Faculty Bibliography

OBJECTIVES/OBJECTIVE:To report a case of isolated third nerve palsy from pituitary apoplexy and perform a systematic literature review. MATERIALS AND METHODS/METHODS:MEDLINE/EMBASE databases were searched up to September 2020. INCLUSION CRITERIA/METHODS:Age≥18, isolated third nerve palsy from pituitary apoplexy. EXCLUSION CRITERIA/METHODS:Age<18, presence of other neurological findings, no hemorrhage or infarction of pituitary. RESULTS:Case report: A 76-year-old woman presented with headache and right-sided ptosis. Right-eye exam revealed complete ptosis, absent pupillary constriction and accommodation, depressed and abducted eye on primary gaze, and -1 impaired depression, adduction, elevation, without other neurological findings. Brain MRI was suggestive of pituitary apoplexy. Pathology after transsphenoidal resection revealed an infarcted pituitary adenoma. Third nerve palsy resolved completely in 21 days. Systematic review: Twenty-three studies reporting 35 patients were selected from 182 abstracts. Twenty-nine (83%) had complete isolated third nerve palsy. Headache was reported in 31 (97%). Thirty-one had hemorrhage and 1 had infarction of pituitary. Cavernous sinus invasion occurred in 14 (50%). Twenty-eight were managed surgically (80%) and 7 medically (20%). Nerve palsy resolved completely in 27 (82%) and partially in 4 (11%). CONCLUSIONS:Pituitary apoplexy is an important differential diagnosis in patients with isolated third nerve palsy. Isolated third nerve palsy in apoplexy appears to have favorable prognosis.

A yellow bacterial strain, designated LRZ-2^T, was isolated from High Arctic tundra near the settlement Ny-Ålesund in the Svalbard Archipelago, Norway. The cells were Gram-stain-positive, aerobic and non-sporulating. Phylogenetic analysis based on 16S rRNA gene sequence comparisons revealed that strain LRZ-2^T represented a novel member of the suborder Micrococcineae. Its nearest phylogenetic neighbours were the members of the genus Luteimicrobium, with 16S rRNA gene sequence similarity of 95.3-96.9 %. The average nucleotide identity and digital DNA-DNA hybridization values between the genomes of strain LRZ-2^T and its closely related strains were 77.4-74.3 % and 21.4-19.6 %, respectively. The DNA G+C content was 72.4 mol%. The peptidoglycan type of the isolate was A4β with an interpeptide bridge comprising l-ornithine and d-glutamic acid. The predominant menaquinone was MK-9 (H₄) and the major fatty acids were anteiso-C_15 : 0, C_16 : 0, anteiso-C_15 : 1 A, anteiso-C_17 : 0 and iso-C_15 : 0. The polar lipids were diphosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside, phosphatidylinositol dimannoside, unidentified phosphoglycolipid, four unidentified phospholipids and two unidentified polar lipids. Strain LRZ-2^T showed a 16S rRNA gene signature pattern consisting of nucleotides at positions 120 (A), 131-231 (C-G), 196 (C), 342-347 (C-G), 444-490 (A-U), 580-761 (C-G), 602-636 (C-G), 670-736 (A-U), 822-878 (G-C), 823-877 (G-C), 826-874 (C-G), 827 (U), 843 (C), 950-1231 (U-A), 1047-1210 (G-C), 1109 (C), 1145 (G), 1309-1328 (G-C), 1361 (G) and 1383 (C), which clearly distinguished it from all genera previously reported in the suborder Micrococcineae. On the basis of the phylogenetic, phenotypic and chemotaxonomic data, strain LRZ-2^T is considered to represent a novel species of a new genus, for which the name Pengzhenrongella sicca gen. nov., sp. nov. is proposed. The type strain of Pengzhenrongella sicca is LRZ-2^T (=CCTCC AB 2012163^T=DSM 100332^T).

Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of NF2 patients with vestibular schwannoma (VS). To assess the pharmacokinetics, pharmacodynamics and potential mechanisms of treatment resistance, we performed a pre-surgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for VS or meningiomas. Eligible patients with meningioma or VS requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately prior to and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and post-operative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/ml and 9.4 ng/ml, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared to control tissues from untreated patients (p=0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited anti-tumor effect of everolimus observed in clinical studies for NF2 patients and will inform the design of future pre-clinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.

