Publications by authors named "Shreyas Panchagnula"

7 Publications

  • Page 1 of 1

Clinical Outcomes between Stand-Alone Zero-Profile Spacers and Cervical Plate with Cage Fixation for Anterior Cervical Discectomy and Fusion: A Retrospective Analysis of 166 Patients.

J Clin Med 2021 Jul 12;10(14). Epub 2021 Jul 12.

Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06519, USA.

Stand-alone (SA) zero-profile implants are an alternative to cervical plating (CP) in anterior cervical discectomy and fusion (ACDF). In this study, we investigate differences in surgical outcomes between SA and CP in ACDF. We conducted a retrospective analysis of 166 patients with myelopathy and/or radiculopathy who had ACDF with SA or CP from Jan 2013-Dec 2016. We measured surgical outcomes including Bazaz dysphagia score at 3 months, Nurick grade at last follow-up, and length of hospital stay. 166 patients (92F/74M) were reviewed. 92 presented with radiculopathy (55%), 37 with myelopathy (22%), and 37 with myeloradiculopathy (22%). The average operative time with CP was longer than SA (194 ± 69 vs. 126 ± 46 min) ( 0.001), as was the average length of hospital stay (2.1 ± 2 vs. 1.5 ± 1 days) ( = 0.006). At 3 months, 82 patients (49.4%) had a follow-up for dysphagia, with 3 patients reporting mild dysphagia and none reporting moderate or severe dysphagia. Nurick grade at last follow-up for the myelopathy and myeloradiculopathy cohorts improved in 63 patients (85%). Prolonged length of stay was associated with reduced odds of having an optimal outcome by 0.50 (CI = 0.35-0.85, = 0.003). Overall, we demonstrate that there is no significant difference in neurological outcome or rates of dysphagia between SA and CP, and that both lead to overall improvement of symptoms based on Nurick grading. However, we also show that the SA group has shorter length of hospital stay and operative time compared to CP.
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http://dx.doi.org/10.3390/jcm10143076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305235PMC
July 2021

DIAPH1 Variants in Non-East Asian Patients With Sporadic Moyamoya Disease.

JAMA Neurol 2021 Jun 14. Epub 2021 Jun 14.

Yale Center for Genome Analysis, West Haven, Connecticut.

Importance: Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals.

Objective: To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk.

Design, Setting, And Participants: A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort.

Main Outcomes And Measures: Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue.

Results: Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways.

Conclusions And Relevance: These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.
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http://dx.doi.org/10.1001/jamaneurol.2021.1681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204259PMC
June 2021

Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia.

iScience 2020 Oct 11;23(10):101552. Epub 2020 Sep 11.

Yale Center for Genome Analysis, West Haven, CT, USA.

Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated mutation (p.Cys188Trp) in the GABA receptor Cl channel γ-1 subunit () exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na and Ca channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca channel Ca3.2 (). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.
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http://dx.doi.org/10.1016/j.isci.2020.101552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554653PMC
October 2020

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.

Nat Med 2020 11 19;26(11):1754-1765. Epub 2020 Oct 19.

Departments of Neurosurgery, Engineering Science & Mechanics, and Physics; Center for Neural Engineering and Infectious Disease Dynamics, The Pennsylvania State University, University Park, PA, USA.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.
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http://dx.doi.org/10.1038/s41591-020-1090-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871900PMC
November 2020

Validating the Transformation of PROMIS-GH to EQ-5D in Adult Spine Patients.

J Clin Med 2019 Sep 20;8(10). Epub 2019 Sep 20.

Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06511, USA.

Spinal disorders and associated interventions are costly in the United States, putting them in the limelight of economic analyses. The Patient-Reported Outcomes Measurement Information System Global Health Survey (PROMIS-GHS) requires mapping to other surveys for economic investigation. Previous studies have proposed transformations of PROMIS-GHS to EuroQol 5-Dimension (EQ-5D) health index scores. These models require validation in adult spine patients. In our study, PROMIS-GHS and EQ-5D were randomly administered to 121 adult spine patients. The actual health index scores were calculated from the EQ-5D instrument and estimated scores were calculated from the PROMIS-GHS responses with six models. Goodness-of-fit for each model was determined using the coefficient of determination (), mean squared error (MSE), and mean absolute error (MAE). Among the models, the model treating the eight PROMIS-GHS items as categorical variables (CAT) was the optimal model with the highest (0.59) and lowest MSE (0.02) and MAE (0.11) in our spine sample population. Subgroup analysis showed good predictions of the mean EQ-5D by gender, age groups, education levels, etc. The transformation from PROMIS-GHS to EQ-5D had a high accuracy of mean estimate on a group level, but not at the individual level.
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http://dx.doi.org/10.3390/jcm8101506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832387PMC
September 2019

Familial Trigeminal Neuralgia Cases Implicate Genetic Factors in Disease Pathogenesis.

JAMA Neurol 2019 01;76(1):9-10

Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1001/jamaneurol.2018.3322DOI Listing
January 2019

De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus.

Neuron 2018 07 5;99(2):302-314.e4. Epub 2018 Jul 5.

Yale Center for Genome Analysis, Yale University, New Haven, CT 06510, USA.

Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10), SMARCC1 (p = 8.15 × 10), and PTCH1 (p = 1.06 × 10). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10). Together, these probands account for ∼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.
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http://dx.doi.org/10.1016/j.neuron.2018.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839075PMC
July 2018
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