Enlargement of the cerebrospinal fluid (CSF)–filled brain ventricles (cerebral ventriculomegaly), the cardinal feature of congenital hydrocephalus (CH), is increasingly recognized among patients with ...autism spectrum disorders (ASD). KATNAL2, a member of Katanin family microtubule-severing ATPases, is a known ASD risk gene, but its roles in human brain development remain unclear. Here, we show that nonsense truncation of Katnal2 ( Katnal2Δ 17 ) in mice results in classic ciliopathy phenotypes, including impaired spermatogenesis and cerebral ventriculomegaly. In both humans and mice, KATNAL2 is highly expressed in ciliated radial glia of the fetal ventricular–subventricular zone as well as in their postnatal ependymal and neuronal progeny. The ventriculomegaly observed in Katnal2 Δ17 mice is associated with disrupted primary cilia and ependymal planar cell polarity that results in impaired cilia-generated CSF flow. Further, prefrontal pyramidal neurons in ventriculomegalic Katnal2 Δ 17 mice exhibit decreased excitatory drive and reduced high-frequency firing. Consistent with these findings in mice, we identified rare, damaging heterozygous germline variants in KATNAL2 in five unrelated patients with neurosurgically treated CH and comorbid ASD or other neurodevelopmental disorders. Mice engineered with the orthologous ASD-associated KATNAL2 F244L missense variant recapitulated the ventriculomegaly found in human patients. Together, these data suggest KATNAL2 pathogenic variants alter intraventricular CSF homeostasis and parenchymal neuronal connectivity by disrupting microtubule dynamics in fetal radial glia and their postnatal ependymal and neuronal descendants. The results identify a molecular mechanism underlying the development of ventriculomegaly in a genetic subset of patients with ASD and may explain persistence of neurodevelopmental phenotypes in some patients with CH despite neurosurgical CSF shunting.
•Psychotropic medication use is common in spinal cord stimulation therapy population.•Spinal cord stimulation therapy does not lower daily psychotropic medication use.•Pre-operative multi-class ...psychotropic use increases the risk of treatment failure.•Multimodal medical therapy can enhance the efficacy of spinal cord stimulation.
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.
Abstract
Clinical improvement following neurosurgical cerebrospinal fluid shunting for presumed idiopathic normal pressure hydrocephalus is variable. Idiopathic normal pressure hydrocephalus patients ...may have undetected Alzheimer’s disease-related cortical pathology that confounds diagnosis and clinical outcomes. In this study, we sought to determine the utility of cortical tissue immuno-analysis in predicting shunting outcomes in idiopathic normal pressure hydrocephalus patients. We performed a pooled analysis using a systematic review as well as analysis of a new, original patient cohort. Of the 2707 screened studies, 3 studies with a total of 229 idiopathic normal pressure hydrocephalus patients were selected for inclusion in this meta-analysis alongside our original cohort. Pooled statistics of shunting outcomes for the 229 idiopathic normal pressure hydrocephalus patients and our new cohort of 36 idiopathic normal pressure hydrocephalus patients revealed that patients with Aβ + pathology were significantly more likely to exhibit shunt nonresponsiveness than patients with negative pathology. Idiopathic normal pressure hydrocephalus patients with Alzheimer’s disease -related cortical pathology may be at a higher risk of treatment facing unfavorable outcomes following cerebrospinal fluid shunting. Thus, cortical tissue analysis from living patients may be a useful diagnostic and prognostic adjunct for patients with presumed idiopathic normal pressure hydrocephalus and potentially other neurodegenerative conditions affecting the cerebral cortex.
•Opioid dependence is a major problem in chronic pain patients.•The effects of spinal cord stimulation (SCS) on opioid use in chronic low back pain remain controversial.•We characterized long-term ...patterns of opioid usage after SCS implantation in patients who underwent device removal.•Changes in opioid consumption were variable 1-year after implantation.•Daily opioid use did not decrease in most patients 1-year after SCS implantation.
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.
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.
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.
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.
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.
Hydrocephalus (HC) is a heterogenous disease characterized by alterations in cerebrospinal fluid (CSF) dynamics that may cause increased intracranial pressure. HC is a component of a wide array of ...genetic syndromes as well as a secondary consequence of brain injury (intraventricular hemorrhage (IVH), infection, etc.) that can present across the age spectrum, highlighting the phenotypic heterogeneity of the disease. Surgical treatments include ventricular shunting and endoscopic third ventriculostomy with or without choroid plexus cauterization, both of which are prone to failure, and no effective pharmacologic treatments for HC have been developed. Thus, there is an urgent need to understand the genetic architecture and molecular pathogenesis of HC. Without this knowledge, the development of preventive, diagnostic, and therapeutic measures is impeded. However, the genetics of HC is extraordinarily complex, based on studies of varying size, scope, and rigor. This review serves to provide a comprehensive overview of genes, pathways, mechanisms, and global impact of genetics contributing to all etiologies of HC in humans.
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.
Display omitted
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.
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.
Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1, a component of the BRG1-associated ...factor (BAF) chromatin remodelling complex, as a candidate congenital hydrocephalus gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, congenital hydrocephalus-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Here, we aimed to assess the prevalence of SMARCC1 variants in an expanded patient cohort, describe associated clinical and radiographic phenotypes, and assess the impact of Smarcc1 depletion in a novel Xenopus tropicalis model of congenital hydrocephalus. To do this, we performed a genetic association study using whole-exome sequencing from a cohort consisting of 2697 total ventriculomegalic trios, including patients with neurosurgically-treated congenital hydrocephalus, that total 8091 exomes collected over 7 years (2016-23). A comparison control cohort consisted of 1798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents were sourced from the Simons Simplex Collection. Enrichment and impact on protein structure were assessed in identified variants. Effects on the human fetal brain transcriptome were examined with RNA-sequencing and Smarcc1 knockdowns were generated in Xenopus and studied using optical coherence tomography imaging, in situ hybridization and immunofluorescence. SMARCC1 surpassed genome-wide significance thresholds, yielding six rare, protein-altering de novo variants localized to highly conserved residues in key functional domains. Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common. Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant human fetal brain and Smarcc1-variant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. These results suggest de novo variants in SMARCC1 cause a novel human BAFopathy we term 'SMARCC1-associated developmental dysgenesis syndrome', characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodelling complex for human brain morphogenesis and provide evidence for a 'neural stem cell' paradigm of congenital hydrocephalus pathogenesis. These results highlight utility of trio-based whole-exome sequencing for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest whole-exome sequencing may be a valuable adjunct in clinical management of congenital hydrocephalus patients.
PDF
