Publications by authors named "Phan Q Duy"

40 Publications

Genomics of human congenital hydrocephalus.

Childs Nerv Syst 2021 Jul 7. Epub 2021 Jul 7.

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

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of pathological cerebrospinal fluid (CSF) accumulation and, therefore, treated largely by neurosurgical CSF diversion. The persistence of ventriculomegaly and poor neurodevelopmental outcomes in some post-surgical patients highlights our limited knowledge of disease mechanisms. Recent whole-exome sequencing (WES) studies have shown that rare, damaging de novo and inherited mutations with large effect contribute to ~ 25% of sporadic CH. Interestingly, multiple CH genes are key regulators of neural stem cell growth and differentiation and converge in human transcriptional networks and cell types pertinent to fetal neurogliogenesis. These data implicate genetic disruption of early brain development as the primary pathomechanism in a substantial minority of patients with sporadic CH, shedding new light on human brain development and the pathogenesis of hydrocephalus. These data further suggest WES as a clinical tool with potential to re-classify CH according to a molecular nomenclature of increased precision and utility for genetic counseling, outcome prognostication, and treatment stratification.
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http://dx.doi.org/10.1007/s00381-021-05230-8DOI Listing
July 2021

Inflammatory hydrocephalus.

Childs Nerv Syst 2021 Jun 23. Epub 2021 Jun 23.

Department of Neurosurgery, Yale School of Medicine, New Haven, CT, 06510, USA.

Reparative inflammation is an important protective response that eliminates foreign organisms, damaged cells, and physical irritants. However, inappropriately triggered or sustained inflammation can respectively initiate, propagate, or prolong disease. Post-hemorrhagic (PHH) and post-infectious hydrocephalus (PIH) are the most common forms of hydrocephalus worldwide. They are treated using neurosurgical cerebrospinal fluid (CSF) diversion techniques with high complication and failure rates. Despite their distinct etiologies, clinical studies in human patients have shown PHH and PIH share similar CSF cytokine and immune cell profiles. Here, in light of recent work in model systems, we discuss the concept of "inflammatory hydrocephalus" to emphasize potential shared mechanisms and potential therapeutic vulnerabilities of these disorders. We propose that this change of emphasis could shift our thinking of PHH and PIH from a framework of life-long neurosurgical disorders to that of preventable conditions amenable to immunomodulation.
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http://dx.doi.org/10.1007/s00381-021-05255-zDOI Listing
June 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

Intraventricular CSF Turbulence in Pediatric Communicating Hydrocephalus.

Neurology 2021 Aug 24;97(5):246-247. Epub 2021 May 24.

From the Department of Neurosurgery, Yale School of Medicine, New Haven, CT.

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http://dx.doi.org/10.1212/WNL.0000000000012237DOI Listing
August 2021

A novel signature predicts recurrence risk and therapeutic response in breast cancer patients.

Int J Cancer 2021 Jun 21;148(11):2848-2856. Epub 2021 Feb 21.

School of Medicine, Vietnam National University Ho Chi Minh City, Ho Chi Minh City, Vietnam.

Acetylserotonin O-methyltransferase (ASMT) is a key enzyme in the synthesis of melatonin. Although melatonin has been shown to exhibit anticancer activity and prevents endocrine resistance in breast cancer, the role of ASMT in breast cancer progression remains unclear. In this retrospective study, we analyzed gene expression profiles in 27 data sets on 7244 patients from 11 countries. We found that ASMT expression was significantly reduced in breast cancer tumors relative to healthy tissue. Among breast cancer patients, those with higher levels of ASMT expression had better relapse-free survival outcomes and longer metastasis-free survival times. Following treatment with tamoxifen, patients with greater ASMT expression experienced longer periods before relapse or distance recurrence. Motivated by these results, we devised an ASMT gene signature that can correctly identify low-risk cases with a sensitivity and specificity of 0.997 and 0.916, respectively. This signature was robustly validated using 23 independent breast cancer mRNA array data sets from different platforms (consisting of 5800 patients) and an RNAseq data set from TCGA (comprising 1096 patients). Intriguingly, patients who are classified as high-risk by the signature benefit from adjuvant chemotherapy, and those with grade II tumors who are classified as low-risk exhibit improved overall survival and distance relapse-free outcomes following endocrine therapy. Together, our findings more clearly elucidate the roles of ASMT, provide strategies for improving the efficacy of tamoxifen treatment and help to identify those patients who may maximally benefit from adjuvant or endocrine therapies.
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http://dx.doi.org/10.1002/ijc.33512DOI Listing
June 2021

Opioid use and spinal cord stimulation therapy: The long game.

J Clin Neurosci 2021 Feb 6;84:50-52. Epub 2021 Jan 6.

