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ISSN 0017-8748

Headache

doi: 10.1111/head.12973

V C 2016 American Headache Society

Published by Wiley Periodicals, Inc.

Research Submission

Olfactory Symptoms Reported by Migraineurs With and Without Auras MarcoAur elio Fornazieri, MD, PhD; Anibal Rodrigues Neto; Fabio de Rezende Pinna, MD, PhD; Fabio Henrique Gobbi Porto, MD; Paulo de Lima Navarro, MD; Richard Louis Voegels, MD, PhD; Richard L. Doty, PhD Objective.—Olfaction-related symptoms accompany migraine attacks and some, such as osmophobia, may be useful in differentiating migraine from other types of headaches. However, the types and frequencies of olfactory symptoms associat ed with migraine have not been well characterized. The goal of this study was to better characterize the olfactory symp toms of migraine. Methods.—A cross-sectional study was devised. One hundred and thirteen patients who met the International Classifi cation of Headache Disorders II criteria for migraine were administered a new 65-item questionnaire specifically focused on olfaction-related experiences (eg, odor-related triggers, osmophobia, cacosmia, phantosmia, olfactory hallucinations, olfactory hypersensitivity, and self-perceived olfactory function). Visual analog scale ratings and frequencies were comput ed and compared between migraineurs with and without auras using t -tests and chi-square analyses. Results.—While osmophobia was present in 95.5% of the patients, the prevalence of other olfaction-related symptoms was much lower (interictal olfactory hypersensitivity [IOH], 14.1%; olfactory hallucinations, 6.2%; phantosmia, 4.4%; cacosmia/euosmia, 2.6%). Migraine was commonly triggered by odors (90.2%), with perfume being the most common trig ger (95.1%), followed by cleaning products (81.3%), cigarette smoke (71.5%), and motor vehicle exhaust (70.5%). No sig nificant differences in symptom frequencies were apparent between migraineurs with or without auras ( P > .40). Interestingly, patients with IOH reported being less likely to experience osmophobia and odor-triggered crisis than did those without this symptom (respective percentages: 75% vs. 99% and 69% vs. 94%, P £ .002). Osmophobia and odor trig gered headache were associated with a mild decrease in self-reported olfactory acuity. Conclusion.—Odor-related disturbances were common symptoms of the 113 migraineurs, with nearly all reporting osmophobia. Perfume odor was the most common trigger for the migraine. The reported symptoms did not differ between patients with and without auras. Patients who experienced IOH appeared to fundamentally differ from those who did not experience IOH in terms of the incidence of osmophobia and odor-triggered crisis. Subjects who reported experiencing osmophobia and odor-triggered headache reported having worse olfactory acuity.

Key words: migraine, aura, olfactory symptoms

Abbreviations: ICHD II International Classification of Headache Disorders, IOH interictal olfactory hypersensitivity, MA migraine with aura, MwA migraine without aura, VAS visual analog scale

( Headache 2016;56:1608-1616)

From the Division of Otorhinolaryngology, University of S ~ ao Paulo, S ~ ao Paulo, Brazil (M.A. Fornazieri, F. de Rezende Pinna, and R.L. Voegels); State University of Londrina, Londrina, Brazil (A.R. Neto and P. de Lima Navarro); Division of Neurolo gy, University of S ~ ao Paulo, S ~ ao Paulo, Brazil (F.H. Gobbi Porto); Smell and Test Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA (R.L. Doty). Address all correspondence to M.A. Fornazieri, Division of Otorhinolaryngology, University of S ~ ao Paulo, S ~ ao Paulo, Brazil, e-mail: marcofornazieri@gmail.com

Accepted for publication June 22, 2016.

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( P < .05). More recently, Sj € ostrand et al 10 found that osmophobia was present in 81.7% of 60 wom en they studied; only 32.7% of these were diag nosed as having auras. Moreover, some migraine patient’s characteristics seem to be directly associat ed with osmophobia such as anxiety, 16,24,25 more year of headache history, phonophobia, 24 and aura, which is inversely related to osmophobia. 25 Other olfactory symptoms have been linked to migraine patients. Thus, some studies have reported interictal olfactory hypersensitivity (IOH) in migraineurs. 10,22,23 Interestingly, those with IOH reported experiencing a higher frequency of attacks and a greater number of odor-triggered crisis. 22 Others have found increased cerebral blood flow in the anterior piriform gyrus and superior temporal gyrus in migraineurs—brain regions known to be related to olfaction. 26 Olfactory hallucinations last ing 5–60 minutes, described as an unpleasant burn ing smell, have been reported as a form of aura and have been proposed to be included in the ICHD-II (International Classification of Headache Diseases) diagnostic criteria for migraine. 27,28 While the aforementioned studies indicate that olfactory symptoms are frequently a component of the migraine experience, most have focused only on osmophobia and the role of odors in triggering the migraine attacks. Other potential olfaction-related symptoms, such as olfactory hallucinations, cacos mia, and interictal hypersensitivity, have largely been ignored. Moreover, differentiating olfactory symptoms of migraine with and without aura is important to better characterize these diseases and allow further pathophysiological and imaging stud ies of aura phenomenon and migraine related to the olfactory pathways. Therefore, the aim of this study was to quantify the frequency of a range of olfactory complaints reported by migraineurs with specific questions and to determine whether such complaints differ in frequency between those with and without auras. METHODS Subjects.— To answer our research question we designed a cross-sectional study. The study sample was composed of 113 outpatients recruited at

