The Olfactory Nerve: Anatomy and Pathology.

The human sense of smell is the unique sense through which the olfactory system can identify aromatic molecules within the air and provide a taste sensation. Still, also it plays an essential role in several other functions, warning about environmental safety and even impacts our emotional lives. Recently, olfactory impairment has become an issue of interest due to the COVID-19 pandemic. The dysfunction may vary from only reduced smell detection (hyposmia) to complete loss of it (anosmia) but also includes changes in the normal perception of odors (parosmia). Computed tomography and magnetic imaging resonance are the modalities of choice to evaluate the olfactory pathways. Computed tomography is the initial imaging modality for olfactory disturbances, allowing recognition of sinonasal pathologies, inflammatory processes, or bone-related tumors. Magnetic imaging resonance with dedicated protocols for olfactory disorders enables a detailed assessment of the sinonasal compartment and the anterior cranial fossa. Provides a better depiction of olfactory bulb volume, morphology and signal intensity, as well the status of signal intensity of the central olfactory projection areas. Several diseases can affect the olfactory nerve, such as congenital disorders, trauma, inflammatory or infectious diseases, neoplasms, and even post-operative involvement. This article aims to review the normal anatomy of the olfactory nerve pathway and highlight the spectrum of conditions that most commonly affect it.

Olfactory nerve schwannoma: how human anatomy and electron microscopy can help to solve an intriguing scientific puzzle.

Schwannomas of the olfactory nerve are rare tumors: to the best of our knowledge, 56 cases have been previously reported. Here we describe a new patient presenting with an isolated olfactory schwannoma, highlighting the importance of multiple ancillary tests to approach the intracranial lesion of the anterior skull base, including electron microscopy. We also discuss the enigmatic origin of this entity, moving from the normal histology of the olfactory nerve compared to a peripheral nerve.

A Comparative Study of Site-Specific Distribution of Aging-Related Tau Astrogliopathy and Its Risk Factors Between Alzheimer Disease and Cognitive Healthy Brains: The Hisayama Study.

Knowledge of aging-related tau astrogliopathy (ARTAG) in healthy elderly individuals remains incomplete and studies to date have not focused on the olfactory nerve, which is a vulnerable site of various neurodegenerative disease pathologies. We performed a semiquantitative evaluation of ARTAG in 110 autopsies in the Japanese general population (Hisayama study). Our analysis focused on Alzheimer disease (AD) and cognitive healthy cases (HC), including primary age-related tauopathy. Among the various diseased and nondiseased brains, ARTAG was frequently observed in the amygdala. The ARTAG of HC was exclusively limited to the amygdala whereas gray matter ARTAG in AD cases was prominent in the putamen and middle frontal gyrus following the amygdala. ARTAG of the olfactory nerve mainly consists of subpial pathology that was milder in the amygdala. A logistic regression analysis revealed that age at death and neurofibrillary tangle Braak stage significantly affected the ARTAG of HC. In AD, age at death and male gender had significant effects on ARTAG. In addition, the Thal phase significantly affected the presence of white matter ARTAG. In conclusion, our research revealed differences in the distribution of ARTAG and affected variables across AD and HC individuals.

Sublamina-specific organization of the blood brain barrier in the mouse olfactory nerve layer.

Astrocytes constitute the main glial component of the mammalian blood brain barrier (BBB). However, in the olfactory bulb (OB), the olfactory nerve layer (ONL) is almost devoid of astrocytes, raising the question which glial cells are part of the BBB. We used mice expressing EGFP in astrocytes and tdTomato in olfactory ensheathing cells (OECs), a specialized type of glial cells in the ONL, to unequivocally identify both glial cell types and investigate their contribution to the BBB in the olfactory bulb. OECs were located exclusively in the ONL, while somata of astrocytes were located in deeper layers and extended processes in the inner sublamina of the ONL. These processes surrounded blood vessels and contained aquaporin-4, an astrocytic protein enriched at the BBB. In the outer sublamina of the ONL, in contrast, blood vessels were surrounded by aquaporin-4-negative processes of OECs. Transcardial perfusion of blood vessels with lanthanum and subsequent visualization by electron microscopy showed that blood vessels enwrapped by OECs possessed intact tight junctions. In acute olfactory bulb preparations, injection of fluorescent glucose 6-NBDG into blood vessels resulted in labeling of OECs, indicating glucose transport from the perivascular space into OECs. In addition, Ca2+ transients in OECs in the outer sublamina evoked vasoconstriction, whereas Ca2+ signaling in OECs of the inner sublamina had no effect on adjacent blood vessels. Our results demonstrate that the BBB in the inner sublamina of the ONL contains astrocytes, while in the outer ONL OECs are part of the BBB.

