MMSE and MoCA are feasible assessments in PDD and DLB patients. MoCA was more sensitive in discriminating groups as higher number of DLB patients showed pathological performances on the Digit Span Forward subitem (p = 0.049). The Stroop test in PDD and the Trail Making Tests-A and B, and the Benton's judgment of line orientation tests in both groups were considered not feasible. Among feasible cognitive tests in at least one group, Rey-Osterrieth complex figure test copy (p = 0.013) and semantic fluency (p = 0.038) are sensitive in discriminating DLB from PDD cognitive profile. Trail Making Tests-A and B, the Benton's judgment of line orientation and the Stroop tests are not feasible for assessing patients with frank dementia. Longitudinal studies should not include those tasks to reduce the risk of missing data once disease progresses and dementia develops. DLB patients present more severe and widespread cognitive dysfunction than PDD, particularly in attentive, visuospatial, and language domains.

Non-steroidal anti-inflammatory drugs (NSAIDs), commonly known as COX-1/COX-2 inhibitors, can be effective in treating mild to moderate migraine headache. However, the mechanism by which these drugs act in migraine is not known, nor is the specific contribution of COX-1 versus COX-2 known. We sought to investigate these unknowns using celecoxib, which selectively inhibits the enzymatic activity of COX-2, by determining its effects on several migraine-associated vascular and inflammatory events. Using in vivo two-photon microscopy, we determined intraperitoneal celecoxib effects on CSD-induced blood vessel responses, plasma protein extravasation, and immune cell activation in the dura and pia of mice and rats. Compared to vehicle (control group), celecoxib reduced significantly CSD-induced dilatation of dural arteries and activation of dural and pial macrophages but not dilatation or constriction of pial arteries and veins, or the occurrence of plasma protein extravasation. Collectively, these findings suggest that a mechanism by which celecoxib-mediated COX-2 inhibition might ease the intensity of migraine headache and potentially terminate an attack is by attenuating dural macrophages activation and arterial dilatation outside the blood brain barrier (BBB), and pial macrophages activation inside the BBB.

OBJECTIVE:There has been a rise in urgent care centers throughout the country over the past 10 years, leading to an increase in patients accessing medical care in these locations. These centers advertise an alternative to the Emergency Department (ED) for the evaluation and treatment of urgent medical conditions. The goal of this analysis was to examine the use of urgent care visits for migraine within 2 urgent care centers within a large academic medical system in New York City. We examined the trends in management and treatment of migraine in these urgent care settings, as well as prescriptions and instructions given to this patient population upon discharge. We paid particular attention to whether the medications administered and prescribed on discharge were those recommended by American Headache Society migraine management guidelines. METHODS:We conducted a retrospective chart review of patients with migraine diagnoses at 2 different urgent care locations within 1 large urban medical center. We determined baseline patient demographics, previous migraine characteristics, frequencies of reasons for urgent care visits as well as various medications administered, medications prescribed on discharge, and characteristics of patient outcomes post-discharge. RESULTS:Of the 78 patients who visited urgent care with a migraine diagnosis, 20 (25.6%) had a known primary care provider within the urgent care centers' healthcare system. More than three-fourths of all patients (78.2%) had a self-reported history of either recurrent headache or migraine prior to the urgent care visit. Of those with a documented frequency of prior headaches, 94.1% (32/34) had episodic migraine and 79.4% (27/34) experienced at most 1-2 headache days per month. Of those presenting to the urgent care during an episode of migraine, 12.3% (9/73) were given intravenous metoclopramide and none were given subcutaneous sumatriptan or intravenous prochlorperazine. Of those with reported nausea or vomiting with their migraine, 46.2% (18/39) received an anti-emetic at the visit and 33.3% (13/39) were given an anti-emetic prescription. Only 11.1% (6/54) of patients who did not have a record of previous triptan use were given a triptan prescription at the urgent care visit. CONCLUSIONS:The majority of patients in our study who sought medical treatment for migraine in these 2 urgent care centers were not established patients within the urgent care centers' healthcare system. While 93.6% (73/78) of patients were experiencing current pain upon presentation to the urgent care centers, only 12.3% (9/73) received administration of the medications with the highest level of evidence by the American Headache Society (Level B) for acute migraine treatment in an ED. In addition, the majority of patients with a migraine history presenting to the urgent care setting were not given triptans or anti-emetic prescriptions upon discharge from their urgent care visit. Having these migraine-specific prescriptions may improve self-treatment at home should a migraine attack recur.

