Molecular Evidence for Olfactory Neuroblastoma as a Tumor of Malignant Globose Basal Cells.

Olfactory neuroblastoma (ONB, esthesioneuroblastoma) is a sinonasal cancer with an underdeveloped diagnostic toolkit, and is the subject of many incidents of tumor misclassification throughout the literature. Despite its name, connections between the cancer and normal cells of the olfactory epithelium have not been systematically explored and markers of olfactory epithelial cell types are not deployed in clinical practice. Here, we utilize an integrated human-mouse single-cell atlas of the nasal mucosa, including the olfactory epithelium, to identify transcriptomic programs that link ONB to a specific population of stem/progenitor cells known as olfactory epithelial globose basal cells (GBCs). Expression of a GBC transcription factor NEUROD1 distinguishes both low- and high-grade ONB from sinonasal undifferentiated carcinoma, a potential histologic mimic with a distinctly unfavorable prognosis. Furthermore, we identify a reproducible subpopulation of highly proliferative ONB cells expressing the GBC stemness marker EZH2, suggesting that EZH2 inhibition may play a role in the targeted treatment of ONB. Finally, we study the cellular states comprising ONB parenchyma using single-cell transcriptomics and identify evidence of a conserved GBC transcriptional regulatory circuit that governs divergent neuronal-versus-sustentacular differentiation. These results link ONB to a specific cell type for the first time and identify conserved developmental pathways within ONB that inform diagnostic, prognostic, and mechanistic investigation.

Olfactory Nomenclature: An Orchestrated Effort to Clarify Terms and Definitions of Dysosmia, Anosmia, Hyposmia, Normosmia, Hyperosmia, Olfactory Intolerance, Parosmia, and Phantosmia/Olfactory Hallucination.

BACKGROUND: Definitions are essential for effective communication and discourse, particularly in science. They allow the shared understanding of a thought or idea, generalization of knowledge, and comparison across scientific investigation. The current terms describing olfactory dysfunction are vague and overlapping. SUMMARY: As a group of clinical olfactory researchers, we propose the standardization of the terms "dysosmia," "anosmia," "hyposmia," "normosmia," "hyperosmia," "olfactory intolerance," "parosmia," and "phantosmia" (or "olfactory hallucination") in olfaction-related communication, with specific definitions in this text. KEY MESSAGES: The words included in this paper were determined as those which are most frequently used in the context of olfactory function and dysfunction, in both clinical and research settings. Despite widespread use in publications, however, there still exists some disagreement in the literature regarding the definitions of terms related to olfaction. Multiple overlapping and imprecise terms that are currently in use are confusing and hinder clarity and universal understanding of these concepts. There is a pressing need to have a unified agreement on the definitions of these olfactory terms by researchers working in the field of chemosensory sciences. With the increased interest in olfaction, precise use of these terms will improve the ability to integrate and advance knowledge in this field.

Therapies for Olfactory Dysfunction - an Update.

PURPOSE OF REVIEW: Olfactory dysfunction is a prevalent condition affecting 5-15% of the general population, with significant impact on quality of life. This review summarizes the most recent and relevant literature in the treatment of olfactory dysfunction. RECENT FINDINGS: Current evidence supports the short-term use of topical corticosteroids and systemic therapy. These treatments may occur in conjunction with olfactory training, which is well supported by the literature. While there are several additional treatments currently under investigation, meaningful conclusions are not yet able to be made regarding their efficacy. The treatment of olfactory dysfunction is targeted at the suspected etiology when possible. After normal aging, chronic rhinosinusitis, post-infectious sequelae including as a result SARS-CoV-2 infection (COVID-19), and head trauma are the most common causes. Current evidence supports the short-term use of topical corticosteroids and systemic therapy. Several additional treatments are under investigation but recommendations for their use cannot currently be made.

Posterior Ischemic Optic Neuropathy in the Setting of Cocaine-Induced Orbital and Sinonasal Inflammation.

