Conventional clinical signs and symptoms are poor predictors of postoperative cerebrospinal fluid leak: A single-centre cohort perspective.

BACKGROUND: Postoperative cerebrospinal fluid (CSF) leak remains a concerning complication of the endoscopic endonasal approach (EEA) for skull base pathology. Signs and symptoms suggesting CSF leak often trigger additional workup during the postoperative course. We systematically evaluate associations between subjectively reported clinical signs/symptoms noted during the immediate postoperative period and incidence of postoperative CSF leaks. METHODS: Retrospective chart review was conducted at a tertiary academic medical centre including 137 consecutive patients with intraoperative CSF leak during EEA with primary repair between July 2018 and August 2022. Postoperative CSF leak associations with clinical signs and symptoms were evaluated using positive (PPV) and negative predictive values (NPV), sensitivity, specificity and odds ratio (OR) via univariate logistic regression. RESULTS: Seventy-nine patients (57.7%) had high-flow leaks repaired and 5 (3.6%) developed CSF leaks postoperatively. Of reported symptoms, rhinorrhea was most common (n = 52, 38.0%; PPV [95% CI] = 7.6% [4.8%, 11.9%]), followed by severe headache (n = 47, 34.3%; 6.3% [3.1%, 12.5%]), dizziness (n = 43, 31.4%; 2.3% [0.4%, 12.1%]), salty or metallic taste (n = 20, 14.6%; 9.9% [3.3%, 25.8%]), and throat drainage (n = 10, 7.3%; 9.9% [1.7%, 41.4%]). Nausea or vomiting constituted the most reported sign concerning for CSF leak (n = 73, 53.3%; PPV [95% CI] = 4.1% [2.0%, 8.1%]). On univariate regression, no sign or symptom, including rhinorrhea (OR [95% CI] = 7.00 [0.76-64.44]), throat drainage (3.42 [0.35-33.86]), salty/metallic taste (4.22 [0.66-27.04]), severe headache (3.00 [0.48-18.62]), dizziness (0.54 [0.06-4.94]), fever (3.16 [0.50-19.99]), and nausea/vomiting (1.33 [0.22-8.21]), associated with postoperative CSF leak. CONCLUSIONS: A range of subjectively reported symptoms and signs failed to predict postoperative CSF leak. Further investigation is warranted to inform appropriate attention and response.

The Effect of Cyclic Strain on Human Fibroblasts With Lamin A/C Mutations and Its Relation to Heart Disease.

Although mutations in the Lamin A/C gene (LMNA) cause a variety of devastating diseases, the pathological mechanism is often unknown. Lamin A/C proteins play a crucial role in forming a meshwork under the nuclear membrane, providing the nucleus with mechanical integrity and interacting with other proteins for gene regulation. Most LMNA mutations result in heart diseases, including some types that primarily have heart disease as the main pathology. In this study, we used cells from patients with different LMNA mutations that primarily lead to heart disease. Indeed, it is a mystery why a mutation to the protein in every nucleus of the body manifests as a disease of primarily the heart in these patients. Here, we aimed to investigate if strains mimicking those within the myocardial environment are sufficient to cause differences in cells with and without the LMNA mutation. To test this, a stretcher device was used to induce cyclic strain upon cells, and viability/proliferation, cytoskeleton and extracellular matrix organization, and nuclear morphology were quantified. The properties of cells with Hutchinson-Gilford progeria syndrome (HGPS) were found to be significantly different from all other cell lines and were mostly in line with previous findings. However, the properties of cells from patients who primarily had heart diseases were not drastically different when compared to individuals without the LMNA mutation. Our results indicated that cyclic strain alone was insufficient to cause any significant differences that could explain the mechanisms that lead to heart diseases in these patients with LMNA mutations.

Anatomic Relationship Between the Head of the Middle Turbinate and First Olfactory Filum: A Radiographic Assessment.

