Faculty Bibliography

Objective: The FOCUS study of fremanezumab, a fullyhumanised monoclonal antibody (IgG2DELTAa) that selectively targets calcitonin gene-related peptide (CGRP), was the first and largest study of a migraine preventive treatment in adults with both chronic and episodic migraine (CM and EM) and documented inadequate response to 2-4 classes of migraine preventive medications. Efficacy in a subgroup of patients with medication overuse (use of any acute medication on >=15 days/month or triptans/ergots/combination medications on >=10 days/month) at baseline (BL) was evaluated.
Method(s): Patients were randomised (1:1:1) to quarterly (qtly) fremanezumab (Month [Mo] 1: 675 mg; Mo 2 and 3: placebo), monthly (mthly) fremanezumab (Mo 1: CM, 675 mg; EM, 225 mg; Mo 2 and 3: 225 mg), or matched mthly placebo for 12 weeks. Changes from BL in mthly migraine days and headache days of at least moderate severity at 4 weeks and during 12 weeks of treatment were compared using a mixed-effect model for repeated measures.
Result(s): Of 838 randomised patients, 427 had medication overuse. Reductions from BL in mthly average migraine days and headache days of at least moderate severity at 4 weeks and during 12 weeks of treatment were significantly greater with both fremanezumab regimens vs placebo (all P<=0.0001; Table).
Conclusion(s): Qtly and mthly fremanezumab provided early and sustained reductions in migraine and headache days vs placebo in patients with medication overuse and documented inadequate response to 2-4 classes of migraine preventive medications. (Table Presented)

Objective: To investigate cognitive deficits in African Americans (AA) with MS.
Background(s): Cognitive impairment is one of the most frequent and burdensome symptoms of MS. Although a more severe disease course has been descibed in AA in comparison with Caucasians (CA) patients, an objective assessment of the cognitive profile of AA and potential differences with CA patients has not been investigated yet.
Method(s): Fifty-one AA patients (40F, mean age 38.45 +/- 11.13 yrs, mean disease duration 7.88 +/- 5.39 yrs), 37 AA healthy controls (HC) (25F, mean age 35.97 +/- 12.44 yrs), 43 CA patients (32F, mean age 39.00 +/- 10.56 yrs, mean disease duration 6.67 +/- 7.00 yrs) and 18 CA HC (12F, mean age 30.72 +/- 6.94 yrs) were prospectively enrolled as part of an ongoing longitudinal study. In all subjects, an extensive neuropsychological evaluation was performed, including: Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT), Brief Visuospatial Memory Test-Revised (BVMT), Stroop Color and Word Test (SCVT), Controlled Oral Word Association Test (COWAT), Pattern Comparison Processing Speed Test (PCPST) and a multitasking attention-memory test (MAMT). Each patient's group was compared with a race-matched HC group via ANCOVA analysis, accounting for age, gender, years of education, premorbid intelligence estimated with the Wechsler Test of Adult Reading (WTAR) and socioeconomic status expressed as yearly income.
Result(s): AA patients and HC did not differ in gender, age, years of education, WTAR score or socioeconomic status. CA patients and HC did not differ in gender, years of education and socioeconomic status, while significantly differ in age and WTAR scores (p=0.001 for both). Significant differences in SDMT (p=0.002), BVMT (p=0.012), COWAT (p=0.006), PCPST (p=0.008) and MAMT (p=0.018) scores were identified between AA patients and AA HC. Significant differences in SDMT (p=0.003), CVLT (p=0.009), BVMT (p=0.021), COWAT (p=0.003) and PCPST (p< 0.0001) scores were identified between CA patients and CA HC.
Conclusion(s): AA and CA patients showed similar deficits in information processing speed, attention, visuospatial memory and verbal fluency. CA patients showed additional impairment in the verbal memory domain, while AA patients showed deficits in multitasking capability. These results suggest that the cognitive profile of MS patients mostly overlaps across different races, although it seem to show group-specific deficits in specific domains