Division of Functional Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Spinal cord stimulation (SCS) has been considered as an alternative therapy to reduce opioid requirements in certain chronic pain disorders. However, information on long-term opioid consumption patterns and their impact on SCS device explantation is lacking. We conducted a retrospective study of 45 patients to characterize long-term patterns of opioid usage after SCS implantation. Daily morphine equivalent dosage (MED) increased, decreased, and remained the same in 40%, 40%, and 20% of patients at 1-year follow-up, respectively. Twelve (27%) underwent explantation due to treatment failure at a median of 18 months after implantation. Pre-operative opioid status (naïve vs. active use) was not associated with explantation (18% vs. 29%, p = 0.699) and neither was the daily MED change status (i.e. increased, decreased, unchanged) at 1-year (p = 0.499, 1.000, 0.735, respectively). Following explantation, reduction in the daily MED was seen in 92% of patients with dosages falling below pre-operative baseline in nine. Among the opioid naïve patients, 55% were on opioids at last follow-up (average 32.4 ± 14.6 months). Our results indicate that daily opioid consumption does not decrease in most patients 1-year after SCS implantation. Furthermore, post-operative evaluation beyond 1-year is necessary to assess the efficacy and durability of SCS therapy as well as its impact on opioid requirement. Lastly, rigorous patient selection and pre-operative risk assessment for misuse and dependence are paramount to improving outcome after SCS implantation.
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http://dx.doi.org/10.1016/j.jocn.2020.12.004DOI Listing
February 2021

Spinal cord stimulation and psychotropic medication use: Missing piece to the puzzle?

J Clin Neurosci 2020 Nov 12;81:158-160. Epub 2020 Oct 12.

Division of Functional Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Psychotropic medications have modulatory effects on spinal cord stimulator (SCS) therapy and may play an important role in determining treatment success in chronic pain management. However, it remains unknown how SCS affects psychotropic use and whether the medications affect outcome. We performed a retrospective study to determine the prevalence of psychotropic medication (i.e. anxiolytic, antidepressant, and anticonvulsant) use among new SCS patients immediately before implantation and characterized the dosage changes at 1-year. We also sought to understand whether pre-operative medication status affects outcome, defined as device explantation due to treatment failure. In an analysis of 45 patients, 31%, 51% and 71% were actively taking anxiolytics, antidepressants, and anticonvulsants, respectively, before surgery. In the majority of cases, daily dosages remained the same for all three classes of medication at 1-year. Patients who were on two or more classes of medications pre-operatively had significantly lower explantation rate compared to those with one or none (12% vs. 43%, p = 0.041) and had 5.25 times less likelihood of explanation in the future (OR 5.25, 95%CI 1.18-23.2, p = 0.029). Our study suggest that peri-operative multimodality medical treatment may enhance the therapeutic efficacy and durability of SCS in carefully selected chronic pain patients.
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http://dx.doi.org/10.1016/j.jocn.2020.09.038DOI Listing
November 2020

Self-reported health without clinically measurable benefits among adult users of multivitamin and multimineral supplements: a cross-sectional study.

BMJ Open 2020 11 4;10(11):e039119. Epub 2020 Nov 4.

Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Objective: Multiple clinical trials fail to identify clinically measurable health benefits of daily multivitamin and multimineral (MVM) consumption in the general adult population. Understanding the determinants of widespread use of MVMs may guide efforts to better educate the public about effective nutritional practices. The objective of this study was to compare self-reported and clinically measurable health outcomes among MVM users and non-users in a large, nationally representative adult civilian non-institutionalised population in the USA surveyed on the use of complementary health practices.

Design: Cross-sectional analysis of the effect of MVM consumption on self-reported overall health and clinically measurable health outcomes.

Participants: Adult MVM users and non-users from the 2012 National Health Interview Survey (n=21 603).

Primary And Secondary Outcome Measures: Five psychological, physical, and functional health outcomes: (1) self-rated health status, (2) needing help with routine needs, (3) history of 10 chronic diseases, (4) presence of 19 health conditions in the past 12 months, and (5) Kessler 6-Item (K6) Psychological Distress Scale to measure non-specific psychological distress in the past month.

Results: Among 4933 adult MVM users and 16 670 adult non-users, MVM users self-reported 30% better overall health than non-users (adjusted OR 1.31; 95% CI 1.17 to 1.46; false discovery rate adjusted p<0.001). There were no differences between MVM users and non-users in history of 10 chronic diseases, number of present health conditions, severity of current psychological distress on the K6 Scale and rates of needing help with daily activities. No effect modification was observed after stratification by sex, education, and race.

Conclusions: MVM users self-reported better overall health despite no apparent differences in clinically measurable health outcomes. These results suggest that widespread use of multivitamins in adults may be a result of individuals' positive expectation that multivitamin use leads to better health outcomes or a self-selection bias in which MVM users intrinsically harbour more positive views regarding their health.
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http://dx.doi.org/10.1136/bmjopen-2020-039119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643504PMC
November 2020

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

Light Has Diverse Spatiotemporal Molecular Changes in the Mouse Suprachiasmatic Nucleus.

