[Olfactory function and olfactory bulbs in patients with Kallmann syndrome].

BACKGROUND: The majority of Kallmann patients have anosmia or hyposmia. This is how the disease is diagnosed. Some of them don't have such complaints but olfactory dysfunction is diagnosed via olfactometry. Nowadays there is the lack of information about correlation between olfactometry results and subjective complaints. Correlation between olfactory bulbs size and olfactory dysfunction has been little studied. AIM: To explore olfactory bulb size and olfactory function in patients with congenital isolated hypogonadotropic hypogonadism. To correlate olfactory bulb sizes and smell test scores. MATERIALS AND METHODS: Single-centre comparative study. 34 patients were included. The main group consisted of 19 patients with hypogonadotropic (15 -with Kallmann syndrome, 4 - with normosmic hypogonadism). Olfactory bulbs MRI were provided to all the patients, olfactory test (Sniffin' Sticks Test) and molecular-genetic studies were provided in all patients with hypogonadism. Control group consisted of 15 patients who were provided with orbits MRI. Olfactory bulbs were evaluated additionally in them. RESULTS: Normal size of olfactory bulbs were only in 1 patient with hypogonadism. Olfactory bulbs height and width were significantly smaller in patients with hypogonadism in comparison with control group (p<0.01). Height median of right bulb was 1.0 mm [0.2; 1.8] in patients from the main group vs. 3.0 [2.5; 3.2] in controls, width median of right bulb was 1.0 mm [0.2; 1.9] in patients from the main group vs. 2.5 [2.0; 3.0] in controls. Height median of left bulb was 0.8 mm [0.0; 1.2] in patients from the main group vs. 3.0 [2.7; 3.2] in controls, width median of left bulb was 0.8 mm [0.0; 1.2] in patients from the main group vs. 2.5 [2.0; 3.0] in controls. Correlation has been established between left bulb height (r=0.59) and width (r=0.67) and olfactometry results (p<0.05). 4 patients had no anosmia complaints but had olfactory dysfunction according to Sniffin' Sticks Tests. CONCLUSION: Olfactometry was able to diagnose olfactory dysfunction in 78.5% (i.e. in 15 out of 19 patients with congenital isolated hypogonadotropic hypogonadism. However, anosmia complaints had only 11 out of 19 patients. It is the first results of olfactory bulb sizes in patients with hypogonadotropic hypogonadism in Russia. Uni - or bilateral hypoor aplasia were diagnosed in 94.7% patients with hypogonadism regardless of olfactory dysfunction. Bilateral olfactory bulbs hypoplasia were the most common MRI-finding (36.8%). Unilateral hypoor aplasia was diagnosed in 31.6% patients.

Olfactory bulb and olfactory tract abnormalities in acrocallosal syndrome and Greig cephalopolysyndactyly syndrome.

We describe association of olfactory bulb and olfactory tract abnormalities in a child with acrocallosal syndrome caused by kinesin family membrane 7 (KIF7) mutation in sonic hedgehog pathway. The child also had fontanellar bone in the anterior fontanelle, short sagittal suture, sagittal synostosis, hippocampal malrotation and Joubert malformation. Fontanellar bone has been described in GLI3 mutation and mutant mice models but has not been reported in KIF7 mutation. We briefly review the role of sonic hedgehog pathway and its components KIF7 and GLI3 in forebrain and olfactory system development and also describe olfactory system abnormality in a child with GLI3 mutation.

Septo-optic Dysplasia : Assessment of Associated Findings with Special Attention to the Olfactory Sulci and Tracts.

