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Posttraumatic olfactory dysfunction
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ANL-2014; No. of Pages 7 Auris Nasus Larynx xxx (2015) xxx–xxx
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Posttraumatic olfactory dysfunction Daniel H. Coelho, Richard M. Costanzo * Department of Otolaryngology – Head and Neck Surgery and Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298-0146, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 July 2015 Accepted 26 August 2015 Available online xxx
Impairment of smell may occur following injury to any portion of the olfactory tract, from nasal cavity to brain. A thorough understanding of the anatomy and pathophysiology combined with comprehensively obtained history, physical exam, olfactory testing, and neuroimaging may help to identify the mechanism of dysfunction and suggest possible treatments. Although most olfactory deficits are neuronal mediated and therefore currently unable to be corrected, promising technology may provide novel treatment options for those most affected. Until that day, patient counseling with compensatory strategies and reassurance is essential for the maintenance of safety and QoL in this unique and challenging patient population. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Trauma Olfactory Smell Dysfunction Anosmia Hyposmia Implant
1. Introduction We use our sense of smell every day – to prepare and enjoy foods, to appreciate the fragrances of flowers or wine, to detect and avoid noxious or hazardous odors, to maintain personal hygiene, and in many other complex and subtle ways that effect social and intimate interactions with others. Loss of smell can greatly impair these activities, thereby interfering with both quality of life (QoL) as well as activities of daily living (ADLs). Unfortunately, olfactory dysfunction is particularly common following head trauma, often with substantial negative consequence [1]. Not all injury to smell is complete, and patients can have alterations in detection (i.e. hyposmia, anosmia) or in identification (i.e. parosmia, phantosmia). A comprehensive understanding of the anatomy, pathophysiology, epidemiology, clinical presentation, evaluation, treatment options, and prognosis of posttraumatic olfactory impairment is therefore critical to the successful management of this unique patient population. 2. Anatomy The olfactory system is the primary and most sensitive system for detection and identification of odors. The peripheral elements
* Corresponding author. E-mail addresses: [email protected] (D.H. Coelho), [email protected] (R.M. Costanzo).
of this system are found in approximately 22 cm2 of pseudostratified columnar respiratory epithelium in the superior recesses of the nasal cavity, between the septum and the middle turbinates and below the cribriform plate. This area, termed the olfactory cleft, contains roughly 6 million bipolar olfactory receptor cells [1]. These highly specialized cells possess many unique characteristics. Firstly, they continuously regenerate from horizontal and globose basal cells located within the olfactory neuroepithelium [2] throughout one’s lifespan and even following trauma. This regenerative capacity allows the basal cells to mature into neurons which can then grow back into the olfactory bulb and even re-establish functional connections [2–6]. Secondly, these bipolar receptor cells act both as a sensory receptor and as the first-order neuron that projects directly into the brain – also unique amongst sensory systems [1]. Thirdly, each receptor cell expresses a single odorant receptor gene derived from a single allele. Roughly 1000 distinct transmembrane G-protein olfactory receptor genes have been identified which represent 3–5% of the entire mammalian genome – a discovery for which Drs. Linda Buck and Richard Axel were awarded the 2004 Nobel Prize in Physiology [7]. Although each cell only expresses one gene, the cells which express a particular gene are distributed throughout the olfactory epithelium in a random fashion [7–9]. Central integration of spatial coding is what allows for unique odor perception. In addition to the bipolar receptor cells, a variety of other vital cells and structures comprise the olfactory neuroepithelium. Sustentacular (supporting) cells as well as the cells of Bowman’s
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glands produce the mucous that is critical to the maintenance of the epithelium and transduction of odorants from the gaseous phase to the aqueous phase of the epithelium. Disruption or alteration of the mucous quantity or viscosity may affect olfactory function. After passing through the basal lamina of the epithelium axons from the olfactory receptors types begin to converge with axons of other receptor types. These nerve groupings course through the cribriform plate of the ethmoid bone and comprise the fila of cranial nerve I (CN I). Once through the cribriform these bundles go on to form the first and outermost concentric layer of the olfactory bulb. Within the next deeper layer of the bulb, axons converge and synapse onto dendrites of second-order neurons (mitral and tufted cells) forming oval-like structures known as glomeruli. Upon leaving the olfactory bulb via the olfactory tract, the second-order olfactory neurons synapse in the areas of the primary olfactory cortex. This area is composed of the olfactory tubercle, the pyriform cortex, the amygdala, the periamygdaloid complex, and the entorhinal complex. A secondary olfactory cortex is located in the orbito-frontal region of the brain. Many connections between the primary and secondary cortexes travel via the mediodorsal nucleus of the thalamus; however some connections exist directly between the olfactory bulb and cortical areas – yet another unique characteristic among the sensory systems. All of these areas perform critical roles in the central processing of odor perception including learning, memory, integration of visual and gustatory inputs, and the assignation of emotional significance [10]. In addition to the olfactory system, the trigeminal system plays an important role in the detection of chemical stimuli, though not in odor discrimination. Fibers of CN V innervate the entire nasal cavity and can sense tactile, pain, temperature, and noxious stimuli – oftentimes resulting in reflexive responses that lead to mucous production, mucosal congestion, sneezing, etc. that can indirectly effect olfaction [1]. Because of its deeper, protected course and bilateral innervation, CN V is more resistant to injury and may even be spared in cases of severe injury. Therefore a patient’s subjective inability to detect strong noxious stimuli (i.e. ammonia) may provide a clue to malingering. 3. Pathophysiology Olfaction requires a patent nasal airway, intact nasal mucosa with appropriate mucous coating, and intact neural pathways from the nasal cavity to the higher cortical processing centers. As such, any posttraumatic olfactory dysfunction comes from the disruption of any or all of the following components: 1) sinonasal tract, 2) shearing of the olfactory nerves at the cribriform plate, 3) focal trauma to the olfactory bulb, diffuse injury to primary or secondary olfactory cortex, or injury to the connections between central olfactory structures (Fig. 1).
3.1. Sinonasal tract disruptions Nasal bone or midface fractures can distort the normal airflow, thereby creating a conductive loss of smell by preventing the odorants from reaching the olfactory neuroepithelium. The more extensive the injury (i.e. LeFort fractures), the higher the incidence of smell loss [11]. Soft tissue injuries within the nasal cavity itself leading to blood within the cavity, mucosal or septal hematoma, edema, and scar formation (from the initial injury or from resuscitative airway support) may all distort anatomy and therefore function [12]. Furthermore, injury may lead to blocked sinonasal outflow resulting in rhinosinusitis and inflammatory changes that can further limit airflow or mucous character. As disruptions of the sinonasal tract are the most amenable to medical or surgical treatment, such potential etiologies should not be overlooked, even in cases of complex injury. 3.2. Olfactory nerve injury The small foramina where the olfactory nerve fila traverse the cribriform plate are sites particularly prone to injury. The mechanism by which this happens is usually from either direct bony disruption of the ethmoid roof or cribriform plate, or from a rapid shift in position of the brain relative to the skull base. This latter mechanism is commonly seen following abrupt deceleration experienced in motor vehicle collisions or even ground level falls to the occiput. The olfactory bulb and brain are mobile within the intracranial compartment, insulated by the cerebrospinal fluid (CSF) within the dura. However, the olfactory receptor axons are fixed within the cribriform foramina. This type of injury can result in complete shearing or significant stretching of the olfactory fibers that subsequently result in axonal degeneration [13]. These injuries, commonly referred to as coup-contracoup injuries, are frequently severe and bilateral. 3.3. Central lesions Injury to any central component or connection of olfaction can lead to dysfunction. In the most dramatic form, this may include contusion, but frequently is due to edema, hemorrhage, or hematoma. In 1985 Levin first suggested that such central injury could result in olfactory dysfunction, but was unlikely to lead to complete anosmia [14]. Further work by Yousem elaborated on this notion, proposing that the extensive and bilateral connections to the olfactory cortex were likely to protect against anosmia [15]. Nonetheless, the olfactory bulbs sit precariously inferior to the frontal lobe and superior to the fixed cribriform plate and particularly vulnerable to compressive forces or secondary ischemia. Isolated injury to the olfactory bulb can occur in the absence of involvement of other brain structures, suggesting a potential increased susceptibility from these mechanisms [13,16].
Fig. 1. Mechanisms of post traumatic anosmia. (A) Sinonasal tract disruption (conductive loss), (B) Olfactory nerve injury – transection, (C) Central lesions – cortical contusions. Adapted from Costanzo and Zasler [27].
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3.3.1. Nontraumatic causes of olfactory dysfunction in trauma patients Clinicians caring for patients after head injury must consider the possibility of preexisting conditions. In some cases it may be difficult to determine either a lack of awareness of deficits, or if posttraumatic cognitive dysfunction prevents recollection of pretraumatic status. Conductive causes such as rhinosinusitis, polyposis, allergic rhinitis, sinonasal neoplasms, or prior nasal or trans-nasal surgeries must be considered. The differential diagnosis for sensorineural causes of smell loss is even wider, including aging, dementia and other neurodegenerative diseases, postviral smell loss previous head trauma, toxins, or congenitally impaired sense of smell. Particular attention should be paid to medications as some medications prescribed for head trauma patients (i.e. anticonvulsants) can interfere with smell. 4. Epidemiology The earliest known reports of posttraumatic smell dysfunction appear in the late 1800s, mostly attributed to falls from horses or blows to the head [17–21]. Early estimates of anosmia following head injury suggested an incidence of 4–7%, though these reports varied widely in severity of injury as well as the methods used to assess the dysfunction [22–26]. In their 1991 review, Costanzo and Zasler reported anosmia in 25–30% of patients with severe head injury, 15–19% in those with moderate head injury, and 0–16% in those with mild injuries [27]. Other studies, but not all subsequent studies, have reported similar correlations between severity of injury and degree of olfactory dysfunction [28–30]. Interestingly Fortin et al. found that 69% of 49 individuals admitted to an outpatient’s rehabilitation program demonstrated impaired olfaction with no difference in rates according to TBI severity [31]. The demographics of olfactory loss following head trauma largely mirror the overall demographics of head trauma. Costanzo and Becker evaluated olfactory disturbances in 592 head injury patients and found that disturbance of smell occurred most commonly in young adult males, most often due to motor vehicle collisions. Despite recent attention on the effects of mild traumatic brain injury (TBI) in athletes, a paucity of literature on the olfactory effects exists. In their study of boxers, many of whom were active and had sustained ‘‘knock out’’ punches, Vent et al. reported impaired smell in 28% when compared to matched controls [32]. However, other studies found no difference in olfactory testing relative to controls in athletes reporting concussion [33]. In the older adult population, falls and assaults were the most common causes of olfactory dysfunction. This was particularly true when the fall resulted in strikes to the occiput [27]. Although patients with head trauma are more likely to have olfactory dysfunction, most patients who acquired smell loss did so through nontraumatic mechanisms. A recent study by Fornazieri and colleagues reported an 8% incidence of posttraumatic loss among all patients complaining of subjective loss of smell, though this may reflect selection bias as demographics of and referral patterns to individual clinics can vary [28].