Patients with migraine often experience a num ber of debilitating symptoms associated with the headache. These include visual disturbances, 1 nau sea, cognitive dysfunction, and fatigue, 2 as well as increased sensitivity to light, 3 sound, 3 touch, 4 and smell. 2,4,5 Many environmental and behavioral fac tors are closely related to the triggering or worsen ing of the crisis. For example, sleep disorders, diet, stress, hormonal factors, and odors are known trig gers. 6,7 Some of these conditions can be prevented or mitigated by altered behavior of the patients. It is now well established that odors in particular trigger and aggravate the crisis (osmophobia). 6,8–12 There is some evidence that the presence of osmo phobia may be useful in differentiating migraine without auras from episodic tension type head ache, 8,13,14 although the sensitivity of such differenti ation ranges from 23% to 86% and specificity 69% to 94%. 9,12,14–17 One longitudinal prospective study found osmophobia to be an important predictor of migraine development in children initially classified as having tension type headache. 18 The odors most frequently noted as triggers of the crisis were per fumes, cigarette smoke, motor vehicle exhaust, and, to a lesser extent, cleaning products and some foods. 7,11,19 The prevalence of osmophobia in migraineurs has been reported to be relatively high, although its relationship with other olfactory symptoms is rarely assessed and considerable variation in the reported frequencies is present. 7–9,11,20–23 This reflects, in part, the fact that patients often fail to report symp toms unless directly asked about them. 20,21 Howev er, even in studies in which specific questioning occurs, considerable variation exists in the reported frequency of such symptoms. 9,10 For example, Saisu et al 6 found osmophobia to be present in 63% of 80 migraineurs. In those cases with auras, the prev alence of osmophobia was significantly higher than in those without auras (71% vs 57%; P < .05). In contrast, Zanchin et al 9 noted, in a study of 707 migraineurs, that 43% reported experiencing osmo phobia, of which 38.5% of those with auras and 43.9% of those without auras, reported osmophobia

Conflict of Interest : None.

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Olfactory symptoms

a. Do you feel any odor that does not exist right before the beginning of your headache crisis? (OLFACTORY HALLUCINATION)

1 – YES

2 – NO

b. Which one? (subjective question)

a. Do you have hypersensitivity to any odor in the period between the crisis?(IOH)

1 – YES

2 – NO

b. Which one? (subjective question)

3 a. Do you have any odor aversion during the headache crisis? In other words, headache worsens when you feel that odor? (OSMOPHOBIA)

1 – YES

2 – NO

b. Which one? (subjective question)

a. Is there any odor which can start your migraine attack? (ODOR TRIGGER)

1 – YES

2 – NO

b. Which one? (subjective question)

Fig. 1.—Main questions of olfactory symptoms questionnaire regarding olfactory hallucination, interictal olfactory hypersensi tivity, osmophobia, and odor triggers.

and interictal hypersensitivity, as well as to the nature of odors that trigger the migraine. A list of presumed triggering odors was provided in the ques tionnaire to help the patient to identify which, if any, may be involved. The main questions are repre sented in Figure 1. Phantosmia was considered a sensation of an odor or odors in the absence of a stimulus not directly related to headache onset (ie, odor percep tion without a subsequent headache). In contrast, an olfactory hallucination was characterized as the perception of an odor 5–60 minutes before head ache onset (ie, as a kind of aura phenomenon). The perception of an unpleasant fecal-like odor differ ent from normal was considered cacosmia and euosmia was defined as a pleasurable distortion of a real odorous stimulation (eg, like a perfume). The patient assessed his or her olfactory ability during the interictal period using a visual analog scale (VAS) with 0% defining one extreme of absence of olfactory sensation and 100% defining the other extreme of having normal olfactory function. Based on these responses, four categories of olfactory func tion were formed: (1) 0–25%; (2) 26–50%; (3) 51– 75%; and (4) 76–100%. The VAS method has been shown to correlate moderately with psychophysical

routine visits of medical primary care and volun teers, in the period from January to August 2014, who met the ICHD-II criteria for episodic migraine 29 (27 men and 86 women; respective mean (SD) ages 5 28.7 ( 6 8.2) and 34.3 [ 6 11.8]). The sample size was based on previous experience and other studies. Exclusion criteria included a previous history of olfactory disorders due to neuropsychiat ric disease (except depression), head trauma, rhino sinusitis diagnosed by a physician, and neurological disease (eg, Parkinson’s, Alzheimer’s, epilepsy, stroke, brain tumors, and palsy of arms or legs). No physical examination was performed. All patients provided written informed consent and the study was approved by the local ethics committee of State University of Londrina, no 402.435. There was no external funding source. Questionnaire for Quantitative and Qualitative Olfactory Assessment.— A team of five trained research specialists administered a 65-item question naire to the subjects. This questionnaire contained specific olfaction-related questions designed to char acterize the olfactory symptoms of migraineurs with and without auras. Included were questions related to phantosmia, olfactory hallucinations, cacosmia/ euosmia, self-related olfactory ability, osmophobia,

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Table 1.—Demographics of the Study Group, Clinical Features of migraine, and Comparison of Olfactory Symptoms Between MA (Migraine With Aura) and MwA (Migraine Without Aura)

Group Without Aura, N (%) (n 5 56)

Group withAura, N (%) (n 5 57)

NTotal (%) (n 5 113)

Variable

Category

P -Value

Gender

Men

27 (23) 86 (77)

13 (48) 43 (76)

14 (51) 43 (75)

.87

Women

Age (years 6 SD)

32.5 6 11.0

33.4 6 11.7

Nausea

104 (92) 105 (93)

50 (89) 53 (94)

54 (94) 52 (91) 52 (91) 40 (70) 54 (94) 51 (89) 8 (14)

.32

Photophobia/phonophobia

Visual aura

Sensitive aura Osmophobia

108 (95) 102 (90) 16 (14)

54 (96) 51 (91) 8 (14)

.5 .7

Crisis triggered by odors

Interictal olfactory hypersensitivity

1.0

Olfactory hallucination

7 (6) 5 (4) 3 (2)

2 (3) 2 (3) 2 (3)

5 (8) 3 (5) 1 (1)