Survival and Integration of Transplanted Olfactory Ensheathing Cells are Crucial for Spinal Cord Injury Repair: Insights from the Last 10 Years of Animal Model Studies.

Olfactory ensheathing cells (OECs), the glial cells of the primary olfactory nervous system, support the natural regeneration of the olfactory nerve that occurs throughout life. OECs thus exhibit unique properties supporting neuronal survival and growth. Transplantation of OECs is emerging as a promising treatment for spinal cord injury; however, outcomes in both animals and humans are variable and the method needs improvement and standardization. A major reason for the discrepancy in functional outcomes is the variability in survival and integration of the transplanted cells, key factors for successful spinal cord regeneration. Here, we review the outcomes of OEC transplantation in rodent models over the last 10 years, with a focus on survival and integration of the transplanted cells. We identify the key factors influencing OEC survival: injury type, source of transplanted cells, co-transplantation with other cell types, number and concentration of cells, method of delivery, and time of transplantation after the injury. We found that two key issues are hampering optimization and standardization of OEC transplantation: lack of (1) reliable methods for identifying transplanted cells, and (2) three-dimensional systems for OEC delivery. To develop OEC transplantation as a successful and standardized therapy for spinal cord injury, we must address these issues and increase our understanding of the complex parameters influencing OEC survival.

Nasal thallium-201 uptake in patients with parosmia with and without hyposmia after upper respiratory tract infection.

BACKGROUND: In this study, we aimed to determine whether nasal thallium-201 uptake of the olfactory cleft and olfactory bulb (OB) differs between patients with parosmia with and without hyposmia after upper respiratory tract infection (URTI). METHODS: Twenty patients with parosmia after URTI were enrolled in this study (15 women and 5 men, 28 to 76 years old). Nasally administered thallium-201 migration to the OB, nasal thallium-201 uptake ratio in the olfactory cleft, and OB volume were determined in 10 patients with normal T&T olfactometry (Daiichi Yakuhin Sangyo, Tokyo, Japan) odor recognition thresholds (≤2.0) who still complained of parosmia (parosmia group), and 10 patients with T&T odor recognition thresholds >2.0 (parosmia and hyposmia group). RESULTS: The nasal thallium-201 uptake ratio in the olfactory cleft was significantly higher in the parosmia group than in the parosmia and hyposmia group (p = 0.0015). Thallium-201 migration to the OB was not significantly different between the 2 groups (p = 0.31). The OB volume was significantly larger in the parosmia group than that in the parosmia and hyposmia group (p = 0.029); however, the mean OB volume in both the groups was lower than the normal threshold value in healthy individuals. CONCLUSION: Our results signify the recovery of the olfactory epithelium; however, the olfactory neural projections to the OB and regeneration of OB were not complete in patients with parosmia with normal T&T recognition thresholds after URTI.

Rhinocerebral Zygomycosis Due to a Lichtheimia ramosa Infection in a Calf: Neural Spread Through the Olfactory Nerves.

Here, we report a case of rhinocerebral zygomycosis due to a Lichtheimia ramosa infection in a calf. A histopathological examination revealed that a fungus had invaded the brain through the olfactory nerves. Lichtheimia ramosa was detected by polymerase chain reaction analysis of DNA extracted from formalin-fixed paraffin-embedded samples of the affected tissue. This is the first case of rhinocerebral zygomycosis to involve cattle. Also, this is the first such case to involve fungal invasion into the central nervous system through the cranial nerve itself, rather than through perineural tissue.

Prognostic value of olfactory nerve damage measured with thallium-based olfactory imaging in patients with idiopathic olfactory dysfunction.