J Biol Rhythms 2020 12 8;35(6):576-587. Epub 2020 Oct 8.

Section on Light and Circadian Rhythms, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.

To be physiologically relevant, the period of the central circadian pacemaker, located in the suprachiasmatic nucleus (SCN), has to match the solar day in a process known as circadian photoentrainment. However, little is known about the spatiotemporal molecular changes that occur in the SCN in response to light. In this study, we sought to systematically characterize the circadian and light effects on activity-dependent markers of transcriptional (cFos), translational (pS6), and epigenetic (pH3) activities in the mouse SCN. To investigate circadian versus light influences on these molecular responses, we harvested brains from adult wild-type mice in darkness at different circadian times (CT) or from mice exposed to a 15-min light pulse at the middle of the subjective day (CT6, no phase shifts), early subjective night (CT14, large phase delays), or late subjective night (CT22, small phase advances). We found that cFos and pS6 exhibited rhythmic circadian expression in the SCN with distinct spatial rhythms, whereas pH3 expression was undetectable at all circadian phases. cFos rhythms were largely limited to the SCN shell, whereas pS6 rhythms encompassed the entire SCN. pH3, pS6, and cFos showed gating in response to light; however, we were surprised to find that the expression levels of these markers were not higher at phases when larger phase shifts are observed behaviorally (CT14 versus CT22). We then used animals lacking melanopsin (melanopsin knockout [MKO]), which show deficits in phase delays, to further investigate whether changes in these molecular markers correspond to behavioral phase shifts. Surprisingly, only pS6 showed deficits in MKOs at CT14. Therefore, our previous understanding of the molecular pathways that lead to circadian photoentrainment needs to be revised.
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http://dx.doi.org/10.1177/0748730420961214DOI Listing
December 2020

Worse overall health status negatively impacts satisfaction with breast reconstruction.

J Plast Reconstr Aesthet Surg 2020 Nov 11;73(11):2056-2062. Epub 2020 Sep 11.

Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA. Electronic address:

Background: BREAST-Q is a validated measure of patient satisfaction and health-related quality of life following breast surgery. Limited evidence exists with regard to the influence of preoperative overall health status on BREAST-Q outcomes. The American Society of Anesthesiologists (ASA) physical status classification is representative of preoperative overall health and its impact on patient-reported outcomes can be assessed.

Methods: Patients who received breast reconstruction at Yale New Haven Hospital between 2013 and 2018 and completed the BREAST-Q were enrolled in the study. Associations between BREAST-Q scores within modules and between modules and ASA were analyzed. Pearson's correlation and Spearman's Rho were used to characterize correlations between patient factors and BREAST-Q scores. Significantly correlated factors were entered into a general linear model (GLM) to control for confounding variables and isolate the effect of ASA on BREAST-Q scores.

Results: A total of 1136 patients underwent breast reconstruction of whom 489 patients completed the BREAST-Q. Increasing ASA indicative of worsening overall health was associated with a decreased BREAST-Q score for all modules except Physical Well-being of the Abdomen (p<0.01 to p = 0.029). In a GLM controlling for relevant covariates, ASA remained a significant contributor for all modules except Physical Well-being of the Chest (p<0.01 to p = 0.021). BREAST-Q scores decreased by approximately twice as much from ASA 1 to 2 compared to ASA 2 to 3.

Conclusion: ASA classification is an independent predictor of BREAST-Q patient-reported outcomes following breast reconstruction. Communicating the potential impact of overall health may help reduce the discrepancy in postoperative satisfaction across ASA classifications.
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http://dx.doi.org/10.1016/j.bjps.2020.08.093DOI Listing
November 2020

Derivation and validation of genome-wide polygenic score for urinary tract stone diagnosis.

Kidney Int 2020 11 12;98(5):1323-1330. Epub 2020 Jun 12.

The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; The BioMe Phenomics Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA; The Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Renal Program, James J Peters Veterans Affairs Medical Center at Bronx, New York, New York, USA. Electronic address:

Urinary tract stones have high heritability indicating a strong genetic component. However, genome-wide association studies (GWAS) have uncovered only a few genome wide significant single nucleotide polymorphisms (SNPs). Polygenic risk scores (PRS) sum cumulative effect of many SNPs and shed light on underlying genetic architecture. Using GWAS summary statistics from 361,141 participants in the United Kingdom Biobank, we generated a PRS and determined association with stone diagnosis in 28,877 participants in the Mount Sinai BioMe Biobank. In BioMe (1,071 cases and 27,806 controls), for every standard deviation increase, we observed a significant increment in adjusted odds ratio of a factor of 1.2 (95% confidence interval 1.13-1.26). In comparison, a risk score comprised of GWAS significant SNPs was not significantly associated with diagnosis. After stratifying individuals into low and high-risk categories on clinical risk factors, there was a significant increment in adjusted odds ratio of 1.3 (1.12-1.6) in the low- and 1.2 (1.1-1.2) in the high-risk group for every standard deviation increment in PRS. In a 14,348-participant validation cohort (Penn Medicine Biobank), every standard deviation increment was associated with a significant adjusted odds ratio of 1.1 (1.03 - 1.2). Thus, a genome-wide PRS is associated with urinary tract stones overall and in the absence of known clinical risk factors and illustrates their complex polygenic architecture.
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http://dx.doi.org/10.1016/j.kint.2020.04.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606592PMC
November 2020

Antiepileptic drug withdrawal and seizure severity in the epilepsy monitoring unit.

