Intranasal Insulin for the Treatment of Persistent Post-COVID-19 Olfactory Dysfunction.

OBJECTIVE: To investigate if intranasal insulin could be a treatment option for those suffering from recalcitrant olfactory dysfunction due to COVID-19. STUDY DESIGN: Prospective interventional cohort with a single group. SETTING: Sixteen volunteers with anosmia, severe hyposmia, or moderate hyposmia for more than 60 days as sequelae of severe acute respiratory syndrome coronavirus 2 infections were selected for the study. All volunteers reported that standard therapies, such as corticosteroids, have failed to improve their olfactory function. METHODS: Olfactory function was assessed by the Chemosensory Clinical Research Center test of olfaction (COT) before and after the intervention. Changes in qualitative, quantitative, and global COT scores were investigated. The insulin therapy session consisted of placing into each olfactory cleft 2 pieces of gelatin sponge soaked with neutral protamine Hagedorn (NPH) insulin, 40 IU on each side. The procedure was repeated twice a week for 1 month. Glycaemic blood level was measured before and after each session. RESULTS: The qualitative COT score rose 1.53 points, p = .0001, 95% confidence interval (CI) (-2.12 to -0.94). The quantitative COT score increased by 2.00 points, p = .0002, 95% CI (-3.59 to -1.41). Global COT score had an improvement of 2.01 points, p = .00003, 95% CI (-2.7 to -1.3). Glycaemic blood level dropped on average 10.4 mg/dL, p < .00003, 95% CI (8.1-12.8). CONCLUSION: Our results suggest that the administration of NPH insulin into the olfactory cleft yields a rapid improvement in the sense of smell of patients suffering from persistent post-COVID-19 olfactory dysfunction. Moreover, the procedure seems to be safe and tolerable.

Olfaction in nasal polyp patients after Reboot surgery: an endotype-based prospective study.

PURPOSE: To report biomarkers present in the olfactory mucosa in chronic rhinosinusitis with nasal polyps (CRSwNP) in comparison with nasal polyps and to nasal mucosal tissues from control patients. To evaluate the kinetics of smell over 6 months in patients who underwent Reboot surgery. METHODS: Cohort study from May 2021 to May 2022. We collected samples of olfactory mucosa and nasal polyps from 16 CRSwNP patients and inferior turbinate samples from 20 control subjects. The study was not randomized for surgical and/or medical treatment. Samples were analyzed by Luminex and Unicap 100 to measure biomarkers of inflammation (IL1-ß, IL4, IL5, IL6, IL17, CCL3, CCL4, G-CSF, SE-IgE, total IgE and ECP). 12 of the CRSwNP patients underwent Extended Sniffin'tests at timepoints 1-4 days pre-surgery, and 1, 3 and 6 months after Reboot surgery. RESULTS: Type-2 markers were significantly elevated in OM and polyp tissue in CRSwNP (n = 16) vs. controls (n = 20), P < 0.05. TDI scores improved already 1 month (P < 0.05) after surgery and remained stable for 6 months. Type-2 inflammation in nasal polyps was associated with decreased sense of smell and taste before surgery, but improved after surgery (P = 0.048). Type-3 inflammation was present in the olfactory mucosa and was associated with a better sense of smell before surgery, but a smaller improvement of smell afterward. CONCLUSIONS: Type-2 inflammation is present in the olfactory mucosa in CRSwNP patients and is associated with smell loss. Reboot surgery, aiming to completely remove inflamed sinus mucosa, significantly improves the smell in this group of patients.

Self-awareness of olfactory dysfunction in elderly individuals without neurodegenerative diseases.

PURPOSE: The decrease in smell in the elderly population is frequent and considered a natural process. However, sometimes it can be associated with the decline of cognitive functions, and it is considered a warning for the early stage of neurodegenerative diseases and social impairment. OBJECTIVE: To assess the prevalence of olfactory dysfunction in previous healthy elderly that attended a tertiary hospital in Brazil as escorts and the clinical alterations associated in this population. METHODS: Subjects 60 years or over attending the University Hospital of Campinas were evaluated. Each participant answered a questionnaire, followed by an otorhinolaryngological exam with flexible nasal endoscopy and the Connecticut smell test produced by the Connecticut Chemosensory Clinical Research Center (CCCRC). Elderly people with nasosinusal diseases or with a history of nasal surgery were excluded. RESULTS: Of the total of 103 participants, 16 (15.5%) reported olfactory complaints and 68 (66%) presented impairment in the olfactory test. It was observed that older individuals showed more changes in olfactory function (p = 0.001). Gender, education, lifestyle, comorbidities, medications in use and exposure to pollutants did not influence the impairment olfactory function of this population. CONCLUSIONS: There is a significant prevalence of olfactory dysfunction in the elderly population evaluated. Most of these elderlies also present an inability to identify odours, not having awareness of this olfactory impairment.

