Empty nose syndrome: etiopathogenesis and management

Empty nose syndrome (ENS) is an iatrogenic disorder most often recognized by the presence of paradoxical nasal obstruction despite an objectively wide patent nasal cavity. It occurs after inferior and/or middle turbinate resection; however, individuals with normal turbinates and intranasal volume may also complain of ENS. Its pathophysiology remains unclear, but it is probably caused by wide nasal cavities affecting the neurosensitive receptors and inhaled air humidification. Neuropsychological involvement is also suspected. Not every patient undergoing radical turbinate resection experiences the symptoms of ENS. ENS can affect the normal breathing function of the nasal cavity, with subsequent deterioration in patients’ quality of life. The diagnosis is made on the basis of the patients’ history, endoscopic examination of the nasal cavity, imaging (computed tomography imaging and functional MRI), and rhinomanometry. Prevention is the most important strategy; thus, the inferior and middle turbinate should not be resected without adequate justification. Management is problematic including nasal cavity hygiene and humidification, with surgery reserved for the most severe cases. The surgery aims at partial filling of the nasal cavity using different techniques and implant materials. In this paper, we review both the etiology and the clinical presentation of ENS, and its conservative and surgical management. Core tip Empty nose syndrome (ENS) is encountered after inferior and/or middle turbinate resection; however, it can occur in patients with seemingly normal turbinates. Rhinologists should avoid routine resection of the inferior and middle turbinates. It is not certain why some patients develop ENS, whereas others do not. The frequent association with psychiatric disorders and possibly psychosomatic pathologies indicate the possible role of psychological stress in some patients. Its diagnosis relies on clinical suspicion and physical examination. Nasal augmentation surgery can improve the quality of life of patients by restoring nasal anatomy toward the premorbid state.


Introduction
The descriptive term 'empty nose syndrome (ENS)' was originally coined in 1994 by Kern and Stenkvist to describe empty space in the region of the inferior and middle turbinates on coronal computed tomographic images of the patients [1]. They observed that these patients suffered from endonasal crusting and dryness, and some of them also experienced a paradoxical sensation of nasal obstruction, despite adequate intranasal airspace [2].
The term 'empty nose' has broader applications than 'empty nose syndrome' and the two terms should not be used interchangeably. As its name implies, ENS is an iatrogenic disorder that has clinical manifestations that often cause significant distress to the patients, as opposed to 'empty nose', which may or may not have associated symptoms [3].
ENS is a complication of middle and/or inferior turbinate surgery, most frequently total turbinate excision, but also with minor procedures such as submucosal cautery, submucosal resection, laser therapy, and cryosurgery if performed in an aggressive manner [4]. The onset of this condition occurs at an interval of months or years after the procedure [3]. One point of concern is the frequent association with psychiatric disorders and psychosomatic pathologies, for example, fibromyalgia and functional colopathy, in addition to the possible role of psychological stress and neurological component in certain patients [5][6][7].
The diagnosis of ENS is difficult because there are no reliable objective tests; thus, the diagnosis relies on the patient's subjective symptoms. Most rhinologists often miss the diagnosis because they look for physical signs of dryness and atrophy after turbinectomies and objective long-term complications, and neglect the patients' subjective complaints of nasal obstruction or shortness of breath, which are often viewed as psychological manifestations [2]. Like some otolaryngologic disorders (e.g. tinnitus), the fact that the symptoms are subjective and cannot be verified objectively does not imply that they are not real. In fact, many studies have found a lack of correlation between subjective and objective measures of nasal patency [8][9][10].
The occurrence rate of ENS after turbinectomies is not known, but the condition is rare [2,11]. It is uncertain why some patients develop ENS after turbinectomies, whereas others do not. One hypothesis is that a 'twohit' phenomenon must take place, in which (a) the tissue is excised or damaged and (b) the sensory nerves to the area regenerate poorly. The differences in the nerve recovery after surgery and the unique patients anatomy may explain why only some patients develop ENS despite identical turbinate surgeries [3].
ENS is a diagnosis of exclusion as it must be distinguished from other diseases such as chronic rhinosinusitis, autoimmune diseases of the nose, and primary atrophic rhinitis [2]. Confusion results from similarities in the symptoms of ENS and atrophic rhinitis. Paradoxic congestion, dryness, and crusting may present in both disorders. However, atrophic rhinitis may be classified as primary or secondary, with a clear underlying cause or idiopathic in nature. In addition, resorption of the turbinate and adjacent mucosa that results from atrophic rhinitis is reflective of the underlying pathophysiology of the disease, whereas ENS is an iatrogenic disorder. Also, atrophic rhinitis has pathogenic links to the organisms isolated from nasal cultures, but as yet, there is no pathogen associated with ENS [3].