Epilepsy Behav 2020 08 14;109:107128. Epub 2020 May 14.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Objective: The goal of this study was to identify a strategy for antiepileptic drug (AED) reduction to allow efficient recording of focal seizures (FS) in patients undergoing video-electroencephalography (EEG) in an epilepsy monitoring unit (EMU) while avoiding the risk of complications associated with more severe seizure types.

Methods: We retrospectively reviewed consecutive patients admitted to our institution's EMU from July 1, 2016 to December 31, 2017. We included 114 presurgical patients who had AEDs reduced and at least one seizure during the admission. We compared AED dosages at which FS versus focal to bilateral tonic-clonic seizures (f-BTCS), seizure clusters, and lorazepam administration occurred. We also examined rate of AED reduction and seizure types. We used a receiver-operating characteristic (ROC) curve to identify a dose maximizing FS and minimizing other seizure types.

Results: Antiepileptic drug withdrawal rates ranged from 0 to 100% in the first 24 h (mean: 20%, standard deviation: 20%). Focal to bilateral tonic-clonic seizures and lorazepam administration occurred at a lower median AED dose than did FS (0%, 7.2%, and 43.8%, respectively, expressed as a percentage of the patient's outpatient daily AED dose; p < 0.001). A daily EMU-administered dose of one-third of the patient's outpatient AED dose allowed 55.0% of FS to occur while avoiding 82.0% of more severe seizure types. The seizure types had no difference in rate of AED withdrawal in the first 24 h of EMU stay.

Conclusions: Focal seizures occurred at a higher AED dose than did f-BTCS. This may imply that a low minimally effective dose of AED could allow FS to be recorded while providing protection against f-BTCS. This strategy could improve efficacy and safety in the EMU.
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http://dx.doi.org/10.1016/j.yebeh.2020.107128DOI Listing
August 2020

Retinal innervation tunes circuits that drive nonphotic entrainment to food.

Nature 2020 05 22;581(7807):194-198. Epub 2020 Apr 22.

National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, MD, USA.

Daily changes in light and food availability are major time cues that influence circadian timing. However, little is known about the circuits that integrate these time cues to drive a coherent circadian output. Here we investigate whether retinal inputs modulate entrainment to nonphotic cues such as time-restricted feeding. Photic information is relayed to the suprachiasmatic nucleus (SCN)-the central circadian pacemaker-and the intergeniculate leaflet (IGL) through intrinsically photosensitive retinal ganglion cells (ipRGCs). We show that adult mice that lack ipRGCs from the early postnatal stages have impaired entrainment to time-restricted feeding, whereas ablation of ipRGCs at later stages had no effect. Innervation of ipRGCs at early postnatal stages influences IGL neurons that express neuropeptide Y (NPY) (hereafter, IGL neurons), guiding the assembly of a functional IGL-SCN circuit. Moreover, silencing IGL neurons in adult mice mimicked the deficits that were induced by ablation of ipRGCs in the early postnatal stages, and acute inhibition of IGL terminals in the SCN decreased food-anticipatory activity. Thus, innervation of ipRGCs in the early postnatal period tunes the IGL-SCN circuit to allow entrainment to time-restricted feeding.
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http://dx.doi.org/10.1038/s41586-020-2204-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291822PMC
May 2020

Preclinical insights into therapeutic targeting of KCC2 for disorders of neuronal hyperexcitability.

Expert Opin Ther Targets 2020 07 5;24(7):629-637. Epub 2020 May 5.

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

Introduction: Epilepsy is a common neurological disorder of neuronal hyperexcitability that begets recurrent and unprovoked seizures. The lack of a truly satisfactory pharmacotherapy for epilepsy highlights the clinical urgency for the discovery of new drug targets. To that end, targeting the electroneutral K/Cl cotransporter KCC2 has emerged as a novel therapeutic strategy for the treatment of epilepsy.

Areas Covered: We summarize the roles of KCC2 in the maintenance of synaptic inhibition and the evidence linking KCC2 dysfunction to epileptogenesis. We also discuss preclinical proof-of-principle studies that demonstrate that augmentation of KCC2 function can reduce seizure activity. Moreover, potential strategies to modulate KCC2 activity for therapeutic benefit are highlighted.