Intranasal cocaine abuse can lead to significant sinus and orbital complications, including optic neuropathy. A 46-year-old man with a history of recurrent cocaine-induced sino-orbital inflammation and infection with bony destruction presented with acute, painless, vision loss. Examination revealed no light perception vision. MRI of the orbits demonstrated new restricted diffusion of the right optic nerve on diffusion-weighted imaging and apparent diffusion coefficient sequences, consistent with posterior ischemic optic neuropathy. This is the first among cases of cocaine-induced optic neuropathy in the literature to illustrate ischemic changes on MRI in the optic nerve, highlighting the utility of diffusion-weighted imaging/apparent diffusion coefficient sequences when optic neuropathy is suspected and further suggesting an underlying ischemic etiology in similar cases.

Clinical Olfactory Working Group consensus statement on the treatment of postinfectious olfactory dysfunction.

BACKGROUND: Respiratory tract viruses are the second most common cause of olfactory dysfunction. As we learn more about the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with the recognition that olfactory dysfunction is a key symptom of this disease process, there is a greater need than ever for evidence-based management of postinfectious olfactory dysfunction (PIOD). OBJECTIVE: Our aim was to provide an evidence-based practical guide to the management of PIOD (including post-coronavirus 2019 cases) for both primary care practitioners and hospital specialists. METHODS: A systematic review of the treatment options available for the management of PIOD was performed. The written systematic review was then circulated among the members of the Clinical Olfactory Working Group for their perusal before roundtable expert discussion of the treatment options. The group also undertook a survey to determine their current clinical practice with regard to treatment of PIOD. RESULTS: The search resulted in 467 citations, of which 107 articles were fully reviewed and analyzed for eligibility; 40 citations fulfilled the inclusion criteria, 11 of which were randomized controlled trials. In total, 15 of the articles specifically looked at PIOD whereas the other 25 included other etiologies for olfactory dysfunction. CONCLUSIONS: The Clinical Olfactory Working Group members made an overwhelming recommendation for olfactory training; none recommended monocycline antibiotics. The diagnostic role of oral steroids was discussed; some group members were in favor of vitamin A drops. Further research is needed to confirm the place of other therapeutic options.

Observed progression from melanosis with melanocyte hyperplasia to sinonasal melanoma with distant metastasis and a unique genetic rearrangement.

Melanosis, clinically presenting as a benign macular hyperpigmentation, consists of increased pigmentation (melanotic or melanocytic) either in the mucosal epithelial cells or as subepithelial pigment-laden macrophages. On the other hand, primary sinonasal mucosal melanoma (SNMM) is a rare disease with poor prognosis and high rates of local recurrence and metastasis. We report follow-up on a previously presented case of a 53-year-old man with recurrent clinical melanosis that progressed from histopathological melanocytic hyperplasia to melanoma in situ over a period of 4.8 years (Yao et al. Allergy Rhinol (Providence), 2016;7(3):164-167). The patient experienced multiple recurrences and local spread despite multiple extensive surgeries. We now report that this patient ultimately developed bilateral invasive SNMM and died with metastatic melanoma. Molecular analysis of the invasive melanoma revealed ALK rearrangement, specifically an EML4-ALK fusion, which represents the first report of this particular genetic variant in mucosal melanoma.

The Neuroregenerative Capacity of Olfactory Stem Cells Is Not Limitless: Implications for Aging.

The olfactory epithelium (OE) of vertebrates is a highly regenerative neuroepithelium that is maintained under normal conditions by a population of stem and progenitor cells, globose basal cells (GBCs), which also contribute to epithelial reconstitution after injury. However, aging of the OE often leads to neurogenic exhaustion, the disappearance of both GBCs and olfactory sensory neurons (OSNs). Aneuronal tissue may remain as olfactory, with an uninterrupted sheet of apically arrayed microvillar-capped sustentacular cell, or may undergo respiratory metaplasia. We have generated a transgenic mouse model for neurogenic exhaustion using olfactory marker protein-driven Tet-off regulation of the A subunit of Diphtheria toxin such that the death of mature OSNs is accelerated. At as early as 2 months of age, the epithelium of transgenic mice, regardless of sex, recapitulates what is seen in the aged OE of humans and rodents. Areas of the epithelium completely lack neurons and GBCs; whereas the horizontal basal cells, a reserve stem cell population, show no evidence of activation. Surprisingly, other areas that were olfactory undergo respiratory metaplasia. The impact of accelerated neuronal death and reduced innervation on the olfactory bulb (OB) was also examined. Constant neuronal turnover leaves glomeruli shrunken and affects the dopaminergic interneurons in the periglomerular layer. Moreover, the acceleration of OSN death can be reversed in those areas where some GBCs persist. However, the projection onto the OB recovers incompletely and the reinnervated glomeruli are markedly altered. Therefore, the capacity for OE regeneration is tempered when GBCs disappear.SIGNIFICANCE STATEMENT A large percentage of humans lose or suffer a significant decline in olfactory function as they age. Therefore, quality of life suffers and safety and nutritional status are put at risk. With age, the OE apparently becomes incapable of fully maintaining the neuronal population of the epithelium despite its well known capacity for recovering from most forms of injury when younger. Efforts to identify the mechanism by which olfactory neurogenesis becomes exhausted with age require a powerful model for accelerating age-related tissue pathology. The current OMP-tTA;TetO-DTA transgenic mouse model, in which olfactory neurons die when they reach maturity and accelerated death can be aborted to assess the capacity for structural recovery, satisfies that need.

