The axons of the olfactory sensory neurons meet and form several fascicles consisting of olfactory filae. After leaving the nasal cavity the olfactory filae cross the lamina cribrosa of the ethmoid bone and receive synaptic contacts. from terminal axon smell enter to brain, in brain nerve The olfactory ends in the olfactory bulb which is located on the inferior surface of the frontal lobe. ⁴

The olfactory tract passes backwards on the basal surface of the frontal lobe and, appropriate before reach level chiasma optics , part big tract fibers olfactory turn to lateral, to form stripe olfactory lateral . These fibers pass into the lateral fissure, where they cross to reach the temporal lobe. They end the main thing in cortex olfactory primary on uncus , on aspect inferomedial temporal lobe, and in the amygdala adjacent to these structures. Adjacent with uncus , part front from girus parahippocampal, or entorhinal area, there is an olfactory association cortex . The primary and association cortex are called Also as cortex piriformis And responsible answer to appreciate stimulation olfactory. Projection olfactory consists of on order two neuron just in between sensory receptors and the cerebral cortex and does not project past the thalamus. ^3.5

Physiology Olfactory And Neurotransmitters Which Playing a role

A specialized mucosal area often referred to as the olfactory epithelium can be distinguished by its faint yellowish color from the more reddish respiratory mucosa. In each exhaled breath, more than 10-50 very fine hairs called cilia (0.3 μm in diameter) arise from each receptor cell. smell Which sensitive to compound aromatic in air. Axon unmyelinated fibers of the olfactory receptor cells (about 0.2 μm in diameter) coalesce into about 20 fascicles, collectively referred to as the olfactory nerve , and ascend about 30 mm from the nasal cavity through the cribriform plate and enter the cranial cavity. The cribriform plate (like a sieve) is marked by foramina that allow the passage of axons from the sensory cells to the brain. ⁴ Smell must moreover formerly reach neuroepithelium smell, Then smell will dissolve in the mucus layer and bind to olfactory receptors, which are found on the dendritic cilia of the anterior olfactory nucleus. Olfactory receptors are G-coupled receptors and binding of odorant ligands leads to a downstream signaling cascade involving activation of adenylcyclase and opening of cation-dependent channels. on cAMP next. Matter This will cause activation cell with the opening of the ion gate causing the entry of sodium (Na+) and calcium (Ca2+) into the cell, resulting in depolarization and impulse transmission to the olfactory bulb , then distributed to the structures described above. Human gene studies have shown up to 400 active olfactory receptor genes, although humans are able to detect thousands of different odors. This is possible through complex combinatorial coding, where each odorant ligand is recognized by various combinations of olfactory receptors. In addition, other types of chemoreceptors have been identified that are likely involved in human chemoreceptors. ³

Etiopathogenesis Anosmia

Anosmia is the inability to smell. This condition is estimated to occur in 3-20% of the population. The incidence of anosmia increases with age and can occur due to chronic sinonasal disease, severe head trauma, upper respiratory tract infections, and neurodegenerative diseases. This disorder impairs a person's ability to recognize odors, Good smell Which dangerous and also smell from food And environment, thus reducing the quality of life related to social interaction. ^1,3,9

The pathogenesis of anosmia based on the location of anatomical lesions can be divided into three locations, namely conductive, sensorineural, and central dysfunction. Conductive dysfunction is the result of blockade of odor transmission to the olfactory neuroepithelium. Sensorineural dysfunction is the result of damage/loss of neuroepithelium or nerves. While central dysfunction is the result of damage/loss of the olfactory processing pathway in the central nervous system. ^3-4

Chronic rhinosinusitis is a common inflammatory condition affecting the nasal mucosa and one or more paranasal sinuses. It has several distinct phenotypic subtypes including chronic rhinosinusitis with or without polyps. The hyposmia and anosmia associated with chronic rhinosinusitis are due to mechanical obstruction of odor transmission to the olfactory cleft due to mucosal edema or polyps. Thus, olfactory cleft opacification on CT has been correlated with decreased olfactory function. Chronic rhinosinusitis causes conductive olfactory dysfunction. According to research, inflammation in the neuroepithelium can cause transient, reversible impairment to bind/perceive odors. In addition, long-term inflammation is believed to cause neuroepithelial remodeling and replacement with respiratory-type epithelium. In addition, olfactory bulb volume is decreased in patients with chronic rhinosinusitis. Previous studies have shown that olfactory bulb volume can increase significantly after treatment in patients with chronic rhinosinusitis, compared with controls. ³

