Neurology Commons^™

Development Of A Novel Pharmacophore Model To Screen Specific Inhibitors For The Serine-Threonine Protein Phosphatase Calcineurin, Abhisek Mukherjee, Karina Cuanalo-Contreras, Abha Sood, Claudio Soto

Faculty, Staff and Student Publications

Calcineurin (CaN) is a calcium/calmodulin-dependent serine/threonine phosphatase with a crucial role in cellular homeostasis. It is also the target of the Food and Drug Administration (FDA) approved immunosuppressant drugs FK506 and cyclosporine A. Recent work from our group and others indicated that an uncontrolled increase in CaN activity causes synaptic dysfunction and neuronal death in various models of neurodegenerative diseases associated with calcium dysregulation. Furthermore, pharmacological normalization of CaN activity can prevent disease progression in animal models. However, none of the FDA-approved CaN inhibitors bind CaN directly, leading to adverse side effects. The development of direct CaN inhibitors is required …

Treating Phantom Limb Pain: Cryoablation Of The Posterior Tibial Nerve, Matthew Fiala, Abana Azariah, Jean Woo, Ahmed Kamel Abdel Aal, Alexa Levey

Faculty, Staff and Student Publications

Phantom limb pain (PLP) is a complex pathophysiologic process involving both the central and peripheral nervous system for which there is no definitive treatment. The number of individuals living with amputated limbs is predicted to increase to 3.5 million by 2050, and up to 80% of these patients will have PLP. In this case report, we will demonstrate successful reduction of PLP in a patient with bilateral phantom toe pain utilizing nerve blockade and subsequent cryoablation of the posterior tibial nerves.

Duration Of Ischemia Affects Outcomes Independent Of Infarct Size In Stroke, Youngran Kim, Swapnil Khose, Osama O Zaidat, Ameer E Hassan, Johanna T Fifi, Ashish Nanda, Benjamin Atchie, Britton Woodward, Arnd Doerfler, Alejandro Tomasello, Albert J Yoo, Sunil A Sheth

Faculty, Staff and Student Publications

Background: Delays in endovascular reperfusion for patients with large vessel occlusion stroke are known to worsen outcomes, and the mechanism is believed to be time-dependent expansion of the ischemic infarction. In this study, we hypothesize that delays in onset to reperfusion (OTR) assert an effect on outcomes independent of effects of final infarct (FI).

Methods: We performed a subgroup analysis from the prospective multicenter COMPLETE (International Acute Ischemic Stroke Registry With the Penumbra System Aspiration Including the 3D Revascularization Device; Penumbra, Inc) registry for 257 patients with anterior circulation large vessel occlusion who underwent endovascular therapy with successful reperfusion (modified …

Altered Bladder-Related Brain Network In Multiple Sclerosis Women With Voiding Dysfunction, Zhaoyue Shi, Christof Karmonik, Amelia Soltes, Khue Tran, John A Lincoln, Timothy Boone, Rose Khavari

Faculty, Staff and Student Publications

Objectives:

A number of neuro-urology imaging studies have mainly focused on investigating the brain activations during micturition in healthy and neuropathic patients. It is, however, also necessary to study brain functional connectivity (FC) within bladder-related regions in order to understand the brain organization during the execution of bladder function. This study aims to identify the altered brain network associated with bladder function in multiple sclerosis (MS) women with voiding dysfunction through comparisons with healthy subjects via concurrent urodynamics (UDS)/fMRI.