Idiopathic olfactory disorder is resistant to treatment, and the recovery time is long. This study investigated the prognostic value of the migration of nasally administered thallium-201 to the olfactory bulb (thallium migration to the OB), a measure of olfactory nerve damage, in patients with idiopathic olfactory disorders. Twenty-four patients with idiopathic olfactory disorders were enrolled in the study (7 women and 17 men; aged 23-73 years). We retrospectively analyzed potential prognostic markers in subjects who underwent thallium-based olfactory imaging with the nasal administration of thallium-201 before conventional treatment with the Japanese herbal medicine tokishakuyakusan and compared those data with the prognosis. Log-rank tests were performed to assess the relationship between thallium migration to the OB (<4.6% [low] vs. ≥4.6% [high]; data dichotomized at the optimal cutoff value) and the duration until recovery of the odor recognition threshold determined by a standard olfactory function test (T&T olfactometry) after the treatment. Upon statistical analysis, we found that high thallium migration to the OB was significantly correlated with better prognosis in patients. Our results suggest that patients with intact olfactory nerve fibers could be selected using thallium-based imaging for the long-term follow-up of olfactory dysfunction.

Tumor necrosis factor-α antagonist suppresses local inflammatory reaction and facilitates olfactory nerve recovery following injury.

OBJECTIVE: Olfactory dysfunction is a common finding in head trauma due to injury to the olfactory nerve. We previously reported that anti-inflammatory treatment with steroids improves recovery outcome in olfactory nerve injury models. Clinically, however, steroid administration is not recommended in the acute phase of head injury cases because of concerns regarding its side effects. Tumor necrosis factor (TNF-α) is known to play a key role in inflammatory response to injury. The present study examines if the inhibition of TNF-α can facilitate functional recovery in the olfactory system following injury. MATERIALS AND METHODS: Olfactory nerve transection (NTx) was performed in olfactory marker protein (OMP-tau-lacZ) mice to establish injury models. We measured TNF-α gene expression in the olfactory bulb using semi-quantitative and real time polymerase chain reaction (PCR) assays and found that they increase within hours after NTx injury. A TNF-α antagonist (etanercept) was intraperitoneally injected immediately after the NTx and histological assessment of recovery within the olfactory bulb was performed at 5-70 days. X-gal staining labeled OMP in the degenerating and regenerating olfactory nerve fibers, and immunohistochemical staining detected the presence of reactive astrocytes and macrophages/microglia. RESULTS: Etanercept-injected mice showed significantly smaller areas of injury-associated tissue, fewer astrocytes and macrophages/microglia, and an increase in regenerating nerve fibers. Olfactory function assessments using both an olfactory avoidance behavioral test and evoked potential recordings showed improved functional recovery in etanercept-injected animals. CONCLUSION: These findings suggest that inhibition of TNF-α could provide a new therapeutic strategy for the treatment of olfactory dysfunction following head injuries.

Ganglioglioma arising from olfactory sheath: A rare site of an uncommon tumor.

Gangliogliomas are rare slow growing tumors with a mixed population of dysplastic ganglion cells and glial components, reported at variable sites within the central nervous system, including the frontal, parietal and occipital lobes, the striatum, cerebellum, pituitary and pineal glands as well as the spinal cord. Rarely gangliogliomas have been reported arising within the cranial nerves, including the optic and trigeminal nerve. We present the first patient, to our knowledge, where such a tumor originated from the olfactory sheath. Migration defects leading to entrapment of sensory neurons during development is believed to be responsible for the pathogenesis of these lesions. The extent of surgical extirpation and histopathological anaplasia are important prognosticators. While gangliogliomas are rare tumors, it is crucial to consider them in the differential diagnosis of non-enhancing, poorly localized lesions along the cranial nerves.

Height of aneurysm neck and estimated extent of brain retraction: powerful predictors of olfactory dysfunction after surgery for unruptured anterior communicating artery aneurysms.

