DNA methylation-based reclassification of olfactory neuroblastoma.

Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is known about its molecular pathogenesis. For this study, a retrospective cohort of n = 66 tumor samples with the institutional diagnosis of ONB was analyzed by immunohistochemistry, genome-wide DNA methylation profiling, copy number analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated genes. DNA methylation profiles were compared to those of relevant differential diagnoses of ONB. Unsupervised hierarchical clustering analysis of DNA methylation data revealed four subgroups among institutionally diagnosed ONB. The largest group (n = 42, 64%, Core ONB) presented with classical ONB histology and no overlap with other classes upon methylation profiling-based t-distributed stochastic neighbor embedding (t-SNE) analysis. A second DNA methylation group (n = 7, 11%) with CpG island methylator phenotype (CIMP) consisted of cases with strong expression of cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in all cases. T-SNE analysis clustered these cases together with sinonasal carcinoma with IDH2 mutation. Four cases (6%) formed a small group characterized by an overall high level of DNA methylation, but without CIMP. The fourth group consisted of 13 cases that had heterogeneous DNA methylation profiles and strong cytokeratin expression in most cases. In t-SNE analysis, these cases mostly grouped among sinonasal adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma. Copy number analysis indicated highly recurrent chromosomal changes among Core ONB with a high frequency of combined loss of chromosome 1-4, 8-10, and 12. NGS sequencing did not reveal highly recurrent mutations in ONB, with the only recurrently mutated genes being TP53 and DNMT3A. In conclusion, we demonstrate that institutionally diagnosed ONB are a heterogeneous group of tumors. Expression of cytokeratin, chromogranin A, the mutational status of IDH2 as well as DNA methylation patterns may greatly aid in the precise classification of ONB.

A lost track in ICHD 3 beta: A comprehensive review on osmophobia.

Background Osmophobia (Os) has been reported to be much more prevalent in migraine (M) than in other primary headaches, and its high specificity in the differential diagnosis between M and tension-type headache (TTH) has been reported. Os was included in the ICHD II Appendix as a diagnostic criterion of M. It disappeared in ICHD-3 beta. To understand this choice, we reviewed the literature after 2004. Methods This was a systematic review. We searched in PubMed, MEDLINE and Cochrane library for "osmophobia", "odour/odorphobia AND headache", "odour/odor hypersensitivity AND headache" and "olfactory hypersensitivity AND headache". Results 112 papers cited Os as an accompanying symptom of headache; 16 focused on Os in M diagnosis. With the data from 40 articles, we calculated the pooled prevalence of Os in 14,360 patients (2281 pediatric) affected by M (n = 12,496) and TTH (n = 1864). In M, the prevalence was 48.5% (CI 95% 41.4 to 55.8%) in adults and 23.4% (CI 95% 15.7 to 33.4%) in pediatric patients; in TTH, the prevalence was 8.9% (CI 95% 4.6 to 13.5%) in adults and 7.9% (CI 95% 3.3 to 18.1%) in pediatric patients. Ten of these papers allowed us to calculate the sensibility and specificity of Os in differential diagnosis between M and TTH. In adults, the value of specificity was 94.1% (CI 95% 88.9 to 96.9%), and sensitivity was 51.4% (CI 95% 38.4 to 64.2%). In pediatric patients, specificity was 92.0% (CI 95% 81.9 to 96.7%), and sensitivity was 22.1% (CI 95% 10.1 to 41.8%). Conclusion The literature endorses the inclusion of Os among M diagnostic criteria. On this ground, the decision to remove Os from ICHD 3 beta appears unjustified and a revision of this choice is recommended.

[Olfactory disorders ­ history, classification and implications]. / Riechstörung.

Smell disorders are common and can be found in 3 ­ 5 % of the population under 65 years. With growing age these numbers increase up to 50 % and more. Qualitative disorders which cannot be measured are differentiated from quantitative disorders. Self-assessment of olfactory function is rather poor therefore olfactory testing is mandatory in cases of patients complaining about an olfactory disorder. Olfactory screening smell tests are available for orientation, however, for detailed testing or in cases of a pathological screening test an extensive psychophysical olfactory test battery such as the Sniffin' Sticks Test battery should be used. According to the result of the test battery olfactory function can be qualified as norm, hyp- or anosmic. Additionally, in cases of medicolegal questions, olfactory evoked potentials can be recorded. Smell disorders are classified according to the history, clinical and endoscopic examination of the nose. Imaging techniques such as magnetic resonance imaging (MRI) or computertomography may contribute to classify the disorder. Sinunasal olfactory disorders are considered to be the most common ones. If the etiology remains unclear a neurological examination has to be performed in order to rule out a concomitant neurodegenerative disease. Olfactory disorders in the elderly might have to be considered as a sign of a reduced regeneration capacity in general being depicted in an increase in overall mortality in affected subjects.