Photobiomodulation therapy for treatment olfactory and taste dysfunction COVID-19-related: A case report.

It is postulated that the inflammatory process resulting from SARS-CoV-2 infection is the main cause of smell and taste dysfunctions in patients. In view of this, photobiomodulation, due to its anti-inflammatory and antioxidant effects, may be a promising therapeutic modality to treat these disorders. In the present case report, we observed clinical improvement in the symptoms of anosmia and ageusia related to COVID-19 after treatment with photobiomodulation. Due to the inflammatory nature of COVID-19 and the anti-inflammatory effects, photobiomodulation antioxidants already proven in the literature make it a promising therapeutic modality, especially sequela COVID-related, including olfactory (anosmia) and taste (ageusia) dysfunction. In the present case report, the patient's olfactory and gustatory functions were re-established after 10 treatment sessions with photobiomodulation.

Síntomas atípicos en enfermedad por COVID-19: reporte de caso / Atypical symptoms in COVID-19 disease: case report

The infection caused by the SARS-CoV-2 virus, recently described in Wuhan, China, has put numerous health systems around the world in check. Given its high contagiousness and the exponential growth of cases, it was declared a pandemic by the world health organization. Although the majority of those infected will present mild symptoms, a smaller percentage will present severe manifestations of the disease, such as acute respiratory distress syndrome, requiring ventilator support measures and stays in intensive care units. The main symptoms described in SARS-CoV-2 infection are fever, fatigue, dry cough and myalgia. Despite this, there is a not insignificant number of patients who present with atypical symptoms of the disease, some described are anosmia, ageusia, gastrointestinal symptoms like diarrhea, dermatological manifestations, among others. In these patients it is particularly where the diagnosis is made late, delaying isolation and prevention measures, thus increasing the risk of contagion within the population.

Ageusia and anosmia, a common sign of COVID-19? A case series from four countries.

Over the course of the pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), multiple new clinical manifestations, as the consequence of the tropism of the virus, have been recognized. That includes now the neurological manifestations and conditions, such as headache, encephalitis, as well as olfactory and taste disorders. We present a series of ten cases of RT-PCR-confirmed SARS-CoV-2-infected patients diagnosed with viral-associated olfactory and taste loss from four different countries.

Neurological complications in patients with SARS-CoV-2 infection: a systematic review.

BACKGROUND: As the COVID-19 pandemic unfolds worldwide, different forms of reports have described its neurologic manifestations. OBJECTIVE: To review the literature on neurological complications of SARS-CoV-2 infection. METHODS: Literature search performed following systematic reviews guidelines, using specific keywords based on the COVID-19 neurological complications described up to May 10th, 2020. RESULTS: A total of 43 articles were selected, including data ranging from common, non-specific symptoms, such as hyposmia and myalgia, to more complex and life-threatening conditions, such as cerebrovascular diseases, encephalopathies, and Guillain-Barré syndrome. CONCLUSION: Recognition of neurological manifestations of SARS-CoV-2 should be emphasized despite the obvious challenges faced by clinicians caring for critical patients who are often sedated and presenting other concurrent systemic complications.

Neurological complications in patients with SARS-CoV-2 infection: a systematic review / Complicações neurológicas em pacientes infectados pelo SARS-CoV-2: uma revisão sistemática

ABSTRACT Background: As the COVID-19 pandemic unfolds worldwide, different forms of reports have described its neurologic manifestations. Objective: To review the literature on neurological complications of SARS-CoV-2 infection. Methods: Literature search performed following systematic reviews guidelines, using specific keywords based on the COVID-19 neurological complications described up to May 10th, 2020. Results: A total of 43 articles were selected, including data ranging from common, non-specific symptoms, such as hyposmia and myalgia, to more complex and life-threatening conditions, such as cerebrovascular diseases, encephalopathies, and Guillain-Barré syndrome. Conclusion: Recognition of neurological manifestations of SARS-CoV-2 should be emphasized despite the obvious challenges faced by clinicians caring for critical patients who are often sedated and presenting other concurrent systemic complications.