Characterization and Correction of Olfactory Deficits in Kidney Disease.

Patients with CKD suffer from food aversion, anorexia, and malnutrition. Although olfaction has a significant role in determining food flavor, our understanding of olfactory impairment and of the olfaction-nutrition axis in patients with kidney disease is limited. We quantified odor identification, odor threshold, and subjective odor perception in a cohort (n=161) comprising 36 participants with CKD, 100 participants with ESRD, and 25 controls. We investigated olfaction-nutrition associations in these participants and examined a novel intervention to improve olfaction in ESRD. The mean odor identification score was lower in patients with CKD (75.6%±13.1%; P=0.02) and ESRD (66.8%±15.1%; P<0.001) than in controls (83.6%±11.4%). Patients with ESRD exhibited higher odor threshold than the remaining participants exhibited. All groups had similar scores for subjective smell assessment. In multivariable adjusted analyses, kidney disease associated with increased odds of odor identification deficits (odds ratio, 4.80; 95% confidence interval, 1.94 to 11.89). A reduction in odor identification score was associated with higher subjective global assessment score and lower serum total cholesterol, LDL cholesterol, and albumin concentrations. We found no associations between odor threshold and nutritional parameters. In a proof of concept, 6-week, open-label clinical trial, intranasal theophylline (an epithelial membrane transport and proton secretion activator) increased odor identification score in five out of seven (71%) patients with ESRD. In conclusion, patients with kidney disease have olfactory deficits that may influence their nutritional status. Our preliminary results regarding olfactory improvement using intranasal theophylline warrant confirmation in a randomized controlled trial.

Meningoencephalocele and Cerebrospinal Fluid Leak Complicating Orbital Decompression.

A 51-year-old man who had undergone right orbital decompression 5 months earlier developed a meningoencephalocele extending in the right sphenoid sinus through a skull base defect of the right ethmoid, sphenoid, and frontal bones. The authors report the third case to their knowledge of meningoencephalocele with cerebrospinal fluid leak after orbital decompression and discuss its management and measures that can be taken to prevent this rare but serious complication.

The regeneration of P2 olfactory sensory neurons is selectively impaired following methyl bromide lesion.

The capacity of the peripheral olfactory system to recover after injury has not been thoroughly explored. P2-IRES-tauLacZ mice were exposed to methyl bromide, which causes epithelial damage and kills 90% of the P2 neurons. With subsequent neuronal regeneration, P2 neurons recover within their usual territory to equal control numbers by 1 month but then decline sharply to roughly 40% of control by 3 months. At this time, the P2 projection onto the olfactory bulb is erroneous in several respects. Instead of converging onto 1 or 2 glomeruli per surface, small collections of P2 axons innervate multiple glomeruli at roughly the same position in the bulb as in controls. Within these glomeruli, the P2 axons are aggregated near the edge, whereas the remainder of the glomerulus contains olfactory marker protein (+), non-P2 axons, violating the one receptor-one glomerulus rule normally observed. The aggregates are denser than found in control P2-innervated glomeruli, suggesting that the P2 axons may not be synaptically connected. Based on published literature and other data, we hypothesize that P2 neurons lose out in an activity-based competition for synaptic territory within the glomeruli and are not maintained at control numbers due to a lack of trophic support from the bulb.