Damage anatomy on post trauma depicted consequence break up olfactory nerve filaments as they cross the cribriform plate to reach the olfactory bulb . Dysfunction smell Also often happen on damage central with effect delayed such as cortical edema. In addition, the degree of post-traumatic olfactory loss can be correlated with central lesions, which can be demonstrated by magnetic resonance imaging of the brain. Facial injuries sustained during head injury can cause cleft olfactory airflow obstruction , thus contributing as a conductive cause to olfactory dysfunction. ³

The underlying etiology has been associated with olfactory dysfunction, the main causes of which are as follows: ³

• Dysfunction smell secondary consequence sinonasal disease

• Dysfunction smell post infection

• Dysfunction smell post trauma

• Dysfunction smell Which relate with neurological disease

• Dysfunction smell related with exposure drugs / poison

• Dysfunction congenital olfactory disorder

• Dysfunction smell Which related with aging

• Other possible causes: iatrogenic damage (sinonasal and skull base surgery, laryngectomy), tumors, multiple systemic comorbidities.

• Dysfunction idiopathic olfaction

Diagnosis Anosmia

Anosmia can be caused by many underlying diseases. The most common causes are sinonasal disease, post-infectious disorders, and post-traumatic disorders. In patients with olfactory disorders, the first step in diagnosis is the patient's medical history. The clinician should evaluate how the disorder began, for example suddenly, after trauma or gradually after a severe cold, which then makes post-traumatic disorders or disorders after an upper respiratory tract infection very likely. Conversely, if the patient has difficulty remembering the exact time of the disorder, started And describe fluctuation smell, disturbance sinonasal can be assumed. Onset gradually And difficulty in remember incident trigger may also indicate an age-related idiopathic disorder, or a disorder due to neurodegenerative disease. In contrast to patients with sinonasal disorders, patients with neurodegenerative diseases also describe the loss of smell as "gradual" or "sudden" but rarely fluctuate. Patient Also asked whether have disturbance smell since childhood to rule out congenital abnormalities. ⁸

Medication use should be evaluated as well as previous surgery or exposure to toxins, for example, in the occupational environment. A thorough ENT examination for olfactory disorders should include nasal endoscopy to visualize the olfactory cleft and to exclude endonasal pathology. Particular attention is paid to septal deviation, tumors, and signs of acute or chronic sinonasal disease such as secretions, crusts, and polyps. Olfactory function testing use test Which validated And standard is matter Which mandatory because subjective assessment of olfactory function is not always reliable. ⁸

A complete cranial nerve examination should be performed if a neurological cause of olfactory disturbance is suspected. If there are signs of increased intracranial pressure (papilledema, paralysis of N VI, N III, and decreased consciousness) should be suspected. presence of lesions intracranial. Suspicion to direction of abnormality neurology other or cognitive disorders should be consulted to the neurology department. ^4,8

CT scan examination can be performed both in diagnosing inflammation due to disease sinonasal as well as to see the anatomy of the paranasal sinuses, but it is difficult to help assess olfactory disorders. Recently, techniques have been developed volumetric on CT scan Which can. ⁴ Inspection use magnetic resonance imaging (MRI) should be performed when suspected intracranial pathology, including suspected post-traumatic dysfunction or intracranial lesions. ¹ Assessment function smell use electrophysiology or imaging functional requires special equipment, trained operators, and time longer processing, so that the examination is usually only performed in research. Examples of such modalities are Electro-olfactography (EOG) or chemosensory electroencephalography (EEG). ^4,8

2.4.1.1 Profit And Excess Inspection Alcohol Sniff Test

On inspection smell qualitative will rated identification (patient's ability to name odorant types) and discrimination (ability to differentiate between odorant types). However, to assess identification and discrimination, patient must know or Once exposed odorant mentioned earlier, so the type of odorant chosen depends on the local culture. ^1-2 It is estimated that that test threshold the sense of smell threshold reflect olfactory disorders in peripheral (level epithelium olfactory), whereas test suprathreshold who judges discrimination And identification reflect disturbance smell in central. Ideally, olfactory function tests are performed to at least assess the threshold. added with Wrong One from mark suprathreshold (discrimination or identification). ²