PURPOSE: Septo-optic dysplasia is a congenital disorder consisting of optic nerve hypoplasia and absent septum pellucidum. While associated anomalies have been described, olfactory sulcus and bulb-tract hypoplasia have been scantily reported and was the focus of this study. METHODS: The picture archival and communications system and radiology information system (PACS-RIS) was searched over 15 years for patients with suspected septo-optic dysplasia (n = 41) and cerebral magnetic resonance imaging (MRI). Included patients had coronal (≤3 mm), axial (≤4 mm), and sagittal (≤4 mm) imaging reviewed by two staff neuroradiologists by consensus. Both olfactory sulcus and bulb-tract hypoplasia were ascribed a grade of 0 (normal) to 3 (complete hypoplasia). Other associated congenital anomalies were recorded, if present. Incidence of anomalies were compared to age-matched and gender-matched control patients. RESULTS: Out of 41 septo-optic dysplasia patients 33 were included (mean age = 120.7 months), with 8 excluded due to isolated septum pellucidum absence (n = 5), isolated bilateral optic hypoplasia (n = 2), or inadequate imaging (n = 1). An olfactory sulcus was hypoplastic on one or both sides in 14/33 (42.4%). Olfactory bulb hypoplasia was noted in one or both tracts in 15/33 (45.4%). A significant correlation was found between degree of olfactory sulcal and bulb-tract hypoplasia (ρ = 0.528, p = 0.0009). Other anomalies were: anterior falx dysplasia (n = 16, 48.5%), incomplete hippocampal inversion (n = 14, 42.4%), polymicrogyria (n = 11, 33.3%), callosal complete or partial agenesis (n = 10, 30.3%), schizencephaly (n = 8, 24.2%), ectopic posterior pituitary (n = 6, 18.2%), and nodular heterotopia (n = 4, 12.1%). Of the age-matched control patients 10/33 (30.3%) had at least mild anterior falx hypoplasia, and 1 control patient was noted to have unilateral incomplete hippocampal inversion (IHI); none of the age-matched control patients had olfactory sulcus or bulb-tract hypoplasia. CONCLUSION: Olfactory sulcus and bulb-tract hypoplasia are fairly common in septo-optic dysplasia and can be discordant between sides. Of the other associated anomalies, anterior falx dysplasia seems to be the most common.

Retronasal Olfaction Test Methods: A Systematic Review

Background: This report produces a bibliographic study of psychophysical tests proposed clinical assessments of retronasal olfaction. Aims: We review how these tests can be utilized and discuss their methodological properties. Study Design: Systematic review. Methods: We undertook a systematic literature review investigating the retronasal olfaction test methods. PubMed, the free online MEDLINE database on biomedical sciences, was searched for the period from 1984 to 2015 using the following relevant key phrases: "retronasal olfaction", "orthonasal olfaction", "olfaction disorders", and "olfaction test". For each of the selected titles cited in this study, the full manuscript was read and analyzed by each of the three authors of this paper independently before collaborative discussion for summation and analytical reporting. Two reviewers independently read the abstracts and full texts and categorised them into one of three subgroups as follow, suitable, not-suitable, and unsure. Then they cross-checked the results, and a third reviewer decided assigned the group "unsure" to either the suitable group or the not-suitable group. Fifty eight studies revealed as suitable for review by two authors whereas 13 found not suitable for review. The total amount of 60 uncertain (unsure) or differently categorized articles were further examined by the third author which resulted in 41 approvals and 19 rejections. Hence 99 approved articles passed the next step. Exclusion criteria were reviews, case reports, animal studies, and the articles of which methodology was a lack of olfaction tests. By this way excluded 69 papers, and finally, 30 original human research articles were taken as the data. Results: The study found that the three most widely used and accepted retronasal olfaction test methods are the retronasal olfaction test, the candy smell test and odorant presentation containers. All of the three psychophysical retronasal olfaction tests were combined with orthonasal tests in clinical use to examine and understand the smell function of the patient completely. There were two limitations concerning testing: "the lack concentrations and doses of test materials" and "performing measurements within the supra-threshold zone". Conclusion: The appropriate test agents and optimal concentrations for the retronasal olfaction tests remain unclear and emerge as limitations of the retronasal olfaction test technique. The first step to overcoming these limitations will probably require identification of retronasal olfaction thresholds. Once these are determined, the concept of retronasal olfaction and its testing methods may be thoroughly reviewed.

Genetic Deletion of Soluble Epoxide Hydroxylase Causes Anxiety-Like Behaviors in Mice.