BACKGROUND AND PURPOSE/OBJECTIVE:We reviewed the literature to evaluate cerebrospinal fluid (CSF) results from patients with coronavirus disease 2019 (COVID-19) who had neurological symptoms and had an MRI that showed (1) central nervous system (CNS) hyperintense lesions not attributed to ischemia and/or (2) leptomeningeal enhancement. We sought to determine if these findings were associated with a positive CSF severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR). METHODS:We performed a systematic review of Medline and Embase from December 1, 2019 to November 18, 2020. CSF results were evaluated based on the presence/absence of (1) ≥ 1 CNS hyperintense lesion and (2) leptomeningeal enhancement. RESULTS:In 117 publications, we identified 193 patients with COVID-19 who had an MRI of the CNS and CSF testing. There were 125 (65%) patients with CNS hyperintense lesions. Patients with CNS hyperintense lesions were significantly more likely to have a positive CSF SARS-CoV-2 PCR (10% [9/87] vs. 0% [0/43], p = 0.029). Of 75 patients who had a contrast MRI, there were 20 (27%) patients who had leptomeningeal enhancement. Patients with leptomeningeal enhancement were significantly more likely to have a positive CSF SARS-CoV-2 PCR (25% [4/16] vs. 5% [2/42], p = 0.024). CONCLUSION/CONCLUSIONS:The presence of CNS hyperintense lesions or leptomeningeal enhancement on neuroimaging from patients with COVID-19 is associated with increased likelihood of a positive CSF SARS-CoV-2 PCR. However, a positive CSF SARS-CoV-2 PCR is uncommon in patients with these neuroimaging findings, suggesting they are often related to other etiologies, such as inflammation, hypoxia, or ischemia.

A sound performance validity test is accurate for detecting invalid neuropsychological test performance and relatively insensitive to actual cognitive ability or impairment. This study explored the relationship of several cognitive abilities to several performance indices on the Victoria Symptom Validity Test (VSVT), including accuracy and response latency. This cross-sectional study examined data from a mixed clinical sample of 88 adults identified as having valid neurocognitive test profiles via independent validity measures, and who completed the VSVT along with objective measures of working memory, processing speed, and verbal memory during their clinical neuropsychological evaluation. Results of linear regression analyses indicated that cognitive test performance accounted for 5% to 14% of total variance for VSVT performance across indices. Working memory was the only cognitive ability to predict significant, albeit minimal, variance on the VSVT response accuracy indices. Results show that VSVT performance is minimally predicted by working memory, processing speed, or delayed verbal memory recall.

Background/Purpose: Interferon (IFN)-alpha contributes to susceptibility and severe manifestations in systemic lupus erythematosus (SLE). The PRKG1 rs7897633 variant has been previously identified as the top hit in European ancestry patients with SLE and high IFN-alpha compared to those with low circulating IFN activity. However, the mechanisms by which PRKG1 polymorphisms impact the immune system remain unknown. PRKG1 codes for the cGMP-dependent protein kinase I (PKGI). Activation of PKGI leads to VASP phosphorylation, and the inhibition of RhoA and Rho-associated kinases (ROCK). A subgroup of patients with SLE exhibit higher ROCK activity in circulating immune cells compared to healthy controls. ROCK inhibition decreases IFN-alpha production and ameliorates disease in murine models of lupus. Accordingly, we aimed to assess whether the PRKG1 gene variant was associated with decreased gene expression and activity of PRKG1, hyperactivation of the ROCK pathway, and altered response to type I IFN.
Method(s): We used B lymphoblastoid cell lines (LCL) derived from healthy subjects of European ancestry (Coriell repositories) homozygous (AA or CC) and heterozygous (AC) at the rs7897633 SNP for all experiments. Gene expression of PRKG1, RHOA, and ROCK was assessed by RT-qPCR using gene-specific primers, normalized by GAPDH, and measured by the 2-DELTADELTACT method. IFN score at baseline and after treatment of LCL with increasing doses of IFN-alpha was measured by quantifying 3 canonical IFN-stimulated genes (IFIT1, MX1 and PKR) and summing to generate a score reflecting the degree of IFN-induced gene expression in the cells. Abundance of PKGI and VASP phosphorylation (as a surrogate of PKGI activity) were determined by Western blotting at baseline and after treatment with a PKGI agonist. ROCK2 enzymatic activity was performed by a colorimetric assay (Cell Biolabs). Unstimulated and stimulated cells were compared among PRKG1 genotype categories. Statistically significant differences were determined by Mann Whitney U test or sum-of-squares F test, as appropriate.
Result(s): PRKG1 expression was lower in the homozygous AA genotype as compared with the homozygous CC genotype in LCL (p< 0.05). In contrast, ROCK expression was higher in LCL with the AA rs7897633 genotype (p< 0.05). Compared to LCL with the homozygous AA variant of rs7897633, homozygous CC LCL have greater abundance of PKGI, phosphorylated VASP/total VASP ratio in response to a PKGI agonist (indicating increased PKGI activity), and lower baseline ROCK activity (sum-of-squares F test, p< 0.05). The IFN score was significantly higher in the homozygous CC allele LCL, both at baseline and with increasing doses of IFN-alpha, suggesting increased sensitivity to type I IFN (p< 0.05).
Conclusion(s): PRKG1 AA genotype associates with lower PRKG1 and higher ROCK mRNA expression, decreased PKGI abundance and activity, and greater ROCK baseline activity. In contrast, the rs7897633 CC genotype is associated with increased response to IFNalpha. Overall, these findings suggest an important role of genetic variation at PRKG1 in modulating the RhoA-ROCK pathway and regulating response to type I IFNs in LCL, which may have therapeutic implications in patients with SLE