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The nature of the olfactory deficit should be characterized. Is the loss one of detection or sensitivity (anosmia, hyposmia) or of discrimination or quality (dysosmia) [37]. Many patients with severe head injury are likely to have undergone multiple treatments that may affect smell. This includes the administration of multiple medications, the placement of oral and nasal tubes for pulmonary or enteral support, or surgeries. Any pre-injury nasal or sinus disease or surgery, viral infections, chemotherapy, and radiation treatment to the head and neck is essential as is a thorough review of all medications taken. As many of these may occur early in the posttraumatic period, patients may have no recollection of these interventions and therefore careful review of the medical record can play an important role. For imaging, both the report and the images themselves should be reviewed by the treating clinician, with special attention paid to the anterior skull base and orbitofrontal lobes. Subtle changes can be missed, especially when initial scans are ordered for life-threatening intracranial injuries. The nature of the injury and the events surrounding the event should be discussed with patient or obtained from the record as some characteristics can help to predict the likelihood of sensory dysfunction and possibly even recovery. Posttraumatic amnesia has been a well-documented predictor of olfactory dysfunction, particularly if it lasts greater than 5 min following injury [38,39]. In addition, severity of head injury has been closely correlated with impaired smell. Green et al. found that patients with the Glasgow Coma Scale [GCS] <13 were 10–12 times more likely to have olfactory deficits that those with less severe injuries [38]. Direction and location of head strike may also predict olfactory deficit, with posterior–anterior directed blows to the occiput and frontal areas resulting in the highest incidence of anosmia [40]. Cerebrospinal (CSF) rhinorrhea, which also suggests substantial traumatic forces to the ethmoid areas, correlates highly with olfactory dysfunction [38,41,42]. Associations have been reported between posttraumatic anosmia and hearing loss (41%), tinnitus (22.6%), disequilibrium (14.2%), and visual disturbances (7%) [26]. Patients with olfactory dysfunction following trauma are at high risk of executive function impairment [35,43–46]. Sigurdardottir et al. found marked decision-making deficits and poor performance on verbal fluency tests 3 months postinjury [47]. Likewise, Callahan and Hinkebein reported that patients with anosmia were more likely to suffer from deficits in complex attention, new learning and memory, problem solving, and even awareness of their deficit [35]. This is also true in children where those who suffered TBI with associated decrease in smell were 3 times more likely to manifest behavioral self-regulation compared to children with similar severity of TBI without decrease in smell [45]. Inconsistencies in the medical record and the patients stated history may be indicative of executive dysfunction, though malingering, particularly patients involved in legal action, must be considered. In all patients with loss of smell, though particularly those who may have secondary gain, objective assessment through olfactory testing and neuroimaging is imperative. 5.2. Physical examination
5. History and physical 5.1. History Many patients with posttraumatic olfactory dysfunction may be completely unaware of their loss [31,34–36]. For those in whom the presence of olfactory disturbance is recognized, it may be days, weeks, or months after the traumatic event. In patients with lifethreatening injuries, chemosensory deficits are understandably not among the primary concerns. Altered mental status can reduce patient awareness, and could delay resumption of oral feeding.
Physical examination should include a thorough examination of the entire head and neck, not only those areas of pathophysiologic dysfunction addressed above. Close inspection of laceration, ecchymosis, edema, tenderness, etc. may suggest a possible coup-contracoup injury. Both mastoid ecchymosis (Battle’s sign) and periorbital ecchymosis (‘‘raccoon eyes’’) suggest basilar skull fractures. Telecanthus classically predicts nasoethmoid complex fractures, and may strongly predict shearing or stretching of the olfactory nerves at the cribriform plate. The maxilla-facial skeleton should be palpated to assess for step-offs or mobile segments, both
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suggestive of more severe (i.e. LeFort) injury. The external nose should be assessed for bony or cartilaginous displacement that affect nasal airflow, and thus olfaction. Initial anterior rhinoscopy with a nasal speculum can help to rule out septal or nasal hematomas, septal deviation, turbinate enlargement or deformities, laceration, edema, ecchymosis, or CSF leak. A more thorough evaluation can be performed following application of topical decongestants (spray or pledgets). Nasal endoscopy is a valuable tool in the evaluation of the entire sinonasal area, including the posterior nasal cavity and the nasopharynx. It can be performed both before and after decongestion so as to better appreciate the degree of reversible mucosal edema. The improved visualization afforded by this technology further allows for evaluation of the olfactory neuroepithelium itself and for the detection of mucosal injury, scarring, polypoid disease, or even neoplasia. 6. Testing 6.1. Olfactory testing All patients complaining of olfactory deficits following head trauma should undergo olfactory testing to both confirm the loss and to quantify the severity of loss. Unfortunately, no one single test has been accepted as the standard test of olfactory function, though several validated methods are commonly used [31,35,48–50]. All tests involve odorant detection or odorant identification, though they can vary greatly in time of testing, cost, ease and manner of administration, supplies needed, and potential for self-administration. Among the most commonly used tests, the University of Pennsylvania Smell Identification Test (UPSIT) is a self-administered multiple choice test that uses booklets containing 10 ‘‘scratch and sniff’’ odorants [51,52]. The Alberta Smell Test uses scented markers inhaled into each nostril separately and is another example of a ‘‘forced-choice’’ test [31,53]. It is a good screening tool as the markers are reusable and therefore inexpensive, though patients with abnormal results should be tested with more comprehensive tests such as the UPSIT [54]. In Europe, the most commonly used method is the ‘‘Sniffin’ Sticks’’ test, comprises of odor threshold, odor discrimination, and odor identification [55]. It is similar to both the UPSIT and the Alberta Smell test in that it involves forced multiple choice of 7 odors. In Japan commonly used tests are T&T olfactometry, the Alinamin test, and the Open Essence test. T&T uses a kit that includes 5 different odorants presented at multiple concentrations in order to determine both detection and recognition thresholds [30]. More recently JetStream Olfactometry (Nagashima Medical Instruments Company, Tokyo, Japan) has been used in conjunction with T&T to avoid contamination with other ambient odors. The Alinamin test involves the intravenous injection of thiamine propyldisulfide (a vitamin B1 derivative) which results in a garlictype smell sensation compared to no smell for normal saline [56]. There is a normal latency (7–8 s) and normal duration of sensation (1–2 min) of smell sensation with the derivative that is typically unknown by the subject and can be used to detect malingering. The Open Essence test is stick and card test similar to the UPSIT, though with odors confirmed as familiar to healthy Japanese subjects with normal olfaction [57–59]. The University of Connecticut Chemosensory Clinical Research Center (CCCRC) test measures both detection and discrimination. Detection threshold is assessed by double-blind, forced-choice of serial dilutions of butanol versus water [54,60]. Detection threshold is defined as the dilution at which the patient correctly identifies the butanol bottle four times consecutively. Anosmic patients would identify the correct bottle in approximately 50%
of trials whereas scores consistently below 50% (or choosing the water four times consecutively) would suggest possible malingering. Discrimination is tested by assessing the subject’s ability to recognize 7 common odorants. Trigeminal stimuli are included and can be used to detect malingering as bilateral complete trigeminal loss is extremely rare. The CCCRC test is the preferred method used in our clinic. 6.2. Neuroimaging Although in many patients the severity of olfactory loss can be determined by tests listed above, the exact location of that injury can be difficult to determine without high-resolution imaging. The modality of choice to assess both bony and soft-tissue structures and injuries of the sinonasal cavity is computed tomography (CT). Images should be obtained with thin-cut (1 mm or less) resolution in both the axial and coronal planes, though as coronal images are usually taken with the patient prone in the gantry, patients with cervical spine injuries may be limited to axial images only. CT is very sensitive for detecting any abnormalities of the sinonasal areas that may impede airflow. CT of the brain can detect areas of hemorrhage or edema in higher olfactory pathways and olfactory processing centers, though it is much better assessed with MRI, magnetic resonance imaging (Fig. 2). MRI is superior for the detection of abnormalities of the parenchyma including hemorrhage, infarct, contusion, or diffuse axonal injury. It is particularly useful in the evaluation of structures near the skull base, such as the olfactory bulb, where volume averaging and artifact compromise from bone compromise the quality of CT scans. Yousem et al. investigated MRI findings in patients with poor scores on olfactory tests and found 88% of anosmic patients had injuries of the olfactory bulbs and tracts, 60% within the subfrontal region, and 32% within the temporal lobes [15]. These findings were corroborated more recently by Kim and colleagues, who also studied the timing of imaging following injury [61]. They found that MRIs on patients obtained early (average 2.2 months post-injury) showed much greater detail than those
Fig. 2. MRI of a 47-year-old woman who fell and hit the back of her head (right occipital). This resulted in a coup-contracoup injury and contusion to the left orbitofrontal lobe). Olfactory function testing at 2 months post injury revealed the patient had a complete bilateral loss of smell function (anosmia).