Materials and Methods:

Ten healthy adult women and nine adult ambulatory women with clinically stable MS for ≥ 6 months and …

Mir-486 Is Essential For Muscle Function And Suppresses A Dystrophic Transcriptome, Adrienne Samani, Rylie M Hightower, Andrea L Reid, Katherine G English, Michael A Lopez, J Scott Doyle, Michael J Conklin, David A Schneider, Marcas M Bamman, Jeffrey J Widrick, David K Crossman, Min Xie, David Jee, Eric C Lai, Matthew S Alexander

Faculty, Staff and Student Publications

miR-486 is a muscle-enriched microRNA, or “myomiR,” that has reduced expression correlated with Duchenne muscular dystrophy (DMD). To determine the function of miR-486 in normal and dystrophin-deficient muscles and elucidate miR-486 target transcripts in skeletal muscle, we characterized mir-486 knockout mice (mir-486 KO). mir-486 KO mice developed disrupted myofiber architecture, decreased myofiber size, decreased locomotor activity, increased cardiac fibrosis, and metabolic defects were exacerbated in mir-486 KO:mdx5cv (DKO) mice. To identify direct in vivo miR-486 muscle target transcripts, we integrated RNA sequencing and chimeric miRNA eCLIP sequencing to identify key transcripts and pathways that contribute towards mir-486 …

Anti-Nmda Receptor Encephalitis Presenting With Severe Episodic Hypertension: A Case Report, Tehreem Arshad, Musarrat Hussain, Abdul Wahab Yousafzai, Arsalan Ahmad

Pakistan Journal of Neurological Sciences (PJNS)

Anti-N-methyl-D-aspartate receptor (Anti-NMDAR) encephalitis is one of the most commonly emerging autoimmune encephalitis in children and young adults in recent years. Clinical manifestations range from prodromal symptoms to seizures, movement disorder, psychiatric manifestations, cognitive/speech impairment, and autonomic dysfunction. Our case presented with initial symptoms of severe episodic hypertension, sweating, agitation, and tachycardia. She received early care for pheochromocytoma and panic disorder in Qatar, but there was no relief. Three weeks later, she presented in our emergency room with seizures, cognitive/speech impairment, and orofacial dyskinesia. Electroencephalography (EEG) revealed right hemispheric delta activity and cerebrospinal fluid CSF anti-NMDA Receptor IgG was positive. …

Predictors Of Early Seizures After First Acute Stroke, Malik Muhammad Adil, Sumaira Nabi, Maryam Khalil, Zeeshan Munawar, Nayab Aslam, Zaid Waqar

Pakistan Journal of Neurological Sciences (PJNS)

Background and objective: There is a lack of local data regarding the frequency and predictors of early seizures after stroke. The objective of this study was to determine the frequency of early seizures after stroke and identify the predictors which lead to them after first acute stroke.

Methods: This cross-sectional observational study was conducted in the Department of Neurology, Pakistan Institute of Medical Sciences, Islamabad from October 2021 to June 2022. A total of 310 consecutive eligible patients of acute stroke were recruited. Key inclusion criteria included any patient of >20 years of age with confirmed diagnosis of stroke on …

Experience With Anti Nmda Receptor Antibody Encephalitis In A Tertiary Care Hospital In Pakistan, Haris Majid Rajput, Zaid Waqar, Muhammad Hassan, Neelma Naz Khattak, Umair Hassan, Iqra Athar, Mazhar Badshah Badshah

Pakistan Journal of Neurological Sciences (PJNS)

Background and objective: Anti NMDA receptor (Anti-NMDAR) antibody encephalitis is an increasingly recognized form of auto immune encephalitis. The objective of this study was to determine the demographic, clinical and laboratory factors associated with this syndrome.

Methods: All cases presenting to neurology, Pakistan institute of medical sciences, Islamabad, from June 2017 till January 2020 were reviewed retrospectively. Patients fulfilling the diagnostic criteria for Anti NMDA receptor (Anti-NMDAR) antibody encephalitis were included. All patients were evaluated with cerebrospinal fluid (CSF)routine examination, MRI brain, autoimmune encephalitis profile and for presence of oligoclonal bands (OCB) in CSF. Statistical analysis was done using SPSS …

The Impact Of Intraoperative Image-Guidance Modalities And Neurophysiologic Monitoring In The Safety Of Sacroiliac Fusions., Thiago Montenegro, Christian Hoelscher, Md, Kevin Hines, Md, Sara Thalheimer, Caio Matias, Bryan Wilent, James Harrop, Joshua E. Heller

Department of Neurosurgery Faculty Papers

STUDY DESIGN: Retrospective observational cohort.