OBJECTIVE: The highest incidence of olfactory dysfunction following a pterional approach and its modifications for an intracranial aneurysm has been reported in cases of anterior communicating artery (ACoA) aneurysms. The radiological characteristics of unruptured ACoA aneurysms affecting the extent of retraction of the frontal lobe and olfactory nerve were investigated as risk factors for postoperative olfactory dysfunction. METHODS: A total of 102 patients who underwent a pterional or superciliary keyhole approach to clip an unruptured ACoA aneurysm from 2006 to 2013 were included in this study. Those patients who complained of permanent olfactory dysfunction after their aneurysm surgery, during a postoperative office visit or a telephone interview, were invited to undergo an olfactory test, the Korean version of the Sniffin' Sticks test. In addition, the angiographic characteristics of ACoA aneurysms, including the maximum diameter, the projecting direction of the aneurysm, and the height of the neck of the aneurysm, were all recorded based on digital subtraction angiography and sagittal brain images reconstructed using CT angiography. Furthermore, the extent of the brain retraction was estimated based on the height of the ACoA aneurysm neck. RESULTS: Eleven patients (10.8%) exhibited objective olfactory dysfunction in the Sniffin' Sticks test, among whom 9 were anosmic and 2 were hyposmic. Univariate and multivariate analyses revealed that the direction of the ACoA aneurysm, ACoA aneurysm neck height, and estimated extent of brain retraction were statistically significant risk factors for postoperative olfactory dysfunction. Based on a receiver operating characteristic (ROC) analysis, an ACoA aneurysm neck height > 9 mm and estimated brain retraction > 12 mm were chosen as the optimal cutoff values for differentiating anosmic/hyposmic from normosmic patients. The values for the area under the ROC curves were 0.939 and 0.961, respectively. CONCLUSIONS: In cases of unruptured ACoA aneurysm surgery, the height of the aneurysm neck and the estimated extent of brain retraction were both found to be powerful predictors of the occurrence of postoperative olfactory dysfunction.

Lesion of the olfactory epithelium accelerates prion neuroinvasion and disease onset when prion replication is restricted to neurons.

Natural prion diseases of ruminants are moderately contagious and while the gastrointestinal tract is the primary site of prion agent entry, other mucosae may be entry sites in a subset of infections. In the current study we examined prion neuroinvasion and disease induction following disruption of the olfactory epithelium in the nasal mucosa since this site contains environmentally exposed olfactory sensory neurons that project directly into the central nervous system. Here we provide evidence for accelerated prion neuroinvasion and clinical onset from the olfactory mucosa after disruption and regeneration of the olfactory epithelium and when prion replication is restricted to neurons. In transgenic mice with neuron restricted replication of prions, there was a reduction in survival when the olfactory epithelium was disrupted prior to intranasal inoculation and there was >25% decrease in the prion incubation period. In a second model, the neurotropic DY strain of transmissible mink encephalopathy was not pathogenic in hamsters by the nasal route, but 50% of animals exhibited brain infection and/or disease when the olfactory epithelium was disrupted prior to intranasal inoculation. A time course analysis of prion deposition in the brain following loss of the olfactory epithelium in models of neuron-restricted prion replication suggests that neuroinvasion from the olfactory mucosa is via the olfactory nerve or brain stem associated cranial nerves. We propose that induction of neurogenesis after damage to the olfactory epithelium can lead to prion infection of immature olfactory sensory neurons and accelerate prion spread to the brain.

Activating transcription factor 5 is required for mouse olfactory bulb development via interneuron.

Activating transcription factor 5 (ATF5) is a stress response transcription factor of the cAMP-responsive element-binding/ATF family. Earlier, we reported that ATF5 expression is up-regulated in response to stress, such as amino acid limitation or arsenite exposure. Although ATF5 is widely expressed in the brain and the olfactory epithelium, the role of ATF5 is not fully understood. Here, the olfactory bulbs (OBs) of ATF5-deficient mice are smaller than those of wild-type mice. Histological analysis reveals the disturbed laminar structure of the OB, showing the thinner olfactory nerve layer, and a reduced number of interneurons. This is mainly due to the reduced number of bromodeoxyuridine-positive proliferating cells in the subventricular zone, where the interneuron progenitors are formed and migrate to the OBs. Moreover, the olfaction-related aggressive behavior of ATF5-deficient mice is reduced compared to wild-type mice. Our data suggest that ATF5 plays a crucial role in mouse OB development via interneuron.