Soluble epoxide hydrolase (sEH), an enzyme with COOH-terminal hydrolase and NH2-terminal lipid phosphatase activities, is expressed in regions of the brain such as the cortex, white matter, hippocampus, substantia nigra, and striatum. sEH is involved in the regulation of cerebrovascular and neuronal function upon pathological insults. However, the physiological significance of sEH and its underlying mechanism in modulating brain function are not fully understood. In this study, we investigated the role of sEH in anxiety and potential underlying mechanisms in mice. Western blot for protein phosphorylation and expression was performed. Immunohistochemical analyses and Nissl and Golgi staining were performed for histological examination. Mouse behaviors were evaluated by open field activity, elevated plus maze, classical fear conditioning, social preference test, and Morris water maze. Our results demonstrated that the expression of sEH was upregulated during postnatal development in wild-type (WT) mice. Genetic deletion of sEH (sEH-/-) in mice resulted in anxiety-like behavior and disrupted social preference. Increased olfactory bulb (OB) size and altered integrity of neurites were observed in sEH-/- mice. In addition, ablation of sEH in mice decreased protein expression of tyrosine hydroxylase and reduced dopamine production in the brain. Moreover, the level of phosphorylated calmodulin kinase II (CaMKII) and glycogen synthase kinase 3 α/ß (GSK3α/ß) was higher in sEH-/- mice than in WT mice. Collectively, these findings suggest that sEH is a key player in neurite outgrowth of neurons, OB development in the brain, and the development of anxiety-like behavior, by regulating the CaMKII-GSK3α/ß signaling pathway.

Olfactory bulb agenesis with normal sexual hormones.

An 18-year-old Caucasian man presented with a lack of sense of surrounding smell. The problem was first noticed when a family member discussed the smell of the food, which he had no idea what it was. The patient had normal development and sexual function, no history of trauma, surgery, chemical exposure or infection. Physical examination revealed no significant abnormalities. Smell threshold test using phenyl-ethyl-alcohol revealed bilateral anosmia. MRI showed bilateral aplastic olfactory bulbs and tracts associated with absent cortical growth of the olfactory sulci and asymmetrical gyrus rectus. Circulating hormones including cortisol, growth hormone, insulin-like growth factor 1, adrenocorticotropic hormone, thyroid hormones, follicle-stimulating hormone, luteinizing hormone, prolactin and testosterone were within normal ranges. Doppler ultrasound showed normal testis with bilateral supratesticular varicoceles. Given the loss of warning smell sensation, counselling for daily living precautions especially those related to gas, fire and rotten food was given.

Reconsidering olfactory bulb magnetic resonance patterns in Kallmann syndrome.

OBJECTIVE: The aim of this retrospective study was to perform magnetic resonance imaging assessment of olfactory pathway and skull base abnormalities in Kallmann syndrome (KS) patients with hypogonadotropic hypogonadism and olfaction disorder. METHODS: Magnetic resonance brain patterns were retrospectively studied in 19 patients clinically classified as KS. Qualitative assessment of olfactory bulb region comprised bulb atrophy and rectus and medial orbital gyrus ptosis; quantitative assessment measured olfactory fossa depth and width, sulcus depth and ethmoid angle. Results were compared to an age- and sex-matched control population (n=19) with no impairment in the region of interest. Sixteen of the 19 KS patients were genetically screened for mutations associated with KS. RESULTS: On the above qualitative criteria, 15 of the 19 patients presented either unilateral (n=2) or bilateral (n=13) olfactory bulb agenesis; 16 showed tract agenesis and 16 showed gyrus malformation (ptosis or absence). On the quantitative criteria, 18 of the 19 patients showed abnormal sulcus depth and/or olfactory fossa malformation and/or abnormal ethmoid angle. CONCLUSION: The presence of malformation abnormalities in the olfactory fossae of 18 of the 19 patients appears to be a key factor for etiological diagnosis of hypogonadotropic hypogonadism, and should enable targeted study of genes involved in KS.

In utero and lactational dioxin exposure induces Sema3b and Sema3g gene expression in the developing mouse brain.

In the developing mammalian brain, neural network formation is regulated by complex signaling cascades. In utero and lactational dioxin exposure is known to induce higher brain function abnormalities and dendritic growth disruption in rodents. However, it is unclear whether perinatal dioxin exposure affects the expression of genes involved in neural network formation. Therefore, we investigated changes in gene expression in the brain regions of developing mice born to dams administered 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dose: 0, 0.6, or 3.0 µg/kg) on gestational day 12.5. Quantitative RT-PCR showed that TCDD exposure induced Ahrr expression in the cerebral cortex, hippocampus, and olfactory bulb of 3-day-old mice. Gene microarray analysis indicated that the mRNA expression levels of Sema3b and Sema3g, which encode proteins that are known to control axonal projections, were elevated in the olfactory bulb of TCDD-exposed mice, and the induction of these genes was observed during a 2-week postnatal period. Increased Sema3g expression was also observed in the brain but not in the kidney, liver, lung, and spleen of TCDD-exposed neonatal mice. These results indicate that the Sema3b and Sema3g genes are sensitive to brain-specific induction by dioxin exposure, which may disrupt neural network formation in the mammalian nervous system, thereby leading to abnormal higher brain function in adulthood.