Trends of Odontogenic Sinusitis Incidence During the COVID-19 Pandemic.

OBJECTIVES: The COVID-19 pandemic affected the epidemiology of several diseases. This study aims to compare the incidence of surgically treated odontogenic sinusitis (ODS) before and during the COVID-19 pandemic and identify unique features. METHODS: A retrospective chart review of patients who underwent at least maxillary antrostomy at a tertiary referral center was performed. The patients were divided into two cohorts: "pre-COVID" (March 2018 to February 2020) and "COVID" (March 2020 to February 2022). Data on demographics, comorbidities, and treatment interventions were collected and analyzed. RESULTS: Of the 734 patients who underwent maxillary antrostomy, 370 (50.4%) were operated on during the COVID period, with a mean age of 53.1 ± 15.7 years. ODS was found as the etiology of 22 (6%) and 45 (12.2%) of the pre-COVID and COVID cases, respectively (p = 0.006). Although no difference was found in the incidence of diabetes (p = 0.9) or obesity (p = 0.7) between groups, a trend toward higher incidence of immunosuppression was found in the pre-COVID patients (18.2% vs. 0%, p = 0.06). A higher incidence of sphenoid sinus involvement (31.8% vs. 8.9%, p < 0.05) was identified in the pre-COVID group; however, no differences in ethmoid (86.4% vs. 86.7%, p = 0.999) or frontal sinus involvement (54.5% vs. 37.8%, p = 0.3) were found between the groups. CONCLUSION: There was an increase in the incidence of ODS during the first 2 years of the COVID-19 pandemic compared to the 2 years prior. Similar clinical characteristics were found in both groups. Future studies focusing on specific etiologies to explain ODS preponderance may help determine optimal treatment and prevention strategies. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:1597-1602, 2024.

Five-year EuroQol 5-Dimension Outcomes After Endoscopic Sinus Surgery.

OBJECTIVE: The EuroQol 5-Dimension (EQ-5D) is a general health survey that is quick to administer, widely used, and directly convertible to health utility values (HUV). We aim to describe the five-year EQ-5D outcomes among patients who undergo surgical treatment for chronic rhinosinusitis (CRS). STUDY DESIGN: Prospective observational cohort study. METHODS: Patients with CRS completed the EQ-5D questionnaire preoperatively and annually for five years following endoscopic sinus surgery. Paired t-tests and McNemar's tests were used to compare preoperative and postoperative scores. Mixed-effects modeling was used for multivariate analysis. RESULTS: Among 1296 patients enrolled in our study, 812 (74.7%) completed the postoperative survey at one year and 336 (38.9%) completed it at five years. There was a significant and sustained reduction of patients reporting pain/discomfort (74.9% vs. 58.0%, p < 0.001) and anxiety/depression (49.6% vs. 38.1%, p = 0.01) out to five years. Frequency of problems reported in the usual activity domain decreased at one year and was sustained through year four (30.6% vs 19.7%, p = 0.003). After multivariable modeling, female gender (p = 0.02), prior sinus surgery (p = 0.01), tobacco use (p = 0.038), headaches (p = 0.013), allergies (p = 0.001), diabetes (p = 0.022), hypertension (p = 0.036), higher preoperative SNOT-22 score (p < 0.001), and a lower preoperative Lund-Mackay score (p < 0.001) were associated with significantly worse EQ-5D HUV over time. Similarly, a worse EQ-5D Visual Analog Scale (VAS) over time was associated with allergies (p = 0.03), diabetes (p < 0.001), hypertension (p = 0.04), higher preoperative SNOT-22 score (p < 0.001), and prior sinus surgery (p < 0.001). CONCLUSION: Patients with chronic rhinosinusitis experience significant sustained improvements in health-related quality of life up to five years after ESS as measured by the EQ-5D instrument. LEVEL OF EVIDENCE: Level 2 Laryngoscope, 134:2592-2601, 2024.

Endoscopic endonasal approach for olfactory groove meningioma resection: Strategies and outcomes in a retrospective case series.