[Expert opinion of ORL for private accident insurance]. / HNO-ärztliche Begutachtung für private Unfallversicherungen.

The provisions and the aims of private accident insurance are not comparable to those of the statutory accident insurance. The ear nose throat- (ENT-)specialist is often consulted on the question of a possible causality between an accident and sequelae. Loss of smell, taste disorder and loss of hearing are specified in a table with a fixed percentage for compensation. The individual invalidity for ear ringing, vertigo and other disorders have to be determined separately from this table. In private accident insurance a probability bordering on absolute certainty must be given when establishing a possible causal connection whereby mental reactions are excluded from compensation and all sequelae have to have continued for at least 3 years. The occupation or specific skills of the injured person are not essential for the judgement. The current jurisdiction and conditions of private accident insurance for tinnitus and vertigo have to be taken into consideration.

Intranasal Helicobacter pylori colonization does not correlate with the severity of chronic rhinosinusitis.

OBJECTIVE: To investigate the prevalence of Helicobacter pylori (HP) in the nasal cavity of patients with chronic rhinosinusitis (CRS) and to correlate it with the severity of CRS. STUDY DESIGN AND SETTING: Intranasal HP was investigated using rapid urease (CLO) testing and immunohistochemical (IHC) analysis and confirmed with transmission electron microscopy. To evaluate the severity of sinusitis, CT scans were graded according to the Lund-MacKay scoring system, and CRS symptom scores were recorded. RESULTS: Twelve of 48 patients (25.0%) were positive, but only 1 of 29 (3.4%) controls was positive for both CLO testing and IHC analysis (P = 0.025). The mean preoperative CT grade (P = 0.439) and symptom scores (P = 0.515) were not related to the severity of CRS. CONCLUSIONS: Intranasal HP was more prevalent in patients with CRS than healthy controls. However, there was no significant correlation observed between the severity of sinusitis and intranasal HP colonization. SIGNIFICANCE: HP has a limited role in pathogenesis of CRS.

Olfactory impairment in Parkinson's disease is a consequence of central nervous system decline.

Early diagnosis and timely treatment of Parkinson's disease are essential factors to provide these patients with a longer period of a better quality of life. Olfactory loss is among the first non-motor symptoms of the disease; however, in light of the many causes of smell loss, it is a very unspecific biomarker and should only be used as part of a diagnostic test battery. In this study, we investigated the olfactory response in 71 subjects, consisting of Parkinson's disease patients, hyposmic and anosmic patients of other causes, and normosmic individuals searching for sensitive, distinct biomarkers for which we used scalp event-related 64-channel electroencephalography and psychophysical tests. The analysis of the global field power indicated significant measurable differences between patients with Parkinson's disease and otherwise olfactory dysfunctional and normosmic individuals. The localization of brain sources, in particular, provides evidence for differences in mainly late EEG-components suggesting a decline of central brain networks as a causal factor for olfactory loss in Parkinson's disease. The findings indicate a different pattern of olfactory processing in patients with Parkinson's disease compared to olfactory dysfunctions of other origin, which provide further insights into the mechanisms behind olfactory dysfunction in Parkinson's.

Olfactory function and quality of life after olfaction rehabilitation in total laryngectomees. / Função olfatória e qualidade de vida após a reabilitação do olfato em laringectomizados totais.

PURPOSE: To evaluate the effects of olfaction rehabilitation in the olfactory function and quality of life of total laryngectomized patients. METHODS: Pre-post intervention clinical study conducted with total laryngectomees submitted to olfaction rehabilitation by means of the Nasal Airflow-Inducing Maneuver (NAIM) using the University of Pennsylvania Smell Identification Test (UPSIT), Olfactory Acuity Questionnaires, a Monitoring Questionnaire, and the University of Washington Quality of Life Questionnaire (UW-QOL). RESULTS: Participants were 45 total laryngectomees. Before olfaction rehabilitation, 48.9% of the participants had their olfactic abilities classified as anosmia, 46.8% as microsmia, and 4.4% were considered within the normal range. After olfaction rehabilitation, 4.4% of the participants were classified as anosmia and 31.1% were within the normal range. In the Smell Identification Test, the mean score after rehabilitation showed statistically significant improvement. Reponses to the Olfactory Acuity Questionnaires after rehabilitation showed improvement in the frequency of perception regarding smell, taste, and the ability to smell perfume, food, leaking gas, and smoke, after learning the maneuver. Although the scores in the Quality of Life Questionnaire already indicated good quality of life before the surgery, post-intervention values were statistically significant. CONCLUSION: Olfaction rehabilitation improves olfactory function and has a positive impact on the activities of daily living and quality of life of total laryngectomized patients.