Types
Houser distinguished several subtypes of ENS according to the resected turbinate: inferior, middle, both, or a subtype in which turbinates appear normal [4]. ENS-IT (empty nose syndrome-inferior turbinate) is the most frequent type (Fig. 1a). The basic complaint is paradoxical nasal obstruction [12]. ENS-MT (empty nose syndrome-middle turbinate) is rarer; in addition to the nasal obstruction, patients may complain of pain on respiration because of circulating cool air striking the area of the sphenopalatine ganglion, which is no longer protected by the MT (Fig. 1b) [13]. ENS-both is mostly associated with a nasal cripple and the patient is iatrogenically disabled (Fig. 1c) [13]. In the ENS type, a patient has seemingly normal turbinates, but suffers from ENS symptoms after surgery [2].

Pathophysiology
The pathophysiology of ENS remains poorly elucidated, but several hypotheses can be found in the literature. ENS may result from loss of the physiological nasal functions (humidification, warming, and cleansing of the inhaled air) because of reduced mucosal area [14].
Passali et al. [15] reported a disruption of nasal physiology (mucociliary clearance, IgA secretion rates, and general heating and humidification capacities) in 45 patients who had undergone total inferior turbinectomies. Naftali et al. [16] and Elad et al. [17] used computerized simulations to show that removal of the inferior turbinate reduces the overall heat and water vapor flux in the nose by 16% and removal of the middle turbinate or removal of the  inferior and middle turbinates together reduces vaporization by 12 and 23%, respectively.
Naftali et al. [16] also reported that the turbinates and nearby septal and lateral wall mucosa were responsible for about 60-70% of the air conditioning and the overall heating of the inspired air. The efficacy of nasal air conditioning was reduced by 12% when the middle turbinate was missing and by 16% when the inferior turbinate was missing.
In a study carried out by Scheithauer [1], the airconditioning function of the nose was examined in a group of 10 ENS patients using MRI-based numerical airflow dynamics simulation models during inspiration and expiration; compared with the healthy control group, absolute humidity at all measuring points was lower in ENS patients, especially in the nostril region. These lowered humidity values are responsible for the dry nose sensation and increased crust formation experienced by ENS patients.

Role of thermoreceptors in empty nose syndrome
The specific trigeminal cool thermoreceptors involved in the sensation of nasal patency are TRPM8, which are activated when high-speed air moves through the nostril and induces evaporation of water from the epithelial lining fluid. The fluid remaining has a lower temperature, which leads to reduced fluidity of membrane phospholipids that is sensed by TRPM8 receptors, causing depolarization of neurons that connect to the brainstem respiratory center [18]. The 'cool' message is interpreted as patent nostrils and open airways, leading to a decrease in the intercostal and accessory muscle work of breathing [18]. The brain interprets the lack of stimulation as an 'uncool' signal, which induces apnea and increases the work of breathing with sensations of nasal 'fullness' [2,18]. These receptors fail to be activated in the following cases: (1) ENS patients as the surface area of the nasal passages are reduced and the airflow pattern is altered, which compromises mucosal cooling [2]. (2) Nasal mucosal thickening and excessive mucus production, which limit the evaporation and hinder the degree of mucosal cooling. (3) Anesthetized nasal mucosa.