RESUMO Introdução: À medida que a pandemia da COVID-19 se desenvolve em todo o mundo, diferentes tipos de publicações descreveram suas manifestações neurológicas. Objetivo: Revisar a literatura sobre complicações neurológicas da infecção por SARS-CoV-2. Métodos: A pesquisa bibliográfica foi realizada seguindo diretrizes de revisões sistemáticas, usando palavras-chave específicas baseadas nas complicações neurológicas da COVID-19 descritas até 10 de maio de 2020. Resultados: Foram selecionados 43 artigos, incluindo descrições que variam de sintomas comuns e inespecíficos, como hiposmia e mialgia, a condições mais complexas e com risco de vida, como doenças cerebrovasculares, encefalopatias e síndrome de Guillain-Barré. Conclusão: O reconhecimento das manifestações neurológicas da SARS-CoV-2 deve ser enfatizado apesar dos óbvios desafios enfrentados pelos clínicos que cuidam de pacientes críticos, muitas vezes sedados e apresentando outras complicações sistêmicas concomitantes.

Osmophobia and Odor-Triggered Headaches in Children and Adolescents: Prevalence, Associated Factors, and Importance in the Diagnosis of Migraine.

OBJECTIVE: The objectives of this study are to study osmophobia and odor-triggered headaches among headache pediatric patients. BACKGROUND: Achieving the correct diagnosis for headaches in younger children can be challenging. The presence of osmophobia could constitute a helpful piece of information for making the correct diagnosis of headaches among adults. METHODS: This was a cross-sectional study. Children and adolescents with headaches who were seen consecutively at a pediatric outpatient service and had at least 1 headache attack over the previous 12 months were included. We used a semi-structured questionnaire, Pediatric Migraine Disability Assessment, State-Trait Anxiety Inventory, and Children's Depression Inventory. RESULTS: About 300 patients were included; 253 had migraine, 47 had a tension-type headache; 137 had osmophobia during headaches (135 were migraineurs). "Osmophobia during headaches" for diagnosing migraine: Sensitivity: 54.4% (95% CI: 48.2%-60.5%); specificity: 95.8% (95% CI: 85.8%-98.8%); positive predictive value (PPV): 98.5% (95% CI: 94.8%-99.6%); negative predictive value (NPV): 28.5% (95% CI: 22.0%-36.0%). Osmophobia was associated with higher intensity (OR: 2.90; 95% CI: 1.63, 5.15; P < .001) and duration of the headache (OR: 5.73; 95% CI: 2.29, 14.3; P < .001) and with vomiting (OR: 3.56; 95% CI: 1.83, 6.96; P < .001) (logistic regression). There were 62 patients (all of them migraineurs) with odor-triggered headaches: sensitivity for diagnosing migraine: 24.9% (95% CI: 19.9%-30.6%); specificity: 100% (95% CI: 92.4%-100%), PPV: 100% (95% CI: 94.8%-100%), NPV: 20% (95% CI: 16%-26.0%). Odor-triggered headaches were associated with higher intensity (OR: 3.47; 95% CI: 1.64, 7.35; P = .001) and duration of the headache (OR: 3.28; 95% CI: 1.37, 7.86; P = .001), vomiting (OR: 2.37; 95% CI: 1.19, 4.74; P = .014), and phonophobia (OR: 2.40; 95% CI: 1.08, 5.32; P = .031) (logistic regression). Osmophobia was associated with higher-impact migraine (OR: 4.65; 95% CI: 1.30, 16.6; P = .018) and emergency care (OR: 4.65; 95% CI: 1.81, 12.0; P = .001) (logistic regression). CONCLUSIONS: Osmophobia and odors as triggers for headaches are useful in diagnosing migraine and are markers for the severity of migraine in the pediatric population.

Gross Olfaction Before and After Laparoscopic Gastric Bypass.

