Recovery of Olfactory Function Following Closed Head Injury Or Infections of the Upper Respiratory Tract

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ORIGINAL ARTICLE Recovery of Olfactory Function Following Closed Head Injury or Infections of the Upper Respiratory Tract

Jens Reden, MD; Antje Mueller, MD; Christian Mueller, MD; Iordanis Konstantinidis, MD; Johannes Frasnelli, MD; Basile N. Landis, MD; Thomas Hummel, MD

Objective: To investigate the outcome of olfactory func- 32% of the patients improved, but in the posttraumatic tion in patients with olfactory loss following infections group (n=99) only 10% improved. In patients with post- of the upper respiratory tract (post-URTI) or head trauma. URTI olfactory loss, a negative correlation was found between age and recovery of olfactory function. In gen- Design: Retrospective patient-based study. eral, the factor “sex” had no significant effect on recovery Setting: Smell and Taste Outpatient Clinic at a univer- of smell function. sity hospital. Conclusions: To our knowledge, the series of patients Patients: A total of 361 patients (228 women, 133 men) presented herein is the largest in the literature to date in were included. which standardized testing methods were used to assess the progression of impaired olfaction. It showed that the Main Outcome Measures: Olfactory function was as- rate of improvement of olfactory function was signifi- sessed using the “Sniffin’ Sticks” test battery, which result cantly higher in patients with post-URTI dysosmia com- in a threshold, discrimination, and identification score. The pared with patients with posttraumatic dysosmia. Dur- mean interval between first and last visit was 14 months. ing an observation period of approximately 1 year, more than 30% of patients with post-URTI olfactory loss ex- Results: In comparing the overall threshold, discrimi- perienced improvement, whereas only 10% of patients nation, and identification scores between the last and first with posttraumatic olfactory loss experienced improve- visit, olfactory function improved in 26% of the patients ment. Furthermore, age plays a significant role in the re- whereas it decreased in 6%. The cause of olfactory im- covery of olfactory function. pairment had a significant effect on the recovery rate of olfactory function. Within the post-URTI group (n=262), Arch Otolaryngol Head Neck Surg. 2006;132:265-269

LFACTORY DISORDERS OC- Because no therapy has yet been proven cur at a much higher rate to be effective in post-URTI and posttrau- thanpreviouslythought,as matic smell disorders, correct informa- demonstrated in recent tion on the nature of the disorder and its population-based stud- prognosis appears to be essential in the ies.O1,2 The frequency of a decreased olfactory counseling of these patients. Until now, function was as high as 16% in one studied only few studies have addressed long- population, with at least 5% of the general term changes of olfactory function in pa- population being functionally anosmic.1 In tients with post-URTI or posttraumatic another study, the prevalence of impaired ol- smell disorders, often in relatively small Author Affiliations: Smell & factionwas25%inadults50yearsandolder.3 samples. Thus, the aim of this retrospec- Taste Clinic, Department of These surveys report that upper respiratory tive study was to investigate the change of Otorhinolaryngology, University tract infections (URTIs) and trauma are olfactory function in a large group of pa- of Dresden Medical School, tients with the use of standardized testing Dresden, Germany (Drs Reden, among the most frequent causes of dysos- 4 methods with strict criteria. A. Mueller, Konstantinidis, mias. In contrast to a slowly progressive de- Frasnelli, and Hummel); crease of olfactory function, patients with Department of post-URTI and posttraumatic dysosmia ex- METHODS Otorhinolaryngology, University periencesuddenolfactoryloss.Thishasbeen of Vienna, Vienna, Austria reported to have a more severe impact on PATIENTS (Dr C. Mueller); and Unite´de quality of life5 compared with progressive ol- Rhinologie-Olfactologie, Service 2,6 All participants were evaluated at the Smell and d’ Oto-Rhinologie-Laryngologie, factory loss, which may go unrecognized. Taste Clinic of the Department of Otorhinolar- Hopitaux Universitaires de Apart from the psychological strain in these yngology of the University of Dresden Medical Genève, Genève, Switzerland patients, most of them experience hazard- School, Dresden, Germany. A total of 361 pa- (Dr Landis). ous events.7 tients were included (228 women [63.2%] and