Effect of change of airflow pattern
(1) Turbulent airflow is required not only for cooling of the nasal mucosa but also for inspired particulate material to come in contact with the nasal mucosa [19]. With reduced mucosal surface area and a lack of physiologic turbulent airflow in ENS patients, the nasal mucosa cannot carry out its primary functions of air conditioning and cleansing. Similarly, olfactory particles are less likely to deposit in the olfactory cleft, reducing the capacity to smell [2]. (2) Another observation made in the context of flow simulation in the ENS patients is that the inspired air is accelerated through the posterior apertures of the nose, hitting the back wall of the nasopharynx at a high speed [1], together with insufficient air humidification by nasal mucosa, causing dehydration and dryness of the pharyngeal mucosa. (3) During normal expiration, warm moist air from the lungs mixes with a cool moist environment within the nose; thus, the portion of the temperature and humidity given off to the mucosa by convection during inspiration can be extracted from the mucosa again during expiration [1]. In ENS patients, warm dry air is met instead, and so this process is disrupted that, in conjunction with reduced mucosal surface area, does not allow the moisture from the lungs to be reabsorbed during exhalation, thus perpetuating nasal dryness [2].

Dyspnea in empty nose syndrome
(1) Cool thermoreceptors in the nasal mucosa are connected to the respiratory centers. Thus, if the mucosal cooling fails to stimulate such receptors, the brain perceives a lack of airflow and produces the sensation of congestion and shortness of breath. This is supported by the following: (a) In animal experiments, menthol as a specific stimulant of cool thermoreceptors causes respiratory depression [20]. (b) A study conducted by McBride and Whitelaw [21] showed that the degree of diaphragm contraction inhibition increased with increasing nasal flow and cooler air during inspiration. The effect was no longer observed following local anesthesia of the nose and pharynx. (c) Breathing cool air through the nose inhibits the ventilatory response to the carbon dioxide [22]. (2) The turbinates are related to the nasal meati, which offer resistance to limit the total amount of airflow and serves to increase the velocity of airflow, ensuring a mostly laminar pattern. As a result, a maximal conductive air-mucosal interface exists, which provides maximum sensation. In patients with loss of turbinate tissue, there is eventual disruption and destruction of the meatal structure, causing turbulent, less efficient, and less sensate airflow [23,24]. These patients seem to be in a constant state of dyspnea and may describe the sensation as suffocating. (3) The nasal resistance is centrally important in providing wider opening of the peripheral bronchioles and enhancing alveolar ventilation. This in turn improves gas exchange, increases negative thoracic pressure, and enhances cardiac and pulmonary venous return [3]. Clinical research indicates that nasal resistance to expiration helps to maintain lung volumes and may indirectly affect arterial oxygenation [25]. (4) Although air entering the nose in ENS patients fails to stimulate the cool thermoreceptors in the nasal mucosa, it still activates pulmonary stretch receptors, signaling the brain that adequate ventilation is occurring [2]. This conflicting message may explain the distress associated with breathing in ENS patients. This conflicting message has been reported in a study that used functional MRI to measure brain activity by detecting associated changes in blood flow. The differences in areas of brain activation between ENS patients and controls indicated abnormal signaling to the brain that may contribute toward the feeling of respiratory distress in ENS patients. Because ENS patients are in a constant state of dyspnea, they become highly preoccupied with their breathing, which leads to the inability to concentrate (aprosexia nasalis), chronic fatigue, frustration, irritability, anger, anxiety, and depression [4,14].  [26] examined sensation deficits in postherniotomy patients and found that cutaneous sensory detection thresholds were increased for all sensory modalities on the operated side (cold, warmth, and mechanical pressure), along with decreased brush sensation during mapping. Relating this to the ENS patients, an increased detection threshold for cold means that a greater degree of mucosal cooling must occur to activate nasal mucosa cool thermoreceptors [14].
(2) The turbinates are recognized as a source of nerve growth factor, a protein critical for the survival, maintenance, and repair of sympathetic and sensory neurons [27,28]. When the turbinates are removed or their mucosa are severely damaged, there is no conductor to orchestrate the healing process. Anomalous nerve connections could be formed during the healing process, whereas some nerves could be lost altogether. Consequently, some corrupted pathways would be activated where the message is not carried to the correct destination, whereas some nerve pathways would fail to be activated at all [2].