Alcohol Sniff test is an assessment of the olfactory threshold, carried out using 70% isopropyl alcohol and can use alcohol pad to make it easier examination. Alcohol pad opened 0.5cm until the tip of the alcohol cotton is visible. Alcohol Then placed in lower nose patient And patient requested to withdraw breath Then say If sniff existence smell. This aims to introduce smell the on patient. ⁴ Alcohol sniff test is test Which Enough fast, reliable, and uses odorants readily available in the medical setting. The examination can provide a measure of olfactory nerve function in non-surgical situations. there is inspection smell other. Reliability Which tall on children show that this test is an appropriate screening test for children. Alcohol is well suited for functional smell testing because only at high concentrations does it cause trigeminal effects. An anosmic, because he cannot detect the odor of alcohol, would be forced to use trigeminal reactivity to detect the presence of alcohol and would do so only when very near with nose. Because intended For become rapid screening instrument, a protocol for the alcohol sniff test has been developed for bilateral testing. ²

Interpretation of this examination, if the distance < 5 cm the patient can identify the smell, then the patient is said to have anosmia, a distance of 6 - 15 cm is said to be hyposmia, and a distance > 15 cm is normosmia. This examination can identify patient with deficit sniff, especially on patient Which can not identify smell from memory or do inspection alternative others in identifying the name and odor presented. Like the visual screening test, the alcohol sniff test can be performed by non-specialists and testing is recommended. more carry on on person Which show deficit. Inspection This not designed to detect malingerers and would be less likely to diagnose parosmia. For detect parosmia in inspection comprehensive, test identification smell is recommended. The alcohol sniff test is a short and easy-to-perform test that has good reliability, sensitivity, and specificity and is performed with common odorants available in health care settings. ²

Depending on the cultural background, olfactory testing is usually performed using the UPSIT or Sniffin Sticks test or other validated tests. Test the can evaluate potential smell Which caused but not performed routinely and due to the relatively high price, although it is often applied in medicolegal cases. Endonasal findings in post-infectious disorders, age-related disorders, neurodegenerative diseases or trauma usually without pathology whatever. If required, imaging addition (tomography computer or imaging resonance magnetic) can done. Olfactory bulb (OB) volume can be used to predict the prognosis of olfactory dysfunction. Therapy for olfactory dysfunction should be tailored to the etiology of the disorder. ⁸

Regeneration Nerve Olfactory As well as Average Healing Time

Olfactory sensory neurons are also capable of regeneration from basal cells found in the olfactory neuroepithelium although the turn-over time in humans is unknown. clear. Cell sheath olfactory support cell glial, Which there is in peripheral and central olfactory system (epithelial neurons and olfactory bulb ). Olfactory sheath cells play a facilitative role in the regeneration of olfactory sensory neurons and are thought to have a future use in the treatment of nerve lesions.

Loss of smell not only entails the broad social, emotional, and behavioral consequences described above but also initiates the process of reorganization in brain. All system sensory We very practical, understanding of the neural processes that occur after loss of smell is still largely unknown. This plasticity, which can be observed at both the cellular and cognitive levels, provides an adaptive opportunity to optimize sensory function in cases of learning and experience. In contrast to gains in function, events such as trauma, injury, disease, and sensory deprivation can induce plasticity among sensory systems in a reductive manner. The neural system that processes olfactory information consists of many more components and regions than just the piriform and orbitofrontal cortices. ⁸

The olfactory epithelium is one of several systems, in the adult nervous system, that contain neural stem cells that support active neurogenesis throughout the life span of the animal. Olfactory sensory neurons are normally turned over every 30–60 days and are replaced through the proliferation and differentiation of a series of immature precursors and multipotent progenitor cells. Two classes of multipotent progenitor cells exist in the postnatal olfactory epithelium: HBCs and GBCs. Globose basal cells are actively mitotic and support the normal replacement of sensory neurons and other cell types in the epithelium smell. On the contrary, cell basal horizontal part big silent inready condition. After injury resulting in the destruction of mature cells in the olfactory epithelium, horizontal basal cells are stimulated to proliferate and differentiate into globose basal cells and all mature olfactory cell types. In response to injury, horizontal basal cells proliferate more vigorously to reconstitute all cellular constituents of this sensory epithelium. Therefore, olfactory progenitor cells provide a potential therapeutic avenue for cell replacement strategies aimed at restoring olfactory function through regeneration of olfactory sensory neurons. ^3-4