OBJECTIVE:To assay EEG signal quality recorded with tripolar concentric ring electrodes (TCREs) compared to regular EEG electrodes. METHODS:EEG segments were recorded simultaneously by TCREs and regular electrodes, low-pass filtered at 35 Hz (REG35) and 70 Hz (REG70). Clips were rated blindly by nine electroencephalographers for presence or absence of key EEG features, relative to the "gold-standard" of the clinical report. RESULTS:TCRE showed less EMG artifact (F = 15.4, p < 0.0001). Overall quality rankings were not significantly different. Focal slowing was better detected by TCRE and spikes were better detected by regular electrodes. Seizures (n = 85) were detected by TCRE in 64 cases (75.3%), by REG70 in 75 (88.2%) and REG35 in 69 (81.2%) electrodes. TCRE detected 9 (10.6%) seizures not detected by one of the other 2 methods. In contrast, 14 seizures (16.5%) were not detected by TCRE, but were by REG35 electrodes. Each electrode detected interictal spikes when the other did not. CONCLUSIONS:TCRE produced similar overall quality and confidence ratings versus regular electrodes, but less muscle artifact. TCRE recordings detected seizures in 7% of instances where regular electrodes did not. SIGNIFICANCE/CONCLUSIONS:The combination of the two types increased detection of epileptiform events compared to either alone.

De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father's sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.

Background and Purpose/UNASSIGNED:The ideal dosing regimen of 4-factor prothrombin complex concentrate (4FPCC) after warfarin-induced intracranial hemorrhage (WICH) remains unclear. We sought to compare the safety and efficacy of the 4FPCC package insert dosing strategy (standard dose [SD]) with our institutional guideline for high-dose (HD) 4FPCC for patients with WICH. Methods/UNASSIGNED:We compared the percentage of SD and HD patients who achieved an international normalized ratio (INR) ≤1.3 at a single institution between January 2014 and July 2017. Additionally, we assessed hematoma expansion, recurrence of INR > 1.3, and occurrence of thrombotic events within 7 days of 4FPCC administration. Results/UNASSIGNED:= .243). Conclusions/UNASSIGNED:High-dose 4FPCC appears to be more effective at lowering INR and preventing bleed expansion in patients with WICH, while maintaining a similar safety profile.

BACKGROUND:Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome. METHODS:In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. FINDINGS/RESULTS:Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7-72·8, p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2-52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. INTERPRETATION/CONCLUSIONS:In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. FUNDING/BACKGROUND:Zogenix.

In health and disease, the somatosensory system has been interrogated with standardized research techniques, collectively referred to as quantitative sensory testing (QST). In neuropathic pain, QST has been used to characterize multiple sensory derangements. However, the use of QST outside the lab has been limited by several factors, including a lack of standardization, variability in procedural technique, and duration of testing that would be unacceptable for clinic. To address these shortcomings, the Neuropathic Pain Research Consortium (NPRC) designed an easy and low-cost "bedside" QST procedure. To test the hypothesis that this procedure would be clinically reliable over time and across different examiners, a multi-site, blinded study was performed in subjects with postherpetic neuralgia. Generally, agreement between two examiners and over two study visits with one examiner was high. Additionally, intraclass correlation coefficients and Kappa statistics calculated showed that the battery of QST tests included were highly reliable. Interestingly, mechanical modalities (light brush, pinprick, pressure, and vibration) showed the highest reliability. The least reliable modalities were cool (room temperature) and warmth (38°C). These data demonstrate that the NPRC beside QST protocol is reliable across examiner and over time, providing a validated QST tool for use in clinical practice and clinical trials. Perspective: This blinded, multi-center trial in 32 patients with postherpetic neuralgia demonstrates bedside quantitative sensory testing is reliable and suitable as a clinical trial outcome. The novel bedside battery could be used in clinical trials or in clinical practice over time given the reliability data presented in this article.