Phantosmia

1.0

Cacosmia/euosmia

Chi-square, Fisher’s exact, and Student’s t -tests used.

olfactory tests. 30,31 The determination of osmophobia was based on the question, “Do you have any odor aversion during the headache crisis?” IOH was addressed by the question, “Do you have hypersen sitivity to any odor in the period between crisis?” Statistical Analysis.— Stata 10.1 software was used for all statistical analysis. Continuous varia bles, such as age, number of crisis per year, rated olfactory acuity, and total numbers of olfactory symptoms, were expressed as means 6 standard deviations (SD). t -tests were used to compare the means of the migraineurs with and without auras. Categorical variables such as olfactory symptoms (osmophobia, IOH, phantosmia, olfactory hallucina tion, cacosmia/euosmia, groups of self-reported olfactory acuity, and olfactory triggers of the crisis), types of triggers, nausea, and photo/phonophobia were expressed in percentages and their frequencies compared using chi-square analyses, and Fisher’s exact test was applied when needed. A two tailed P value was used, and the cutoff statistical signifi cance was P < .05. RESULTS The demographics and presence of the sensory phenomena for the migraineurs with and without

aura are presented in Table 1. Age and gender did not differ significantly between the two groups. Visual aura was the most prevalent type of aura, present in 91% of the MA (migraine with aura) patients. Osmophobia was the main olfactory symptom, being reported by 95% of all migraineurs. No sta tistical significant difference in the frequency of osmophobia was found between patients with and without auras (Table 1). Those experiencing this symptom reported it to be present in 88% of the headache crisis they experienced. Osmophobia commonly followed odor-triggered crisis (90%). This was not the case for IOH (14%), olfactory hal lucinations (6%), phantosmia (4%), and cacosmia/ euosmia experiences (2%). Olfactory symptoms did not differ among men and women. Moreover, self reported olfactory acuity, as measured by the VAS, was similar in patients with and without auras. The number and type of total olfactory symptoms also did not differ between these two groups ( P > .05). Interestingly, 73% of patients who experienced osmophobia and 75% of those odor triggered head aches reported having 51–75% (group 3) of olfactory acuity according to their VAS ratings, representing therefore most cases, leaving only 27% and 25%,

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Table 2.—Relationship Between Interictal Olfactory Hypersensitivity (IOH) and Other Olfactory Symptoms

0 10 20 30 40 50 60 70 80 90 100

n total MwA MA

No IOH [n (%)] (n 5 97)

IOH [n (%)] (n 5 16)

Olfactory Symptom

P -Value

Osmophobia

96 (98) 91 (93)

12 (75) 11 (68) 3 (18) 4 (25) 3 (18)

.002 .001 .058 .001 .002

Crisis triggered by odors Olfactory hallucinations

4 (4) 1 (1)

Phantosmia

Perfume* Cleaning product

Cigarret Car smoke Rubber Leather Coffee Fish

Cacosmia/euosmia

most highly cited trigger (81%), followed by cigarette smoke (71%), and car smoke (70%). The odors cited as causes of osmophobia were similar. Thus, osmo phobia was most commonly attributed to perfume (88%), followed by cleaning products (70%), ciga rette smoke (68%), and automobile exhaust (62%). The frequency of crisis ( < 10/year; 11–20/year, > 20/year) was not related to the percent of subjects experiencing osmophobia ( P 5 .33). Patients with 1–10 crisis per year did have a higher prevalence of phantosmia than those who have more than 10 cri sis per year ( P 5 .01). Subjects who did not have IOH had higher rates of osmophobia ( P 5 .002) and crisis triggered by odors ( P 5 .001) than those who did have IOH. Subjects with IOH had higher rates of phantosmia ( P 5 .001) and cacosmia/euos mia ( P 5 .002) than those without IOH (Table 2). DISCUSSION The present study is the most definitive study, to date, in characterizing the olfaction-related symptoms experienced by migraineurs. Importantly, it sought to determine differences between such symptoms of migraine patients with and without auras. 6,10 Although our questionnaire of olfactory symptoms has not been previously validated, which is a limitation of this study, their items were based on symptoms and questions from other surveys exploiting the topic. 6,8,14,23 Osmophobia was found in 95% of the subjects, the highest prevalence rate Fig. 3.—Main odorants triggering crisis in migraineurs with auras (MA) and migraineurs without auras (MwA) (n total 5 total number of patients). Chi-square and Fisher’s exact tests, * P < .05.

Chi-square and Fisher’s exact tests used.

respectively, for the other groups of olfactory acuity ( P < .05). As shown in Figure 2, the main trigger of crisis was stress (96%), followed by odors (90%). Howev er, 97% of the subjects who reported that odors triggered their headaches also reported that stress did so as well. Food as a trigger of headache was more frequent in subjects who also reported odors as an initial cause of their headaches ( P 5 .01). Physical exercise was less common trigger of migraine, although it was more prevalent in the group with auras ( P 5 .01). Odors that triggered the crisis are listed in Figure 3. Perfume was the most frequent trigger (95%), with a higher prevalence in the group without auras ( P 5 .02). Cleaning products were the second

Fig. 2.—Percentage of main crisis triggers among migrai neurs with aura (MA) and migraineurs without auras (MwA) (n total 5 total number of patients). Chi-square and Fisher’s exact tests, * P 5 .01.