Expert Opinion: Although KCC2 is a promising drug target, questions remain before clinical translation. It is unclear whether increasing KCC2 activity can reverse epileptogenesis, the ultimate curative goal for epilepsy therapy that extends beyond seizure reduction. Furthermore, the potential adverse effects associated with increased KCC2 function have not been studied. Continued investigations into the neurobiology of KCC2 will help to translate promising preclinical insights into viable therapeutic avenues that leverage fundamental properties of KCC2 to treat medically intractable epilepsy and other disorders of failed synaptic inhibition with attendant neuronal hyperexcitability.
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http://dx.doi.org/10.1080/14728222.2020.1762174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104019PMC
July 2020

Inflammation in acquired hydrocephalus: pathogenic mechanisms and therapeutic targets.

Nat Rev Neurol 2020 May 9;16(5):285-296. Epub 2020 Mar 9.

Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology and Yale-Rockefeller NIH Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT, USA.

Hydrocephalus is the most common neurosurgical disorder worldwide and is characterized by enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles resulting from failed CSF homeostasis. Since the 1840s, physicians have observed inflammation in the brain and the CSF spaces in both posthaemorrhagic hydrocephalus (PHH) and postinfectious hydrocephalus (PIH). Reparative inflammation is an important protective response that eliminates foreign organisms, damaged cells and physical irritants; however, inappropriately triggered or sustained inflammation can respectively initiate or propagate disease. Recent data have begun to uncover the molecular mechanisms by which inflammation - driven by Toll-like receptor 4-regulated cytokines, immune cells and signalling pathways - contributes to the pathogenesis of hydrocephalus. We propose that therapeutic approaches that target inflammatory mediators in both PHH and PIH could address the multiple drivers of disease, including choroid plexus CSF hypersecretion, ependymal denudation, and damage and scarring of intraventricular and parenchymal (glia-lymphatic) CSF pathways. Here, we review the evidence for a prominent role of inflammation in the pathogenic mechanism of PHH and PIH and highlight promising targets for therapeutic intervention. Focusing research efforts on inflammation could shift our view of hydrocephalus from that of a lifelong neurosurgical disorder to that of a preventable neuroinflammatory condition.
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http://dx.doi.org/10.1038/s41582-020-0321-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375440PMC
May 2020

Preresidency Publication Productivity of U.S. Neurosurgery Interns.

World Neurosurg 2020 05 31;137:e291-e297. Epub 2020 Jan 31.

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

Background: Research experience is believed to be an important component of the neurosurgery residency application process. One measure of research productivity is publication volume. The preresidency publication volume of U.S. neurosurgery interns and any potential association between applicant publication volume and the match results of top-ranked residency programs have not been well characterized.

Objective: In this study, we sought to characterize the preresidency publication volume of U.S. neurosurgery residents in the 2018-2019 intern class using the Scopus database.

Methods: For each intern, we recorded the total number of publications, total number of first or last author publications, total number of neuroscience-related publications, mean number of citations per publication, and mean impact factor of the journal per publication. Preresidency publication volumes of interns at the top-25 programs (based on a composite ranking score according to 4 different ranking metrics) were compared with those at all other programs.

Results: We found that 82% of neurosurgery interns included in the analysis (190 interns from 95 programs) had at least 1 publication. The average number of publications per intern among all programs was 6 ± 0.63 (mean ± standard error of the mean). We also found that interns at top-25 neurosurgery residency programs tended to have a higher number of publications (8.3 ± 1.2 vs. 4.8 ± 0.7, P = 0.0137), number of neuroscience-related publications (6.8 ± 1.1 vs. 4.1 ± 0.7, P = 0.0419), and mean number of citations per publication (9.8 ± 1.7 vs. 5.7 ± 0.8, P = 0.0267) compared with interns at all other programs.

Conclusions: Our results provide a general estimate of the preresidency publication volume of U.S. neurosurgery interns and suggest a potential association between publication volume and matching in the top-25 neurosurgery residency programs.
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http://dx.doi.org/10.1016/j.wneu.2020.01.173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202965PMC
May 2020

Identification of KCC2 Mutations in Human Epilepsy Suggests Strategies for Therapeutic Transporter Modulation.

Front Cell Neurosci 2019 15;13:515. Epub 2019 Nov 15.

Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, United States.

Epilepsy is a common neurological disorder characterized by recurrent and unprovoked seizures thought to arise from impaired balance between neuronal excitation and inhibition. Our understanding of the neurophysiological mechanisms that render the brain epileptogenic remains incomplete, reflected by the lack of satisfactory treatments that can effectively prevent epileptic seizures without significant drug-related adverse effects. Type 2 K-Cl cotransporter (KCC2), encoded by , is important for chloride homeostasis and neuronal excitability. KCC2 dysfunction attenuates Cl extrusion and impairs GABAergic inhibition, and can lead to neuronal hyperexcitability. Converging lines of evidence from human genetics have secured the link between KCC2 dysfunction and the development of epilepsy. Here, we review KCC2 mutations in human epilepsy and discuss potential therapeutic strategies based on the functional impact of these mutations. We suggest that a strategy of augmenting KCC2 activity by antagonizing its critical inhibitory phosphorylation sites may be a particularly efficacious method of facilitating Cl extrusion and restoring GABA inhibition to treat medication-refractory epilepsy and other seizure disorders.
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http://dx.doi.org/10.3389/fncel.2019.00515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873151PMC
November 2019

Genomic alterations underlying spinal metastases in pediatric H3K27M-mutant pineal parenchymal tumor of intermediate differentiation: case report.