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images obtained later (average 59.6 months) suggesting limited benefit to MRI beyond the early post-injury period. Other imaging modalities such as single-photon emission computed tomography (SPECT) and positron-emission tomography (PET) have been investigated in patients with olfactory dysfunction with promising findings [62–64]. However as they were not used in patients whose loss was specifically posttraumatic loss the diagnostic role of these tests remains to be elucidated. Nonetheless as existing imaging technologies are refined and as new technologies are developed, the ability to anatomically correlate subjective complaints with objective test findings will continue to improve. 7. Management As for many other sensory systems, there are currently no treatments available for neural injuries of the olfactory pathways. Therefore attention must focus on the identification and management of any reversal etiology. This includes dysfunction both directly related to the injury or indirectly as the sequelae of treatment of the injury. Airflow limitation due to sinonasal bony or mucosal trauma may respond to well to a variety of topical sprays. In the short-term vasoconstrictor decongestant use can help to mitigate the effects of mucosal edema, as can simple nasal saline rinses. Intranasal saline rinses can also provide long-term benefit as can the use of nasal corticosteroid sprays commonly used in the management of nasal allergy or sinusitis [65,66]. When this fails, or in cases of obvious structural derangement of nasoseptal bone or cartilage, surgical intervention may be necessary to restore proper airflow to the olfactory epithelium. In addition, sinusitis secondary to ostial blockage directly by trauma or by nasal intubation may benefit from functional endoscopic sinus surgery [67]. Medications, either preexisting or started since trauma, should be reviewed for those which may cause mucosal drying. Although there are no specific treatments available commercially today for the treatment of post-traumatic sensorineural smell loss, the treating clinician must provide support and counseling. This is essential for this unique patient population as they may already be burdened with other physical or neuropsychiatric deficits secondary to their initial injury [68]. Loss of smell, despite its relatively innocuous presentation, can have devastating long term effects, long after the initial life-threatening injuries have resolved or stabilized. In disability calculation, The American Medical Association impairment ratings has suggested a ‘‘5% impairment of a whole person’’ for those with bilateral anosmia (unilateral loss has no associated impairment) [69]. Yet this does not necessarily correlate to the degree of patient’s subjective impairment, which can be debilitating. This is particularly true in patients whose vocations depend greatly on their ability to smell, e.g. chefs, chemists, plumbers, firefighters, florists, cosmeticians, etc. In fact, anosmia is negatively correlated with the ability with successful vocational reintegrate, though this may also be due to associated neurocognitive dysfunction. There are many other adverse effects of smell loss which affect activities of daily living (ADLs), QoL, safety, appetite, nutrition, hygiene, homemaking, child care, and hobbies. In their 2001 retrospective study of 420 patients (345 of whom complained of substantial impairment of ADLs), Miwa et al. [70] characterized the most commonly cited activities impaired by olfactory dysfunction (Table 1). The two most common adverse effects (spoiled food, gas detection) that involve personal safety must also be considered and discussed with patient. Dating of perishable food items, and proper installation and maintenance of smoke and gas detectors in the home are strongly advised. Santos and colleagues reported at least 1 hazardous event in 45.2% of patients with anosmia, 34.1%
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Table 1 Percentage of patients reporting selected Activities of Daily Living (ADLs) effected by their olfactory impairment (Adapted from Miwa et al. [70]). Olfactory impaired patients (N = 345)
%
Detection of spoiled food Detection of gas leak Eating Detection of smoke Cooking Buying Fresh Food Using perfume/cologne Using scented detergents/soaps Going out to Eat Detection of soiled diaper House Cleaning Working Socializing Gardening Sports/Exercise
75.1 60.9 53.0 50.1 49.3 35.7 32.8 26.4 22.9 16.8 14.8 13.3 8.7 7.5 2.9
with severe hyposmia, 32.8% with moderate hyposmia, and 24.2% with mild hyposmia [71]. Interestingly the authors found that 19.0% of patients with normal olfactory testing had at least 1 hazardous event. Risk of hazardous events appears to be statistically higher in patients over the age of 65, women, and African-Americans [72]. Patients must also be counseled on cooking and nutrition, as olfactory dysfunction will greatly impair the appreciation and tolerance of food, even leading to food aversion in some cases of parosmia. Some patients seek to compensate for loss of flavor perception by adding salty, sweet, crunchy, or spicy food which stimulates intact trigeminal or chorda tympani pathways. However some of these supplements may themselves have negative effects of nutrition and health [73,74]. Beyond the risks to health, patients with diminished smell may have problems with personal hygiene, child care, and pet care. Patients should be made aware of this potential, and schedules should be firmly established. For those of us with intact olfaction, one seldom carefully considers the impact of not being able to enjoy the flavor of your favorite meal, the smell of your morning coffee, or the scents of one’s child or partner. Yet for those afflicted with loss of smell, QoL is greatly impaired. Numerous studies have demonstrated strong relationships between olfactory disturbances and clinical depression [75,76]. In Miwa’s study, 50% of all patients with impaired olfaction reported being either very or somewhat satisfied with life, with 45% reporting being either very or somewhat dissatisfied with life [70]. Patient counseling for compensation strategies is critically important in reassuring a patient population with likely numerous other physical and psychological burdens. Assurance that that they are not alone, combined with hope from emerging technologies, can go a long way to allay fears, frustrations, and further injury. 8. Prognosis Although there are no surgical methods to repair the olfactory nerves, spontaneous recovery may occur. It has been estimated that approximately 1/3 of patients with posttraumatic anosmia may experience some degree of spontaneous recovery [40,77,78]. A recent retrospective study reported that only 17% showed improvement, however in this study the earliest testing was at 4 months when patients who had previous dysfunction may have already recovered [79]. In most cases of posttraumatic injury if recovery is to occur it is usually observed within 6 months to a year following injury [75,80]. Although possible, the probability of recovery beyond 2 years post-injury becomes very low (Fig. 3).
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successful can be applied to treat anosmia. In our research laboratories we have been exploring the use of direct electrical stimulation of the olfactory bulb as a method to bypass damaged olfactory nerves. Ongoing testing in animal models has produced promising results and future clinical trials are being planned for the olfactory implant device (US patent pending, PCT/US2014/ 023945). Though not commercially available yet, neuroprostheses are likely to be a dominant technique in the treatment of anosmia in the coming years. 9. Conclusions Fig. 3. Data from patients who recovered from post-traumatic anosmia. Graph shows the percentage of patients that recovered olfactory function as a function of time. Adapted from Costanzo and Becker [75].
An understanding of the degree of injury, age, and extent of central injury is an essential part of counseling patients with loss of smell. While the likelihood of traumatic head injury is higher in younger patients, animal models suggest that recovery from injury may be more likely in younger than in older individuals [81]. The regenerative capacity of olfactory receptor cells and relative resilience of cortical contusion play important roles in this regard. Yet, in all patients incomplete or abnormal neuronal reconnections that may be established in the olfactory bulb following axonal injury commonly lead to dysosmia, or altered smell sensations during the recovery process – even in cases of early complete anosmia. Despite the paucity of options to address neuronal injury to the olfactory nerves, patients should not be told there is no hope. Progress has been made with a number of experimental approaches and new therapies are on the horizon. Injury to the olfactory nerves and cribriform plate region often results in a localized inflammatory response and the formation of scar tissue. Scar tissue creates a barrier to the axons from regenerating olfactory neurons that may be growing back toward the olfactory bulb. Although nasally directed steroids are not commonplace in the TBI patient, attempts to modulate the inflammatory response to injury and inhibit the formation of scar tissue may prove useful. In a mouse model, Kobayashi and colleagues showed that treatment with steroids improves recovery outcome following olfactory nerve injury [4]. In addition, blockage of specific pathways mediating the inflammatory response could also provide a new strategy for the treatment of posttraumatic olfactory dysfunction. Interleukin-6 reduces astrocytes and macrophages in the areas of olfactory injury and contributes to improved olfactory nerve regeneration and recovery [82]. Other approaches to repair and restore olfactory function involve the grafting or transplantation of olfactory epithelial tissue to sites of injury. Chen and his colleagues transplanted olfactory progenitor cells into the olfactory epithelium of mice after chemical injury and showed that the progenitor cells gave rise to globose basal cells, neurons and sustentacular cells [83]. Yagi and Costanzo found that olfactory grafts survive when transplanted to the olfactory bulb, retaining properties of a normal olfactory epithelium including the bipolar olfactory receptor cells [84]. Direct grafting of the olfactory epithelium to the ventral surface of the olfactory bulb with access to the nasal cavity could provide the basis for a new surgical treatment to restore the sense of smell. The ability to directly stimulate areas of the brain to activate a sensory percept is not without precedent. Cochlear implants used for the restoration of hearing and other sensor-brain interfaces are an increasingly popular modality for those with sensorineural loss. Those principles that have made cochlear implantation so
Impairment of smell may occur following injury to any portion of the olfactory tract, from nasal cavity to brain. A thorough understanding of the anatomy and pathophysiology combined with comprehensively obtained history, physical exam, olfactory testing, and neuroimaging may help to identify the mechanism of dysfunction and suggest possible treatments. Although most olfactory deficits are neuronal mediated and therefore currently unable to be corrected, promising technology may provide novel treatment options for those most affected. Until that day, patient counseling with compensatory strategies and reassurance is essential for the maintenance of safety and QoL in this unique and challenging patient population. Acknowledgements Partial funding for this paper was provided by The Medarva Research Foundation. The authors would like to thank Luke Edelmayer for creating the illustrations used in Fig. 1. Conflicts of Interest: None. References [1] Doty RL, Bromley SM, Panganiban WD. Olfactory function and dysfunction. Head & Neck Surgery - Otolarnygology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2006. p. 289–305. [2] Schwob JE. Neural regeneration and the peripheral olfactory system. Anat Rec 2002 Feb 15;269:33–49. [3] Costanzo RM. Rewiring the olfactory bulb: changes in odor maps following recovery from nerve transection. Chem Senses 2000;25:199–205. [4] Kobayashi M, Costanzo RM. Olfactory nerve recovery following mild and severe injury and the efficacy of dexamethasone treatment. Chem Senses 2009;34:573–80. [5] Costanzo RM. Regeneration and rewiring the olfactory bulb. Chem Senses 2005;30(Suppl 1):i133–4. [6] Yee KK, Costanzo RM. Restoration of olfactory mediated behavior after olfactory bulb deafferentation. Physiol Behav 1995;58:959–68. [7] Axel R. Scents and sensibility: a molecular logic of olfactory perception (Nobel lecture). Angew Chem Int Ed Engl 2005;44:6110–27. [8] Wang F, Nemes A, Mendelsohn M, Axel R. Odorant receptors govern the formation of a precise topographic map. Cell 1998;93:47–60. [9] Mombaerts P, Wang F, Dulac C, Chao SK, Nemes A, Mendelsohn M, et al. Visualizing an olfactory sensory map. Cell 1996;87:675–86. [10] Gottfried JA, Deichmann R, Winston JS, Dolan RJ. Functional heterogeneity in human olfactory cortex: an event-related functional magnetic resonance imaging study. J Neurosci 2002;22:10819–28. [11] Renzi G, Carboni A, Gasparini G, Perugini M, Becelli R. Taste and olfactory disturbances after upper and middle third facial fractures: a preliminary study. Ann Plast Surg 2002;48:355–8. [12] Costanzo RM, DiNardo LJ, Zasler ND. Head injury and taste. In: Doty RL, editor. Handbook of olfaction and gustation. New York: Marcel Dekker Inc.; 1995. p. 775–83. [13] Costanzo RM, DiNardo LJ, Reiter ER. Head injury and olfaction. In: Doty RL, editor. Handbook of olfaction and gustation. 2nd ed., New York: Marcel Dekker Inc.; 2003. p. 629–38. [14] Levin HS, High WM, Eisenberg HM. Impairment of olfactory recognition after closed head injury. Brain 1985;108:579–91. [15] Yousem DM, Geckle RJ, Bilker WB, McKeown DA, Doty RL. Posttraumatic olfactory dysfunction: MR and clinical evaluation. AJNR Am J Neuroradiol 1996;17:1171–9. [16] Costanzo RM, Zasler ND. Epidemiology and pathophysiology of olfactory and gustatory dysfunction in head trauma. J Head Trauma Rehabil 1992;7:15–24. [17] Ferrier D. The Hemispheres considered Physiologically. The functions of the brain. New York: G.P. Putnam’s Sons; 1876. p. 181–211. [18] Legg JW. A case of anosmia following a blow. Lancet 1873;2:659–60.