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reality, more than one trigger can be involved, although complexities abound. For example, migrai neurs who experience auras tend to be more likely to experience a migraine attack after physical activ ity, although compared to olfactory and stress trig gers, only a small proportion of migraine patients without auras have a crisis after such activity. 35 The main odorant that triggered the migraine cri sis of our sample was perfume, a phenomenon reported by others. 6,19,36 We also demonstrated that patients without auras had a higher probability of having perfume as a trigger than those with auras ( P 5 .02). Lima et al 11 have found the same three main odors that we found as being capable of trigger ing a migraine crisis, namely, perfume, cigarette smoke, and cleaning products. Since the odors that trigger the crisis and cause osmophobia are the same, common neurological pathways may well be involved. Other research reported that patients with epi sodic migraine have similar olfactory function as age and sex-matched controls in interictal periods, but a minority exhibited microsmia (lower scores on the University of Pennsylvania Smell Identification Test) during acute attacks. 23 In our study, migraineurs reported having less olfactory acuity using a VAS, dur ing interictal periods, which contrasts to Marmura et al 23 findings. Moreover, there was no difference in self-reported olfactory acuity between the patients with and without auras, although patients who experi enced osmophobia and odor-triggered migraine attacks consistently reported having less olfactory function than migraineurs who did not experience these symp toms. However, it is important to emphasize that we did not use any olfactory test besides the VAS. Phantosmia, considered to be a sensation of odors in the absence of a stimulus, was a rare olfac tory symptom in this study. Interestingly, it was positively related to subjects who have less than 10 crises of migraine per year ( P 5 .01) and subjects with IOH ( P 5 .001). In that context, we character ized olfactory hallucination as an experience of a smell that does not exist right before the crisis, ie, as a kind of aura, as noted by some authors. 28,37 The few migraineurs who experienced an olfactory hallucination found the odor sensation to have a burning and/or putrid-like character.

reported to date. This suggests that osmophobia is as frequent as photophobia and phonophobia in this disease and should be considered as one of its defining features. The lower prevalence rates reported in other studies, which range from 43% 9 to 81.7%, 10 may reflect the fact that, in many cases, different types of populations (eg, only females) 10 or smaller numbers of subjects 9 were studied. Our research confirms the findings of other studies that osmophobia is not specifically related to whether a patient experiences auras or not. 6,9,25 Other olfaction-related symptoms were some what less frequently observed in this study. Among them, our finding of a 14% prevalence rate for IOH is considerably lower than the prevalence rate of 35.2% reported by Demarquay et al 22 for migrain eurs. This investigator found a positive association between odor-induced headaches and IOH patients. In his analysis, those who had IOH also had high rates of odor-induced headaches. Paradoxically, we found the opposite: 93% of no IOH subjects had odor-triggered migraine, while 68% of IOH subjects had odor triggered migraine ( P 5 .002). Moreover, we found that patients with no IOH are more likely to experience osmophobia ( P 5 .002). The basis for this stark discrepancy is not clear, although the ques tions used in our questionnaire were different from those used by Demarquay et al. 22 They asked wheth er the patients regarded themselves as clearly hyper sensitive to odors between attacks and these data were completed using a previously validated chemi cal odor intolerance index. Our findings, along with those of others, clearly demonstrate that odors, like stress, 7,11,32,33 can be a very prevalent trigger of migraine. 11,32 Chakra varty 34 hypothesized that every migraine crisis has a trigger, internal or external, identifiable or not. According to his thinking, triggers induce cortical spreading depression in a hyper-excitable cortex of a migraineurs, beginning the pain process. In our study, 97% of the patients who had stress as a trig ger also had odor as a trigger, suggesting that these two triggers may be related. Interestingly, migrai neurs who have odor as a trigger were also found to have food as a trigger ( P 5 .01), conceivably reflecting the odorous elements of foodstuffs. In

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(c) Analysis and Interpretation of Data Marco Aur elio Fornazieri, Anibal Rodrigues Neto, Fabio de Rezende Pinna, Fabio H.G. Por to, Richard Louis Voegels Category 2 (a) Drafting the Manuscript Marco Aur elio Fornazieri, Anibal Rodrigues Neto, Fabio H.G. Porto, Richard L. Doty (b) Revising It for Intellectual Content Marco Aur elio Fornazieri, Paulo de Lima Nav arro, Richard L. Doty Category 3 (a) Final Approval of the Completed Manuscript MarcoAur elio Fornazieri, Richard L. Doty REFERENCES 1. Jurgens TP, Schulte LH, May A. Migraine trait symptoms in migraine with and without aura. Neu rology. 2014;82:1416-1424. 2. Charles A, Brennan KC. The neurobiology of migraine. Handb Clin Neurol. 2010;97:99-108. 3. Yang W, Chu B, Yang J, Yu Y, Wu J, Yu S. Ele vated audiovisual temporal interaction in patients with migraine without aura. J Headache Pain. 2014;15:44. 4. Harriott AM, Schwedt TJ. Migraine is associated with altered processing of sensory stimuli. Curr Pain Headache Rep. 2014;18:458. 5. Leonardi M, Raggi A. Burden of migraine: Inter national perspectives. Neurol Sci. 2013;34(Suppl. 1): S117-S118. 6. Saisu A, Tatsumoto M, Hoshiyama E, Aiba S, Hirata K. Evaluation of olfaction in patients with migraine using an odour stick identification test. Cephalalgia. 2011;31:1023-1028. 7. Mollao glu M. Trigger factors in migraine patients. J Health Psychol. 2013;18:984-994. 8. Corletto E, Dal Zotto L, Resos A, et al. Osmo phobia in juvenile primary headaches. Cephalalgia. 2008;28:825-831. 9. Zanchin G, Dainese F, Trucco M, Mainardi F, Mampreso E, Maggioni F. Osmophobia in migraine and tension-type headache and its clinical features in patients with migraine. Cephalalgia. 2007;27:1061-1068.