BACKGROUND: The endoscopic modified Lothrop procedure (EMLP) has become a frequently utilized procedure in rhinologic surgery. One of the most serious complications of the procedure is cerebrospinal fluid leak, which may occur due to lack of recognition of the anterior skull base in the region of the first olfactory filum (FOF), or direct injury to the FOF itself. OBJECTIVES: To evaluate the position of the head of the middle turbinate (MT) relative to the FOF, which is an important landmark in the EMLP. METHODS: A series of previously obtained patient computed tomography scans of the sinus were reviewed. A reproducible process was implemented to obtain the measurements. First, the FOF was identified on an axial series. Using a localization feature of the radiographic software, this anteroposterior (AP) position could be visualized in a coronal plane. Subsequently, the MT was viewed in a sagittal plane, where a measurement between the head of the MT and the AP position of the FOF could be performed. RESULTS: The AP distance between the head of the MT and the FOF was measured in 92 patients. The head of the MT was either at or anterior to the FOF in all measured subjects. The mean anterior distance of the head of the MT to FOF was 3.6 mm (±2.4 mm) on the right, and 3.8 mm (±2.2 mm) on the left. The range in AP distance was 0 to 12 mm. There was no significant difference in AP distance between the head of the MT and FOF based on gender (P = .413) or diagnosis (P = .254). CONCLUSIONS: In our study, the head of the MT was reliably at or anterior to the FOF in all subjects, suggesting its utility as a fixed landmark in endoscopic sinus surgery, particularly in the EMLP. LEVEL OF EVIDENCE: N/A.

Tissue Sealant Impact on Skull Base Reconstruction Outcomes: A Systematic Review and Meta-Analysis.

OBJECTIVE: Despite significant advances in understanding of skull base reconstruction principles, the role of tissue sealants in modifying postoperative cerebrospinal fluid (CSF) leak outcomes remains controversial. We evaluate postoperative CSF leak incidence associated with tissue sealant use in skull base defect repair during endoscopic skull base surgery (ESBS). DATA SOURCES: Web of Science, PubMed/MEDLINE, Scopus, and Cochrane Library. REVIEW METHODS: Systematic review and meta-analysis of risk differences (RD). A search strategy identified original studies reporting CSF leakage following ESBS with disaggregation by tissue sealant use and/or type. RESULTS: 27 non-randomized studies (n = 2,403) were included for qualitative and meta-analysis. Reconstruction with a tissue sealant did not significantly reduce postoperative CSF leak risk compared with reconstruction without sealant (RD[95% CI] = 0.02[-0.01, 0.05]). Sub-analyses of dural sealant (-0.02[-0.11, 0.07]) and fibrin glue (0.00[-0.07, 0.07]) compared with no sealant were similarly unremarkable. Postoperative CSF leakage was not significantly modulated in further sub-analyses of DuraSeal (0.02[-0.02, 0.05]), Adherus (-0.03[-0.08, 0.03]), or Bioglue (-0.06[-0.23, 0.12]) versus no dural sealant use, or Tisseel/Tissucol versus fibrin glue nonuse (0.00[-0.05, 0.05]). No significant association was seen comparing dural sealant use versus fibrin glue use on pairwise (0.01[-0.03, 0.05]) or network meta-analysis (-0.01[-0.05, 0.04]). Limitations in source literature prevented sub-analyses stratified by leak characteristics, defect size and location, and accompanying reconstruction materials. CONCLUSION: Tissue sealant use did not appear to impact postoperative CSF leak incidence when compared with nonuse. Higher quality studies are warranted to thoroughly elucidate the clinical value of adjunct sealant use in endoscopic skull base reconstruction. LEVEL OF EVIDENCE: N/A Laryngoscope, 2024.

Comparison of patient-reported outcomes and clinical characteristics among patients with pituitary macroadenomas and giant adenomas.

KEY POINTS: Patients with giant adenomas are more likely to have tumor extension into the paranasal sinuses. Compared to macroadenomas, giant adenomas are not associated with worse preoperative SNOT-22 scores.

Tympanostomy tube placement for pressure-sensitive vertigo.

Objective: To evaluate tympanostomy tube placement in patients with pressure-sensitive vertigo. Methods: Retrospective case series. Results: Six patients with pressure-sensitive vertigo reported resolution of their vertigo and other vestibular symptoms after placement of the tympanostomy tubes. All recurrences of symptoms were due to either extrusion or plugging of the tubes. All patients fulfilled the criteria for vestibular migraine. None of the patients had superior canal dehiscence on imaging or precedent event that triggered the problem, and all had a negative fistula test. Conclusion: Tympanostomy tube placement should be considered in selected patients with vertigo exacerbated by seemingly small changes in atmospheric pressure (e.g., just prior to thunderstorms, air travel, or travel to the mountains). By eliminating the capability of the tympanic membrane to sense changes in pressure with a tube, patients with pressure-induced vertigo (in the absence of perilymph fistula or superior canal dehiscence) may have relief of their symptoms.

DNA methylation analysis reveals epimutation hotspots in patients with dilated cardiomyopathy-associated laminopathies.