Diagnosis
It is difficult to diagnose the ENS because of the lack of a consensual clinical definition, the variety of symptoms, and the associated psychological and sometimes social distress.

Clinical diagnosis Subjective symptomatology
The characteristic presenting symptom is the paradoxical nasal obstruction, sometimes associated with sensations of suffocation, breathlessness, dyspnea, or difficult breathing. Other symptoms such as pain, headache, loss of the concentration (nasal aprosexia), chronic fatigue, frustration, anxiety, irritability, and depression are also reported. The patients may also have symptoms of pharyngitis and laryngitis. Symptom intensity varies and may restrict everyday activities [3].
Other reported symptoms are as follows [29,30]: (1) Sensation of excessive airflow and emptiness of the nasal cavity. The SNOT-20 [32] and the modified SNOT-25 [3] are the most common standardized questionnaires useful for the assessment of patient symptoms (Table 1).

Examination
Physical examination indicates wide nasal cavities, with missing or markedly reduced inferior and/or middle turbinates from previous surgery. The mucosa is generally pale and dry, with crusting ( Fig. 2) [5].

Diagnostic test
Cotton test: using an isotonic sodium chloride solution, cotton is moistened and placed within the nasal cavity in a region in which an implant may be feasible, without local anesthesia or decongestant, for better patient selection. The cotton is kept in place for 20-30 min and the patient is asked to breathe comfortably and report any changes in the symptoms. Patients who report a subjective improvement from the cotton test and whose symptoms and physical examination findings seem consistent with ENS are offered submucosal implantation [4].
The cotton test is an office-based procedure that is not only used as a diagnostic tool but also for preoperative evaluations to select the feasible location and the  Endoscopic view of the right nasal cavity in a case with empty nose syndrome.
amount of the implant required to reduce the nasal cavity volume [33].

Imaging
The diagnosis of ENS is clinical, but variable nonpathognomonic signs may still be found on computed tomographic imaging of the patients that include (a) mucosal thickening of the paranasal sinuses, (b) loss of definition of the ostiomeatal complex secondary to destruction of the ethmoid bulla and uncinate process, (c) opacification of the maxillary sinus, (d) enlargement of the nasal cavities, and (e) bony destruction of the inferior and middle turbinates [30,34,35].
Functional MRI study [14,36] shows specific activation patterns in the temporal and cerebellar regions and the amygdala in ENS patients.
Freund et al. [14] compared ENS patients with the control group by functional MRI with inhalation of menthol and limonene in comparison with room air and using rhinomanometry to measure nasal patency. Despite similar results of rhinomanometric measurements, the subjective nasal patency was worse for ENS patients than for controls that improved after menthol or limonene inhalation. Patients are distinguished by specific deactivation of the bilateral (paralimbic) temporal cortex and the Broca's area.

Rhinomanometry
Rhinomanometry is not useful for the diagnosis of ENS [14], but generally confirms the absence of any anatomical obstruction [4].
Rhinomanometry may not correlate with the subjective patient nasal patency as it focuses on the nasal obstruction attributable to anatomical factors. Many studies have documented the sensation of obstruction without any demonstrated anatomical causes, for example, topical application of local anesthetics in the nostril produces an artificial sensation of nasal obstruction with no change in objectively measured patency, whereas topical application of menthol produces the sensation of decongestion without actually altering nasal morphology [37].
Other investigations: (1) Bronchopulmonary functional exploration is useful in case of lower respiratory tract symptoms. (2) Bacteriology is also recommended in case of crusts and suppuration; it enables adapted antibiotic therapy.
(3) The role of cytologic and pathologic analysis together with the mucociliary function of the turbinate mucosa remains to be determined.