The present data strongly suggest that a range of olfactory symptoms are present in migraine headache patients (eg, osmophobia, triggers of headache, olfac tory hallucinations, and olfactory acuity). Although there was no difference between migraineurs with and without auras, this does not exclude the impor tance of such symptoms in migraine attacks, even though such symptoms cannot be used to differenti ate between patients with and without auras. Given the fact that migraine attacks are often related to seizures 29 and can be a risk factor for stroke and oth er serious conditions, 38 it is incumbent upon the phy sician to inform patients about the fact that exposure to certain odors may trigger migraine crisis. CONCLUSION The present study demonstrates that migraineurs experience a wide range of symptoms associated with olfaction. In general, such symptoms do not dif fer among migraineurs with and without auras, being prevalent in both groups. Osmophobia had a 95% prevalence rate. Other olfactory symptoms, although less prevalent, include olfactory hallucinations, cacosmia/euosmia, and phantosmias. The latter two were clearly related to IOH. A major finding of our study is that patients whose headaches are triggered by odors are also patients whose headaches are trig gered by foods. This suggests that the odorous ele ments of food may be involved in such triggering. Common odors, such as perfume, were more likely to trigger crisis without aura than crisis with aura. In such cases, migraine episodes could be prevented by either avoiding odors that trigger an episode or by recognizing the episode of olfactory hallucination (aura) at the beginning of the crisis.

STATEMENT OF AUTHORSHIP

Category 1 (a) Conception and Design

Marco Aur elio Fornazieri, Anibal Rodrigues Neto, Paulo de Lima Navarro, Richard Louis Voegels (b) Acquisition of Data Marco Aur elio Fornazieri, Anibal Rodrigues Neto, Fabio de Rezende Pinna

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10. Sj € ostrand C, Savic I, Laudon-Meyer E, Hillert L, Lodin K, Waldenlind E. Migraine and olfactory stimuli. Curr Pain Headache Rep. 2010;14:244-251. 11. Lima AM, Sapienza GB, Giraud VO, Fragoso YD. Odors as triggering and worsening factors for migraine in men. Arq Neuropsiquiatr. 2011;69: 324-327. 12. Kelman L. The place of osmophobia and taste abnormalities in migraine classification: A tertiary care study of 1237 patients. Cephalalgia. 2004;24: 940-946. 13. Silva-N eto RP, Rodrigues ^ A, Cavalcante DC, et al. May headache triggered by odors be regarded as a differentiating factor between migraine and other primary headaches? Cephalalgia. 2016: doi: 10.1177/ 0333102416636098. 14. Silva-N eto RP, Peres MF, Valenc¸a MM. Accuracy of osmophobia in the differential diagnosis between migraine and tension-type headache. J Neurol Sci. 2014;339:118-122. 15. Kelman L. Validation of the classification of migraine without aura (IHS A1.1) proposed in ICHD-2. Headache. 2005;45:1339-1344. 16. Wang YF, Fuh JL, Chen SP, Wu JC, Wang SJ. Clinical correlates and diagnostic utility of osmo phobia in migraine. Cephalalgia. 2012;32:1180-1188. 17. Rocha-Filho PA, Marques KS, Torres RC, Leal KN. Osmophobia and headaches in primary care: Prevalence, associated factors, and importance in diagnosing migraine. Headache. 2015;55:840-845. 18. De Carlo D, Toldo I, Dal Zotto L, et al. Osmo phobia as an early marker of migraine: A follow up study in juvenile patients. Cephalalgia. 2012;32: 401-406. 19. Silva-N eto RP, Peres MF, Valenc¸a MM. Odorant substances that trigger headaches in migraine patients. Cephalalgia. 2014;34:14-21. 20. Haehner A, Hummel T, Reichmann H. Olfactory loss in Parkinson’s disease. Parkinsons Dis. 2011; 2011:450939. 21. Muller A, Reichmann H, Livermore A, Hummel T. Olfactory function in idiopathic Parkinson’s dis ease (IPD): Results from cross-sectional studies in IPD patients and long-term follow-up of de-novo IPD patients. J Neural Transm. 2002;109:805-811. 22. Demarquay G, Royet JP, Giraud P, Chazot G, Valade D, Ryvlin P. Rating of olfactory judge ments in migraine patients. Cephalalgia. 2006;26: 1123-1130.

23. Marmura MJ, Monteith TS, Anjum W, Doty RL, Hegarty SE, Keith SW. Olfactory function in migraine both during and between attacks. Cephal algia. 2014;34:977–985. 24. Rocha-Filho PA, Sobral Marques K, Santos Torres RC, Ribas Leal KN. Migraine, osmopho bia, and anxiety. PainMed. 2016;17:776-780. 25. Baldacci F, Lucchesi C, Ulivi M, Cafalli M, Vedovello M, Vergallo A, etet al. Clinical features associated with ictal osmophobia in migraine. Neu rol Sci. 2015;36:43–46. 26. Demarquay G, Royet JP, Mick G, Ryvlin P. Olfactory hypersensitivity in migraineurs: A H(2)(15)O-PET study. Cephalalgia. 2008;28:1069 1080. 27. Demarquay G, Cr eac’h C, Peyron R. Olfactory hallucinations in primary headache disorders: Case series and literature review. A comment. Cephalal gia. 2012;32:583-584. 28. Ahmed MA, Donaldson S, Akor S, Cahill F, Akilani R. Olfactory hallucination in childhood primary headaches: Case series. Cephalalgia . 2015; 35:234–239. 29. The International Classification of Headache Dis orders: 2nd edition. Cephalalgia . 2004;24(Suppl. 1): 9-160. 30. Nguyen DT, Nguyen-Thi PL, Jankowski R. How does measured olfactory function correlate with self-ratings of the sense of smell in patients with nasal polyposis? Laryngoscope. 2012;122:947-952. 31. Welge-Luessen A, Hummel T, Stojan T, Wolfensberger M. What is the correlation between ratings and measures of olfactory function in patients with olfactory loss? Am J Rhinol. 2005;19: 567-571. 32. Hauge AW, Kirchmann M, Olesen J. Characteri zation of consistent triggers of migraine with aura. Cephalalgia. 2011;31:416-438. 33. Lipton RB, Buse DC, Hall CB, et al. Reduction in perceived stress as a migraine trigger: Testing the “let-down headache” hypothesis. Neurology. 2014; 82:1395-1401. 34. Chakravarty A. How triggers trigger acute migraine attacks: A hypothesis. Med Hypotheses. 2010;74:750-753. 35. Hougaard A, Amin FM, Hauge AW, Ashina M, Olesen J. Provocation of migraine with aura using natural trigger factors. Neurology. 2013;80:428 431.