OBJECTIVE: Though the endoscopic endonasal approach (EEA) is a widely accepted treatment for skull base tumors, the specific use of EEA for olfactory groove meningiomas (OGMs) is debated, with variable outcomes reported in the literature. We review the surgical results of OGM resections for one surgeon including the operative approach, surgical nuances, and outcomes, with a focus on factors relating to patient selection which favor EEA over transcranial approaches. METHODS: We retrospectively reviewed thirteen cases of endoscopic endonasal resection of olfactory groove meningiomas. Patient characteristics, clinical characteristics, surgical outcomes, and complications were analyzed. Extent of resection was determined based on volumetric analysis of pre- and postoperative MRI. RESULTS: Anatomic characteristics that render a tumor difficult to access fully are lateral extension beyond the mid-orbit and anterior extension to the falx. Simpson Grade I resection was achieved in 11/13 (84.6 %) cases. Mean pre-operative tumor volume was 8.99 cm3 (range 2.19-16.79 cm3), and 92 % of tumors were WHO grade I. We demonstrate 2 cases of smell preservation, possible with small unilateral tumors and tumors that are confined to either the anterior or posterior portion of the cribriform plate. The post-operative CSF leak rate was 7.7 %, without prophylactic lumbar CSF drainage. The mortality rate was 7.7 % (n = 1) after infectious complications following CSF leak. CONCLUSIONS: Endoscopic endonasal resection of olfactory groove meningiomas is an effective and safe operative method with outcomes and complication rates comparable to transcranial approaches. Key considerations include careful patient selection and familiarity with technical nuances of endoscopic endonasal approach for this specific tumor type.

Nasal hamartoma associated with duplicated pituitary.

Nasal hamartomas are rare congenital lesions. We describe a case of nasal hamartoma associated with pituitary duplication and other midline anomalies. A 40-year-old female with a history of breast cancer presented with nasal obstruction. Computed tomography and magnetic resonance imaging revealed a mass arising from the nasal septum, as well as duplication of the pituitary and a skull base canal that extended from the margin of the left pituitary fossa to the nasal mass. The mass was subsequently resected via a transnasal endoscopic approach and histology confirmed the presence of hamartoma. Nasal hamartomas are benign lesions that can be associated with other midline anomalies, such as duplicated pituitary, and can be managed conservatively.

Techniques in Staining of Rodent and Human Olfactory Tissue.

Staining of olfactory tissue allows for evaluation of the organization of specific cell types within the specimen and allows for assessment in abnormalities of function that may be related to changes in normal tissue architecture. Histochemical staining and immunohistochemical (IHC) techniques are the most common methods for visualizing olfactory epithelium and olfactory bulbs. Here we describe the method of IHC for olfactory tissue utilizing both fluorescent and peroxidase-based methods of visualization.

Safety, tolerability, and effectiveness of anticoagulation and antiplatelet therapy in hereditary hemorrhagic telangiectasia.

BACKGROUND: Antithrombotic therapy (anticoagulation and antiplatelet therapy) is frequently needed in patients with hereditary hemorrhagic telangiectasia (HHT); however, data describing and guiding its use are very limited. OBJECTIVES: To investigate the safety, tolerability, and effectiveness of antithrombotic therapy in HHT in a cohort large enough to compare agents, evaluate for baseline predictors of premature discontinuation, and evaluate hematologic support requirements and healthcare utilization before and after antithrombitc therapy initiation. METHODS: We performed a multicenter observational cohort study characterizing the outcomes of antithrombic therapy in adults with HHT. RESULTS: A total of 119 patients with HHT with 187 discrete antithrombotic therapy episodes were included. Of these, 59 patients (50%) dose-reduced and/or prematurely discontinued therapy (including 52 patients [44%] who discontinued) due to worsened bleeding complications. Initiation at reduced dose intensity had a similar premature discontinuation rate (49%) as initiation at standard dose intensity (43%). In a multivariable logistic model, a history of gastrointestinal bleeding was associated with 3.25-fold odds of discontinuation (p = .001). Hemoglobin was significantly lower (10.8 g/dL vs 12.2 g/dL, p < .001), and the need for hematologic support (intravenous iron and/or red blood cell transfusion) was significantly higher (29 patients vs 12 patients, p = .004) in the 3 months after antithrombotic therapy initiation vs the 3 months before; emergency department visits and hospital admissions due to bleeding also increased. The rates of dose-reduction and/or premature discontinuation were similar regardless of the anticoagulant class (warfarin, 46%; heparin-based, 48%; direct oral anticoagulants, 44%) or with multiple simultaneous agents (44%) but were slightly lower with single-agent antiplatelet therapy (37%). Thromboembolism despite receiving antithrombotic therapy was common (18 patients, 15%) with varying outcomes. CONCLUSION: Antithrombotic therapy is challenging in HHT, resulting in objectively higher morbidity and health care utilization from worsened bleeding. Discontinuation rates approached 50% regardless of the dose intensity at initiation or type of antithrombotic agent used and were higher in patients with a gastrointestinal bleeding history.