OBJECTIVE: A review of efficiency and safety of fluoroscopy and stereotactic navigation system for minimally invasive (MIS) Sacroiliac (SI) fusion through a lateral technique.

METHODS: Retrospective analysis of an observational cohort of 96 patients greater than 18 years old, that underwent MIS SI fusion guided by fluoroscopy or navigation between January 2013 and April 2020 with a minimum of 3 months follow-up. Intraoperative neuromonitoring (IONM) with a variable combination of electromyography (EMG), somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs) was also utilized.

RESULTS: The overall complication rate in the study was 9.4%, and …

Pharmacokinetic Evaluation Of Intravenous Vitamin C: A Classic Pharmacokinetic Study., Ping Chen, Greg Reed, Joyce Jiang, Yaohui Wang, Jean Sunega, Ruochen Dong, Yan Ma, Anna E. Esparham, Ryan Ferrell, Mark Levine, Jeanne Drisko, Qi Chen

Manuscripts, Articles, Book Chapters and Other Papers

Purpose: Intravenous vitamin C (IVC) is used in a variety of disorders with limited supporting pharmacokinetic data. Herein we report a pharmacokinetic study in healthy volunteers and cancer participants with IVC doses in the range of 1-100 g.

Methods: A pharmacokinetic study was conducted in 21 healthy volunteers and 12 oncology participants. Healthy participants received IVC infusions of 1-100 g; oncology participants received IVC infusions of 25-100 g. Serial blood and complete urine samples were collected pre-infusion and for 24 h post-infusion. Pharmacokinetic parameters were computed using noncompartmental methods. Adverse events were monitored during the study.

Results: In both cohorts, …

Removal Of Kcnq2 From Parvalbumin-Expressing Interneurons Improves Anti-Seizure Efficacy Of Retigabine, Junzhan Jing, Corrinne Dunbar, Alina Sonesra, Ana Chavez, Suhyeorn Park, Ryan Yang, Heun Soh, Maxwell Lee, Anastasios V Tzingounis, Edward C Cooper, Xiaolong Jiang, Atul Maheshwari

Duncan NRI Faculty and Staff Publications

Anti-seizure drug (ASD) targets are widely expressed in both excitatory and inhibitory neurons. It remains unknown if the action of an ASD upon inhibitory neurons could counteract its beneficial effects on excitatory neurons (or vice versa), thereby reducing the efficacy of the ASD. Here, we examine whether the efficacy of the ASD retigabine (RTG) is altered after removal of the Kv7 potassium channel subunit KCNQ2, one of its drug targets, from parvalbumin-expressing interneurons (PV-INs). Parvalbumin-Cre (PV-Cre) mice were crossed with Kcnq2-floxed (Kcnq2fl/fl) mice to conditionally delete Kcnq2 from PV-INs. In these conditional knockout mice (cKO, PV-Kcnq2 …

Phenotypic And Genetic Spectrum Of Atp6v1a Encephalopathy: A Disorder Of Lysosomal Homeostasis, Renzo Guerrini, Davide Mei, Katalin Kerti-Szigeti, Sara Pepe, Mary Kay Koenig, Gretchen Von Allmen, Megan T Cho, Kimberly Mcdonald, Janice Baker, Vikas Bhambhani, Zöe Powis, Lance Rodan, Rima Nabbout, Giulia Barcia, Jill A Rosenfeld, Carlos A Bacino, Cyril Mignot, Lillian H Power, Catharine J Harris, Dragan Marjanovic, Rikke S Møller, Trine B Hammer, Riikka Keski Filppula, Päivi Vieira, Clara Hildebrandt, Stephanie Sacharow, Luca Maragliano, Fabio Benfenati, Katherine Lachlan, Andreas Benneche, Florence Petit, Jean Madeleine De Sainte Agathe, Barbara Hallinan, Yue Si, Ingrid M Wentzensen, Fanggeng Zou, Vinodh Narayanan, Naomichi Matsumoto, Alessandra Boncristiano, Giancarlo La Marca, Mitsuhiro Kato, Kristin Anderson, Carmen Barba, Luisa Sturiale, Domenico Garozzo, Roberto Bei, Laura Masuelli, Valerio Conti, Gaia Novarino, Anna Fassio