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table. Descriptive Statistics for Patients With Post-URTI or Posttraumatic Olfactory Loss*

Statistic Total Female Male Patients With Post-URTI Olfactory Loss No. 262 187 75 Age, y 58.0 ± 0.6 58.4 ± 0.8 57.3 ± 1.1 TDI score: first visit 19.5 ± 0.4 19.8 ± 0.5 18.7 ± 0.8 TDI score: last visit 23.3 ± 0.5 23.8 ± 0.5 21.9 ± 0.9 Time between first and last visit, mo 13.7 ± 0.8 14.1 ± 0.9 12.7 ± 1.3 Time between infection and first visit, mo 17.1 ± 1.4 14.9 ± 1.4 22.4 ± 3.6 Patients With Posttraumatic Olfactory Loss No. 99 41 58 Age, y 48.1 ± 1.5 52.1 ± 2.4 45.2 ± 1.9 TDI score: first visit 13.6 ± 0.7 11.9 ± 0.9 14.8 ± 1.0 TDI score: last visit 13.9 ± 0.7 12.7 ± 0.9 14.8 ± 1.0 Time between first and last visit, mo 13.4 ± 0.9 12.8 ± 1.3 13.7 ± 1.2 Time between trauma and first visit, mo 18.2 ± 2.6 19.4 ± 5.5 17.3 ± 2.1

Abbreviations: TDI, threshold, discrimination, and identification; URTI, upper respiratory tract infection. *Data are given as mean ± SEM value unless otherwise specified.

133 men [36.8%]). The mean±SEM age was 55.3±0.7 years (range, mum of 48 points. As defined in Hummel et al8 and Kobal et 17-82 years). The patients were thoroughly examined by expe- al,9 a score of 32 points or more indicates normosmia, a score rienced otorhinolaryngologists, including an endoscopic inves- between 16 and 32 points indicates reduced olfactory func- tigation of the nasal cavity. Depending on the clinical examination in terms of hyposmia, and a score of less than 16 points tion and the detailed, structured history, olfactory dysfunction indicates functional anosmia. was classified as either postinfectious or posttraumatic, follow- To categorize progression of olfactory function, an in- ing an infection of the upper respiratory tract or a closed head crease of more than 6 points in the TDI score was regarded as injury, respectively. The “postinfection group” comprised 262 pa- a clinically significant improvement of olfactory function. In tients (187 women and 75 men; mean±SEM age, 58 years), and contrast, a significant decrease of olfactory function was as- the “posttraumatic group” comprised 99 patients (41 women and sumed if the TDI score decreased by more than 6 points. 58 men; mean±SEM age, 48.1 years). Because the presentation The “Sniffin’ Sticks” test has been used in many patients and of the patients to our clinic is dependent on their subjective de- subjects to assess olfactory performance since it was devel- gree of complaint and on the often ignoring attitude of clinicians oped in 1996. Its correlation with previously established tests and the social environment toward olfaction and its problems, of olfactory function (eg, the 12-item Cross-Cultural Smell Iden- the time span between appearance of olfactory disturbance and tification Test [CC-SIT, a subtest of the University of Pennsyl- first visit varied from 1 to 216 months (mean±SEM, 17.4±1.7 vania Smell Identification Test “UPSIT”] and the Connecticut months). The mean±SEM interval between the first and last visit Chemosensorial Clinical Research Center Test [CCCRC] has was 13.6±0.6 months. been demonstrated in various studies).8,10