BACKGROUND: Mutations in LMNA, encoding lamin A/C, lead to a variety of diseases known as laminopathies including dilated cardiomyopathy (DCM) and skeletal abnormalities. Though previous studies have investigated the dysregulation of gene expression in cells from patients with DCM, the role of epigenetic (gene regulatory) mechanisms, such as DNA methylation, has not been thoroughly investigated. Furthermore, the impact of family-specific LMNA mutations on DNA methylation is unknown. Here, we performed reduced representation bisulfite sequencing on ten pairs of fibroblasts and their induced pluripotent stem cell (iPSC) derivatives from two families with DCM due to distinct LMNA mutations, one of which also induces brachydactyly. RESULTS: Family-specific differentially methylated regions (DMRs) were identified by comparing the DNA methylation landscape of patient and control samples. Fibroblast DMRs were found to enrich for distal regulatory features and transcriptionally repressed chromatin and to associate with genes related to phenotypes found in tissues affected by laminopathies. These DMRs, in combination with transcriptome-wide expression data and lamina-associated domain (LAD) organization, revealed the presence of inter-family epimutation hotspots near differentially expressed genes, most of which were located outside LADs redistributed in LMNA-related DCM. Comparison of DMRs found in fibroblasts and iPSCs identified regions where epimutations were persistent across both cell types. Finally, a network of aberrantly methylated disease-associated genes revealed a potential molecular link between pathways involved in bone and heart development. CONCLUSIONS: Our results identified both shared and mutation-specific laminopathy epimutation landscapes that were consistent with lamin A/C mutation-mediated epigenetic aberrancies that arose in somatic and early developmental cell stages.

A Study of Gene Expression, Structure, and Contractility of iPSC-Derived Cardiac Myocytes from a Family with Heart Disease due to LMNA Mutation.

Genetic mutations to the Lamin A/C gene (LMNA) can cause heart disease, but the mechanisms making cardiac tissues uniquely vulnerable to the mutations remain largely unknown. Further, patients with LMNA mutations have highly variable presentation of heart disease progression and type. In vitro patient-specific experiments could provide a powerful platform for studying this phenomenon, but the use of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) introduces heterogeneity in maturity and function thus complicating the interpretation of the results of any single experiment. We hypothesized that integrating single cell RNA sequencing (scRNA-seq) with analysis of the tissue architecture and contractile function would elucidate some of the probable mechanisms. To test this, we investigated five iPSC-CM lines, three controls and two patients with a (c.357-2A>G) mutation. The patient iPSC-CM tissues had significantly weaker stress generation potential than control iPSC-CM tissues demonstrating the viability of our in vitro approach. Through scRNA-seq, differentially expressed genes between control and patient lines were identified. Some of these genes, linked to quantitative structural and functional changes, were cardiac specific, explaining the targeted nature of the disease progression seen in patients. The results of this work demonstrate the utility of combining in vitro tools in exploring heart disease mechanics.

Dupuytren's and Ledderhose Diseases in a Family with LMNA-Related Cardiomyopathy and a Novel Variant in the ASTE1 Gene.

Dupuytren's disease (palmar fibromatosis) involves nodules in fascia of the hand that leads to flexion contractures. Ledderhose disease (plantar fibromatosis) is similar with nodules of the foot. While clinical aspects are well-described, genetic mechanisms are unknown. We report a family with cardiac disease due to a heterozygous LMNA mutation (c.736C>T, p.Gln246Stop) with palmar/plantar fibromatosis and investigate the hypothesis that a second rare DNA variant increases the risk for fibrotic disease in LMNA mutation carriers. The proband and six family members were evaluated for the cardiac and hand/feet phenotypes and tested for the LMNA mutation. Fibroblast RNA studies revealed monoallelic expression of the normal LMNA allele and reduced lamin A/C mRNAs consistent with LMNA haploinsufficiency. A novel, heterozygous missense variant (c.230T>C, p.Val77Ala) in the Asteroid Homolog 1 (ASTE1) gene was identified as a potential risk factor in fibrotic disease using exome sequencing and family studies of five family members: four LMNA mutation carriers with fibromatosis and one individual without the LMNA mutation and no fibromatosis. With a possible role in epidermal growth factor receptor signaling, ASTE1 may contribute to the increased risk for palmar/plantar fibromatosis in patients with Lamin A/C haploinsufficiency.

iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases.

Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGLs) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer's disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates. iMGLs were used to examine the effects of Aß fibrils and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning. Furthermore, iMGLs transplanted into transgenic mice and human brain organoids resemble microglia in vivo. Together, these findings demonstrate that iMGLs can be used to study microglial function, providing important new insight into human neurological disease.