Prevention of empty nose syndrome
Because the nasal mucosa is the functional entity involved in the air conditioning, minimally invasive surgery on the turbinate that preserves the nasal mucosa and cool thermoreceptors is the key to achieve optimal results and reduce the risk of developing ENS [2].
Surgical techniques for the management of the inferior turbinate hypertrophy vary widely and have evolved considerably in the past four decades as new technologies have emerged [38]. They include turbinate outfracture, partial turbinectomy with resection of the anteromedial 1/3 of the inferior turbinate, and extramucosal destruction of the inferior turbinates by diathermy or laser [most commonly with a carbon dioxide (CO 2 ) or an Nd : YAG laser]. Along with the laser, cryosurgery can be used, which enables intracellular formation of ice crystals with cell membrane destruction. Although lasers and cryosurgery gained favor in the 1990s and the early 2000s, they are less frequently used nowadays [38].
Currently, many of the surgical techniques for inferior turbinate reduction fall into the category of submucous resection and turbinoplasty, which involve remodeling of the inferior turbinate with removal of submucosal tissue with or without bone removal. Anterior turbinoplasty where the mucoperiosteal flap is detached from the turbinate bone, followed by resection of the turbinate head including bone, together with the lateral mucosal plate are performed; then, the remaining medial mucoperiosteal flap is placed laterally across the defect and secured with a tamponade. Submucosal diathermy and radiofrequency are also used to shrink the submucosal tissue, but they produce high tissue temperatures and can cause significant injury to the surrounding tissue and thermal damage of the overlying mucosa. Radiofrequency ablation using a Coblator is a more recent technique that causes less thermal damage to the surrounding tissues and can be performed using a method similar to that of electrocautery. Submucosal tissue removal by a microdebrider or a bipolar equipped microdebrider can also be used for submucosal tissue removal. The ultrasonic bone aspirator is the newest technique used in inferior turbinate surgery. The key feature of this During the follow-up period of 3-18 months,all patients reported subjective symptom improvements and a statistically significant improvement in the Sino-Nasal Outcome Test-20 (SNOT-20) scores. The endoscopy imagings and computed tomography scans confirmed that the positive outcomes of the surgery were maintained and proved that there was no evident trace of implantation depletion. Mucociliary clearance assessments showed improvements at 3, 6, and 12 months postoperatively. Acoustic rhinometry assessments showed postoperative improvements in nasal resistance, nasal volume, and minimum cross-sectional area, with a significant overall average score Bastier et al. [46] Five patients B-tricalcium phosphate  Both groups showed a significant improvement in SNOT-25 scores following surgery; the group that received costal cartilage implants showed more significant improvements than the conchal cartilage group in terms of the mean difference between preoperative and postoperative SNOT-25 scores Modrzynski [29] Three patients with ENS and atrophic rhinitis

Hyaluronic acid preparations
Submucosal injections of hyaluronic acid preparations into the inferior nasal concha and under the mucous membrane of the septum under local anesthesia as an officebased procedure He reported positive results and has recommended this implant for the treatment of less severe forms of ENS instrument is tissue selectivity as it vibrates rather than spinning like a drill burr or a microdebrider blade, which results in effective bone removal while causing relatively less damage to the surrounding soft tissue. Multiple techniques (especially outfracture) may be combined to maximize effectiveness [1,38].
Kennedy [39] argued against routine resection of the middle turbinate and he described its protective and physiologic functions. Therefore, it is better to preserve the middle turbinate during the nasal surgeries, except when there is severe inflammation of its mucosa with or without neosteogenesis or in the case of symptomatic concha bullosa; in such cases, it can be partially resected [1].