J Neurosurg Pediatr 2019 Oct 25:1-10. Epub 2019 Oct 25.

7Pathology, Yale School of Medicine.

Pediatric midline tumors are devastating high-grade lesions with a dismal prognosis and no curative surgical options. Here, the authors report the clinical presentation, surgical management, whole-exome sequencing (WES), and clonality analysis of a patient with a radically resected H3K27M-mutant pineal parenchymal tumor (PPT) and spine metastases consistent with PPT of intermediate differentiation (PPTID). They identified somatic mutations in H3F3A (H3K27M), FGFR1, and NF1 both in the original PPT and in the PPTID metastases. They also found 12q amplification containing CDK4/MDM2 and chromosome 17 loss of heterozygosity overlapping with NF1 that resulted in biallelic NF1 loss. They noted a hypermutated phenotype with increased C>T transitions within the PPTID metastases and 2p amplification overlapping with the MYCN locus. Clonality analysis detected three founder clones maintained during progression and metastasis. Tumor clones present within the PPTID metastases but not the pineal midline tumor harbored mutations in APC and TIMP2.While the majority of H3K27M mutations are found in pediatric midline gliomas, it is increasingly recognized that this mutation is present in a wider range of lesions with a varied morphological appearance. The present case appears to be the first description of H3K27M mutation in PPTID. Somatic mutations in H3F3A, FGFR1, and NF1 have been suggested to be driver mutations in pediatric midline gliomas. Their clonality and presence in over 80% of tumor cells in our patient's PPTID are consistent with similarly crucial roles in early tumorigenesis, with progression mediated by copy number variations and chromosomal aberrations involving known oncogenes and tumor suppressors. The roles of APC and TIMP2 mutations in progression and metastasis remain to be investigated.
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http://dx.doi.org/10.3171/2019.8.PEDS18664DOI Listing
October 2019

Recessive Inheritance of Congenital Hydrocephalus With Other Structural Brain Abnormalities Caused by Compound Heterozygous Mutations in .

Front Cell Neurosci 2019 26;13:425. Epub 2019 Sep 26.

Department of Neurosurgery, School of Medicine, Yale University, New Haven, CT, United States.

Background: encodes the α3 subunit of the Na/K ATPase, a fundamental ion-transporting enzyme. Primarily expressed in neurons, is mutated in several autosomal dominant neurological diseases. To our knowledge, damaging recessive genotypes in have never been associated with any human disease. deficiency in zebrafish results in hydrocephalus; however, no known association exists between and human congenital hydrocephalus (CH).

Methods: We utilized whole-exome sequencing (WES), bioinformatics, and computational modeling to identify and characterize novel mutations in a patient with CH. We performed immunohistochemical studies using mouse embryonic brain tissues to characterize expression during brain development.

Results: We identified two germline mutations in (p. Arg19Cys and p.Arg463Cys), each of which was inherited from one of the patient's unaffected parents, in a single patient with severe obstructive CH due to aqueductal stenosis, along with open schizencephaly, type 1 Chiari malformation, and dysgenesis of the corpus callosum. Both mutations are predicted to be highly deleterious and impair protein stability. Immunohistochemical studies demonstrate robust expression in neural stem cells (NSCs), differentiated neurons, and choroid plexus of the mouse embryonic brain.

Conclusion: These data provide the first evidence of a recessive human phenotype associated with mutations in , and implicate impaired Na/K ATPase function in the pathogenesis of CH.
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http://dx.doi.org/10.3389/fncel.2019.00425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775207PMC
September 2019

Clinical Trial Publication Trends Within Neurology.

Transl Neurosci 2019 20;10:233-234. Epub 2019 Aug 20.

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

Timely dissemination of results from clinical studies is crucial for the advancement of knowledge and clinical decision making. A large body of research has shown that up to half of clinical trials do not publish their findings. In this study, we sought to determine whether clinical trial publication rates within neurology have increased over time. Focusing on neurology clinical trials completed between 2008 to 2014, we found that while the overall percentage of published trials has not changed (remaining at approximately 50%), time to publication has significantly decreased. Our findings suggest that clinical trials within neurology are being published in a more timely manner.
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http://dx.doi.org/10.1515/tnsci-2019-0037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708287PMC
August 2019

Description and Assessment of a Neurosurgery Shadowing and Research Program: A Paradigm for Early and Sustained Exposure to Academic Neurosurgery.

Transl Neurosci 2019 9;10:195-199. Epub 2019 Aug 9.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objective: To describe and assess the educational value of a functional neurosurgery clinical shadowing and research tutorial for pre-medical trainees.