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36. Hirsch AR. Osmophobia and taste abnormality in migraineurs: A tertiary care study. Headache. 2005;45:763-764. 37. Coleman ER, Grosberg BM, Robbins MS. Olfac tory hallucinations in primary headache disorders:

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Acta Oto-Laryngologica, 2012; 132: S27 – S31

REVIEW ARTICLE

Distorted olfactory perception: A systematic review

SEOK-CHAN HONG 1 , ERIC H. HOLBROOK 2 , DONALD A. LEOPOLD 3 & THOMAS HUMMEL 4

1 Department of Otorhinolaryngology, Konkuk University Hospital, Seoul, Korea, 2 Department of Otolaryngology, Massachusetts Eye and Ear In fi rmary, Harvard Medical School, Boston, MA, USA, 3 Department of Otolaryngology-Head and Neck Surgery, University of Nebraska Medical Center, Omaha, NE, USA and 4 Department of Otorhinolaryngology, University of Dresden Medical School, Dresden, Germany

Abstract The sense of smell provides people with valuable input from the chemical environment around them. The human sense of smell generally fails in three ways; one is an intensity reduction and the other two are the quality of changes. Smell disorders can be classi fi ed into central or peripheral depending on their origin. Central causes can be related to an area of hyper functioning brain cells generating this odor perception, thus olfactory distortions have also been observed with epilepsy and migraine. In this paper, we present a review of the current clinical understanding of olfactory distortions and discuss how they can be evaluated and therapies to treat this debilitating condition. Keywords: Olfactory nerve diseases, olfaction disorders, smell

Introduction

repeatedly being reminded of the problem. This can cause deleterious effects on fl avor and quality of life, resulting in weight loss and nutritional problems. In the analysis of a series of 56 patients with parosmia, 31 patients (55.4%) viewed their olfactory alteration as severely affecting their quality of life [2]. The terms used to describe olfactory distortions have been confusing in the past, but generally the following terms are now used. ‘ Dysosmia ’ canbeused to describe any reduction or distortion of the sense of smell. ‘ Phantosmia ’ (lasting longer than a few seconds) and ‘ olfactory hallucination ’ (lasting only a few seconds) describe the perceived distortion (usu ally unpleasant) when there is no odorant stimulus present. ‘ Cacosmia ’ is the perception of a bad smell with or without an odorant stimulus. ‘ Euosmia ’ has been described as a pleasant parosmia to selected odorants [3]. Both ‘ cacosmia ’ and ‘ euosmia ’ can be summarized under the term ‘ parosmia. ’ Smell distortions can be classi fi ed into central or peripheral depending on their respective origins.

The sense of smell provides people with valuable input from the chemical environment around them. When this input is distorted, disability and decreased quality of life are reported [1]. The purpose of this paper is to present a review of the current clinical understanding of olfactory distortions, how they can be evaluated, and therapies to treat this debilitating condition. The human sense of smell generally fails in one of three ways. One is an intensity reduction resulting in decreased olfactory sensitivity (hyposmia or anosmia). The other two are quality changes with a distortion of the perceived odor. One type of distortion occurs when inhaled odorants do not have the same smell or odor as remembered (parosmia). The other type of distortion is the perception of an odor (usually unpleasant) when there is no odorant in the environ ment (phantosmia, hallucination). These distortions are usually much more disruptive to a person ’ s life than a simple loss, because those who are affected are

Correspondence: Seok-Chan Hong MD, Department of Otorhinolaryngology, Konkuk University Hospital, Hwayang-dong, Gwangjin-gu, Seoul, 4-12, Korea. Tel: +82 10 4250 9875. Fax: +82 2 2030 5299. E-mail: 20050692@kuh.ac.kr

(Received 11 October 2011; accepted 17 January 2012) ISSN 0001-6489 print/ISSN 1651-2251 online 2012 Informa Healthcare DOI: 10.3109/00016489.2012.659759

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Abnormalities in axonal targeting from regenera ting axons after injury may also explain olfactory distortions. In animal experiments, alterations in sensory perception after recovery from nerve transec tion are observed, and restoration of odor quality discrimination requires that the animal must again learn to associate individual odor sensations with a behavioral response [10]. This suggests that the origi nal olfactory map changes after signi fi cant injury, which then needs to be relearned in these animals. Support for this theory is observed using a mono clonal antibody to OCAM/mamFas (olfactory cell adhesion molecules/mammalian homolog of fasciclin II) that demonstrates a speci fi c reproducible pattern of staining of the olfactory neurons within the epithelium as well as their projections to the olfactory bulb. The terminal projections in the bulb after tran section contrasted with the restoration of the normal zonal patterning of the projection after recovery from methyl bromide lesion, but were consistent with reports of mistargeting by a receptor-de fi ned subset of neurons after transection [11]. While obtaining a clinical history from someone with a complaint of olfactory distortion it is important to be sympathetic, since many of these individuals are anxi ous about their symptoms. The fi rst determination should be whether the distortion is real or a product of the environment. Questions relating to time and place of phantosmia occurrence revealing a repetitive pattern can help recognize an environmental source for the abnormal smell. A medical history pointing to recent acute or chronic rhinosinusitis can identify infection as a possible cause. Next, the clinician should attempt to establish the distortion as centrally or peripherally related. A history of seizure disorder, migraine symptoms, psychiatric/neurologic disorders, or cognitive dysfunction favors a central cause. Peripheral causes of distortions are commonly expe rienced with a perception of hyposmia and/or dimini shed fl avor. According to the analysis of a series of 56 patients with parosmia, all patients noted quantitative olfactory dysfunction. Hyposmia was found in 40 patients (71.4%) and 16 patients (28.6%) were con fi rmed to have anosmia [2]. These patients can sometimes identify one side for the distortion and may report alleviating the abnormal smell with unilateral occlusion. They often report the lack of distortion on awakening in the middle of the night or fi rst thing in the morning. Forced crying is often reported to temporarily alleviate symptoms [12]. Clinical evaluation History