Medical treatment
Nasal hygiene with regular intranasal irrigation remains the standard of conservative therapy by minimizing crusting and restoring nasal hydration [11,40]. Medical treatment includes nasal lavage, topical ointment, antibiotic therapy, aerosols, and local corticosteroids, although such treatments seem to be less effective in ENS than in atrophic rhinitis [30]. Adding menthol to the local treatments may be beneficial; however, its effect on the nasal patency is because of a sensory illusion rather than altered airflow [41,42].

Surgical treatment
The aims of the endonasal surgery are to reduce nasal cavity volume, increase resistance to the airflow, reduce the airflow to increase air humidity, and deviate the airflow from the surgical site toward a healthy or a nonoperated side [13].
The creation of a neoturbinate is the most common surgical solution for ENS. Techniques vary from team to team, but the results have been very encouraging ( Table 2). The principle consists of positioning an implant in a pocket in the septum, floor, or lateral wall of the nose [3,30,44].
The location of the implant is based on the patient's history, examination, computed tomography scan findings, and the results of the cotton test in the office. Patients who gain no benefit from the cotton test are deemed poor candidates for implantation [3].
The location of the implant should recreate the natural airflow patterns within the nose. To simulate the inferior turbinate, the implant is placed at the septum, floor, or the lateral nasal wall ( Fig. 3a and b). As the head of the natural inferior turbinate enters the nasal valve region, the graft should be sufficiently anterior to replace the former inferior turbinate head [3]. A septal implant located anteriorly might function similarly. The lateral wall implant is tethered by the nasolacrimal duct and does not extend sufficiently to the anterior area, and thus may not provide adequate relief.
The treatment of ENS-MT has the least number of options because of the surrounding anatomy. It is better to avoid lateral implants because of the presence of thin mucosa within the middle meatus and the possibility of obstructing the drainage pathways of the paranasal sinuses. However, the septum may be used for grafting, which simulates a 'Bolgerized' MT [13]. In a patient who has ENS-both, the septum will be the target for grafting, with a large implant spanning the region of the middle and inferior turbinates [49].  Patients with ENS-IT without any IT remnant (or a minimal remnant) may present a difficult reconstructive problem. The work of Michael Friedman and Lee [50] suggests limited success with lateral wall augmentation (0 of three patients benefited from the procedure) and the nasolacrimal duct might be obstructed.
The material used to reduce the nasal cavity volume should have cartilage-like elasticity, immunologic inertness, and combine minimal risk of extrusion, rejection, and infection with sufficient restoration of nasal cavity volume. Various materials are available including autologous (bone, cartilage, and fat) and exogenic materials (hydroxyapatite [44], goretex [29,51], teflon, plastipore) [3,4]. Although all of the synthetic implants may be effective, the use of autologous materials, such as cartilage, is considered ideal as it is cheap and available with a high level of biocompatibility. General evidence indicates long-term positive outcomes associated with the use of cartilage implants in rhinological surgeries. Septal cartilage is the most common material used in rhinological grafts; however, it is usually not enough in some patients, especially those who have undergone previous septal surgery. Conchal and costal cartilages can also be used in the procedure [48].

Conclusion
ENS may be encountered after inferior and/or middle turbinate resection; however, it can occur with normal turbinates. It is not clear why some patients develop ENS, whereas others do not. One point of concern is the frequent association with psychiatric disorders and psychosomatic pathologies, which indicate the possible role of psychological stress in some patients. The hallmark complaint of the patients is paradoxical nasal obstruction. Patients are preoccupied with their breathing and nasal sensations, leading to inability to concentrate, chronic fatigue, frustration, irritability, anger, anxiety, and depression, which points out that ENS is not a single disease entity and has a major impact on the quality of life of the patients. Its diagnosis relies on clinical suspicion and physical examination. Prevention of ENS is very important by preservation of the middle and inferior turbinate as much as possible. The quality of life of patients with ENS can be improved by using nasal augmentation as it restores nasal volume toward the premorbid state.