OLFACTORY TESTING STATISTICAL ANALYSIS

Olfactory testing was performed using the “Sniffin’ Sticks” test For statistical analyses, SPSS version 12.0 (SPSS Inc, Chicago, Ill) kit,8 which involves tests for odor threshold, odor discrimina- was used. Comparisons between the first and last visit were per- tion, and odor identification. With the use of commercially avail- formed using the t test for paired samples. Correlation analyses able felt-tip pens, the odorants were presented approximately were performed according to Pearson. The ␣ level was set at .05. 2 cm in front of both nostrils for 2 seconds. Phenylethyl alco- hol odor threshold was assessed by a single-staircase, 3-alter- RESULTS native, forced-choice procedure. Three pens were presented to the patient in a randomized order, 2 contained an odorless sol- vent (propylene glycol) and the other contained the odorant Of the 361 patients, 93 (25.8%) exhibited an increase in in a certain dilution. The patients’ task was to indicate the pen having a TDI score of more than 6 points, indicating sig- with the odorant. Concentration was increased if one of the nificant improvement of olfactory function, whereas 22 pa- blanks was chosen and decreased if the correct pen was iden- tients (6.1%) exhibited a decrease in olfactory function. De- tified twice. The mean of the last 4 of 7 reversal points was used scriptive statistics for the patients with post-URTI or as detection threshold. The second subtest assessed the ability posttraumatic olfactory loss are given in the Table. of the patient to discriminate different odors. Therefore, 16 trip- lets of pens were offered, each including 2 identical and 1 dif- PATIENTS WITH POST-URTI OLFACTORY LOSS ferent odor. The patient’s task was to indicate the pen that had a different smell. Threshold and discrimination testing were performed with the patient being blindfolded. For testing odor iden- Of the 262 patients with post-URTI olfactory loss, 83 per- tification, 16 pens containing common odors were offered. The formed significantly better at the second visit (ie, 31.7% patient had to identify each of the odorants from a list of 4 de- of the patients exhibited improvement of olfactory func- scriptors. The sum of the 3 subtests resulted in the threshold, tion). However, a significant decrease of the TDI score discrimination, and identification (TDI) score, with a maxi- was observed in 15 subjects (5.7%), and 164 patients

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40 100

35 80 67%

60 30 66%

No. of Patients 40 33% 25 34% 93% 65% 20 20 53% 47% 35% 7% 0 TDI Score First Visit <40 40-49 50-59 60-69 >69 15 Age, y

10 Figure 3. Age distribution and recovery rate in patients with olfactory loss following infections of the upper respiratory tract. 5

05101520 25 30 35 40 45 TDI Score Last Visit 45

40 Figure 1. Threshold, discrimination, and identification (TDI) scores of the first and last visit of patients with olfactory loss following infections of the upper respiratory tract. 35

300 Improvement 25 No Improvement 250 20 200

68% TDI Score First Visit 15 150 70%

100 10 No. of Patients 32% 30% 65% 50 35% 5

0 Female Male Total Sex 0 525101520 30 35 40 45 TDI Score Last Visit

Figure 2. Sex distribution and recovery rate in patients with olfactory loss following infections of the upper respiratory tract. Figure 4. Threshold, discrimination, and identification (TDI) scores of first and last visit of posttraumatic patients. (62.6%) exhibited no change. Across all subjects, the mean±SEM TDI score changed by 3.8±0.4 points. This [n=17; 6.5%]; 40-49 years [n=31; 11.8%]; 50-59 years change, as well as differences in each of the subtests [n=76; 29.0%]; 60-69 years [n=110; 42.0%]; and Ͼ69 years (threshold, discrimination, and identification) were sta- [n=28; 10.7%]). The number of patients exhibiting recov- tistically significant (PϽ.001) (Figure 1). ery decreased continuously with age (Ͻ40 years, 47.1%; The mean±SEM interval between the first and last visit 40-49 years, 35.5%; 50-59 years, 34.2%; 60-69 years, 32.7%; was 13.7±0.8 months. The time between infection and and Ͼ69 years, 7.1%) (Figure 3). This also resulted in a first visit varied from 1 to 204 months (mean±SEM, significant negative correlation between the patients’ age 17.1±1.4 months). Patients with a shorter duration of and recovery rate (r262=−0.18; P=.003). olfactory loss had a higher chance to exhibit improvement of overall olfactory function, expressed as the change PATIENTS WITH POSTTRAUMATIC of TDI score (r262=−0.17; P=.006). In contrast, no sig- OLFACTORY DISORDER nificant correlation could be found between the interval between first and last visit and improvement of olfac- A total of 99 patients had olfactory dysfunction follow- tory function (r259=0.11; P=.08). ing head trauma. There was no significant difference in There were more women among patients with post- mean±SEM TDI scores (0.3±0.47 points; P=.52) be- URTI olfactory loss than men (187 women vs 75 men). tween the first and last visit for patients with head trauma However, the factor “sex” had no significant effect on re- (Figure 4). Of the 99 patients, 10 (10.1%) improved; covery (P=.34) (Figure 2). 82 (82.8%) did not change in olfactory function; and To investigate the effect of age on recovery from olfac- 7 (7.1%) exhibited a decreased test result at their last visit. tory loss, patients were divided into 5 age groups (Ͻ40 years On average (mean±SEM), they consulted our clinic

