Olfactory Dysfunction After Oral and Maxillofacial Surgery

Background: Although anesthesia can contribute to olfactory dysfunction, it is a rare complication after oral and maxillofacial surgery by general anesthesia. Cases presentation: In this study, we introduced 3 cases of patient suffering from anosmia (complete loss of smell), after oral and maxillofacial surgery by general anesthesia. We also investigated possible etiologies of anosmia. Conclusions: There are some evidences that anosmia is caused by nasotracheal intubation, which may cause OM injury and/or swing of the nasal septum in patients with nasal septum deviation. Olfactory dysfunction via general anesthetic drugs, however, may have a different etiology.


Case 3
A 22-year-old female, non-smoker, was diagnosed with mandibular excess, and received a BSSRO.
Midazolam and etomidate were used for the induction of anesthesia, while sufentanil, propofol, and iso urane were used to maintain it. Endotracheal intubation was performed though the right nostril. After recovery from general anesthesia, she complained of loss of smell. A month later, she regained her sense of smell without any speci c therapy ( Table 1). The preoperative and postoperative posteroanterior cepholametry are presented in Fig. 4.

Discussion
The formation of the sense of smell is extremely complex. It involves olfactory mucosa (OM), located in the upper regions of the nasal cavity [4], which is composed of a pseudo-strati ed columnar epithelial layer [5], averaging 1 cm 2 of surface area in each nostril [6]. Also, involved in this process, are olfactory nerve, trigeminal nerve, glossopharyngeal nerve, and vagus nerve [6]. Interestingly, a person's sense of smell is also in uenced by personal hobbies, age, culture, and experience [7]. Among the olfactory epithelium that makes up the OM, there are 4 categories of cells, namely olfactory receptor cells, sustentacular cells, microvillar cells, and basal cells [5].  [9]. The olfactory receptor cells are replaced every 30-60 days [10] and act as bipolar neurons with its dendrite reaching the OM surface and axons approaching the olfactory bulb. Generally, the dendritic terminal expands to form an olfactory vesicle and sends out several cilia to capture odorant molecules in the air. The axons join together and pass through the cribriform plate to synapse within the olfactory bulb. The olfactory bulb, located in the anterior cranial fossa, is composed of six layers: the olfactory nerve layer, the glomerular layer, the external plexiform layer, the mitral cell layer, the internal plexiform layer, and the granule cell layer. Changcheng Sun [11] reported that the leptin-mediated reduction in odor discrimination may be correlated with reduced neural activity in mitral cells, prompted by alterations in potassium channels. The olfactory bulb axons project to the cerebral cortex, where different odors can be recognized, however the transmission mechanism in olfactory cortex remain unclear. Emerging studies have demonstrated that odor memories are stored in the anterior olfactory nucleus, and their activities are crucial and necessary for the animal's odor cognitive and behavioral demands [12]. Interestingly, a study of perceptual asymmetry in olfactory discrimination once demonstrated a right-nostril advantage, but the nature and origin of this advantage remains unclear [13].
When odorants bind to olfactory receptor cells, they depolarize neurons and send signals along axons. These axons project to the mitral and tufted cell layer of the olfactory bulb through the cribriform plate.
The axon terminals of neural receptors synapse within the same glomeruli. The corresponding glomeruli of the olfactory bulb become activated and generate a unique excitation pattern for each odor in the olfactory bulb [6]. The axons of all the glomeruli cells project to different cerebral structures, including the anterior olfactory nucleus, thalamus, and numerous cortical regions that together form the primary olfactory cortex, the piriform, and periamygdaloid cortices, rostral entorhinal cortex, amygdala, and olfactory tubercle [14].
Factors affecting this pathway may lead to olfactory dysfunction, such as upper respiratory tract infection, nasal and sinonasal disease, head trauma, endoscopic sinus surgery, congenital anosmia, and other causes like intoxication and brain surgery, even COVID-19 can cause olfactory dysfunction. The leading etiology of adult olfactory disorder is upper respiratory tract infection [15]. Unlike adult patients, about 2/3 of the olfactory dysfunction in children are congenital [16]. In addition, olfactory dysfunction occurs in patients who suffer from neurological diseases such as Alzheimer's [17]and Parkinson's disease [18].
None of the patients, reported in this paper, underwent nasal surgery. In one case, a patient underwent cyst curettage, due to a maxillary dentigerous cyst close to the maxillary sinus, the operation itself did not involve the maxillary sinus. The CBCT exhibited left maxillary sinusitis after the operation. The oral and maxillofacial surgery, received by the patients in this paper, did not involve the olfactory system, so surgical damage to the olfactory pathway can be ruled out.