Please cite this article in press as: Coelho DH, Costanzo RM. Posttraumatic olfactory dysfunction. Auris Nasus Larynx (2015), http:// dx.doi.org/10.1016/j.anl.2015.08.006
G Model
ANL-2014; No. of Pages 7 D.H. Coelho, R.M. Costanzo / Auris Nasus Larynx xxx (2015) xxx–xxx [19] Jackson JH. Illustrations of diseases of the nervous system. London Hospital Report 1864;1:470–1. [20] Ogle W. Anosmia or cases illustrating the physiology and pathology of the sense of smell. Med Chir Trans 1870;53:263. [21] Notta A. Recherches sur la perte de l’odorat. Arch Gen Med 1870;15:385–407. [22] Kraus W, Fife D, Ramstein K. The relationship of family income to the incidence, external causes, and outcomes of serious brain injury, San Diego County, California. Am J Public Health 1986;1345–7. [23] Leigh AD. Defects in smell after head injury. Lancet 1943;1:38–40. [24] Mifka P. Post-traumatische anosmie. Wien Med Wochenschr 1964;114:793. [25] Zusho H, Asaka H, Fukushima Y, Sanada S, Oka T, Kuroishi T, et al. A study of olfactory threshold vs. fatigue in intravenous olfaction test (author’s transl). Nippon Jibiinkoka Gakkai Kaiho 1978;81:562–8. [26] Zusho H. Posttraumatic anosmia. Arch Otolaryngol 1982;108:90–2. [27] Costanzo RM, Zasler ND. Head trauma. In: Getchell TV, Doty RL, Bartoshuk LM, Snow Jr JB, editors. Smell and taste in health and disease. New York: Raven Press; 1991. p. 711–30. [28] Cain WS. Testing olfaction in a clinical setting. Ear Nose Throat J 1989;68:322– 416. 328. [29] Ikeda K, Tabata K, Oshima T, Nishikawa H, Hidaka H, Takasaka T. Unilateral examination of olfactory threshold using the Jet Stream Olfactometer. Auris Nasus Larynx 1999;26:435–9. [30] Kondo H, Matsuda T, Hashiba M, Baba S. A study of the relationship between the T&T olfactometer and the University of Pennsylvania Smell Identification Test in a Japanese population. Am J Rhinol 1998;12:353–8. [31] Fortin A, Lefebvre MB, Ptito M. Traumatic brain injury and olfactory deficits: the tale of two smell tests! Brain Inj 2010;24:27–33. [32] Vent J, Koenig J, Hellmich M, Huettenbrink KB, Damm M. Impact of recurrent head trauma on olfactory function in boxers: a matched pairs analysis. Brain Res 2010;1320:1–6. [33] Charland-Verville V, Lassonde M, Frasnelli J. Olfaction in athletes with concussion. Am J Rhinol Allergy 2012;26:222–6. [34] Neumann D, Zupan B, Babbage DR, Radnovich AJ, Tomita M, Hammond F, et al. Affect recognition, empathy, and dysosmia after traumatic brain injury. Arch Phys Med Rehabil 2012;93:1414–20. [35] Callahan CD, Hinkebein JH. Assessment of anosmia after traumatic brain injury: performance characteristics of the University of Pennsylvania Smell Identification Test. J Head Trauma Rehabil 2002;17:251–6. [36] Callahan CD, Hinkebein J. Neuropsychological significance of anosmia following traumatic brain injury. J Head Trauma Rehabil 1999;14:581–7. [37] Hong SC, Holbrook EH, Leopold DA, Hummel T. Distorted olfactory perception: a systematic review. Acta Otolaryngol 2012;132(Suppl 1):S27–31. [38] Green P, Rohling ML, Iverson GL, Gervais RO. Relationships between olfactory discrimination and head injury severity. Brain Inj 2003;17:479–96. [39] Swann AC, Gottesfeld Z. Deafferentation elicits a transient decrease in Na+, K+ATPase activity and ouabain binding in the olfactory tubercle. Brain Res 1987;404:323–6. [40] Doty RL, Yousem DM, Pham LT, Kreshak AA, Geckle R, Lee WW. Olfactory dysfunction in patients with head trauma. Arch Neurol 1997;54:1131–40. [41] Nakayama H, Ishikawa T, Yamashita S, Fukui I, Mutoh T, Hikichi K, et al. [CSF leakage and anosmia in aneurysm clipping of anterior communicating artery by basal interhemispheric approach]. No Shinkei Geka 2011;39: 263–8. [42] Jin H, Wang S, Hou L, Pan C, Li B, Wang H, et al. Clinical treatment of traumatic brain injury complicated by cranial nerve injury. Injury 2010;41: 918–23. [43] Doty RL. The olfactory system and its disorders. Semin Neurol 2009;29:74–81. [44] Varney NR. Prognostic significance of anosmia in patients with closed-head trauma. J Clin Exp Neuropsychol 1988;10:250–4. [45] Roberts MA, Simcox AF. Assessing olfaction following pediatric traumatic brain injury. Appl Neuropsychol 1996;3:86–8. [46] Martzke JS, Swan CS, Varney NR. Posttraumatic anosmia and orbital frontal damage: neuropsychological and neuropsychiatric correlates. Neuropsychology 1991;5:213–25. [47] Sigurdardottir S, Jerstad T, Andelic N, Roe C, Schanke AK. Olfactory dysfunction, gambling task performance and intracranial lesions after traumatic brain injury. Neuropsychology 2010;24:504–13. [48] Doty RL, Smith R, McKeown DA, Raj J. Tests of human olfactory function: principal components analysis suggests that most measure a common source of variance. Percept Psychophys 1994;56:701–7. [49] Wrobel BB, Leopold DA. Clinical assessment of patients with smell and taste disorders. Otolaryngol Clin North Am 2004;37:1127–42. [50] Cain WS, Rabin MD. Comparability of two tests of olfactory functioning. Chem Senses 1989;14:479–85. [51] Doty RL, Shaman P, Kimmelman CP, Dann MS. University of Pennsylvania Smell Identification Test: a rapid quantitative olfactory function test for the clinic. Laryngoscope 1984;94:176–8. [52] Doty RL, Agrawal U. The shelf life of the University of Pennsylvania Smell Identification Test (UPSIT). Laryngoscope 1989;99:402–4. [53] Green P, Iverson GL. Effects of injury severity and cognitive exaggeration on olfactory deficits in head injury compensation claims. NeuroRehabilitation 2001;16:237–43.
7
[54] Cain WS, Gent JF, Goodspeed RB, Leonard G. Evaluation of olfactory dysfunction in the Connecticut Chemosensory Clinical Research Center. Laryngoscope 1988;98:83–8. [55] Kobal G, Hummel T, Sekinger B, Barz S, Roscher S, Wolf S. Sniffin’ sticks’’: screening of olfactory performance. Rhinology 1996;34:222–6. [56] Furukawa M, Kamide M, Miwa T, Umeda R. Significance of intravenous olfaction test using thiamine propyldisulfide (Alinamin) in olfactometry. Auris Nasus Larynx 1988;15:25–31. [57] Kobayashi M, Saito S, Kobayakawa T, Deguchi Y, Costanzo RM. Cross-Cultural Comparison of Data Using the Odor Stick Identification Test for Japanese (OSIT-J). Chem Senses 2006;31:335–42. [58] Saito S, yabe-Kanamura S, Takashima Y, Gotow N, Naito N, Nozawa T, et al. Development of a smell identification test using a novel stick-type odor presentation kit. Chem Senses 2006;31:379–91. [59] Okutani F, Hirose K, Kobayashi T, Kaba H, Hyodo M. Evaluation of ‘‘Open Essence’’ odor-identification test card by application to healthy volunteers. Auris Nasus Larynx 2013;40:76–80. [60] Cain WS, Gent J, Catalanotto FA, Goodspeed RB. Clinical evaluation of olfaction. Am J Otolaryngol 1983;4:252–6. [61] Kim SW, Kim DW, Yim YJ, Rhee CS, Lee CH, Kim JW. Cortical magnetic resonance imaging findings in patients with posttraumatic olfactory dysfunction: comparison according to the interval between trauma and evaluation. Clin Exp Otorhinolaryngol 2014;7(3):188–92. [62] Atighechi S, Salari H, Baradarantar MH, Jafari R, Karimi G, Mirjali M. A comparative study of brain perfusion single-photon emission computed tomography and magnetic resonance imaging in patients with post-traumatic anosmia. Am J Rhinol Allergy 2009;23(4):409–12. [63] Varney NR, Pinkston JB, Wu JC. Quantitative PET findings in patients with posttraumatic anosmia. J Head Trauma Rehabil 2001;16(3):253–9. [64] Wong KK, Muller ML, Kuwabara H, Studenski SA, Bohnen NI. Olfactory loss and nigrostriatal dopaminergic denervation in the elderly. Neurosci Lett 2010;484(3):163–7. [65] Fujii M, Fukazawa K, Takayasu S, Sakagami M. Olfactory dysfunction in patients with head trauma. Auris Nasus Larynx 2002;29:35–40. [66] Ikeda K, Sakurada T, Takasaka T, Okitsu T, Yoshida S. Anosmia following head trauma: preliminary study of steroid treatment. Tohoku J Exp Med 1995;177:343–51. [67] Delank KW, Stoll W. Olfactory function after functional endoscopic sinus surgery for chronic sinusitis. Rhinology 1998;36:15–9. [68] Zasler ND, McNeney R, Heywood PG. Rehabilitative management of olfactory and gustatory dysfunction following brain injury. J Head Trauma Rehabil 1992;7:66–75. [69] Rondinelli RD, Genovese E, Brigham CR. Guides to the evaluation of permanent impairment. 6th ed. Chicago, IL: American Medical Association; 2008. [70] Miwa T, Furukawa M, Tsukatani T, Costanzo RM, DiNardo LJ, Reiter ER. Impact of olfactory impairment on quality of life and disability. Arch Otolaryngol Head Neck Surg 2001;127:497–503. [71] Santos DV, Reiter ER, DiNardo LJ, Costanzo RM. Hazardous events associated with impaired olfactory function. Arch Otolaryngol Head Neck Surg 2004;130:317–9. [72] Pence TS, Reiter ER, DiNardo LJ, Costanzo RM. Risk factors for hazardous events in olfactory-impaired patients. JAMA Otolaryngol Head Neck Surg 2014;140:951–5. [73] Mattes RD, Cowart BJ. Dietary assessment of patients with chemosensory disorders. J Am Diet Assoc 1994;94:50–6. [74] Duffy VB, Ferris AM. Nutritional management of patients with chemosensory disturbances. Ear Nose Throat J 1989;68:395–7. [75] Costanzo RM, Becker DP. Smell and taste disorders in head injury and neurosurgery patients. In: Meiselman HL, Rivlin RS, editors. Clinical measurements of taste and smell. New York: MacMillian Publishing Company; 1986. p. 565–78. [76] Temmel AF, Quint C, Schickinger-Fischer B, Klimek L, Stoller E, Hummel T. Characteristics of olfactory disorders in relation to major causes of olfactory loss. Arch Otolaryngol Head Neck Surg 2002;128:635–41. [77] Costanzo RM, DiNardo LJ, Zasler ND. Head injury and olfaction. In: Doty RL, editor. Handbook of olfaction and gustation. New York: Marcel Dekker Inc.; 1995. p. 493–502. [78] Welge-Lussen A, Hilgenfeld A, Meusel T, Hummel T. Long-term follow-up of posttraumatic olfactory disorders. Rhinology 2012;50:67–72. [79] Fan LY, Kuo CL, Lirng JF, Shu CH. Investigation of prognostic factors for posttraumatic olfactory dysfunction. J Chin Med Assoc 2015;78:299–303. [80] Sumner D. Post-traumatic anosmia. Brain 1964;87:107–20. [81] Suzukawa K, Kondo K, Kanaya K, Sakamoto T, Watanabe K, Ushio M, et al. Agerelated changes of the regeneration mode in the mouse peripheral olfactory system following olfactotoxic drug methimazole-induced damage. J Comp Neurol 2011;519:2154–74. [82] Kobayashi M, Tamari K, Miyamura T, Takeuchi K. Blockade of interleukin-6 receptor suppresses inflammatory reaction and facilitates functional recovery following olfactory system injury. Neurosci Res 2013;76:125–32. [83] Chen X, Fang H, Schwob JE. Multipotency of purified, transplanted globose basal cells in olfactory epithelium. J Comp Neurol 2004;469:457–74. [84] Yagi S, Costanzo RM. Grafting the olfactory epithelium to the olfactory bulb. Am J Rhinol Allergy 2009;23:239–43.