Faculty, Staff and Student Publications

Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease. Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased …

Somatic Variants In Diverse Genes Leads To A Spectrum Of Focal Cortical Malformations, Dulcie Lai, Meethila Gade, Edward Yang, Hyun Yong Koh, Jinfeng Lu, Nicole M Walley, Anne F Buckley, Tristan T Sands, Cigdem I Akman, Mohamad A Mikati, Guy M Mckhann, James E Goldman, Peter Canoll, Allyson L Alexander, Kristen L Park, Gretchen K Von Allmen, Olga Rodziyevska, Meenakshi B Bhattacharjee, Hart G W Lidov, Hannes Vogel, Gerald A Grant, Brenda E Porter, Annapurna H Poduri, Peter B Crino, Erin L Heinzen

Faculty, Staff and Student Publications

Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly …

A Patient With Erdheim-Chester Disease Limited To Central Nervous System, Rajesh K Gupta, Anam Haque, Thejasvi A Reddy, Carlos A Pérez

Faculty, Staff and Student Publications

Erdheim-Chester disease (ECD) is a rare, sporadic, non-Langerhans cell histiocytosis, a multisystem disorder, which has higher mortality when presented with CNS involvement. We report a 46-year-old woman who has ECD with exclusive CNS involvement. She presented with intracranial hemorrhage and had a poor response to corticosteroid and interferon. She required multiple debulking procedures and eventually responded well to cobimetinib. She has not had any other organ involvement thus far. This report highlights that CNS involvement may be the only manifestation of ECD and sometimes may require a repeat biopsy with IHC testing for excellent treatment outcomes.

Cancer-Driving Mutations Are Enriched In Genic Regions Intolerant To Germline Variation, Dimitrios Vitsios, Ryan S Dhindsa, Dorota Matelska, Jonathan Mitchell, Xuequing Zou, Joshua Armenia, Fengyuan Hu, Quanli Wang, Ben Sidders, Andrew R Harper, Slavé Petrovski

Duncan NRI Faculty and Staff Publications

Large reference datasets of protein-coding variation in human populations have allowed us to determine which genes and genic subregions are intolerant to germline genetic variation. There is also a growing number of genes implicated in severe Mendelian diseases that overlap with genes implicated in cancer. We hypothesized that cancer-driving mutations might be enriched in genic subregions that are depleted of germline variation relative to somatic variation. We introduce a new metric, OncMTR (oncology missense tolerance ratio), which uses 125,748 exomes in the Genome Aggregation Database (gnomAD) to identify these genic subregions. We demonstrate that OncMTR can significantly predict driver mutations …

Modeling Neonatal Intraventricular Hemorrhage Through Intraventricular Injection Of Hemoglobin, Brandon A Miller, Shelei Pan, Peter H Yang, Catherine Wang, Amanda L Trout, Dakota Defreitas, Sruthi Ramagiri, Scott D Olson, Jennifer M Strahle

Faculty, Staff and Student Publications

Neonatal intraventricular hemorrhage (IVH) is a common consequence of premature birth and leads to brain injury, posthemorrhagic hydrocephalus (PHH), and lifelong neurological deficits. While PHH can be treated by temporary and permanent cerebrospinal fluid (CSF) diversion procedures (ventricular reservoir and ventriculoperitoneal shunt, respectively), there are no pharmacological strategies to prevent or treat IVH-induced brain injury and hydrocephalus. Animal models are needed to better understand the pathophysiology of IVH and test pharmacological treatments. While there are existing models of neonatal IVH, those that reliably result in hydrocephalus are often limited by the necessity for large-volume injections, which may complicate modeling of …