Anosmia Management

In sinonasal disorders, therapy consists of steroids, either topical or systemic. Topical steroids have so far only been shown to be effective for allergic rhinitis, especially when used in combination with antihistamines such as azelastinhydrochloride . ⁹ The head-down forward position. In sinonasal disorders, oral steroids have been shown to be effective, although the duration and dosage of steroids used show great variation and remain controversial. ¹⁰ Although not frequently encountered by otorhinolaryngologists , steroid side effects such as osteonecrosis must considered. Therapy surgery in the form of surgery sine functional endoscopic surgery can improve some cases of olfactory dysfunction, the goal is For increase ventilation And with thus reduce inflammation in the olfactory cleft area that may contribute to the disorder. ¹¹ However, since it is very difficult to predict whether olfactory function will improve with surgery, conservative treatment is recommended in cases of chronic rhinosinusitis with polyps. Several attempts have been made For identify factor Which predict results surgery And success rate in terms of olfactory function. ¹²

In post-infectious upper respiratory tract disorders, spontaneous recovery is observed in 32-66% of patients. Different therapeutic approaches have been reported to support spontaneous regeneration. Olfactory training, first described by Hummel et al. (2009), appears to be the most effective. Olfactory training consists of from four aroma different Which must sniffed in a way intense two time a day for a few seconds each for at least 4 months. The effect has been confirmed in large multicenter crossover studies as well as by a recent meta-analysis, and appears to be more effective when different scents are repeated over time. And training extended. Giving drug drops nose vitamin A may provide additional benefits but this remains to be proven, whereas providing vitamin A oral No increase function smell. Implementation Intranasal citrate may also be beneficial in these patients. ^13-14

The rate of spontaneous recovery in post-traumatic olfactory disorders occurs in percentage patient Which Far more low, Possible Because network scar post-traumatic injury in the lamina cribrosa area , accompanied by intracranial lesions and shear injuries. Attempts have been made to improve olfactory outcomes with the administration of steroids, either orally or intranasally, which have been shown to improve olfactory function. Olfactory training as described above, may be given to post-traumatic disorders and Parkinson's disease with some potential for improvement in olfactory function. ^14-15 Further studies with larger patient numbers are needed to prove the clinical significance of treatment for individuals with olfactory dysfunction associated with sinonasal disease, upper respiratory tract infection, and post-traumatic. ¹⁵

Olfactory training is a therapeutic treatment that is a long-term practice of smelling odorants. This method was first discovered by Thomas Hummel on year 2009. Exercise the done twice a day using aromas: phenylethyl alcohol (rose), eucalyptol (eucalyptus), citronellal (lemon), and eugenol (clove) are done every day. These aromas are inhaled alternately one by one for 15 seconds and with a 10-second rest period between scents. When practicing, it is important to inhale scents for a short duration and there should be a break between scent changes. This is because inhaling scents for a long duration will cause nerve fatigue and make the patient become “accustomed” to the scent. As a result exposure to the same odor is no longer effective in stimulating the olfactory nerves. Olfactory training is recommended for 3 months. On study Hummel, after 3 month exercise, happen repair function significantly improved sense of smell in 30% of patients and this improvement in olfactory function did not only happen on hyposmia consequence infection channel breath on, but Also in idiopathic hyposmia and hyposmia due to head injury. ²

Effect Olfactory Training To Patient with Anosmia

Olfactory training appears to be a promising therapy for patients with postviral olfactory loss to regain some sense of smell. they. Remember reorganization nerve Which happen in here, study The future should also look at longitudinal changes. Combining different neuroimaging methods, structural and functional, may lead to insights in process reorganization Which more fine And Possible will encourage the development of biomarkers to predict future therapeutic success. ⁸

The effect of Olfactory training on olfactory dysfunction has been shown to improve olfactory function in healthy people of all ages as well as in patients with olfactory dysfunction due to various causes (e.g. nasal disease, head trauma, upper respiratory tract infections, and neurodegenerative diseases). A study show that after period olfactory training for 12 weeks in healthy children exposed to 4 odor mixtures, children in the training group not only increased their sensitivity to smell Which trained, but Also experience improvement significant in general olfactory sensitivity compared to children in the control group . ¹⁹ Olfactory training for 6 weeks in 8-year-old children improved ability identification smell they, but No sensitivity odor. ²⁰ In a study of patients aged >45 years with olfactory disorders, using modified olfactory training with 12 odors, almost half of the 29 participants showed improvements in their olfactory threshold, discrimination, and identification. In another study of older adults, participants in the olfactory training group had improved olfactory function, improved verbal function and subjective well-being, and reduced depressive symptoms, thereby improving their quality of life. ²¹