BACKGROUND: Obesity leads to olfaction alterations, and this can further impact food choices, appetite, and nutritional status. Bariatric procedures induce weight loss and change in taste and smell perception, but more information is needed, especially using objective olfaction tests. METHODS: A prospective study was conducted during 6 months, with candidates to laparoscopic gastric bypass at a single institution. A preoperative nasofibroscopy and gross smell identification test (The Pocket Smell Test ®) were performed in those meeting the inclusion criteria. After 6 months, a new test was performed, and the primary objective was to determine if there was an improvement in the olfaction score. Weight loss and comorbidities improvement were also analyzed. RESULTS: From the 30 patients with morbid obesity enrolled, 21 met the inclusion criteria and ENT evaluation. At baseline, 42.8% of patients scored 3 points, 53.3% scored 2 points, and 4.7% scored 1 point. After 6 months, there was a -81.1% of change. Seventeen patients scored 3 points (p = 0.002 vs initial) and two scored 2 points (p = 0.006 vs initial). There were no patients with less than 2 points. Weight and comorbidities had a significant improvement as well. CONCLUSION: Laparoscopic gastric bypass improves the olfaction scores of the Pocket Smell Test in morbidly obese patients 6 months after their procedure. More complex tests can be used in candidates to bariatric surgery if low scores are detected initially. Other causes of olfaction dysfunctions should be determined if there is no improvement after weight loss.

The smell of "anxiety": Behavioral modulation by experimental anosmia in zebrafish.

Olfaction is strongly involved in the regulation of fish behavior, including reproductive, defensive, social and migration behaviors. In fish, anosmia (the lack of olfaction) can be induced experimentally, impairing their ability to respond to various olfactory stimuli. Here, we examine the effects of experimental lidocaine-induced anosmia on anxiety-like behavior and whole-body cortisol levels in adult zebrafish (Danio rerio). We show that experimentally-induced anosmia reduces anxiolytic-like behavioral effects of fluoxetine and seems to interact with anxiogenic effect of stress also paralleling cortisol responses in zebrafish. These findings provide first experimental evidence that temporary anosmia modulates anxiety-like behaviors and physiology in adult zebrafish.

Comparison of Olfactory Identification Patterns among Parkinson's Disease Patients from Different Countries.

Olfactory function assessment is an important screening tool and also may differentiate Parkinson's disease (PD) patients from other parkinsonisms, including nondegenerative ones, such as, normal pressure hydrocephalus, vascular, drug induced, or infectious parkinsonism. Several authors in different countries have reported various sets of odors that best differentiate between these conditions. It is debated if distinctive patterns of "restrictive" or "selective" hyposmia in PD may be affected by cultural aspects. To compare the olfactory identification function in PD across different countries, we analyzed Sniffin' Sticks identification task results between 112 PD patients from Argentina and previously reported data of PD patients from Brazil (106 patients), the Netherlands (400 patients), Germany (40 patients), China (110 patients), and Sri Lanka (89 patients). Categorical principal component analysis (CATPCA) was performed to find components reflecting groups of odors similarly perceived across subjects. CATPCA analysis found 2 components for each group which shared 10 out of 16 odors amongst each other. We found that only the shared items of component 2 (orange, mint, banana, garlic, coffee, cloves, and fish) showed uniform results across all of the included countries, whereas variations in component 1 (licorice, turpentine, and apple) were attributed mostly to differences across control groups.

Amyloid-aß Peptide in olfactory mucosa and mesenchymal stromal cells of mild cognitive impairment and Alzheimer's disease patients.

Patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD) might develop olfactory dysfunction that correlates with progression of disease. Alteration of olfactory neuroepithelium associated with MCI may be useful as predictor of cognitive decline. Biomarkers with higher sensitivity and specificity would allow to understand the biological progression of the pathology in association with the clinical course of the disease. In this study, magnetic resonance images, apolipoprotein E (ApoE) load, Olfactory Connecticut test and Montreal Cognitive Assessment (MoCA) indices were obtained from noncognitive impaired (NCI), MCI and AD patients. We established a culture of patient-derived olfactory stromal cells from biopsies of olfactory mucosa (OM) to test whether biological properties of mesenchymal stromal cells (MSC) are concurrent with MCI and AD psychophysical pathology. We determined the expression of amyloid Aß peptides in the neuroepithelium of tissue sections from MCI and AD, as well as in cultured cells of OM. Reduced migration and proliferation of stromal (CD90(+) ) cells in MCI and AD with respect to NCI patients was determined. A higher proportion of anosmic MCI and AD cases were concurrent with the ApoE ε4 allele. In summary, dysmetabolism of amyloid was concurrent with migration and proliferation impairment of patient-derived stem cells.