All patients received inhalational anesthesia, combined with intravenous anesthesia. The endotracheal intubation, often performed during oral surgeries, is completely different from the intubations conducted during other forms of surgery. The nasotracheal intubation is the best form of oral general anesthesia while, in other cases, the orotracheal intubation is preferred. As described previously, OM is distributed throughout the upper regions of the nasal cavity [4]. Additionally, emerging evidence revealed that OM contains sensory neurons, but their functional signi cance remains unknown [19]. The top of the nasal septum is adjacent to the cribriform plate, and the olfactory receptor axon pass through the cribriform plate to synapse with the olfactory bulb. The incidence rate of the nasal septum deviation is high. In this study, the nasal septum deviation was found in all three cases via X-ray (posteroanterior cepholametry and CBCT presented in in Figs. 1, 3, and 4), and all 3 cases underwent nasotracheal intubation. Olfactory dysfunction may be related to intubation because of the deviation of nasal septum. The olfactory pathway is likely injured during intubation. Intubation may cause swing of the deviated septum and affect the conduction of the axon. When the swing amplitude is too large, it can fracture the axon and cause olfactory dysfunction.
Olfactory dysfunction, after general anesthesia, is reported in prior literature, with special criticism given to the general anesthetic drugs for causing the olfactory disorders. In one such study, Konstantinidis et al. reported the case of a 60-year-old female who experienced general anesthetics-induced olfactory dysfunction for 3 months post urological surgery [20]. Baker et al. disclosed that a 69-year-old male lost his ability to smell and taste, due to receiving general anesthesia, namely, remifentanil and propofol, for a laparoscopic inguinal hernia repair [21]. Similarly, in another report, a 57-year-old female who underwent laparoscopic cholecystectomy, under general anesthesia, namely midazolam, fentanyl, propofol, and sevo urane, also experienced a loss of smell and taste, likely due to adverse reaction to the anesthesia [22]. Lastly, a 32-year-old woman, who underwent a uterine curettage surgery, experienced anesthesiainduced anosmia and hypogeusia after recovering from anesthesia, induced by propofol [23].
The neurotoxicity of anesthetic drugs is mostly reported in animal studies. Deng et al. reported that iso urane induced the neuronal cell death in newborn mice forebrain, and the dentate gyrus and olfactory bulb nerve were also damaged in juvenile and young adult mice [24]. Moreover, it has been shown that the basal ganglia and primary olfactory system are vulnerable to neurodegeneration after prolonged sevo urane exposure in perinatal rats [25]. It was also found that ketamine or midazolam resulted in a dose-dependent, statistically signi cant increase in nerve cell apoptosis, and that the combination of the two drugs produced a higher rate of nerve cell apoptosis than either drug alone [26]. Moreover, induction of neuroapoptosis in young mice requires only propofol at 1/4 anesthetic dose [27]. Clinical trials revealed that although sevo urane does not alter olfactory activity, it is detrimental to olfactory memory [28].
Sevo urane also produced a shortterm olfactory identi cation impairment, and simultaneously suppressed melatonin levels [29]. This may be related to its in uence on the binding of GABAA receptor ligand [30]. However, some studies have shown that general anesthesia, using des urane (6%), has no marked impact on short-term olfactory memory [31]. In another study, it was demonstrated that general anesthesia can induce reversible short-term memory loss, which corrects itself once the anesthetic drug is removed from the body [32].
In summary, 3 patients suffered from olfactory dysfunction after general anesthesia during oral and maxillofacial surgery. This was likely caused by nasotracheal intubation, which may produce OM injury and/or swing of the nasal septum in patients with nasal septum deviation. Olfactory dysfunction via general anesthetic drugs, however, may have a different etiology. The conclusions from this study would aid the perioperative team in increasing their understanding of postoperative complications of the oral and maxillofacial surgery by general anesthesia, and, therefore, provide basis for strengthening the management of perioperative patients, such as the choice of intubation mode of oral general anesthesia, need for X-ray examination to clarify the nasal septum, strategies to avoid injury to the nasal septum during operation, and the choice of narcotic drugs.

Declarations
Ethics approval and consent to participate Postoperative CBCT of case 2 Figure 4