Central causes can be related to an area of hyper-functioning brain cells generating this odor perception [4]. It is known that an olfactory aura can sometimes accompany seizures. This typically lasts only a few seconds. Some individuals with phantosmias have commented that they can feel a phantom odor coming before it actually arrives. Psychiatric etiologies for olfactory distortion can exist with schizophrenia, depression, alcoholic psychosis, and olfactory reference syndrome [5]. Olfactory distortions have also been observed with epilepsy and migraine. Are there different types of parosmias? Most parosmias appear in relation with olfactory loss, often after upper respiratory tract infection (URTI); the majority of them disappear within 1 year. A small minority of parosmias is idiopathic, associated with normosmia, and can often vary with head movements, Valsalva maneuver, etc. This second form has a poor prognosis, and may even become worse over time. A peripheral etiology for distorted smells is sug gested by the fi nding that many of the individuals without a central cause have hyposmia or anosmia associated with the distortion and often the degree of loss is asymmetric. Phantosmia is almost always worse in the nostril with the least olfactory ability and those phantosmias that occur in only one nostril can be eliminated by occluding the air fl ow or anesthetizing the olfactory mucosa in that nostril. Patients thought to have a peripheral cause for distortions will also say that the abnormality was worse while the loss was occurring, suchasthe fi rst few hours after head trauma or an URTI loss. Support for peripheral causes also comes from imaging studies performed after treatment. Brain imaging using PET scans of individuals with phantos mia has revealed increased activity in the contralateral frontal, insular, and temporal regions, which decreased after excision of the olfactory epithelium from the nasal cavity involved [4]. In addition, structural MRI indi cates that hyposmic patients with parosmia exhibit smaller olfactory bulb volumes compared with hypos mic patients without parosmia [6,7]. Here it has been hypothesized that a decreased number of interneurons in the olfactory bulb might result in a decrease of neuronal inhibition that might be the cause for ‘ aberrant ’ odorous sensations. One common hypothesis to explain peripheral causes for distortions is that ‘ rogue ’ neurons that emit abnormal signals to the brain or loss of inhibitory cells to normally functioning olfactory neurons could be playing a role [8,9]. The olfactory histopathology of individuals with phantosmia shows a decreased number of neurons, a greater ratio of immature to mature neurons, and distorted growth of olfactory axons with intraepithelial and submucosal neuromas [8,9].

Olfactory distortion

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importantly, whether the sensation persists or not. If it persists, it would be called a phantosmia. If it goes away, it would be called parosmia. Nasal endoscopy is indicated to examine the olfactory pathways in the nose and rule out a sinus infection or fungal myce toma. The olfactory cleft should be examined for signs of edema and purulent discharge. If the distortion is unilateral, application of an anesthetic to the same nostril resulting in resolution of the abnormal odor perception suggests a peripheral cause. Olfactory testing is a useful tool in identifying a peripheral cause for olfactory distortions. The evalu ation should include unilateral olfactory assessment with available standardized identi fi cation and/or threshold tests. Identifying a signi fi cant de fi cit in one side over the other can indicate that the nasal cavity is responsible for triggering the distortion. This not only helps to con fi rm a peripheral cause for the disorder, but also directs the physician to concentrate therapy on one side only, allowing for preservation of function on the contralateral side. According to recent research, the human olfactory bulb is a highly plastic structure that responds to individual changes in olfactory status [21]. Olfactory bulb volume decreases with the duration of the olfac tory loss. Patients with parosmia following infections or head trauma presented with signi fi cantly smaller olfactory bulbs than patients without parosmia [6,7]. In patients with post-traumatic loss of smell, the presence of parosmia was clearly associated with the presence of cerebral damage, especially in the fronto-orbital and anterior temporal cortices [22]. With a clear etiology by history and a negative exami nation such as with URTI, imaging may not be necessary. However, history or physical examination often guides the choice of imaging, which may con fi rm the suspicion. Imaging of the brain and nasal cavity is necessary to rule out tumors, infections, and obstructions. This can be done with contrast enhanced axial and coronal computed tomography (CT) scans or magnetic resonance imaging (MRI) scans. Especially in patients with distortions of no clear cause, the authors recommend MRI to rule out central mass lesions or neurodegenerative disorders. Olfactory testing Imaging