Number-Time Interaction: Search For A Common Magnitude System In A Cross-Modal Setting, Anuj Shukla, Raju S Bapi

Faculty, Staff and Student Publications

A theory of magnitude (ATOM) suggests that a generalized magnitude system in the brain processes magnitudes such as space, time, and numbers. Numerous behavioral and neurocognitive studies have provided support to ATOM theory. However, the evidence for common magnitude processing primarily comes from the studies in which numerical and temporal information are presented visually. Our current understanding of such cross-dimensional magnitude interactions is limited to visual modality only. However, it is still unclear whether the ATOM-framework accounts for the integration of cross-modal magnitude information. To examine the cross-modal influence of numerical magnitude on temporal processing of the tone, we conducted …

A Sparse Representation Strategy To Eliminate Pseudo-Hfo Events From Intracranial Eeg For Seizure Onset Zone Localization, Behrang Fazli Besheli, Zhiyi Sha, Jay R Gavvala, Candan Gurses, Sacit Karamursel, Michael M Quach, Daniel J Curry, Sameer A Sheth, David J Francis, Thomas R Henry, Nuri F Ince

Faculty, Staff and Student Publications

Objective.

High-frequency oscillations (HFOs) are considered a biomarker of the epileptogenic zone in intracranial EEG recordings. However, automated HFO detectors confound true oscillations with spurious events caused by the presence of artifacts.

Approach.

We hypothesized that, unlike pseudo-HFOs with sharp transients or arbitrary shapes, real HFOs have a signal characteristic that can be represented using a small number of oscillatory bases. Based on this hypothesis using a sparse representation framework, this study introduces a new classification approach to distinguish true HFOs from the pseudo-events that mislead seizure onset zone (SOZ) localization. Moreover, we further classified the HFOs into ripples and …

Novel Dominant And Recessive Variants In Human Robo1 Cause Distinct Neurodevelopmental Defects Through Different Mechanisms, Yan Huang, Mengqi Ma, Xiao Mao, Davut Pehlivan, Oguz Kanca, Feride Un-Candan, Li Shu, Gulsen Akay, Tadahiro Mitani, Shenzhao Lu, Sukru Candan, Hua Wang, Bo Xiao, James R Lupski, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

The Roundabout (Robo) receptors, located on growth cones of neurons, induce axon repulsion in response to the extracellular ligand Slit. The Robo family of proteins controls midline crossing of commissural neurons during development in flies. Mono- and bi-allelic variants in human ROBO1 (HGNC: 10249) have been associated with incomplete penetrance and variable expressivity for a breath of phenotypes, including neurodevelopmental defects such as strabismus, pituitary defects, intellectual impairment, as well as defects in heart and kidney. Here, we report two novel ROBO1 variants associated with very distinct phenotypes. A homozygous missense p.S1522L variant in three affected siblings with nystagmus; and …

Immunohistochemical Detection And Prognostic Significance Of P53, Epidermal Growth Factor Receptor, Murine Double Minute 2, And Isocitrate Dehydrogenase 1 In Glioblastoma Multiforme Patients Of Pakistan, Syed Muhammad Adnan Ali, Muhammad Shahzad Shamim, Syed Ather Enam, Zubair Ahmad, Yumna Adnan, Hasnain Ahmed Farooqui

Department of Surgery Docs

Introduction: Glioblastoma multiforme (GBM) is one of the deadliest cranial tumors occurring in adults. Various biomarkers have been tested for their significance in diagnosis, prognosis, and treatment of GBM. Some well-studied markers in GBM are Isocitrate dehydrogenase 1 (IDH1), Murine double minute 2 (MDM2), Epidermal Growth Factor Receptor (EGFR), and p53. The aim of this study was to investigate the protein expression of these markers in GBM patients of Pakistan.
Methods: A total of 102 surgically resected formalin-fixed paraffin-embedded specimens from patients diagnosed and treated at Aga Khan University Hospital were included in this study. Immunohistochemistry (IHC) for IDH1, MDM2, …