Reduced olfactory bulb volume in post-traumatic and post-infectious olfactory dysfunction.

The olfactory bulb is a highly plastic structure the volume of which partly reflects the degree of afferent neural activity. In this study, 22 patients with post-infectious olfactory deficit, nine participants with post-traumatic olfactory deficit, and 17 healthy controls underwent magnetic resonance volumetry of the olfactory bulb. Patients presented with significantly smaller olfactory bulb volumes than controls; significant correlations between olfactory function and bulb volume were observed. Patients with parosmia exhibited smaller olfactory bulb volumes than those without parosmia. Findings indicate that smell deficits leading to a reduced sensory input to the olfactory bulb result in structural changes at the level of the bulb. Reduced olfactory bulb volumes may also be considered to be characteristic of parosmia.

Smell disorders in ENT clinic.

Olfactory disorders may have several causes. Nasal polyposis or chronic sinusitis can result in nasal obstructions that block the access of odorants to the olfactory epithelium, and this can explain the development of olfactory disorders. On the other hand, when nasal endoscopy has revealed that the nasal cleft is free of inflammatory or tumoural disease, olfactory disorders may be explained by neuroepithelial or central nervous system disturbances. This paper will provide information about current approaches to smell disorders in otorhinolaryngology. Major causes will be reviewed as outcomes after medical or surgical treatment. An algorithm will also be given to standardise clinical investigations, including psychophysical olfactory testing, imaging and electrophysiological examinations.

Proposed classification scheme for quantitative olfactory function alterations.

Given the need for a clinical classification for daily patient examinations to refer to each type of quantitative alteration in the sense of smell, we have created a topographic classification of such alterations, establishing groups to distinguish among patients with decreased or total loss of olfaction. Because the classification is based on the diagnosis of the different causes of anosmia, it implicitly includes etiologic and topographic considerations. We have established 3 main groups on the basis of the site of the causal lesion: conduction, sensorineural, and mixed anosmias. In addition, within the sensorineural anosmias, we distinguish between the epithelial, retroepithelial, and central anosmias.

Screening of olfactory function using the Biolfa olfactory test: investigations in patients with dysosmia.

OBJECTIVE: To present a statistical evaluation of a new olfactory test, Biolfa. MATERIAL AND METHODS: The olfactory test was carried out in individuals with normal olfactory function (n=67; 31 males; mean age 27.4 years) and in patients with mild, moderate or severe hyposmia (n=155; 61 males; mean age 54.6 years). The main diagnoses of the hyposmic patients were upper respiratory tract infection (32%), nasal polyposis (24%), head trauma (8%), idiopathic (8%), old age (5%) and chronic rhinitis (5%). In the first part of the test, olfactory thresholds were measured for three different substances (eugenol, aldehyde C14 and phenyl ethyl alcohol). The second part comprised an odor identification test for determining olfactory function for a large panel of common odors of Southern European countries. RESULTS: Mean olfactory thresholds were determined for subjects with normal olfaction and hyposmic patients; there was a statistically significant relationship between olfactory thresholds and degree of olfaction (mild to moderate hyposmia versus severe hyposmia). For the odor identification test, a global score was determined to allow the differentiation of normosmic subjects from patients with mild, moderate or severe hyposmia. The principles of decision theory (i.e. analysis of the receiver operating characteristic curve) were applied to the problem of evaluating the ability of Biolfa to distinguish subnormal subjects from hyposmic subjects. CONCLUSION: This study provides a basis for the routine clinical use of Biolfa.

Correspondence between three olfactory tests and suprathreshold odor intensity ratings.