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Posttraumatic olfactory dysfunction Daniel H. Coelho, Richard M. Costanzo * Department of Otolaryngology – Head and Neck Surgery and Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298-0146, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 July 2015 Accepted 26 August 2015 Available online xxx
Impairment of smell may occur following injury to any portion of the olfactory tract, from nasal cavity to brain. A thorough understanding of the anatomy and pathophysiology combined with comprehensively obtained history, physical exam, olfactory testing, and neuroimaging may help to identify the mechanism of dysfunction and suggest possible treatments. Although most olfactory deficits are neuronal mediated and therefore currently unable to be corrected, promising technology may provide novel treatment options for those most affected. Until that day, patient counseling with compensatory strategies and reassurance is essential for the maintenance of safety and QoL in this unique and challenging patient population. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Trauma Olfactory Smell Dysfunction Anosmia Hyposmia Implant
1. Introduction We use our sense of smell every day – to prepare and enjoy foods, to appreciate the fragrances of flowers or wine, to detect and avoid noxious or hazardous odors, to maintain personal hygiene, and in many other complex and subtle ways that effect social and intimate interactions with others. Loss of smell can greatly impair these activities, thereby interfering with both quality of life (QoL) as well as activities of daily living (ADLs). Unfortunately, olfactory dysfunction is particularly common following head trauma, often with substantial negative consequence [1]. Not all injury to smell is complete, and patients can have alterations in detection (i.e. hyposmia, anosmia) or in identification (i.e. parosmia, phantosmia). A comprehensive understanding of the anatomy, pathophysiology, epidemiology, clinical presentation, evaluation, treatment options, and prognosis of posttraumatic olfactory impairment is therefore critical to the successful management of this unique patient population. 2. Anatomy The olfactory system is the primary and most sensitive system for detection and identification of odors. The peripheral elements
* Corresponding author. E-mail addresses: [email protected] (D.H. Coelho), [email protected] (R.M. Costanzo).
of this system are found in approximately 22 cm2 of pseudostratified columnar respiratory epithelium in the superior recesses of the nasal cavity, between the septum and the middle turbinates and below the cribriform plate. This area, termed the olfactory cleft, contains roughly 6 million bipolar olfactory receptor cells [1]. These highly specialized cells possess many unique characteristics. Firstly, they continuously regenerate from horizontal and globose basal cells located within the olfactory neuroepithelium [2] throughout one’s lifespan and even following trauma. This regenerative capacity allows the basal cells to mature into neurons which can then grow back into the olfactory bulb and even re-establish functional connections [2–6]. Secondly, these bipolar receptor cells act both as a sensory receptor and as the first-order neuron that projects directly into the brain – also unique amongst sensory systems [1]. Thirdly, each receptor cell expresses a single odorant receptor gene derived from a single allele. Roughly 1000 distinct transmembrane G-protein olfactory receptor genes have been identified which represent 3–5% of the entire mammalian genome – a discovery for which Drs. Linda Buck and Richard Axel were awarded the 2004 Nobel Prize in Physiology [7]. Although each cell only expresses one gene, the cells which express a particular gene are distributed throughout the olfactory epithelium in a random fashion [7–9]. Central integration of spatial coding is what allows for unique odor perception. In addition to the bipolar receptor cells, a variety of other vital cells and structures comprise the olfactory neuroepithelium. Sustentacular (supporting) cells as well as the cells of Bowman’s
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glands produce the mucous that is critical to the maintenance of the epithelium and transduction of odorants from the gaseous phase to the aqueous phase of the epithelium. Disruption or alteration of the mucous quantity or viscosity may affect olfactory function. After passing through the basal lamina of the epithelium axons from the olfactory receptors types begin to converge with axons of other receptor types. These nerve groupings course through the cribriform plate of the ethmoid bone and comprise the fila of cranial nerve I (CN I). Once through the cribriform these bundles go on to form the first and outermost concentric layer of the olfactory bulb. Within the next deeper layer of the bulb, axons converge and synapse onto dendrites of second-order neurons (mitral and tufted cells) forming oval-like structures known as glomeruli. Upon leaving the olfactory bulb via the olfactory tract, the second-order olfactory neurons synapse in the areas of the primary olfactory cortex. This area is composed of the olfactory tubercle, the pyriform cortex, the amygdala, the periamygdaloid complex, and the entorhinal complex. A secondary olfactory cortex is located in the orbito-frontal region of the brain. Many connections between the primary and secondary cortexes travel via the mediodorsal nucleus of the thalamus; however some connections exist directly between the olfactory bulb and cortical areas – yet another unique characteristic among the sensory systems. All of these areas perform critical roles in the central processing of odor perception including learning, memory, integration of visual and gustatory inputs, and the assignation of emotional significance [10]. In addition to the olfactory system, the trigeminal system plays an important role in the detection of chemical stimuli, though not in odor discrimination. Fibers of CN V innervate the entire nasal cavity and can sense tactile, pain, temperature, and noxious stimuli – oftentimes resulting in reflexive responses that lead to mucous production, mucosal congestion, sneezing, etc. that can indirectly effect olfaction [1]. Because of its deeper, protected course and bilateral innervation, CN V is more resistant to injury and may even be spared in cases of severe injury. Therefore a patient’s subjective inability to detect strong noxious stimuli (i.e. ammonia) may provide a clue to malingering. 3. Pathophysiology Olfaction requires a patent nasal airway, intact nasal mucosa with appropriate mucous coating, and intact neural pathways from the nasal cavity to the higher cortical processing centers. As such, any posttraumatic olfactory dysfunction comes from the disruption of any or all of the following components: 1) sinonasal tract, 2) shearing of the olfactory nerves at the cribriform plate, 3) focal trauma to the olfactory bulb, diffuse injury to primary or secondary olfactory cortex, or injury to the connections between central olfactory structures (Fig. 1).
3.1. Sinonasal tract disruptions Nasal bone or midface fractures can distort the normal airflow, thereby creating a conductive loss of smell by preventing the odorants from reaching the olfactory neuroepithelium. The more extensive the injury (i.e. LeFort fractures), the higher the incidence of smell loss [11]. Soft tissue injuries within the nasal cavity itself leading to blood within the cavity, mucosal or septal hematoma, edema, and scar formation (from the initial injury or from resuscitative airway support) may all distort anatomy and therefore function [12]. Furthermore, injury may lead to blocked sinonasal outflow resulting in rhinosinusitis and inflammatory changes that can further limit airflow or mucous character. As disruptions of the sinonasal tract are the most amenable to medical or surgical treatment, such potential etiologies should not be overlooked, even in cases of complex injury. 3.2. Olfactory nerve injury The small foramina where the olfactory nerve fila traverse the cribriform plate are sites particularly prone to injury. The mechanism by which this happens is usually from either direct bony disruption of the ethmoid roof or cribriform plate, or from a rapid shift in position of the brain relative to the skull base. This latter mechanism is commonly seen following abrupt deceleration experienced in motor vehicle collisions or even ground level falls to the occiput. The olfactory bulb and brain are mobile within the intracranial compartment, insulated by the cerebrospinal fluid (CSF) within the dura. However, the olfactory receptor axons are fixed within the cribriform foramina. This type of injury can result in complete shearing or significant stretching of the olfactory fibers that subsequently result in axonal degeneration [13]. These injuries, commonly referred to as coup-contracoup injuries, are frequently severe and bilateral. 3.3. Central lesions Injury to any central component or connection of olfaction can lead to dysfunction. In the most dramatic form, this may include contusion, but frequently is due to edema, hemorrhage, or hematoma. In 1985 Levin first suggested that such central injury could result in olfactory dysfunction, but was unlikely to lead to complete anosmia [14]. Further work by Yousem elaborated on this notion, proposing that the extensive and bilateral connections to the olfactory cortex were likely to protect against anosmia [15]. Nonetheless, the olfactory bulbs sit precariously inferior to the frontal lobe and superior to the fixed cribriform plate and particularly vulnerable to compressive forces or secondary ischemia. Isolated injury to the olfactory bulb can occur in the absence of involvement of other brain structures, suggesting a potential increased susceptibility from these mechanisms [13,16].
Fig. 1. Mechanisms of post traumatic anosmia. (A) Sinonasal tract disruption (conductive loss), (B) Olfactory nerve injury – transection, (C) Central lesions – cortical contusions. Adapted from Costanzo and Zasler [27].
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3.3.1. Nontraumatic causes of olfactory dysfunction in trauma patients Clinicians caring for patients after head injury must consider the possibility of preexisting conditions. In some cases it may be difficult to determine either a lack of awareness of deficits, or if posttraumatic cognitive dysfunction prevents recollection of pretraumatic status. Conductive causes such as rhinosinusitis, polyposis, allergic rhinitis, sinonasal neoplasms, or prior nasal or trans-nasal surgeries must be considered. The differential diagnosis for sensorineural causes of smell loss is even wider, including aging, dementia and other neurodegenerative diseases, postviral smell loss previous head trauma, toxins, or congenitally impaired sense of smell. Particular attention should be paid to medications as some medications prescribed for head trauma patients (i.e. anticonvulsants) can interfere with smell. 4. Epidemiology The earliest known reports of posttraumatic smell dysfunction appear in the late 1800s, mostly attributed to falls from horses or blows to the head [17–21]. Early estimates of anosmia following head injury suggested an incidence of 4–7%, though these reports varied widely in severity of injury as well as the methods used to assess the dysfunction [22–26]. In their 1991 review, Costanzo and Zasler reported anosmia in 25–30% of patients with severe head injury, 15–19% in those with moderate head injury, and 0–16% in those with mild injuries [27]. Other studies, but not all subsequent studies, have reported similar correlations between severity of injury and degree of olfactory dysfunction [28–30]. Interestingly Fortin et al. found that 69% of 49 individuals admitted to an outpatient’s rehabilitation program demonstrated impaired olfaction with no difference in rates according to TBI severity [31]. The demographics of olfactory loss following head trauma largely mirror the overall demographics of head trauma. Costanzo and Becker evaluated olfactory disturbances in 592 head injury patients and found that disturbance of smell occurred most commonly in young adult males, most often due to motor vehicle collisions. Despite recent attention on the effects of mild traumatic brain injury (TBI) in athletes, a paucity of literature on the olfactory effects exists. In their study of boxers, many of whom were active and had sustained ‘‘knock out’’ punches, Vent et al. reported impaired smell in 28% when compared to matched controls [32]. However, other studies found no difference in olfactory testing relative to controls in athletes reporting concussion [33]. In the older adult population, falls and assaults were the most common causes of olfactory dysfunction. This was particularly true when the fall resulted in strikes to the occiput [27]. Although patients with head trauma are more likely to have olfactory dysfunction, most patients who acquired smell loss did so through nontraumatic mechanisms. A recent study by Fornazieri and colleagues reported an 8% incidence of posttraumatic loss among all patients complaining of subjective loss of smell, though this may reflect selection bias as demographics of and referral patterns to individual clinics can vary [28].