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 18.2±2.6 months after the trauma and returned 41±0.9 In the present study, post-URTI olfactory loss was observed months after the trauma for the last visit. In these pa- in more than 70% of the group aged 50 to 69 years, which tients, neither sex nor age affected the recovery rate (sex- confirms findings of previous studies.11,17 The decline of ol- related difference in recovery, P=.40; correlation be- faction with age and the higher number of elderly patients tween age and recovery rate, r99=0.05; P=.62), nor was in the post-URTI group indicate that age is among the most there a significant effect of the duration of olfactory loss important factors in terms of recovery of smell function. Rea- (correlation between duration of head trauma and re- sons for this may be found in the fact that regeneration of covery rate, r99=0.19; P=.054). olfactory receptor neurons decreases with age, leading to a decreased number of olfactory receptor neurons18,19 As a COMMENT possible result, the size of olfactory epithelium decreases with aging.20-23 These pathophysiological findings explain, at least in part, why nasal mucosa and olfactory epithelium The present study provided the following major results: in elderly people are more vulnerable for infections and that (1) During an observation period of approximately 1 year, the chance of recovery of olfaction in post-URTI olfactory 32% of the patients with post-URTI olfactory dysfunc- loss becomes smaller with increasing age, which was already tion improved, but only 10% of patients with posttrau- observed in 1930 by Bedna´r24 in a study of 27 post-URTI matic olfactory loss improved. (2) Patients with post- patients. The present results showed that 47% of patients URTI olfactory loss exhibited a negative correlation younger than 40 years improved during approximately 1 between age and the recovery of olfactory function, which year of observation. In contrast, only 7% of patients recov- was not seen for patients with posttraumatic smell dys- ered if they were 70 years or older. function. (3) The factor “sex” had no significant effect Another prognostic factor is the duration of disease. on recovery of the sense of smell. As reported previously,25-27 the likelihood for recovery decreases with the duration of olfactory loss. This can POST-URTI OLFACTORY LOSS be confirmed by the negative correlation between duration of olfactory impairment and change in TDI score seen Previous studies reported a wide range of patients with re- in the present data. To investigate this effect in greater covery of the sense of smell following URTI. Mori et al11 detail, we divided the patients into 4 groups with regard reported that 58% (n=190) of patients with post-URTI ol- to the duration of disease. This analysis revealed that factory disturbance improved in terms of their olfactory 31.6% (n=155) of the patients who showed up within sensitivity. However, olfactory function was not tested, 1 year after infection improved in terms of olfactory func- but patients were only interviewed with regard to recov- tion; the percentage of recovery was 37.5% (21 of 56 pa- ery of their sense of smell. These data may be biased by tients) after 1 to 2 years, 36.8% (7 of 19 patients) after the fact that the patients’ self-assessments have been shown 2 to 3 years, and 18.8% (6 of 32 patients) after 3 years or tobenotoriouslyunreliable.6 Therefore,inthepresentstudy, later. Thus, within the first 3 years after infection, the subjective reports were not considered and only results proportion of patients who show improvement remains from quantitative olfactory testing were taken into account. constant at about one third, whereas after 3 years we see Duncan and Seiden12 found in their long-term fol- an obvious decrease in the recovery rate. These data in- low-up study of olfactory loss an improvement in 62% of dicate that functional regenerative processes in periph- the patients based on the patients’ ratings. When tested with eral and/or central regions may be effective not only within the UPSIT, even more (66%) showed an increased score the first year but even after a relatively long latency. of 4 UPSIT points or more. Investigations were performed after a mean duration of disease of 36.9 months. It has to POSTTRAUMATIC OLFACTORY LOSS be kept in mind, however, that this study included only 21 subjects. In addition, the observation period was ap- The investigation of olfactory function of patients with proximately 3 times longer than that in the present study, posttraumatic olfactory loss revealed no significant dif- which might explain the higher recovery rate. ference in olfactory sensitivity between the first and last In contrast to these relatively high rates of recovery, Hen- visit. While this result is in agreement with previous ob- driks13 reported in his excellent summary of the literature servations,12,26 the presently observed recovery rate of up to 1988 that spontaneous recovery occurs in 35% of the 10.1% over an observation period of 13 months is com- patients over a period of approximately 12 months. Fur- parable only to that in the study by Jimenez et al.28 Other thermore, an investigation on the effectiveness of lipoic acid authors reported higher recovery rates of 25% to 35%.11,12,29 in the treatment of smell dysfunction following a URTI Although the olfactory system has the capacity for re- (which has proven to be as effective as placebo [T.H., un- generation, with olfactory receptor axons known to re- published data, 2005]) showed that 35% of the patients ex- establish functional connections with sectioned olfac- hibited a remarkable increase in olfactory function over an tory bulb,30 this low recovery rate is disappointing. Speed average period of 4 months.14 In line with these observa- and extent of growth of disrupted axons depends on the tions, the present study indicates that approximately one degree of injury.31 Even though a correlation between se- third (32%) of patients with post-URTI olfactory loss ex- verity of trauma and recovery rate has not been demon- hibit improvement over a period of approximately 1 year. strated, it is assumed that this is an important prognos- The effect of aging on the sense of smell has been inves- tic factor. In fact, some authors reported associations tigated extensively, and it has been shown in many stud- between likelihood and/or level of olfactory impairment ies that olfactory function decreases as a function of age.2,15,16 and severity of the injury.32-34