Spectrum of Clinical and Associated MR Imaging Findings in Children with Olfactory Anomalies.

BACKGROUND AND PURPOSE: The olfactory apparatus, consisting of the bulb and tract, is readily identifiable on MR imaging. Anomalous development of the olfactory apparatus may be the harbinger of anomalies of the secondary olfactory cortex and associated structures. We report a large single-site series of associated MR imaging findings in patients with olfactory anomalies. MATERIALS AND METHODS: A retrospective search of radiologic reports (2010 through 2014) was performed by using the keyword "olfactory"; MR imaging studies were reviewed for olfactory anomalies and intracranial and skull base malformations. Medical records were reviewed for clinical symptoms, neuroendocrine dysfunction, syndromic associations, and genetics. RESULTS: We identified 41 patients with olfactory anomalies (range, 0.03-18 years of age; M/F ratio, 19:22); olfactory anomalies were bilateral in 31 of 41 patients (76%) and absent olfactory bulbs and olfactory tracts were found in 56 of 82 (68%). Developmental delay was found in 24 (59%), and seizures, in 14 (34%). Pituitary dysfunction was present in 14 (34%), 8 had panhypopituitarism, and 2 had isolated hypogonadotropic hypogonadism. CNS anomalies, seen in 95% of patients, included hippocampal dysplasia in 26, cortical malformations in 15, malformed corpus callosum in 10, and optic pathway hypoplasia in 12. Infratentorial anomalies were seen in 15 (37%) patients and included an abnormal brain stem in 9 and an abnormal cerebellum in 3. Four patients had an abnormal membranous labyrinth. Genetic testing was performed in 23 (56%) and findings were abnormal in 11 (48%). CONCLUSIONS: Olfactory anomalies should prompt careful screening of the brain, skull base, and the pituitary gland for additional anomalies. Genetic testing should be considered.

Maturation and Dysgenesis of the Human Olfactory Bulb.

The olfactory bulb with its unique architecture was studied for neuronal maturation in human fetuses. Neuroblasts stream into the olfactory bulb from the rostral telencephalon and secondarily migrate radially. The transitory olfactory ventricular recess regresses postnatally. Olfactory is the only sensory system without thalamic projections but incorporates intrinsic thalamic equivalents. The bulb is a repository of progenitor cells. Maturation of the bulb and tract was studied in 18 normal human fetuses of 16-41 weeks gestation; mid-gestational twins with hydrocephalus; 7 arrhinencephaly/holoprosencephaly; 2 olfactory dysgeneses. Multiple immunoreactivities were performed. Synaptophysin around mitral neurons, in a few synaptic glomeruli and concentric lamination of the outer granular layer, was seen at 16 weeks. Outer granular neurons exhibited NeuN at 16 weeks, only 2/3 were reactive at term. Concentric alternating sheets of granular neurons and their dendrodendritic synapses are seen during maturation. Calretinin reactivity is seen in neurons and neurites, primary olfactory nerve axons, periglomerular cells and neuroepithelial cells surrounding the ventricular recess; reactivity occurs later in synaptic glomeruli than with synaptophysin; not all glomeruli are strongly reactive even at term. Nestin- and vimentin-reactive bipolar progenitor cells were demonstrated at all ages and extend into the olfactory tract. Myelin is demonstrated by Luxol fast blue (LFB) only postnatally. In hydrocephalus, the olfactory recess is dilated. Mitral cell dispersion, disrupted glomeruli, heterotopia and maturational delay are seen in some dysgeneses. Malformations exhibit unique findings. Fusion of hypoplastic bulbs can occur. Abnormal architecture is seen in hemimegalencephaly. More documentation of olfactory dysgenesis is needed in other major brain malformations.

Drácula tenía razón: el elixir de la juventud podría ser la sangre joven / Dracula was right: The elixir of youth could be the young blood

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Olfactory neuroblastoma and olfactory ventricle. A case report.