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The nature of the olfactory deficit should be characterized. Is the loss one of detection or sensitivity (anosmia, hyposmia) or of discrimination or quality (dysosmia) [37]. Many patients with severe head injury are likely to have undergone multiple treatments that may affect smell. This includes the administration of multiple medications, the placement of oral and nasal tubes for pulmonary or enteral support, or surgeries. Any pre-injury nasal or sinus disease or surgery, viral infections, chemotherapy, and radiation treatment to the head and neck is essential as is a thorough review of all medications taken. As many of these may occur early in the posttraumatic period, patients may have no recollection of these interventions and therefore careful review of the medical record can play an important role. For imaging, both the report and the images themselves should be reviewed by the treating clinician, with special attention paid to the anterior skull base and orbitofrontal lobes. Subtle changes can be missed, especially when initial scans are ordered for life-threatening intracranial injuries. The nature of the injury and the events surrounding the event should be discussed with patient or obtained from the record as some characteristics can help to predict the likelihood of sensory dysfunction and possibly even recovery. Posttraumatic amnesia has been a well-documented predictor of olfactory dysfunction, particularly if it lasts greater than 5 min following injury [38,39]. In addition, severity of head injury has been closely correlated with impaired smell. Green et al. found that patients with the Glasgow Coma Scale [GCS] <13 were 10–12 times more likely to have olfactory deficits that those with less severe injuries [38]. Direction and location of head strike may also predict olfactory deficit, with posterior–anterior directed blows to the occiput and frontal areas resulting in the highest incidence of anosmia [40]. Cerebrospinal (CSF) rhinorrhea, which also suggests substantial traumatic forces to the ethmoid areas, correlates highly with olfactory dysfunction [38,41,42]. Associations have been reported between posttraumatic anosmia and hearing loss (41%), tinnitus (22.6%), disequilibrium (14.2%), and visual disturbances (7%) [26]. Patients with olfactory dysfunction following trauma are at high risk of executive function impairment [35,43–46]. Sigurdardottir et al. found marked decision-making deficits and poor performance on verbal fluency tests 3 months postinjury [47]. Likewise, Callahan and Hinkebein reported that patients with anosmia were more likely to suffer from deficits in complex attention, new learning and memory, problem solving, and even awareness of their deficit [35]. This is also true in children where those who suffered TBI with associated decrease in smell were 3 times more likely to manifest behavioral self-regulation compared to children with similar severity of TBI without decrease in smell [45]. Inconsistencies in the medical record and the patients stated history may be indicative of executive dysfunction, though malingering, particularly patients involved in legal action, must be considered. In all patients with loss of smell, though particularly those who may have secondary gain, objective assessment through olfactory testing and neuroimaging is imperative. 5.2. Physical examination
5. History and physical 5.1. History Many patients with posttraumatic olfactory dysfunction may be completely unaware of their loss [31,34–36]. For those in whom the presence of olfactory disturbance is recognized, it may be days, weeks, or months after the traumatic event. In patients with lifethreatening injuries, chemosensory deficits are understandably not among the primary concerns. Altered mental status can reduce patient awareness, and could delay resumption of oral feeding.
Physical examination should include a thorough examination of the entire head and neck, not only those areas of pathophysiologic dysfunction addressed above. Close inspection of laceration, ecchymosis, edema, tenderness, etc. may suggest a possible coup-contracoup injury. Both mastoid ecchymosis (Battle’s sign) and periorbital ecchymosis (‘‘raccoon eyes’’) suggest basilar skull fractures. Telecanthus classically predicts nasoethmoid complex fractures, and may strongly predict shearing or stretching of the olfactory nerves at the cribriform plate. The maxilla-facial skeleton should be palpated to assess for step-offs or mobile segments, both
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suggestive of more severe (i.e. LeFort) injury. The external nose should be assessed for bony or cartilaginous displacement that affect nasal airflow, and thus olfaction. Initial anterior rhinoscopy with a nasal speculum can help to rule out septal or nasal hematomas, septal deviation, turbinate enlargement or deformities, laceration, edema, ecchymosis, or CSF leak. A more thorough evaluation can be performed following application of topical decongestants (spray or pledgets). Nasal endoscopy is a valuable tool in the evaluation of the entire sinonasal area, including the posterior nasal cavity and the nasopharynx. It can be performed both before and after decongestion so as to better appreciate the degree of reversible mucosal edema. The improved visualization afforded by this technology further allows for evaluation of the olfactory neuroepithelium itself and for the detection of mucosal injury, scarring, polypoid disease, or even neoplasia. 6. Testing 6.1. Olfactory testing All patients complaining of olfactory deficits following head trauma should undergo olfactory testing to both confirm the loss and to quantify the severity of loss. Unfortunately, no one single test has been accepted as the standard test of olfactory function, though several validated methods are commonly used [31,35,48–50]. All tests involve odorant detection or odorant identification, though they can vary greatly in time of testing, cost, ease and manner of administration, supplies needed, and potential for self-administration. Among the most commonly used tests, the University of Pennsylvania Smell Identification Test (UPSIT) is a self-administered multiple choice test that uses booklets containing 10 ‘‘scratch and sniff’’ odorants [51,52]. The Alberta Smell Test uses scented markers inhaled into each nostril separately and is another example of a ‘‘forced-choice’’ test [31,53]. It is a good screening tool as the markers are reusable and therefore inexpensive, though patients with abnormal results should be tested with more comprehensive tests such as the UPSIT [54]. In Europe, the most commonly used method is the ‘‘Sniffin’ Sticks’’ test, comprises of odor threshold, odor discrimination, and odor identification [55]. It is similar to both the UPSIT and the Alberta Smell test in that it involves forced multiple choice of 7 odors. In Japan commonly used tests are T&T olfactometry, the Alinamin test, and the Open Essence test. T&T uses a kit that includes 5 different odorants presented at multiple concentrations in order to determine both detection and recognition thresholds [30]. More recently JetStream Olfactometry (Nagashima Medical Instruments Company, Tokyo, Japan) has been used in conjunction with T&T to avoid contamination with other ambient odors. The Alinamin test involves the intravenous injection of thiamine propyldisulfide (a vitamin B1 derivative) which results in a garlictype smell sensation compared to no smell for normal saline [56]. There is a normal latency (7–8 s) and normal duration of sensation (1–2 min) of smell sensation with the derivative that is typically unknown by the subject and can be used to detect malingering. The Open Essence test is stick and card test similar to the UPSIT, though with odors confirmed as familiar to healthy Japanese subjects with normal olfaction [57–59]. The University of Connecticut Chemosensory Clinical Research Center (CCCRC) test measures both detection and discrimination. Detection threshold is assessed by double-blind, forced-choice of serial dilutions of butanol versus water [54,60]. Detection threshold is defined as the dilution at which the patient correctly identifies the butanol bottle four times consecutively. Anosmic patients would identify the correct bottle in approximately 50%
of trials whereas scores consistently below 50% (or choosing the water four times consecutively) would suggest possible malingering. Discrimination is tested by assessing the subject’s ability to recognize 7 common odorants. Trigeminal stimuli are included and can be used to detect malingering as bilateral complete trigeminal loss is extremely rare. The CCCRC test is the preferred method used in our clinic. 6.2. Neuroimaging Although in many patients the severity of olfactory loss can be determined by tests listed above, the exact location of that injury can be difficult to determine without high-resolution imaging. The modality of choice to assess both bony and soft-tissue structures and injuries of the sinonasal cavity is computed tomography (CT). Images should be obtained with thin-cut (1 mm or less) resolution in both the axial and coronal planes, though as coronal images are usually taken with the patient prone in the gantry, patients with cervical spine injuries may be limited to axial images only. CT is very sensitive for detecting any abnormalities of the sinonasal areas that may impede airflow. CT of the brain can detect areas of hemorrhage or edema in higher olfactory pathways and olfactory processing centers, though it is much better assessed with MRI, magnetic resonance imaging (Fig. 2). MRI is superior for the detection of abnormalities of the parenchyma including hemorrhage, infarct, contusion, or diffuse axonal injury. It is particularly useful in the evaluation of structures near the skull base, such as the olfactory bulb, where volume averaging and artifact compromise from bone compromise the quality of CT scans. Yousem et al. investigated MRI findings in patients with poor scores on olfactory tests and found 88% of anosmic patients had injuries of the olfactory bulbs and tracts, 60% within the subfrontal region, and 32% within the temporal lobes [15]. These findings were corroborated more recently by Kim and colleagues, who also studied the timing of imaging following injury [61]. They found that MRIs on patients obtained early (average 2.2 months post-injury) showed much greater detail than those
Fig. 2. MRI of a 47-year-old woman who fell and hit the back of her head (right occipital). This resulted in a coup-contracoup injury and contusion to the left orbitofrontal lobe). Olfactory function testing at 2 months post injury revealed the patient had a complete bilateral loss of smell function (anosmia).