Design: Program participants observed functional neurosurgery procedures and conducted basic science and clinical research in neurosurgery fields. Former participants completed a brief online survey to evaluate their perspectives and experiences throughout the tutorial.

Setting: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Participants: 15 pre-medical and post-baccalaureate trainees participated in the tutorial. All former tutorial participants were emailed.

Results: 11/15 former participants responded to the survey. Survey results suggest that the tutorial program increased participants' understanding of and interest in neurosurgery and related fields in neuroscience.

Conclusions: The functional neurosurgery medical tutorial provides valuable clinical and research exposure in neurosurgery fields for pre-medical trainees. Our work is a preliminary step in addressing the crucial challenge of training the next generation of neurosurgeon-scientists by providing a pedagogical paradigm for development of formal experiences that integrate original scientific research with clinical neurosurgery exposure.
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http://dx.doi.org/10.1515/tnsci-2019-0034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689215PMC
August 2019

Sex modulates the ApoE ε4 effect on brain tau deposition measured by F-AV-1451 PET in individuals with mild cognitive impairment.

Theranostics 2019 9;9(17):4959-4970. Epub 2019 Jul 9.

Department of Nuclear Medicine, Peking University First Hospital, Beijing, China.

The strongest genetic risk factor for Alzheimer's disease (AD) is the Apolipoprotein E type 4 allele (ApoE ε4). The interaction between sex and ApoE ε4 carrier status on AD risk remains an area of intense investigation. We hypothesized that sex modulates the relationship between ApoE ε4 carrier status and brain tau deposition (a quantitative endophenotype in AD) in individuals with mild cognitive impairment (MCI). : Preprocessed F-AV-1451 tau and F-AV-45 amyloid PET images, T1-weighted structural magnetic resonance imaging (MRI) scans, demographic information, and cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau (p-tau) measurements from 108 MCI subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were included. After downloading pre-processed images from ADNI, an iterative reblurred Van Cittertiteration partial volume correction (PVC) method was applied to all PET images. MRIs were used for PET spatial normalization. Regions of interest (ROIs) were defined in standard space, and standardized uptake value ratio (SUVR) images relative to cerebellum were computed. ApoE ε4 by sex interaction analyses on F-AV-1451 and CSF tau (t-tau, p-tau) were assessed using generalized linear models. The association between F-AV-1451 SUVR and CSF tau (t-tau, p-tau) was assessed. : After applying PVC and controlling for age, education level and global cortical F-AV-45 SUVR, we found that the entorhinal cortex, amygdala, parahippocampal gyrus, posterior cingulate, and occipital ROIs exhibited a significant ApoE ε4 by sex interaction effect (false discovery rate < 0.1) among MCI individuals. We also found a significant ApoE ε4 by sex interaction effect on CSF t-tau and p-tau. F-AV-1451 SUVR in the 5 ROIs with ApoE ε4 by sex interaction was significantly correlated with CSF p-tau and t-tau. : Our findings suggest that women are more susceptible to ApoE ε4-associated accumulation of neurofibrillary tangles in MCI compared to males. Both CSF tau (p-tau, t-tau) and brain tau PET are robust quantitative biomarkers for studying ApoE ε4 by sex effects on brain tau deposition in MCI participants.
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http://dx.doi.org/10.7150/thno.35366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691387PMC
August 2020

Muscle precursor cell movements in zebrafish are dynamic and require Six family genes.

Development 2019 05 15;146(10). Epub 2019 May 15.

Department of Molecular Genetics, The Ohio State University, Columbus, OH 43210, USA

Muscle precursors need to be correctly positioned during embryonic development for proper body movement. In zebrafish, a subset of hypaxial muscle precursors from the anterior somites undergo long-range migration, moving away from the trunk in three streams to form muscles in distal locations such as the fin. We mapped long-distance muscle precursor migrations with unprecedented resolution using live imaging. We identified conserved genes necessary for normal precursor motility (, , , and ). These genes are required for movement away from somites and later to partition two muscles within the fin bud. During normal development, the middle muscle precursor stream initially populates the fin bud, then the remainder of this stream contributes to the posterior hypaxial muscle. When we block fin bud development by impairing retinoic acid synthesis or Fgfr function, the entire stream contributes to the posterior hypaxial muscle indicating that muscle precursors are not committed to the fin during migration. Our findings demonstrate a conserved muscle precursor motility pathway, identify dynamic cell movements that generate posterior hypaxial and fin muscles, and demonstrate flexibility in muscle precursor fates.
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http://dx.doi.org/10.1242/dev.171421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550023PMC
May 2019

Trim71/lin-41 Links an Ancient miRNA Pathway to Human Congenital Hydrocephalus.

Trends Mol Med 2019 06 8;25(6):467-469. Epub 2019 Apr 8.

Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA; Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA; Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA; Yale-Rockefeller NIH Centers for Mendelian Genomics, Yale University, New Haven, CT, USA; Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, USA. Electronic address:

Tripartite motif 71 (Trim71)/lineage defective 41 (lin-41) is the primary target of the ancient lethal 7 (let-7) miRNA that is essential for survival and development across animal phylogeny. Recent work identified Trim71 as a critical regulator of mammalian neural stem cell (NSC) fate and a bona fide human disease gene in congenital hydrocephalus (CH). Studying TRIM71 as a paradigm of NSC involvement in CH is a remarkable opportunity to better understand the mechanisms that regulate the timing of brain development and the pathogenesis of the most common pediatric neurosurgical disorder.
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http://dx.doi.org/10.1016/j.molmed.2019.03.004DOI Listing
June 2019

Timing and prevalence of revision and removal surgeries after spinal cord stimulator implantation.

J Clin Neurosci 2019 Apr 14;62:80-82. Epub 2019 Jan 14.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

We performed a retrospective study to characterize the timing and prevalence of revision and removal surgeries after spinal cord stimulator (SCS) implantation in patients with chronic pain. In our analysis of 100 patients who had SCS implants, we found that 34% of patients underwent revision surgery and 53% of patients had their implant removed. Of the patients who required revision surgeries, the majority (56%) eventually opted for removal of their SCS system. The median time to the first revision surgery was 16 months post implantation and the median time to removal was 39 months post implantation. Our findings demonstrate that most SCS systems are removed within a few years post implantation, highlighting the clinical need for a more complete understanding of SCS technology in order to refine patient selection criteria.
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http://dx.doi.org/10.1016/j.jocn.2018.12.028DOI Listing
April 2019

Fragile X-Associated Disorders in Serbia: Baseline Quantitative and Qualitative Survey of Knowledge, Attitudes and Practices Among Medical Professionals.

Front Neurosci 2018 21;12:652. Epub 2018 Sep 21.

School of Medicine, Belgrade University, Belgrade, Serbia.

We conducted a knowledge, attitude, and practice (KAP) survey of fragile X-associated disorders (FXD) in Serbia in order to obtain baseline quantitative and qualitative KAP data on fragile X mental retardation 1 gene () pre- and full mutations (PM, FM). The survey's 16-item questionnaire included a knowledge component (12/16), such as self-assessment knowledge (SAK) and factual knowledge (FK, 2/5 questions for PM, FXTAS and FXPOI). Education-directed attitudes in the FXD field and testing practices had 4/16 items, including brief case vignettes of FXTAS and FXPOI, respectively. The study's cohort consisted of primary care physicians (referred to as "physicians" in the rest of the text) throughout Serbia ( = 284, aged 26-64 years, 176/284, 62.2% in Belgrade, Serbia) and senior medical students ( = 245, aged 23-30 years; 33.5% males) at the Belgrade School of Medicine. Strikingly, half of the survey respondents indicated "not having any" knowledge for the fragile X gene premutation and FXD. Physicians were more likely to indicate "not having any" knowledge than students (41.2% of physicians vs. 13.1% of students, < 0.05). Roughly half of the students had "minimal knowledge" (53.5 vs. 30.5% of physicians, < 0.05). Low FK was common in the cohort, as few physicians had "all correct answers" (7.5 vs. 3.7% of students, < 0.05; 16.5 vs. 9.5% of students for the 2/5 premutation-related questions). Statistical analyses identified physicians' practice setting and length of clinical experience as predictors of the lack of FK on questions related to FXD. Physicians were more likely than students to indicate "strongly agreed" to expand their knowledge of the gene premutation and FXD (90.9 vs. 66.7% of students, < 0.01). However, students more frequently indicated that they are willing to recommend DNA testing in their future practices than physicians (93.5 vs. 64.8% of physicians, < 0.001). In , there is a major gap in knowledge regarding fragile X gene PM and FXD among the study's participants in Serbia. The study's informative-educational survey serves as an initial step in the process of enhancing the KAP of medical professionals with regards to the fragile X gene premutation and FXD.
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http://dx.doi.org/10.3389/fnins.2018.00652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160902PMC
September 2018

Two Surgeries Do Not Always Make a Right: Spinal Cord Stimulation for Failed Back Surgery Syndrome.

Yale J Biol Med 2018 09 21;91(3):323-331. Epub 2018 Sep 21.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD.

Failed back surgery syndrome (FBBS) is characterized by chronic pain that persists following spine surgery. In this review, we discuss the use of spinal cord stimulation (SCS) for FBBS treatment and how the clinical use of SCS may be influenced by private manufacturers. While SCS therapy can be promising for the appropriate patient, there remain knowledge gaps in understanding the full potential of SCS technology for delivering optimal therapeutic benefit. We caution that the use of SCS without a complete understanding of the technology may create exploitative situations that private manufacturers can capitalize on while subjecting patients to potentially unnecessary health and financial burdens.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153614PMC
September 2018
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