A case of dumbbell nasal and intracerebral olfactory neuroblastoma (ONB) related to possible seeding through an "olfactory ventricle" in the olfactory bulb and nerve is reported. This anatomic variant was recognized at operation for the first time: it consists of a hollow cavity within the olfactory bulb and nerve which may be connected to the subventricular zone of the frontal horn of the lateral ventricle. Better scrutiny of this structure is necessary in view of its possible interference with the course and diffusion of ONBs.

The olfactory system.

Any dysfunction in olfaction requires a radiological exploration comprising the nasal cavity, the anterior base of the skull, in particular the frontal and temporal lobes. MRI is the reference examination, due to the frontal plane and the T1, T2 volume maps. In the child, aplasia of the olfactory bulbs falls within a polymalformation (CHARGE) or endocrine (Kallman) context. In the adult, rhino sinus disease and meningiomas are the most common etiologies. Frontal or temporal impairment: tumoral or vascular and neurodegenerative disorders (Parkinson's disease) may accompany a loss of olfaction.

Fascin regulates the migration of subventricular zone-derived neuroblasts in the postnatal brain.

After birth, stem cells in the subventricular zone (SVZ) generate neuroblasts that migrate along the rostral migratory stream (RMS) to become interneurons in the olfactory bulb (OB). This migration is a fundamental event controlling the proper integration of new neurons in a pre-existing synaptic network. Many regulators of neuroblast migration have been identified; however, still very little is known about the intracellular molecular mechanisms controlling this process. Here, we show that the actin-bundling protein fascin is highly upregulated in mouse SVZ-derived migratory neuroblasts. Fascin-1ko mice display an abnormal RMS and a smaller OB. Bromodeoxyuridine labeling experiments show that lack of fascin significantly impairs neuroblast migration, but does not appear to affect cell proliferation. Moreover, fascin depletion substantially alters the polarized morphology of rat neuroblasts. Protein kinase C (PKC)-dependent phosphorylation of fascin on Ser39 regulates its actin-bundling activity. In vivo postnatal electroporation of phosphomimetic (S39D) or nonphosphorylatable (S39A) fascin variants followed by time-lapse imaging of brain slices demonstrates that the phospho-dependent modulation of fascin activity ensures efficient neuroblast migration. Finally, fluorescence lifetime imaging microscopy studies in rat neuroblasts reveal that the interaction between fascin and PKC can be modulated by cannabinoid signaling, which controls neuroblast migration in vivo. We conclude that fascin, whose upregulation appears to mark the transition to the migratory neuroblast stage, is a crucial regulator of neuroblast motility. We propose that a tightly regulated phospho/dephospho-fascin cycle modulated by extracellular signals is required for the polarized morphology and migration in neuroblasts, thus contributing to efficient neurogenesis.

Computed tomography of the anterior skull base in Kallmann syndrome reveals specific ethmoid bone abnormalities associated with olfactory bulb defects.

CONTEXT: Kallmann syndrome (KS) is characterized by congenital hypogonadotropic hypogonadism (CHH) and an impaired sense of smell related to defective development of the olfactory system. OBJECTIVE: The aim of the study was to use high-resolution computed tomography (CT) to detect specific abnormalities in the ethmoid bone region surrounding the olfactory bulbs in patients with KS. PATIENTS: Thirty-seven KS patients were compared to normosmic CHH (nCHH) patients (n = 15) and controls (n = 30) of similar age. DESIGN AND METHODS: We conducted a prospective study in a single referral center. Subjects underwent CT in bone windows with axial, coronal, and sagittal reconstructions centered on the olfactory fossa (OF) and cribriform plate (CP). We characterized the OF structure by measuring OF height, width, and surface area and a series of angles. The CP foramina were counted bilaterally. Olfactory bulb magnetic resonance imaging, performed in parallel, was compared with CT findings. RESULTS: OF height, width, and surface area were all significantly lower in KS patients than in nCHH patients and controls (P < .0001). KS patients also had wider angles than nCHH patients and controls (P < .0001). KS subjects with olfactory bulb agenesis on magnetic resonance imaging or who harbored KAL1 mutations had the most marked changes in OF measurements and angles. Coronal OF height distinguished KS patients from controls with the best sensitivity and specificity. The mean number of CP foramina was similar in KS, nCHH, and control subjects. CONCLUSIONS: KS is associated with specific ethmoid bone abnormalities. The preserved number of CP foramina in KS patients suggests that the integrity of olfactory structures is not mandatory for their formation during fetal development or their maintenance in adult life.