Defining the Health Utility Value of Medical Management of Chronic Rhinosinusitis: A Prospective Pilot Study.

The extent to which medical management of chronic rhinosinusitis (CRS) may improve health utility value (HUV) remains unknown. We conducted a prospective pilot study to longitudinally assess HUV via the EQ-5D-5L questionnaire in patients with CRS who were receiving medical therapy but did not undergo sinus surgery. The primary study outcome was HUV at 12-month follow-up; secondary end points included HUV at baseline and 3- and 24-month follow-up. Our study enrolled 115 patients who received the following medical treatments: saline irrigations (n = 83, 72.2%), steroid sprays (n = 93, 80.9%), antihistamines (n = 64, 55.7%), steroid irrigations (n = 29, 25.2%), and oral antibiotics (n = 58, 50.4%). There was a statistically significant improvement (mean, +0.073; P = .003) in HUV at 12 months (minimum clinically important difference, 0.055) as compared with baseline. However, there was no statistically significant trend in HUV over time between baseline and 24-month follow-up (P = .3033). These findings can inform cost-effectiveness research as new medical therapies for CRS emerge.

Rapid fluorescent vital imaging of olfactory epithelium.

Olfactory epithelium (OE) undergoes degeneration in disorders such as age-related and post-viral olfactory dysfunction. However, methods for real-time in vivo detection of OE and assessment of total extent within the nasal cavity are currently unavailable. We identified two fluorescence probes for rapidly detecting and evaluating the entire extent of mice OE with topical application. Taking advantage of the differential expression of the enzymes cytochrome p450 (CYP) and γ-glutamyltranspeptidase (GGT) in OE relative to respiratory epithelium, we utilized the conversion of coumarin (a substrate of various CYP subtypes) and gGlu-HRMG (a substrate of GGT) by these enzymes to form metabolites with fluorescent emissions in the duct cells and sustentacular cells of neuron-containing OE. In depleted and regenerated OE model, the emission of these probes remained absent in respiratory metaplasia but appeared in regenerated OE. These substrates could be used to monitor OE degeneration and follow regenerative response to therapeutic interventions.

A Rare Complication of Chronic Otitis Media: Central Skull Base Osteomyelitis Managed With Combined Endoscopic Transmastoid and Transsphenoidal Debridement.

OBJECTIVE: This report describes a case of otogenic central skull base osteomyelitis (CSBO) requiring complex surgical intervention and reviews the literature on management of this entity. PATIENT: A 76-year-old man presented with a nearly 20-year history of chronic otomastoiditis and cholesteatoma with ultimate progression to severe CSBO with involvement of the petrous apex, clivus, and craniocervical junction. INTERVENTIONS: CSBO was managed with culture-directed antibiotic therapy, hyperbaric oxygen, and surgical intervention including serial combined endoscopic transmastoid and transsphenoidal debridements. MAIN OUTCOME MEASURES: Symptom resolution, antibiotic holiday, and stable disease on surveillance imaging. RESULTS: With antibiotic treatment and surgical debridement including creation of a drainage pathway from the skull base to the sphenoid sinus, intermittent stretches of disease quiescence were realized over the course of nearly a decade. Despite extensive debridement and skull base reconstruction, the patient ultimately succumbed to the disease process. CONCLUSIONS: CSBO poses significant management challenges to the otologist. Herein, we present a rare case of CSBO managed over a prolonged period of time with antibiotics and combined anterior and lateral skull base debridement.