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images obtained later (average 59.6 months) suggesting limited benefit to MRI beyond the early post-injury period. Other imaging modalities such as single-photon emission computed tomography (SPECT) and positron-emission tomography (PET) have been investigated in patients with olfactory dysfunction with promising findings [62–64]. However as they were not used in patients whose loss was specifically posttraumatic loss the diagnostic role of these tests remains to be elucidated. Nonetheless as existing imaging technologies are refined and as new technologies are developed, the ability to anatomically correlate subjective complaints with objective test findings will continue to improve. 7. Management As for many other sensory systems, there are currently no treatments available for neural injuries of the olfactory pathways. Therefore attention must focus on the identification and management of any reversal etiology. This includes dysfunction both directly related to the injury or indirectly as the sequelae of treatment of the injury. Airflow limitation due to sinonasal bony or mucosal trauma may respond to well to a variety of topical sprays. In the short-term vasoconstrictor decongestant use can help to mitigate the effects of mucosal edema, as can simple nasal saline rinses. Intranasal saline rinses can also provide long-term benefit as can the use of nasal corticosteroid sprays commonly used in the management of nasal allergy or sinusitis [65,66]. When this fails, or in cases of obvious structural derangement of nasoseptal bone or cartilage, surgical intervention may be necessary to restore proper airflow to the olfactory epithelium. In addition, sinusitis secondary to ostial blockage directly by trauma or by nasal intubation may benefit from functional endoscopic sinus surgery [67]. Medications, either preexisting or started since trauma, should be reviewed for those which may cause mucosal drying. Although there are no specific treatments available commercially today for the treatment of post-traumatic sensorineural smell loss, the treating clinician must provide support and counseling. This is essential for this unique patient population as they may already be burdened with other physical or neuropsychiatric deficits secondary to their initial injury [68]. Loss of smell, despite its relatively innocuous presentation, can have devastating long term effects, long after the initial life-threatening injuries have resolved or stabilized. In disability calculation, The American Medical Association impairment ratings has suggested a ‘‘5% impairment of a whole person’’ for those with bilateral anosmia (unilateral loss has no associated impairment) [69]. Yet this does not necessarily correlate to the degree of patient’s subjective impairment, which can be debilitating. This is particularly true in patients whose vocations depend greatly on their ability to smell, e.g. chefs, chemists, plumbers, firefighters, florists, cosmeticians, etc. In fact, anosmia is negatively correlated with the ability with successful vocational reintegrate, though this may also be due to associated neurocognitive dysfunction. There are many other adverse effects of smell loss which affect activities of daily living (ADLs), QoL, safety, appetite, nutrition, hygiene, homemaking, child care, and hobbies. In their 2001 retrospective study of 420 patients (345 of whom complained of substantial impairment of ADLs), Miwa et al. [70] characterized the most commonly cited activities impaired by olfactory dysfunction (Table 1). The two most common adverse effects (spoiled food, gas detection) that involve personal safety must also be considered and discussed with patient. Dating of perishable food items, and proper installation and maintenance of smoke and gas detectors in the home are strongly advised. Santos and colleagues reported at least 1 hazardous event in 45.2% of patients with anosmia, 34.1%
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Table 1 Percentage of patients reporting selected Activities of Daily Living (ADLs) effected by their olfactory impairment (Adapted from Miwa et al. [70]). Olfactory impaired patients (N = 345)
%
Detection of spoiled food Detection of gas leak Eating Detection of smoke Cooking Buying Fresh Food Using perfume/cologne Using scented detergents/soaps Going out to Eat Detection of soiled diaper House Cleaning Working Socializing Gardening Sports/Exercise
75.1 60.9 53.0 50.1 49.3 35.7 32.8 26.4 22.9 16.8 14.8 13.3 8.7 7.5 2.9
with severe hyposmia, 32.8% with moderate hyposmia, and 24.2% with mild hyposmia [71]. Interestingly the authors found that 19.0% of patients with normal olfactory testing had at least 1 hazardous event. Risk of hazardous events appears to be statistically higher in patients over the age of 65, women, and African-Americans [72]. Patients must also be counseled on cooking and nutrition, as olfactory dysfunction will greatly impair the appreciation and tolerance of food, even leading to food aversion in some cases of parosmia. Some patients seek to compensate for loss of flavor perception by adding salty, sweet, crunchy, or spicy food which stimulates intact trigeminal or chorda tympani pathways. However some of these supplements may themselves have negative effects of nutrition and health [73,74]. Beyond the risks to health, patients with diminished smell may have problems with personal hygiene, child care, and pet care. Patients should be made aware of this potential, and schedules should be firmly established. For those of us with intact olfaction, one seldom carefully considers the impact of not being able to enjoy the flavor of your favorite meal, the smell of your morning coffee, or the scents of one’s child or partner. Yet for those afflicted with loss of smell, QoL is greatly impaired. Numerous studies have demonstrated strong relationships between olfactory disturbances and clinical depression [75,76]. In Miwa’s study, 50% of all patients with impaired olfaction reported being either very or somewhat satisfied with life, with 45% reporting being either very or somewhat dissatisfied with life [70]. Patient counseling for compensation strategies is critically important in reassuring a patient population with likely numerous other physical and psychological burdens. Assurance that that they are not alone, combined with hope from emerging technologies, can go a long way to allay fears, frustrations, and further injury. 8. Prognosis Although there are no surgical methods to repair the olfactory nerves, spontaneous recovery may occur. It has been estimated that approximately 1/3 of patients with posttraumatic anosmia may experience some degree of spontaneous recovery [40,77,78]. A recent retrospective study reported that only 17% showed improvement, however in this study the earliest testing was at 4 months when patients who had previous dysfunction may have already recovered [79]. In most cases of posttraumatic injury if recovery is to occur it is usually observed within 6 months to a year following injury [75,80]. Although possible, the probability of recovery beyond 2 years post-injury becomes very low (Fig. 3).
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successful can be applied to treat anosmia. In our research laboratories we have been exploring the use of direct electrical stimulation of the olfactory bulb as a method to bypass damaged olfactory nerves. Ongoing testing in animal models has produced promising results and future clinical trials are being planned for the olfactory implant device (US patent pending, PCT/US2014/ 023945). Though not commercially available yet, neuroprostheses are likely to be a dominant technique in the treatment of anosmia in the coming years. 9. Conclusions Fig. 3. Data from patients who recovered from post-traumatic anosmia. Graph shows the percentage of patients that recovered olfactory function as a function of time. Adapted from Costanzo and Becker [75].
An understanding of the degree of injury, age, and extent of central injury is an essential part of counseling patients with loss of smell. While the likelihood of traumatic head injury is higher in younger patients, animal models suggest that recovery from injury may be more likely in younger than in older individuals [81]. The regenerative capacity of olfactory receptor cells and relative resilience of cortical contusion play important roles in this regard. Yet, in all patients incomplete or abnormal neuronal reconnections that may be established in the olfactory bulb following axonal injury commonly lead to dysosmia, or altered smell sensations during the recovery process – even in cases of early complete anosmia. Despite the paucity of options to address neuronal injury to the olfactory nerves, patients should not be told there is no hope. Progress has been made with a number of experimental approaches and new therapies are on the horizon. Injury to the olfactory nerves and cribriform plate region often results in a localized inflammatory response and the formation of scar tissue. Scar tissue creates a barrier to the axons from regenerating olfactory neurons that may be growing back toward the olfactory bulb. Although nasally directed steroids are not commonplace in the TBI patient, attempts to modulate the inflammatory response to injury and inhibit the formation of scar tissue may prove useful. In a mouse model, Kobayashi and colleagues showed that treatment with steroids improves recovery outcome following olfactory nerve injury [4]. In addition, blockage of specific pathways mediating the inflammatory response could also provide a new strategy for the treatment of posttraumatic olfactory dysfunction. Interleukin-6 reduces astrocytes and macrophages in the areas of olfactory injury and contributes to improved olfactory nerve regeneration and recovery [82]. Other approaches to repair and restore olfactory function involve the grafting or transplantation of olfactory epithelial tissue to sites of injury. Chen and his colleagues transplanted olfactory progenitor cells into the olfactory epithelium of mice after chemical injury and showed that the progenitor cells gave rise to globose basal cells, neurons and sustentacular cells [83]. Yagi and Costanzo found that olfactory grafts survive when transplanted to the olfactory bulb, retaining properties of a normal olfactory epithelium including the bipolar olfactory receptor cells [84]. Direct grafting of the olfactory epithelium to the ventral surface of the olfactory bulb with access to the nasal cavity could provide the basis for a new surgical treatment to restore the sense of smell. The ability to directly stimulate areas of the brain to activate a sensory percept is not without precedent. Cochlear implants used for the restoration of hearing and other sensor-brain interfaces are an increasingly popular modality for those with sensorineural loss. Those principles that have made cochlear implantation so
Impairment of smell may occur following injury to any portion of the olfactory tract, from nasal cavity to brain. A thorough understanding of the anatomy and pathophysiology combined with comprehensively obtained history, physical exam, olfactory testing, and neuroimaging may help to identify the mechanism of dysfunction and suggest possible treatments. Although most olfactory deficits are neuronal mediated and therefore currently unable to be corrected, promising technology may provide novel treatment options for those most affected. Until that day, patient counseling with compensatory strategies and reassurance is essential for the maintenance of safety and QoL in this unique and challenging patient population. Acknowledgements Partial funding for this paper was provided by The Medarva Research Foundation. The authors would like to thank Luke Edelmayer for creating the illustrations used in Fig. 1. Conflicts of Interest: None. References [1] Doty RL, Bromley SM, Panganiban WD. Olfactory function and dysfunction. Head & Neck Surgery - Otolarnygology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2006. p. 289–305. [2] Schwob JE. Neural regeneration and the peripheral olfactory system. Anat Rec 2002 Feb 15;269:33–49. [3] Costanzo RM. Rewiring the olfactory bulb: changes in odor maps following recovery from nerve transection. Chem Senses 2000;25:199–205. [4] Kobayashi M, Costanzo RM. Olfactory nerve recovery following mild and severe injury and the efficacy of dexamethasone treatment. Chem Senses 2009;34:573–80. [5] Costanzo RM. Regeneration and rewiring the olfactory bulb. Chem Senses 2005;30(Suppl 1):i133–4. [6] Yee KK, Costanzo RM. Restoration of olfactory mediated behavior after olfactory bulb deafferentation. Physiol Behav 1995;58:959–68. [7] Axel R. Scents and sensibility: a molecular logic of olfactory perception (Nobel lecture). Angew Chem Int Ed Engl 2005;44:6110–27. [8] Wang F, Nemes A, Mendelsohn M, Axel R. Odorant receptors govern the formation of a precise topographic map. Cell 1998;93:47–60. [9] Mombaerts P, Wang F, Dulac C, Chao SK, Nemes A, Mendelsohn M, et al. Visualizing an olfactory sensory map. Cell 1996;87:675–86. [10] Gottfried JA, Deichmann R, Winston JS, Dolan RJ. Functional heterogeneity in human olfactory cortex: an event-related functional magnetic resonance imaging study. J Neurosci 2002;22:10819–28. [11] Renzi G, Carboni A, Gasparini G, Perugini M, Becelli R. Taste and olfactory disturbances after upper and middle third facial fractures: a preliminary study. Ann Plast Surg 2002;48:355–8. [12] Costanzo RM, DiNardo LJ, Zasler ND. Head injury and taste. In: Doty RL, editor. Handbook of olfaction and gustation. New York: Marcel Dekker Inc.; 1995. p. 775–83. [13] Costanzo RM, DiNardo LJ, Reiter ER. Head injury and olfaction. In: Doty RL, editor. Handbook of olfaction and gustation. 2nd ed., New York: Marcel Dekker Inc.; 2003. p. 629–38. [14] Levin HS, High WM, Eisenberg HM. Impairment of olfactory recognition after closed head injury. Brain 1985;108:579–91. [15] Yousem DM, Geckle RJ, Bilker WB, McKeown DA, Doty RL. Posttraumatic olfactory dysfunction: MR and clinical evaluation. AJNR Am J Neuroradiol 1996;17:1171–9. [16] Costanzo RM, Zasler ND. Epidemiology and pathophysiology of olfactory and gustatory dysfunction in head trauma. J Head Trauma Rehabil 1992;7:15–24. [17] Ferrier D. The Hemispheres considered Physiologically. The functions of the brain. New York: G.P. Putnam’s Sons; 1876. p. 181–211. [18] Legg JW. A case of anosmia following a blow. Lancet 1873;2:659–60.