Primer caso descrito de parálisis aislada, completa y fluctuante del III nervio craneal como forma de inicio de un mieloma múltiple / First case described of isolated, complete and fluctuating cranial nerve III palsy heralding multiple myeloma

Introducción. El mieloma múltiple es la neoplasia de células plasmáticas más frecuente. Al ser incurable, el tratamiento persigue obtener el mayor tiempo de supervivencia libre de clínica. Constituye una causa extremadamente rara de afectación de los nervios craneales y es producido habitualmente por un plasmocitoma intracraneal. Presentamos un caso de mieloma múltiple, que asociaba un plasmocitoma intracraneal y que comenzó clínicamente con parálisis aislada, completa y fluctuante del III nervio craneal. Caso clínico. Mujer de 63 años que acudió a urgencias por presentar un cuadro clínico oscilante, consistente en diplopía binocular horizontal y, posteriormente, cefalea. La exploración neurooftalmológica reveló una parálisis completa del III nervio craneal derecho. Se solicitó una tomografía axial computarizada craneal urgente, que reveló múltiples lesiones osteolíticas diploicas, asociando una de ellas componente de partes blandas en la hendidura esfenoidal derecha. La paciente fue ingresada, y se le diagnosticó posteriormente un mieloma múltiple IgA-k. Tras recibir inducción quimioterápica y ser sometida a un trasplante autólogo de progenitores hematopoyéticos, alcanzó la remisión completa. Conclusiones. El mieloma múltiple es un trastorno raro de los nervios craneales, una causa muy infrecuente de parálisis aislada y completa del III nervio craneal y menos aún fluctuante, y no se ha encontrado ningún caso publicado con este inicio clínico. Tener en cuenta las posibles manifestaciones neurooftalmológicas del mieloma múltiple puede contribuir a un diagnóstico precoz y a una incidencia positiva sobre el curso de esta enfermedad (AU)

Introduction. Multiple myeloma is the most common plasma-cell malignancy. To be incurable, treatment aims to obtain the longest non-clinical survival time. Cranial nerve palsy in multiple myeloma is extremely rare and is usually due to an intracranial plasmacytoma. We present a multiple myeloma case, with an intracranial plasmacytoma, which debuted clinically with isolated, complete and fluctuating cranial nerve III palsy. Case report. A 63-year-old woman presented an oscillating clinical picture, consisting of horizontal binocular diplopia and later, headache. The neuro-ophthalmologic examination revealed a complete cranial nerve III palsy of the right eye. An urgent cranial CT-scan was requested. It showed multiple diploic osteolytic lesions, associating soft-parts component in the right superior orbital fissure. The patient was admitted, being diagnosed subsequently of IgA-k multiple myeloma. After receiving induction-chemotherapy and undergoing autologous stem cell transplantation, she achieved full remission. Conclusions. Multiple myeloma is a rare cranial nerves disorder, very uncommon cause of cranial nerve III full isolated paralysis and even less fluctuating, not having found any case published with this clinical onset. Awareness of possible multiple myeloma neuro-ophthalmic manifestations may bring about an early diagnosis and a positive impact on the disease course (AU)

The olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system.

The olfactory nerve consists mainly of olfactory receptor neurons and directly connects the nasal cavity with the central nervous system (CNS). Each olfactory receptor neuron projects a dendrite into the nasal cavity on the apical side, and on the basal side extends its axon through the cribriform plate into the olfactory bulb of the brain. Viruses that can use the olfactory nerve as a shortcut into the CNS include influenza A virus, herpesviruses, poliovirus, paramyxoviruses, vesicular stomatitis virus, rabies virus, parainfluenza virus, adenoviruses, Japanese encephalitis virus, West Nile virus, chikungunya virus, La Crosse virus, mouse hepatitis virus, and bunyaviruses. However, mechanisms of transport via the olfactory nerve and subsequent spread through the CNS are poorly understood. Proposed mechanisms are either infection of olfactory receptor neurons themselves or diffusion through channels formed by olfactory ensheathing cells. Subsequent virus spread through the CNS could occur by multiple mechanisms, including trans-synaptic transport and microfusion. Viral infection of the CNS can lead to damage from infection of nerve cells per se, from the immune response, or from a combination of both. Clinical consequences range from nervous dysfunction in the absence of histopathological changes to severe meningoencephalitis and neurodegenerative disease.

A pipeline for neuron reconstruction based on spatial sliding volume filter seeding.