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 The literature favors the hypothesis that shearing or 2. Bramerson A, Johansson L, Ek L, Nordin S, Bende M. Prevalence of olfactory dysfunction: the skovde population-based study. Laryngoscope. 2004;114:733-737. tearing of the fila olfactoria is the most likely cause of 3. Murphy C, Schubert CR, Cruickshanks KJ, Klein BE, Klein R, Nondahl DM. Preva- olfactory loss, although little research has been done in lence of olfactory impairment in older adults. JAMA. 2002;288:2307-2312. this area. Investigations by Delank and Fechner35 indi- 4. Damm M, Temmel A, Welge-Lussen A, et al. Olfactory dysfunctions: epidemiology and therapy in Germany, Austria and Switzerland. HNO. 2004;52:112-120. cate that the vulnerability of the fila varies. This seems 5. Hummel T, Nordin S. Olfactory disorders and their consequences for quality of to confirm reports by Sumner,36 who already observed life—a review. Acta Otolaryngol. 2005;125:116-121. 6. Landis BN, Hummel T, Hugentobler M, Giger R, Lacroix JS. Ratings of overall that even minor trauma can lead to severe olfactory im- olfactory function. Chem Senses. 2003;28:691-694. pairment. In some patients with posttraumatic olfactory 7. Santos DV, Reiter ER, DiNardo LJ, Costanzo RM. Hazardous events associated loss, fractures or edema in the area of the olfactory cleft with impaired olfactory function. Arch Otolaryngol Head Neck Surg. 2004;130: 317-319. can be detected; acute head trauma may also cause ce- 8. Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G. “Sniffin’ sticks”: olfactory per- rebral hemorrhage or contusion, which may lead to ol- formance assessed by the combined testing of odor identification, odor discrimi- factory loss.37 Taken together, posttraumatic lesions and nation and olfactory threshold. Chem Senses. 1997;22:39-52. 9. Kobal G, Klimek L, Wolfensberger M, et al. Multicenter investigation of 1,036 consecutive wound healing leave considerable fibrosis and subjects using a standardized method for the assessment of olfactory function scar tissue in the area of the cribriform plate and olfac- combining tests of odor identification, odor discrimination, and olfactory thresholds. Eur Arch Otorhinolaryngol. 2000;257:205-211. tory bulb. This may result in a major obstacle consider- 10. Kobal G, Hummel T, Sekinger B, Barz S, Roscher S, Wolf S. “Sniffin’ sticks”: screen- ing regrowth of olfactory receptor neurons. ing of olfactory performance. Rhinology. 1996;34:222-226. Even though it is generally assumed that recovery seems 11. Mori J, Aiba T, Sugiura M, et al. Clinical study of olfactory disturbance. Acta Oto- laryngol Suppl. 1998;538:197-201. to be more likely if the incidence occurred less than 1 year 12. Duncan HJ, Seiden AM. Long-term follow-up of olfactory loss secondary to head ago,38 in agreement with the findings of Doty et al,29 the cor- trauma and upper respiratory tract infection. Arch Otolaryngol Head Neck Surg. relationsinthepresentstudybetweenimprovementandtime 1995;121:1183-1187. 