Please cite this article in press as: Coelho DH, Costanzo RM. Posttraumatic olfactory dysfunction. Auris Nasus Larynx (2015), http:// dx.doi.org/10.1016/j.anl.2015.08.006
G Model
ANL-2014; No. of Pages 7 D.H. Coelho, R.M. Costanzo / Auris Nasus Larynx xxx (2015) xxx–xxx [19] Jackson JH. Illustrations of diseases of the nervous system. London Hospital Report 1864;1:470–1. [20] Ogle W. Anosmia or cases illustrating the physiology and pathology of the sense of smell. Med Chir Trans 1870;53:263. [21] Notta A. Recherches sur la perte de l’odorat. Arch Gen Med 1870;15:385–407. [22] Kraus W, Fife D, Ramstein K. The relationship of family income to the incidence, external causes, and outcomes of serious brain injury, San Diego County, California. Am J Public Health 1986;1345–7. [23] Leigh AD. Defects in smell after head injury. Lancet 1943;1:38–40. [24] Mifka P. Post-traumatische anosmie. Wien Med Wochenschr 1964;114:793. [25] Zusho H, Asaka H, Fukushima Y, Sanada S, Oka T, Kuroishi T, et al. A study of olfactory threshold vs. fatigue in intravenous olfaction test (author’s transl). Nippon Jibiinkoka Gakkai Kaiho 1978;81:562–8. [26] Zusho H. Posttraumatic anosmia. Arch Otolaryngol 1982;108:90–2. [27] Costanzo RM, Zasler ND. Head trauma. In: Getchell TV, Doty RL, Bartoshuk LM, Snow Jr JB, editors. Smell and taste in health and disease. New York: Raven Press; 1991. p. 711–30. [28] Cain WS. Testing olfaction in a clinical setting. Ear Nose Throat J 1989;68:322– 416. 328. [29] Ikeda K, Tabata K, Oshima T, Nishikawa H, Hidaka H, Takasaka T. Unilateral examination of olfactory threshold using the Jet Stream Olfactometer. Auris Nasus Larynx 1999;26:435–9. [30] Kondo H, Matsuda T, Hashiba M, Baba S. A study of the relationship between the T&T olfactometer and the University of Pennsylvania Smell Identification Test in a Japanese population. Am J Rhinol 1998;12:353–8. [31] Fortin A, Lefebvre MB, Ptito M. Traumatic brain injury and olfactory deficits: the tale of two smell tests! Brain Inj 2010;24:27–33. [32] Vent J, Koenig J, Hellmich M, Huettenbrink KB, Damm M. Impact of recurrent head trauma on olfactory function in boxers: a matched pairs analysis. Brain Res 2010;1320:1–6. [33] Charland-Verville V, Lassonde M, Frasnelli J. Olfaction in athletes with concussion. Am J Rhinol Allergy 2012;26:222–6. [34] Neumann D, Zupan B, Babbage DR, Radnovich AJ, Tomita M, Hammond F, et al. Affect recognition, empathy, and dysosmia after traumatic brain injury. Arch Phys Med Rehabil 2012;93:1414–20. [35] Callahan CD, Hinkebein JH. Assessment of anosmia after traumatic brain injury: performance characteristics of the University of Pennsylvania Smell Identification Test. J Head Trauma Rehabil 2002;17:251–6. [36] Callahan CD, Hinkebein J. Neuropsychological significance of anosmia following traumatic brain injury. J Head Trauma Rehabil 1999;14:581–7. [37] Hong SC, Holbrook EH, Leopold DA, Hummel T. Distorted olfactory perception: a systematic review. Acta Otolaryngol 2012;132(Suppl 1):S27–31. [38] Green P, Rohling ML, Iverson GL, Gervais RO. Relationships between olfactory discrimination and head injury severity. Brain Inj 2003;17:479–96. [39] Swann AC, Gottesfeld Z. Deafferentation elicits a transient decrease in Na+, K+ATPase activity and ouabain binding in the olfactory tubercle. Brain Res 1987;404:323–6. [40] Doty RL, Yousem DM, Pham LT, Kreshak AA, Geckle R, Lee WW. Olfactory dysfunction in patients with head trauma. Arch Neurol 1997;54:1131–40. [41] Nakayama H, Ishikawa T, Yamashita S, Fukui I, Mutoh T, Hikichi K, et al. [CSF leakage and anosmia in aneurysm clipping of anterior communicating artery by basal interhemispheric approach]. No Shinkei Geka 2011;39: 263–8. [42] Jin H, Wang S, Hou L, Pan C, Li B, Wang H, et al. Clinical treatment of traumatic brain injury complicated by cranial nerve injury. Injury 2010;41: 918–23. [43] Doty RL. The olfactory system and its disorders. Semin Neurol 2009;29:74–81. [44] Varney NR. Prognostic significance of anosmia in patients with closed-head trauma. J Clin Exp Neuropsychol 1988;10:250–4. [45] Roberts MA, Simcox AF. Assessing olfaction following pediatric traumatic brain injury. Appl Neuropsychol 1996;3:86–8. [46] Martzke JS, Swan CS, Varney NR. Posttraumatic anosmia and orbital frontal damage: neuropsychological and neuropsychiatric correlates. Neuropsychology 1991;5:213–25. [47] Sigurdardottir S, Jerstad T, Andelic N, Roe C, Schanke AK. Olfactory dysfunction, gambling task performance and intracranial lesions after traumatic brain injury. Neuropsychology 2010;24:504–13. [48] Doty RL, Smith R, McKeown DA, Raj J. Tests of human olfactory function: principal components analysis suggests that most measure a common source of variance. Percept Psychophys 1994;56:701–7. [49] Wrobel BB, Leopold DA. Clinical assessment of patients with smell and taste disorders. Otolaryngol Clin North Am 2004;37:1127–42. [50] Cain WS, Rabin MD. Comparability of two tests of olfactory functioning. Chem Senses 1989;14:479–85. [51] Doty RL, Shaman P, Kimmelman CP, Dann MS. University of Pennsylvania Smell Identification Test: a rapid quantitative olfactory function test for the clinic. Laryngoscope 1984;94:176–8. [52] Doty RL, Agrawal U. The shelf life of the University of Pennsylvania Smell Identification Test (UPSIT). Laryngoscope 1989;99:402–4. [53] Green P, Iverson GL. Effects of injury severity and cognitive exaggeration on olfactory deficits in head injury compensation claims. NeuroRehabilitation 2001;16:237–43.
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[54] Cain WS, Gent JF, Goodspeed RB, Leonard G. Evaluation of olfactory dysfunction in the Connecticut Chemosensory Clinical Research Center. Laryngoscope 1988;98:83–8. [55] Kobal G, Hummel T, Sekinger B, Barz S, Roscher S, Wolf S. Sniffin’ sticks’’: screening of olfactory performance. Rhinology 1996;34:222–6. [56] Furukawa M, Kamide M, Miwa T, Umeda R. Significance of intravenous olfaction test using thiamine propyldisulfide (Alinamin) in olfactometry. Auris Nasus Larynx 1988;15:25–31. [57] Kobayashi M, Saito S, Kobayakawa T, Deguchi Y, Costanzo RM. Cross-Cultural Comparison of Data Using the Odor Stick Identification Test for Japanese (OSIT-J). Chem Senses 2006;31:335–42. [58] Saito S, yabe-Kanamura S, Takashima Y, Gotow N, Naito N, Nozawa T, et al. Development of a smell identification test using a novel stick-type odor presentation kit. Chem Senses 2006;31:379–91. [59] Okutani F, Hirose K, Kobayashi T, Kaba H, Hyodo M. Evaluation of ‘‘Open Essence’’ odor-identification test card by application to healthy volunteers. Auris Nasus Larynx 2013;40:76–80. [60] Cain WS, Gent J, Catalanotto FA, Goodspeed RB. Clinical evaluation of olfaction. Am J Otolaryngol 1983;4:252–6. [61] Kim SW, Kim DW, Yim YJ, Rhee CS, Lee CH, Kim JW. Cortical magnetic resonance imaging findings in patients with posttraumatic olfactory dysfunction: comparison according to the interval between trauma and evaluation. Clin Exp Otorhinolaryngol 2014;7(3):188–92. [62] Atighechi S, Salari H, Baradarantar MH, Jafari R, Karimi G, Mirjali M. A comparative study of brain perfusion single-photon emission computed tomography and magnetic resonance imaging in patients with post-traumatic anosmia. Am J Rhinol Allergy 2009;23(4):409–12. [63] Varney NR, Pinkston JB, Wu JC. Quantitative PET findings in patients with posttraumatic anosmia. J Head Trauma Rehabil 2001;16(3):253–9. [64] Wong KK, Muller ML, Kuwabara H, Studenski SA, Bohnen NI. Olfactory loss and nigrostriatal dopaminergic denervation in the elderly. Neurosci Lett 2010;484(3):163–7. [65] Fujii M, Fukazawa K, Takayasu S, Sakagami M. Olfactory dysfunction in patients with head trauma. Auris Nasus Larynx 2002;29:35–40. [66] Ikeda K, Sakurada T, Takasaka T, Okitsu T, Yoshida S. Anosmia following head trauma: preliminary study of steroid treatment. Tohoku J Exp Med 1995;177:343–51. [67] Delank KW, Stoll W. Olfactory function after functional endoscopic sinus surgery for chronic sinusitis. Rhinology 1998;36:15–9. [68] Zasler ND, McNeney R, Heywood PG. Rehabilitative management of olfactory and gustatory dysfunction following brain injury. J Head Trauma Rehabil 1992;7:66–75. [69] Rondinelli RD, Genovese E, Brigham CR. Guides to the evaluation of permanent impairment. 6th ed. Chicago, IL: American Medical Association; 2008. [70] Miwa T, Furukawa M, Tsukatani T, Costanzo RM, DiNardo LJ, Reiter ER. Impact of olfactory impairment on quality of life and disability. Arch Otolaryngol Head Neck Surg 2001;127:497–503. [71] Santos DV, Reiter ER, DiNardo LJ, Costanzo RM. Hazardous events associated with impaired olfactory function. Arch Otolaryngol Head Neck Surg 2004;130:317–9. [72] Pence TS, Reiter ER, DiNardo LJ, Costanzo RM. Risk factors for hazardous events in olfactory-impaired patients. JAMA Otolaryngol Head Neck Surg 2014;140:951–5. [73] Mattes RD, Cowart BJ. Dietary assessment of patients with chemosensory disorders. J Am Diet Assoc 1994;94:50–6. [74] Duffy VB, Ferris AM. Nutritional management of patients with chemosensory disturbances. Ear Nose Throat J 1989;68:395–7. [75] Costanzo RM, Becker DP. Smell and taste disorders in head injury and neurosurgery patients. In: Meiselman HL, Rivlin RS, editors. Clinical measurements of taste and smell. New York: MacMillian Publishing Company; 1986. p. 565–78. [76] Temmel AF, Quint C, Schickinger-Fischer B, Klimek L, Stoller E, Hummel T. Characteristics of olfactory disorders in relation to major causes of olfactory loss. Arch Otolaryngol Head Neck Surg 2002;128:635–41. [77] Costanzo RM, DiNardo LJ, Zasler ND. Head injury and olfaction. In: Doty RL, editor. Handbook of olfaction and gustation. New York: Marcel Dekker Inc.; 1995. p. 493–502. [78] Welge-Lussen A, Hilgenfeld A, Meusel T, Hummel T. Long-term follow-up of posttraumatic olfactory disorders. Rhinology 2012;50:67–72. [79] Fan LY, Kuo CL, Lirng JF, Shu CH. Investigation of prognostic factors for posttraumatic olfactory dysfunction. J Chin Med Assoc 2015;78:299–303. [80] Sumner D. Post-traumatic anosmia. Brain 1964;87:107–20. [81] Suzukawa K, Kondo K, Kanaya K, Sakamoto T, Watanabe K, Ushio M, et al. Agerelated changes of the regeneration mode in the mouse peripheral olfactory system following olfactotoxic drug methimazole-induced damage. J Comp Neurol 2011;519:2154–74. [82] Kobayashi M, Tamari K, Miyamura T, Takeuchi K. Blockade of interleukin-6 receptor suppresses inflammatory reaction and facilitates functional recovery following olfactory system injury. Neurosci Res 2013;76:125–32. [83] Chen X, Fang H, Schwob JE. Multipotency of purified, transplanted globose basal cells in olfactory epithelium. J Comp Neurol 2004;469:457–74. [84] Yagi S, Costanzo RM. Grafting the olfactory epithelium to the olfactory bulb. Am J Rhinol Allergy 2009;23:239–43.
Please cite this article in press as: Coelho DH, Costanzo RM. Posttraumatic olfactory dysfunction. Auris Nasus Larynx (2015), http:// dx.doi.org/10.1016/j.anl.2015.08.006