PURPOSE/OBJECTIVE:There is variability in survival within IDH mutant gliomas determined by chromosomal events. Copy number variation (CNV) abundance associated with survival in low-grade and IDH mutant astrocytoma has been reported. Our purpose was to correlate the extent of genome-wide CNV abundance in IDH mutant astrocytomas with MRI features. METHODS:Presurgical MRI and CNV plots derived from Illumina 850k EPIC DNA methylation arrays of 18 cases of WHO grade II-IV IDH mutant astrocytomas were reviewed. IDH mutant astrocytomas were divided into CNV stable group (CNV-S) with ≤ 3 chromosomal gains or losses and lack of focal gene amplifications and CNV unstable group (CNV-U) with > 3 large chromosomal gains/losses and/or focal amplifications. The associations between MR features, relative cerebral blood volume (rCBV), CNV abundance, and time to progression were assessed. Tumor rCBV estimates were obtained using DSC T2* perfusion analysis. RESULTS:There were nine (50%) CNV-S and nine (50%) CNV-U IDH mutant astrocytomas. CNV-U tumors showed larger mean tumor size (P = 0.004) and maximum diameter on FLAIR (P = 0.004) and also demonstrated significantly higher median rCBV than CNV-S tumors (2.62 vs 0.78, P = 0.019). CNV-U tumors tended to have shorter time to progression although without statistical significance (P = 0.393). CONCLUSIONS:Larger size/diameter and higher rCBVs were seen associated CNV-U astrocytomas, suggesting a correlation of aggressive imaging phenotype with unstable and aggressive genotype in IDH mutant astrocytomas.

BACKGROUND:Vagal schwannomas are rare, benign tumors of the head and neck. Nerve damage during surgical resection is associated with significant morbidity. A new technique of continuous intraoperative nerve monitoring (IONM) that allows for real-time intraoperative feedback has recently been used for thyroid and cervical spine surgeries but has not previously been used in vagal schwannoma surgery. METHODS:Case series of three patients who underwent vagal schwannoma excision utilizing this novel IONM technique. The recurrent laryngeal and vagus nerves were monitored via the laryngeal adductor reflex (LAR) using an electromyographic endotracheal tube. RESULTS:Three patients with suspected vagal schwannomas were treated surgically using the intracapsular enucleation approach with a combination of intermittent IONM and continuous IONM of the LAR. CONCLUSION/CONCLUSIONS:This combination of continuous and intermittent IONM can be used to preserve vagal laryngeal innervation and function and may represent the future standard of care for vagal schwannoma excision.

Leigh syndrome and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) are two of the most frequent pediatric mitochondrial diseases. Both cause severe morbidity and neither have effective treatment. Inhibiting the mammalian target of rapamycin (mTOR) pathway has been shown in model mice of Leigh syndrome to extend lifespan and attenuate both the clinical and pathological progression of disease. Based on this observation, we treated two children with everolimus, a rapamycin analogue. The child with Leigh syndrome showed sustained benefit, while the child with MELAS failed to respond and died of progressive disease. We discuss possible mechanisms underlying these disparate responses to mTOR inhibition.

BACKGROUND:Autonomic dysfunction is a hallmark feature of hereditary ATTR amyloidosis. The aim of this study was to summarize the characteristics and natural history of autonomic dysfunction in patients with hereditary ATTR amyloidosis. METHODS:A systematic review of the natural history and clinical trials of patients with ATTR amyloidosis was performed. Alternative surrogate markers of autonomic function were analyzed to understand the prevalence and outcome of autonomic dysfunction. RESULTS:Patients with early-onset disease displayed autonomic dysfunction more distinctively than those with late-onset disease. The nutritional status and some autonomic items in the quality-of-life questionnaires were used to assess the indirect progression of autonomic dysfunction in most studies. Gastrointestinal symptoms and orthostatic hypotension were resent earlier than urogenital complications. Once symptoms were present, their evolution was equivalent to the progression of the motor and sensory neuropathy impairment. CONCLUSION:The development of autonomic dysfunction impacts morbidity, disease progression, and mortality in patients with hereditary ATTR amyloidosis.