13. Hendriks APJ. Olfactory dysfunction. Rhinology. 1988;26:229-251. between trauma and test session did not reach a significant 14. Hummel T, Heilmann S, Huttenbriuk KB. Lipoic acid in the treatment of smell level. Moreover, of the 10 patients who showed improve- dysfunction following viral infection of the upper respiratory tract. Laryngoscope. 2002;112:2076-2080. ment, the trauma dated back more than 1 year in 6 patients 15. Doty RL, Shaman P, Applebaum SL, Giberson R, Siksorski L, Rosenberg L. and more than 3 years in 3 patients. For example, 1 patient Smell identification ability: changes with age. Science. 1984;226:1441-1443. (female; age, 67 years) exhibited an increase of 9.25 points 16. Hummel T, Barz S, Pauli E, Kobal G. Chemosensory event-related potentials change with age. Electroencephalogr Clin Neurophysiol. 1998;108:208-217. in TDI score when olfactory function was tested the first time 17. Sugiura M, Aiba T, Mori J, Nakai Y. An epidemiological study of postviral olfac- 7 years after the injury, and the follow-up examination was tory disorder. Acta Otolaryngol Suppl. 1998;538:191-196. performed another 21 months later, approximately 9 years 18. Conley DB, Robinson AM, Shinners MJ, Kern RC. Age-related olfactory dysfunction: cellular and molecular characterization in the rat. Am J Rhinol. 2003;17:169-175. after the initial trauma. This case demonstrates the possi- 19. Kern RC, Conley DB, Haines GK III, Robinson AM. Pathology of the olfactory mu- bility of a late onset of recovery of olfactory function after cosa: implications for the treatment of olfactory dysfunction. Laryngoscope. 2004; 114:279-285. head trauma. Other factors that would influence the like- 20. Naessen R. An enquiry on the morphological characteristics and possible changes lihood for recovery could not be identified; neither sex nor with age in the olfactory region of man. Acta Otolaryngol. 1971;71:49-62. age seemed to affect the recovery from olfactory loss. 21. Paik SI, Lehman MN, Seiden AM, Duncan HJ, Smith DV. Human olfactory biopsy: the influence of age and receptor distribution. Arch Otolaryngol Head Neck In conclusion, this study addressed the change in ol- Surg. 1992;118:731-738. factory function in a relatively large sample using a con- 22. Rawson NE, Gomez G, Cowart B, Restrepo D. The use of olfactory receptor neu- servative definition of clinically significant improvement. rons (ORNs) from biopsies to study changes in aging and neurodegenerative diseases. Ann N Y Acad Sci. 1998;855:701-707. Patients with post-URTI olfactory loss had a significantly 23. Feron F, Perry C, McGrath JJ, Mackay-Sim A. 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