Neuron's shape and dendritic architecture are important for biosignal transduction in neuron networks. And the anatomy architecture reconstruction of neuron cell is one of the foremost challenges and important issues in neuroscience. Accurate reconstruction results can facilitate the subsequent neuron system simulation. With the development of confocal microscopy technology, researchers can scan neurons at submicron resolution for experiments. These make the reconstruction of complex dendritic trees become more feasible; however, it is still a tedious, time consuming, and labor intensity task. For decades, computer aided methods have been playing an important role in this task, but none of the prevalent algorithms can reconstruct full anatomy structure automatically. All of these make it essential for developing new method for reconstruction. This paper proposes a pipeline with a novel seeding method for reconstructing neuron structures from 3D microscopy images stacks. The pipeline is initialized with a set of seeds detected by sliding volume filter (SVF), and then the open curve snake is applied to the detected seeds for reconstructing the full structure of neuron cells. The experimental results demonstrate that the proposed pipeline exhibits excellent performance in terms of accuracy compared with traditional method, which is clearly a benefit for 3D neuron detection and reconstruction.

Burkholderia pseudomallei penetrates the brain via destruction of the olfactory and trigeminal nerves: implications for the pathogenesis of neurological melioidosis.

ABSTRACT Melioidosis is a potentially fatal disease that is endemic to tropical northern Australia and Southeast Asia, with a mortality rate of 14 to 50%. The bacterium Burkholderia pseudomallei is the causative agent which infects numerous parts of the human body, including the brain, which results in the neurological manifestation of melioidosis. The olfactory nerve constitutes a direct conduit from the nasal cavity into the brain, and we have previously reported that B. pseudomallei can colonize this nerve in mice. We have now investigated in detail the mechanism by which the bacteria penetrate the olfactory and trigeminal nerves within the nasal cavity and infect the brain. We found that the olfactory epithelium responded to intranasal B. pseudomallei infection by widespread crenellation followed by disintegration of the neuronal layer to expose the underlying basal layer, which the bacteria then colonized. With the loss of the neuronal cell bodies, olfactory axons also degenerated, and the bacteria then migrated through the now-open conduit of the olfactory nerves. Using immunohistochemistry, we demonstrated that B. pseudomallei migrated through the cribriform plate via the olfactory nerves to enter the outer layer of the olfactory bulb in the brain within 24 h. We also found that the bacteria colonized the thin respiratory epithelium in the nasal cavity and then rapidly migrated along the underlying trigeminal nerve to penetrate the cranial cavity. These results demonstrate that B. pseudomallei invasion of the nerves of the nasal cavity leads to direct infection of the brain and bypasses the blood-brain barrier. IMPORTANCE Melioidosis is a potentially fatal tropical disease that is endemic to northern Australia and Southeast Asia. It is caused by the bacterium Burkholderia pseudomallei, which can infect many organs of the body, including the brain, and results in neurological symptoms. The pathway by which the bacteria can penetrate the brain is unknown, and we have investigated the ability of the bacteria to migrate along nerves that innervate the nasal cavity and enter the frontal region of the brain by using a mouse model of infection. By generating a mutant strain of B. pseudomallei which is unable to survive in the blood, we show that the bacteria rapidly penetrate the cranial cavity using the olfactory (smell) nerve and the trigeminal (sensory) nerve that line the nasal cavity.

Olfactory ensheathing cells seeded muscle-stuffed vein as nerve conduit for peripheral nerve repair: a nerve conduction study.

We evaluated bridging of 15 mm nerve gap in rat sciatic nerve injury model with muscle-stuffed vein seeded with olfactory ensheathing cells as a substitute for nerve autograft. Neurophysiological recovery, as assessed by electrophysiological analysis was faster in the constructed biological nerve conduit compared to that of autograft.

A surgical case of frontal lobe epilepsy due to focal cortical dysplasia accompanied by olfactory nerve enlargement: case report.

A 45-year-old man came to our clinic due to refractory general tonic seizure and an attack of unintended yelling. Magnetic resonance imaging (MRI) demonstrated mild cortical hyperintensity on fluid attenuated inversion recovery (FLAIR) image in the left basal frontal area. Enlargement of the left olfactory nerve was also detected below the affected gyrus. Subtotal resection of the MRI-visible epileptogenic lesion was performed without any neurological deficit. The final pathological diagnosis was focal cortical dysplasia (FCD) type IIa. Seizures and yelling attacks subsided after surgery. Extracerebral abnormalities, including cranial nerve enlargement, are common in patients with hemimegalencephaly. However, such abnormalities are rare with FCD.