OBJECTIVE:The objective of the study was to compare the performance of intravenous (IV) lorazepam (IVL) and intranasal midazolam (INM) for seizure termination and prevention of seizure clusters in adults admitted to the epilepsy monitoring unit (EMU) in whom seizures were captured on continuous video-electroencephalogram. METHODS:Retrospective cohort of consecutive adults (≥18 years) with epilepsy admitted to the EMU at a single tertiary academic center, who experienced epileptic seizures (confirmed electroencephalographically) and required rescue therapy. The study spanned from January 2015 until December 2016, which included one year before and one year after transitioning from IVL to INM as the standard rescue therapy at our institution. RESULTS:A total of 50 subjects received rescue therapy and were included in the analysis. In the first year, out of 216 patients with epilepsy admitted to the EMU, 27 (13%) received IVL; in the second year, 23/217 (11%) received INM. There were no differences in baseline characteristics and markers of epilepsy severity, the median duration of index seizure (1.7 min [interquartile range (IQR): 1.1-2.7] in IVL vs. 2.0 min [IQR: 1.5-2.6] in INM group, p = 0.20), or in the number of subjects requiring repeat benzodiazepine administrations (IVL 8/27 [29.6%] vs. INM 7/23 [30.4%], p = 0.95). There were no differences in the median number of recurrent seizures in 24 h (1 [IQR: 1-3] in IVL vs. 2 [IQR: 1-4] in INM, p = 0.27), occurrence of status epilepticus (IVL 4/27 [14.8%] subjects vs. INM 1/23 [4.3%] subjects, p = 0.36), incidence of seizure clusters (IVL 8/27 [29.6%] subjects vs. INM 7/23 [30.4%] subjects, p = 0.95), need for transfer to an intensive care unit (ICU), or other adverse events. SIGNIFICANCE:In our retrospective study, INM was comparable with IVL for seizure termination and prevention of seizure clusters in the adult EMU. Intranasal midazolam circumvents the need for IV access to be maintained throughout hospitalization and is an attractive alternative to IVL as a rescue therapy in this setting. Ideally, future large, prospective, randomized, and double blind studies are needed to confirm these findings.

Cognitive science research on learning and instruction is often not directly connected to discipline-based research. In an effort to narrow this gap, this essay integrates research from both fields on five learning and instruction strategies: active retrieval, distributed (spaced) learning, dual coding, concrete examples, and feedback and assessment. These strategies can significantly enhance the effectiveness of science instruction, but they typically do not find their way into the undergraduate classroom. The implementation of these strategies is illustrated through an undergraduate science course for nonmajors called Science in Our Lives. This course provides students with opportunities to use scientific information to solve real-world problems and view science as part of everyday life.

Introduction: A model of individual response to therapy based on demographic and clinical information ('The MSBase model'; Brain. 2017, 140:2426) improves clinicians' ability to predict how individual patient will fare on specific disease-modifying therapy (DMT) during a 4-year follow up period. However, the range of predicted outcomes is often too wide to make it the arbiter of decision- making. MS severity score (MSSS), a decile rank of Extended Disability Severity Scale (EDSS) scores in patients from the reference dataset, was shown to be longitudinally stable in MS cohorts, but not for individual patients.
Objective(s): To test whether the addition of MSSS will improve the accuracy and robustness of the existing MSBase predictive model.
Method(s): All eligible patients from the global MSBase cohort who commenced a new DMT during the prospectively recorded follow-up were included. For each DMT, Andersen-Gill survival models were constructed for confirmed disability and relapse events. Principal component analysis was used to reduce dimensionality of the models, as previously described. MSSS was added to these models separate from the principal components.
Result(s): Among 13,780 MSBase enrollees (72% female; 86% with Relapsing MS; age 38.4 [10.6] years, disease duration 8.49 [7.73] years, EDSS 2.65 [1.80]), the most common DMTs were Interferon (IFN)b-1a sc (18%), IFNb-1b sc (12%) and Glatiramer acetate (11%). Higher MSSS was associated with an increased chance of 6-month confirmed recovery from disability (Hazard ratio (HR) 1.17-1.64 p< 0.003; no evidence of association only for alemtuzumab) and with relapse risk (HR 1.03-1.18 p< 0.04, and non-significant for 3 DMTs), but did not predict risk of confirmed disability progression for any DMT. The amount of variance that MSSS helped to explain in addition to the original MSBase model was modest, largest for disability regression (partial adjusted R2 0.01-0.05) and less substantial for risk of relapses (partial adjusted R2 - 0.001-0.026).
Conclusion(s): Mostly independent of DMT identity, higher MSSS was positively associated with a chance of confirmed disability regression, and relapse risk, but not disability worsening. Addition of MSSS to the MSBase model yielded improvements in its predictive accuracy, especially with regard to disability regression and relapse risk. MSSS adds to the prediction of recovery from disability and relapse activity but is not a suitable indicator of individual treatment response