There are racial and socioeconomic disparities in the care of patients with Parkinson's disease (PD). Bellevue Hospital Center (BHC) in New York City is the oldest public hospital in the United States providing care to a multiracial, socioeconomically diverse and medically underserved population. We investigated racial and social disparities in providing care to patients with PD and related disorders at BHC compared to a NYU Langone Health, a Parkinson's Foundation Center of Excellence. Retrospective chart review of patients with diagnosis of PD or PD-related disorders evaluated at BHC or at NYU outpatient clinics from January 2012 to August 2017. 100 patients were enrolled from each site: BHC (55% men); NYU (49% men). The majority of patients at NYU were White (77%), compared to 14% at BHC; Hispanic patients comprised the majority at BHC (56%) (p < 0.001). BHC patients had more clinic visits per year compared to the NYU cohort (2.88 vs. 2.40, p = 0.001). BHC patients were less likely to self-report exercise (p = 0.047) or participation in physical therapy (p = 0.015). There were no clinically significant differences in diagnosis type, time to diagnosis, average Hoehn & Yahr or levodopa equivalent dose. Compared to a Parkinson's Foundation Center of Excellence, PD patients in a public hospital system are more racially diverse, are less likely to be insured, have higher rates of care utilization and are less likely to access necessary interventions such as physical therapy and exercise.

OBJECTIVE:Appetite disturbance and growth abnormalities are commonly reported in children with Dravet syndrome (DS). Fenfluramine (Fintepla) has demonstrated profound reduction in convulsive seizure frequency in DS and was recently approved for use in DS in the US and EU. Prior to its use in epilepsy, fenfluramine was approved to suppress appetite in obese adults. Here, we evaluated the impact of fenfluramine on weight and growth in patients with DS treated for ≥12 months or ≥24 months and compared the results with growth curves in normative reference populations and published historical controls among patients with DS. METHODS:Historical control data from a recent study of 68 patients with DS show decreases in height and weight Z-scores of ∼0.1 standard deviation (SD) for every 12-month increase in age (Eschbach K. Seizure. 2017;52:117-22). Anthropometric data for fenfluramine were extracted from an open-label extension (OLE) study of eligible patients with DS (2-18 y/o; fenfluramine dose: 0.2-0.7 mg/kg/day). Z-score analyses were based on the Boston Children's Hospital algorithm and assessed potential impact of fenfluramine on growth at OLE baseline, at Month 12, and at Month 24. A mixed-effect model for repeated measures (MMRM) estimated changes in height and weight over time. Height and weight Z-scores were also analyzed by dose group (0.2-<0.3 mg/kg/day, 0.3-<0.5 mg/kg/day, and 0.5-0.7 mg/kg/day), averaged over time. RESULTS:At the time of analysis, 279 patients were treated with fenfluramine for ≥12 months; 128 were treated for ≥24 months. Relative to the reference population with DS, fenfluramine treatment for ≥12 months or for ≥24 months had minimal impact on height or weight over time as assessed by Z-score analyses. No substantial dose-dependent changes from baseline were observed at Month 12 nor at Month 24. MMRM showed that patients treated with fenfluramine for ≥12 months (N = 262) had an estimated change in Z-score per year of -0.056 for height and -0.166 for weight. For patients with data from all three time points (baseline, 12 months, and 24 months; N = 110), estimated changes in Z-scores per year were -0.025 for height and -0.188 for weight. MMRM projections based on normative reference growth curves were comparable to growth data from historical control populations with DS. SIGNIFICANCE/CONCLUSION:Long-term treatment with fenfluramine had minimal impact on the growth of patients with DS as demonstrated by differences in Z-scores for height and weight at 12 months and at 24 months. Changes in Z-scores for height and weight were consistent with published reports on patients with DS.

An increasing number of identified Parkinson's disease (PD) risk loci contain genes highly expressed in innate immune cells, yet their role in pathology is not understood. We hypothesize that PD susceptibility genes modulate disease risk by influencing gene expression within immune cells. To address this, we have generated transcriptomic profiles of monocytes from 230 individuals with sporadic PD and healthy subjects. We observed a dysregulation of mitochondrial and proteasomal pathways. We also generated transcriptomic profiles of primary microglia from brains of 55 subjects and observed discordant transcriptomic signatures of mitochondrial genes in PD monocytes and microglia. We further identified 17 PD susceptibility genes whose expression, relative to each risk allele, is altered in monocytes. These findings reveal widespread transcriptomic alterations in PD monocytes, with some being distinct from microglia, and facilitate efforts to understand the roles of myeloid cells in PD as well as the development of biomarkers.