OBJECTIVES: The capability of three olfactory tests (European Test of Olfactory Capabilities, Sniffin' Sticks and Cross-Cultural Smell Identification Test) to similarly classify subjects as normosmics, hyposmics and anosmics as well as the relation between test performance and suprathreshold ortho- and retronasal odor intensity ratings were examined. MATERIAL AND METHODS: A total of 48 subjects (age range 15-84 years; mean age 49.5 years) completed the 3 olfactory tests, rated aqueous solutions of vanilla (0-0.31%) and lemon aroma (0-0.17%) for odor and flavor intensity and filled in a background questionnaire. Ten subjects had case histories indicating anosmia, with the remainder having subjectively normal olfaction. RESULTS: The test results were highly correlated and differentiated anosmic, hyposmic and normosmic subjects. At an individual level, some discrepancy was seen in the olfactory diagnoses given by the three tests. In principal component analysis, olfactory measurements were loaded on three components: (i) odor detection, discrimination and identification; (ii) suprathreshold intensity ratings; and (iii) threshold for n-butanol. Advanced age was related to impaired olfactory performance. CONCLUSIONS: Although the three olfactory tests diagnosed the individuals slightly differently, all were considered to be valid for clinical evaluation of olfactory capabilities. The tests separated anosmics and normosmics highly significantly, and permitted an assessment of hyposmia. The suprathreshold odor intensity ratings reflected a different dimension of olfaction than the three olfactory tests.

Diagnosis of olfactory disturbance.

The methods of examination for dysosmia were reported. One thousand four hundred cases of dysosmia were treated in the last 5 years by the following examinations: 1) Olfactory acuity (detected and recognized) threshold test using T & T olfactometer. 2) Blast injection method using an applicator permeated with Alinamin solution. 3) Intravenous olfaction test using Alinamin solution. 4) Endoscopic observation of olfactory mucosa using an endoscope. The parts of lesions were diagnosed and various treatments were selected based on the results of these examinations. Nose drops of adrenocortical hormone were mainly used, while medications of peripheral vasodilator or medications for reducing of the mucosa were used in some cases. Many cases were effectively improved by the nose drops of adrenocortical hormone in Japanese patients. More than 70% of total cases were improved by these treatments.

[Remarks on the systematization and terminology of smell and taste disorders]. / Uwagi do systematyki i terminologii zaburzeñ wechu i smaki.

Based on the experience of the Olfactogustometry Laboratories in Halle and in Poznan, a proposal of clinical terminology and systematization of smell and taste disorders has been presented. Individual interpretation of the data from anamnesis in relation to the findings of the olfactogustometric investigations were stressed as indispensable.

Olfactory reference syndrome: a still open nosological and treatment debate.

OBJECTIVE: The objective was to report a case of olfactory reference syndrome (ORS) with several co-occurring disorders and to discuss ORS differential diagnoses, diagnostic criteria and classification. METHOD: Case report. RESULTS: A 37-year-old married woman presented overvalued ideas of having bad breath since adolescence. She met current diagnostic criteria for social anxiety disorder, specific phobia, obsessive-compulsive disorder, generalized anxiety disorder, body dysmorphic disorder and major depressive disorder. ORS similarities and differences with some related disorders are discussed. CONCLUSION: Further studies regarding symptoms, biomarkers and outcomes are needed to fully disentangle ORS from existing depressive, anxiety and obsessive-compulsive spectrum disorders.

Diagnóstico en la patología del olfato: revisión de la literatura / Diagnosis in smell pathology: literature review

La patología del olfato es una afección común en la población, principalmente en adultos mayores, que puede alterar de manera significativa la calidad de vida del paciente, pudiendo ser la manifestación inicial de enfermedades neurológicas como la enfermedad de Parkinson. A pesar de su relevancia, el sentido del olfato continúa siendo poco estudiado en clínica, no obstante la existencia de métodos simples validados para su evaluación. En este articulo realizamos una revisión y análisis de la literatura actual sobre el estudio clínico del olfato, con el objetivo de establecer las herramientas diagnósticas disponibles en la práctica clínica para su estudio.

Olfactory diseases are common to find in the population, mainly in older people, and it can affect significantly life quality. It can also be the first manifestation of neurological diseases, such as Parkinson disease. Despite its relevance, the sense of smell is still not studied although there are simple and validated methods available in the clinical practice. In this article, we make a review and analysis of the actual literature related to smell studies, so that we can establish available diagnosis tools in the clinical practice.

Olfactory phenotypic spectrum in idiopathic hypogonadotropic hypogonadism: pathophysiological and genetic implications.