Antecedent events that precede the olfactory distor tion, especially parosmia, have been described in the literature to include URTI, head trauma, allergic rhini tis, and chronic rhinosinusitis [13-16]. According to the analysis of a series of 56 patients with parosmia [7], quantitative and qualitative alterations occurred simul taneously in 32 patients (57.1%). Parosmia onset occurred within 3 months after quantitative olfactory dysfunction in 19 patients (33.9%) and after 3 months in 5 patients (8.9%). In all patients, the sensation of par osmia was unpleasant and was typically described as a ‘ foul, ’ ‘ rotten, ’ ‘ sewage, ’ or ‘ burn ’ smell. Patients reported phantosmia (10 patients, 17.9%) or stimulant-identi fi able parosmia (46 patients, 82.1%). In these patients, the main odorant stimuli eliciting parosmia were gasoline (30.4%), tobacco (28.3%), cof fee (28.3%), perfumes (21.7%), fruits (15.2%, mainly citrus fruits and melon), and chocolate (13%). All the complaints concerned olfactory alterations alone (4 patients, 7.1%) or in combination with fl avor dys function (49 patients, 87.5%). The most common eti ologyofparosmiawasURTI(24patients,42.8%).Other possible etiologies were nasal andparanasal sinus disease (8 patients), toxic chemical exposure (4 patients), neurological abnormalities (3 patients), head trauma (2 patients), nasal surgery (2 patients), aging (1 patient), and idiopathic causes (12 patients) [7]. In contrast to this, most phantosmias present with no history of URTI, head trauma or aging [17]. Parosmias are most often observed as a consequence of infections of the upper respiratory tract, which typically lead also to olfactory loss [18]. Quanti fi cation of parosmias/phantosmias is dif fi cult. One idea relates to a separation of four grades of parosmia/phantosmia (0 – IV): do the distortions appear daily, are they intense, and do they have social/ other subsequences (e.g. weight loss, depression) [19]. Another idea relates to answers to two question 1: Because of my olfactory problem, food tastes different than itshouldtaste, and question 4:The biggest problem is not that I do not or weakly perceive odors, but that they smell different than they should [20]. To evaluate the patients with olfactory distortions, a thorough physical examination is needed. The patient ’ s general demeanor and psychiatric health should be assessed. A standard head and neck exam ination should be performed, paying special attention to the olfactory cleft, nasal mucosa, and airways. A dental examination should be included for the oral diseases that may produce a foul odor, and detailed cranial nerve examination is also important. Unilateral and bilateral nasal occlusion can be done to assess asymmetry in the distorted perception and, Physical examination

Laboratory testing

There is currently no battery of laboratory tests recommended for smell disorders. If a metabolic disorder is suspected, the patient should be referred

S.-C. Hong et al.

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indications for this endoscopic approach include severe, debilitating unilateral phantosmia that has been present for more than 2 years and can be eliminated with intranasal cocaine anesthesia of the ipsilateral olfactory mucosa. According to Leopold et al. [9], 10 patients underwent an excision of the olfactory epithelium as an endoscopic intranasal approach and 8 patients responded af fi rmatively to the long-term follow-up questionnaire. Two cerebro spinal fl uid (CSF) leaks were noted intraoperatively and these were patched successfully with mucoper iosteal grafts. Because of the related potential serious complications of CSF leak and meningitis, alternative forms of lesioning the epithelium through cauteriza tion techniques are being explored. One needs to spend a considerable amount of time evaluating and counseling patients with olfactory dis tortions. The rare patient who is plagued by these symptoms should be evaluated in a center where expert care can be given and where the most can be learned about this debilitating problem by collect ing information from many patients with the same condition. Since the symptoms usually dissipate over time, conservative management should be exhausted before considering surgical options. There are still many things to learn about olfactory distortion and further research is needed. Further knowledge of olfactory pathophysiology concerning the underlying mechanisms behind the most common forms of olfactory disorders is lacking. With advances in the science of olfaction we hope to discover new treatment strategies to recover smell loss and allow for proper regeneration of olfactory neurons after dam age. Until then, we as physicians need to do our best to counsel these patients and help them manage their occasionally debilitating symptoms. Conclusion

for speci fi c testing. One of our authors (D.A.L.) experienced a patient who had perceived an unpleas ant odor or taste for at least 20 years and was found to have a trimethylaminuria or fi sh-odor syndrome [23].

Treatment of olfactory distortion

Individuals with olfactory distortion need to be reas sured that they do not have a malignant disease or an infection. Most patients will note a gradual decrease in the symptom with time, and this can occur over several years [14,18]. Thus, ‘ watchful waiting ’ is an appropriate course to take. If seizures, migraines, psychiatric diseases or metabolic disturbances are suspected, appropriate referral is needed. If olfactory distortion can be blocked with nasal occlusion, one of the easiest things to try is topical nasal saline drops. These can be placed in limitless quantity every few hours in the head-down-and forward ( ‘ Mecca ’ ) position. Several medications, including sedatives, antide pressants, and anti-epileptic drugs, have been sug gested to treat olfactory distortions [17]. Currently, gabapentin (Neurontin ) is being used by several olfactory centers, although it lacks scienti fi c data supporting its ef fi cacy. Any medications that induce distortions of olfac tion should be identi fi ed and can often be disconti nued and replaced with other types of medications or modes of therapy [24]. Active pharmacologic disruption of the olfactory neurons has been proposed by Zilstorff [17]. The use of topical cocaine HCl will temporarily block most distortions by anesthetizing the neurons. The drug is applied as a drop into the nostril when the neck is fully extended while the patient is supine. Care must be exercised when using it, because undesired effects can occur, and extensive informed consent must be obtained from the patient before its use. In smell dysfunction following viral infection of the upper respiratory tract, alpha-lipoic acid was used orally at a dose of 600 mg/day for an average period of 4.5 months. At the end of treatment parosmias were less frequent (22%) than at the beginning of therapy (48%) [25]. Those who cannot be helped with the medical treatment may bene fi t from surgical therapies. Neurosurgical approaches using a bifrontal craniot omy to remove the olfactory bulbs or nerves have been reported [26,27]. These procedures necessarily result in bilateral permanent anosmia and include the risks and morbidity associated with a craniotomy. To treat a patient ’ s phantosmia and avoid a craniotomy, an excision of the olfactory epithelium as an endoscopic intranasal procedure has been performed [8]. The

Acknowledgment

This work was supported by the Konkuk University.

Declaration of interest: The authors report no con fl icts of interest. The authors alone are responsible for the content and writing of the paper.

References

[1] 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. [2] Bon fi ls P, Avan P, Faulcon P, Malinvaud D. Distorted odorant perception: analysis of a series of 56 patients with

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