Fluoxetine modulates hippocampal cell signaling pathways implicated in neuroplasticity in olfactory bulbectomized mice.

The olfactory bulbectomy (OB) animal model of depression is a well-established model that is capable of detecting antidepressant activity following chronic drug therapy, and the surgery results in behavioral and biochemical changes that are reminiscent of various symptoms of depression. In the present study, we investigated the degree to which 14 days of p.o. administration of the classic antidepressant fluoxetine (10mg/kg) were able to reverse OB-induced changes in behavior (namely, hyperactivity in the open-field test and reduced motivational and self-care behaviors in the splash test) and in the activation of hippocampal cell signaling pathways that are thought to be involved in synaptic plasticity. OB caused significant increases in ERK1 and CREB (Ser(133)) phosphorylation and in the expression of BDNF immunocontent, all of which were prevented by fluoxetine administration. Moreover, fluoxetine administration also caused a significant decrease in ERK2 phosphorylation in mice that had undergone OB. Neither Akt nor GSK-3ß phosphorylation was altered in any experimental condition. In conclusion, the present study shows that OB can induce significant behavioral changes that are accompanied by the activation of hippocampal signaling pathways, namely the ERK1/CREB/BDNF pathway, which is involved in the synaptic plasticity. Conversely, fluoxetine prevented these OB-induced behavioral changes and avoided the activation of ERK1/CREB/BDNF in the hippocampus. Taken together, our results extend the data from the existing literature regarding OB-induced behavioral and neurochemical changes, and suggest a possible underlying mechanism that can account for the antidepressant effect of fluoxetine in this model.

Autoimmune pathology accounts for common manifestations in a wide range of neuro-psychiatric disorders: the olfactory and immune system interrelationship.

Smell has traditionally been considered a less important sense when compared to sight or hearing, but recent research has unraveled important features inherent to the sense of smell. Once considered just a chemical sensor for sampling the environment, data from animal models and human studies currently imply numerous and complex effects of smell on behavior, mood, and on the immune response. In this review we discuss a possible inter-relationship between olfactory impairment, autoimmunity and neurological/psychiatric symptoms in several diseases affecting the central nervous system (CNS) such as Parkinson, Alzheimer's disease, autism, schizophrenia, multiple sclerosis and neuropsychiatric lupus erythematosus. We suggest that common manifestations are not mere coincidences. Current data from animal models show that neuropsychiatric manifestations are intimately associated with smell impairment, and autoimmune dysregulation, via autoantibodies (anti-NMDAR, anti-ribosomal P) or other mechanisms. From clues of pathological manifestations, we propose a novel approach to the understanding of the interactions between the CNS, the smell and the immune system.

Isolated gonadotropin deficiency in boys: clinical characteristics and growth.

Analysis of the clinical findings and growth in 20 boys with isolated gonadotropin deficiency revealed a heterogeneous group of physical abnormalities. Ten of these patients were hyposmic or anosmic (Kallmann syndrome). Abnormalities found in our patients included undescended testes, gynecomastia, and ocular or skeletal anomalies. Regardless of the presence of hyposmia, patients without testicular enlargement (less than 2 cm3), had serum luteinizing hormone (LH) responses to luteinizing hormone-releasing factor (LRF) that were the same as in prepubertal boys. By contrast, five boys with testicular enlargement (greater than 2 cm3), some of whom had hyposmia, had a greater serum LH response to LRF than did prepubertal boys. Adrenarche was moderately delayed; although all boys initially had normal serum levels of dehydroepiandrosterone-sulfate, four boys eventually developed elevated serum levels. Bone ages were delayed compared with chronologic age in boys who had the condition after 15 years of age. The rate of linear growth was normal, and final adult heights were normal with testosterone therapy, although linear growth continued longer in these boys than in boys with normal pubertal progression. Although none of the patients was obese at the time of diagnosis, three patients developed obesity after initiation of testosterone therapy.