CONTEXT: The olfactory phenotype in patients with idiopathic hypogonadotropic hypogonadism (IHH) ranges from complete anosmia (Kallmann syndrome) to normosmia (normosmic IHH). However, the true prevalence of intermediary olfactory phenotypes (hyposmia) in IHH patients has not yet been assessed, and systematic correlations with anatomical and genetic abnormalities have not been reported. OBJECTIVE: The objective of this study was to evaluate olfactory function in a large IHH cohort and correlate these findings with olfactory magnetic resonance imaging (MRI) and underlying genetic etiology. DESIGN AND SETTING: We conducted a cross-sectional case-control study at an academic referral center. PATIENTS: A total of 286 IHH patients (201 males and 85 females) and 2183 healthy historic controls (1011 males and 1172 females) were studied. MAIN OUTCOME MEASURES: We measured olfactory function using the University of Pennsylvania Smell Identification Test; in 208 subjects, the genetic etiology of IHH was ascertained by DNA sequencing; in a minor subset [39 of 286 subjects (13%)], olfactory structures were determined by MRI. RESULTS: In the IHH cohort, 31.5% were anosmic, 33.6% were hyposmic, and 34.9% were normosmic. Most hyposmic (seven of 11) subjects with MRI data exhibited olfactory structure abnormalities. Of hyposmic subjects, 39.5% harbored mutations in genes involved in either GnRH neuronal migration or GnRH secretion. CONCLUSIONS: IHH subjects display a broad spectrum of olfactory function, with a significant hyposmic phenotype in nearly one third of subjects. The hyposmic subjects harbor mutations in genes affecting GnRH neuronal migration and its secretion, suggesting a pathophysiological overlap between Kallmann syndrome and normosmic IHH. Accurate olfactory phenotyping in IHH subjects will inform the pathophysiology of this condition and guide genetic testing.

Função olfatória e qualidade de vida após a reabilitação do olfato em laringectomizados totais / Olfactory function and quality of life after olfaction rehabilitation in total laryngectomees

RESUMO Objetivo Avaliar os efeitos da reabilitação do olfato na função olfatória e na qualidade de vida de laringectomizados totais. Métodos Estudo clínico pré e pós-intervenção em laringectomizados totais submetidos à reabilitação do olfato pela técnica Nasal Airflow- Inducing Maneuver, por meio do Teste de Identificação do Olfato da Universidade da Pensilvânia, dos Questionários sobre a Acuidade Olfatória, do Questionário de Acompanhamento e do Questionário de Qualidade de Vida da Universidade de Washington. Resultados Foram incluídos 45 laringectomizados totais. Antes da reabilitação do olfato, 48,9% dos participantes tiveram o olfato classificado em anosmia, 46,8% apresentaram algum tipo de microsmia e 4,4% tiveram o olfato considerado normal. Depois da reabilitação, 4,4% dos participantes foram classificados como anosmia e 31,1% foram classificados dentro da normalidade. No Teste de Identificação do Olfato, o escore médio após a reabilitação apresentou melhora estatisticamente significante. Nos questionários sobre a acuidade olfatória após a reabilitação do olfato, os resultados demonstram melhora na frequência da percepção com relação ao olfato, paladar e à capacidade de sentir cheiros dos perfumes, alimentos, gás vazando e fumaça, após o aprendizado da manobra. Os escores do Questionário de Qualidade de Vida, embora já indicassem uma boa qualidade de vida antes da intervenção, apresentaram valores estatisticamente significantes após a reabilitação do olfato. Conclusão A reabilitação do olfato melhora a função olfatória e tem impacto positivo nas atividades de vida diária e na qualidade de vida dos laringectomizados totais.

ABSTRACT Purpose To evaluate the effects of olfaction rehabilitation in the olfactory function and quality of life of total laryngectomized patients. Methods Pre-post intervention clinical study conducted with total laryngectomees submitted to olfaction rehabilitation by means of the Nasal Airflow-Inducing Maneuver (NAIM) using the University of Pennsylvania Smell Identification Test (UPSIT), Olfactory Acuity Questionnaires, a Monitoring Questionnaire, and the University of Washington Quality of Life Questionnaire (UW-QOL). Results Participants were 45 total laryngectomees. Before olfaction rehabilitation, 48.9% of the participants had their olfactic abilities classified as anosmia, 46.8% as microsmia, and 4.4% were considered within the normal range. After olfaction rehabilitation, 4.4% of the participants were classified as anosmia and 31.1% were within the normal range. In the Smell Identification Test, the mean score after rehabilitation showed statistically significant improvement. Reponses to the Olfactory Acuity Questionnaires after rehabilitation showed improvement in the frequency of perception regarding smell, taste, and the ability to smell perfume, food, leaking gas, and smoke, after learning the maneuver. Although the scores in the Quality of Life Questionnaire already indicated good quality of life before the surgery, post-intervention values were statistically significant. Conclusion Olfaction rehabilitation improves olfactory function and has a positive impact on the activities of daily living and quality of life of total laryngectomized patients.