1. Neuroplasticity Peripheral: Theory " Bottom -Up ".

Odor receptors expressed in the cilia of the olfactory nerves in the olfactory epithelium detect odors first. These receptors belong to the superfamily of G protein-coupled receptors. The combination of odor and odor receptor triggers an electrical signal and transmits along the axon to the main olfactory bulb , and then the signal is transmitted to other areas of the brain. ²³ Different types of odors can stimulate receptor smell And area projection Which different in olfactory training treatment , thereby improving olfactory function. Research has show improvement response electro-olfactogram in patients who receive repeated exposure to odors. Therefore, odor-specific plasticity may begin at the level of the olfactory epithelium. ²⁴ During the early recovery period, GNAL and ADCY enzyme activities were observed to increase First time on group olfactory training , shown that the receptor smell stimulated more beginning. When olfactory training performed, increased glial fibrillary acidic protein (GFAP), an intermediate filament expressed in astrocytes, can stimulate production or activity OEC. Otherwise, increased expression of neurotrophic factors, such as BDNF and nerve growth factor receptor (NGFR), suggests that olfactory training can stimulate system nerve smell. Studies latest showed that biomarkers such as p75 neurotrophin receptor (P75NTR), O4 antibodies, alpha-actin muscle plain And protein-100 dissolved (S-100) can used For localize OEC. Compared to with group hyposmia And the group that treated with corticosteroids, expression mRNA from alpha-actin muscle plain and S-100 in the olfactory training group increased significantly after 3 weeks of treatment. ³ Marin et al revealed that after olfactory training , the number of migrating neuroblasts and proliferation of neural precursor cells increased in animals with bilateral olfactory bulb damage , which helped recovery. In addition, olfactory training was shown to increase the proliferation and activity of OECs and neural precursor cells to stimulate olfactory regeneration. Other studies have shown that odor deprivation can cause loss of olfactory receptor neuron activity and olfactory bulb atrophy , both of which recovered after odor stimulation. Otherwise, in the reduction of nasal inflammation without odor input, olfactory receptor neurons recovered partially, but no recovery of olfactory bulb atrophy was seen . Only odor input to the olfactory bulb caused complete recovery of atrophy. ²⁵

2. Mechanism Central: “ Top–Down ” process .

   The olfactory bulb receives new cells originating from the subventricular zone and maintain its plasticity. Studies has show that olfactory bulb volume can be significantly increased in patients with olfactory dysfunction and healthy people who do olfactory training , the effect of olfactory function is also relatively increased due to a decrease in the volume of the olfactory bulb in patients after laryngectomy. ²⁶ A recent study found that that volume olfactory bulb can increase in a way significant in patients undergoing total laryngectomy after 6 months of olfactory training. ²⁷ Olfactory bulb volume before and after olfactory training by magnetic resonance imaging of 97 healthy participants who performed olfactory training while blocking the other nostril. Showing that olfactory bulb volume increased also for the untrained nostril. Olfactory training may modulate olfactory bulb volume by a mechanism central. ²⁸ Studies has show subtraction volume grey matter (GM) in brain regions involved in smell-related processes, such as the orbitofrontal cortex, insular cortex, entorhinal cortex, piriform cortex, cingulate cortex, and amygdala, in patients with olfactory dysfunction. ^27-29 Han et al studied changes in gray matter volume in patients with idiopathic olfactory disorders using a longitudinal approach. In their study, they found that patients who underwent OT had larger GM volumes in the medial orbitofrontal cortex and improved odor identification. ⁶ Al Ain et al evaluated 36 healthy young adults and measured brain tissue density and cortical thickness using magnetic resonance imaging. They found that thickness in the right entorhinal cortex, right inferior frontal gyrus , and bilateral fusiform gyrus of those who underwent OT increased compared with healthy controls. ³⁰ Thus increasing activity between the amygdala-hippocampal complex and olfactory neurons. In addition to structural changes, functional reorganization of smell-related brain regions may occur in patients with olfactory dysfunction. The piriform cortex receives input from projection neurons. olfactory bulb And Then project it to area higher sense of smell (brain structures with high involvement in olfactory perception). ⁸

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