Osmophobia as an early marker of migraine: A follow-up study in juvenile patients

Abstract

Background: Osmophobia is frequent in children with migraine (20–35%) but can also occur in up to 14% of cases with tension-type headache (TTH). So far, the prognostic role of this symptom in children with primary headaches has never been evaluated.

Methods: A longitudinal prospective study was conducted on 90 young patients with TTH (37 with osmophobia, 53 without osmophobia). We evaluated whether osmophobia could predict the diagnosis transformation from TTH to migraine after a 3-year follow-up.

Results and Discussion: In our cases the rate of diagnosis change was significantly greater in cases with osmophobia (62%) than in those without (23%). Osmophobia persisted at a 3-year follow-up in the majority of our cases (85%) and it was found to be one of the major predictors for the development of migraine; other predictors of evolution to migraine were phonophobia, a probable rather than certain diagnosis of TTH and olfactory triggers (p < 0.05).

Conclusion: Our data confirm that osmophobia has an important diagnostic and prognostic role in children with primary headaches and should be systematically investigated at diagnosis and during follow-up.

Keywords

Osmophobia tension-type headache migraine without aura follow-up children

Introduction

Osmophobia, an unbearable perception of odours that are non-aversive or even pleasurable outside the headache attacks, is an accompanying symptom included in the Appendix (A1.1) of the International Classification of Headaches Disorders (ICDH-II, 2004) (1) among the diagnostic criteria of migraine without aura (MO).

In the literature there are several studies (2–9) evaluating the role of osmophobia in the diagnosis of MO and the validity of the diagnostic criteria of the Appendix 1.1, both in adults (2) and in children and adolescents (6); however, studies analysing the prognostic role of osmophobia are completely lacking. Osmophobia shows a high specificity for the diagnosis of migraine even in children (10–12) but, differently from adults (7–9), it does not occur exclusively in children with migraine (20–35%) but also in up to 14% of cases with tension type headache (TTH) (10).

Osmophobia could have both a diagnostic and prognostic role of great value, particularly in children, when it is more difficult to make a definite diagnosis of primary headache. This is not only because of the inability of childred to describe their symptoms (13), but also because of the greater tendency at this age for the headache pattern, and thus the diagnosis, to change over time (14–19).

The purpose of this prospective study was to evaluate the prognostic role of osmophobia in young patients with TTH in order to test the hypothesis that the presence of osmophobia could predict the evolution of the headache pattern from TTH to migraine.

Materials and methods

This was a longitudinal prospective study of 90 patients under 18 years of age affected by TTH. These cases were selected among 1020 patients with primary headaches, consecutively diagnosed at ten Italian Juvenile Headache Centres in the years 2005–2010, according to the following inclusion criteria: 1) age 4–18 years at diagnosis; 2) diagnosis of episodic TTH (ETTH) or chronic TTH (CTTH) according to the ICHD-II criteria (1); 3) no prophylactic therapy in the last 6 months; 4) absence of relevant or chronic diseases; 5) adequate cognitive and expressive skills to be able to understand the questionnaire and participate in the interview.

From the initial study population of 1020 cases, previously described (10), there were 328 cases affected by TTH, among whom 37 participants referred to osmophobia (group A). To compare these cases with other cases affected by TTH but not referring to osmophobia, 80 out of the 328 cases were randomly recruited, and 53 of them (group B), age and gender matched, participated in the study.

The adopted sample size (37 children with osmophobia and 53 children without) could assure 82% power to detect a difference between the proportion of migraine at follow-up in the two groups of about 30%. On the basis of previous experience, the expected proportion of migraine was about 60% and the significance level was targeted at 0.05.

The study protocol and consent/assent forms were approved by our Institutional Review Board.

The first semi-structured questionnaire, administered at baseline (T0), contained information about gender, age, family history of headache and osmophobia, migraine precursors, pattern of headache, accompanying symptoms, and characteristics of osmophobia. The questionnaire was completed during the examination by a board-certified child neurologist through an interview to the patient, with the help of the accompanying parents for children under 10 years of age. During the visit an accurate physical and neurological examination was performed. Blood examinations or neuroimaging were undertaken in selected cases to rule out a secondary headache. The second semi-structured questionnaire, administered at a 3-year follow-up (T1), contained information on headache pattern, accompanying symptoms, and characteristics of osmophobia.

Statistical analysis

Descriptive statistics were obtained for quantitative (mean ± standard deviation) and qualitative (prevalence, distributions) characteristics on the whole sample, by headache type and osmophobia (presence/absence). The significance of the differences between mean values was evaluated by means of the Student’s unpaired t-test. To compare distributions, the chi-squared test or Fisher’s exact test were applied, as appropriate. All the tests were two-tailed, and the level for significance was set at 0.05. The analyses were performed by means of SAS version 9.1 (SAS Institute, Inc., Cary, NC, USA).

Results

Demographic and clinical characteristics

Ninety patients were affected by TTH (79 ETTH, 11 CTTH); there were 47 males and 43 females, with a mean age at T0 of 11.5 ± 2.9 years (range 5.6–16.5). This cohort of patients was divided into two groups: group A, including 37 participants referring to osmophobia (18 males and 19 females; mean age at T0: 11.6 ± 2.9 years; range 7.0–17.3) and group B, including 53 participants not referring to osmophobia (29 males and 24 females; mean age at T0: 11.5 ± 2.9 years; range 4.3–16.0). The mean duration of follow-up was 3.1 ± 0.8 years (range 1.6–4.2).

We compared the clinical characteristics at baseline of the two groups and we did not find any significantly statistical association, as shown in Table 1.

Table 1.

Clinical characteristics of the young patients affected by tension type headache with (group A) or without osmophobia (group B) at baseline

Clinical characteristics*	Group A (osmophobia present) (N = 37)	Group B (osmophobia absent) (N = 53)	p
Gender (male)	18 (48.7%)	28 (52.8%)	0.70
Age at diagnosis	11.6 ± 2.9 (7.0–17.3)	11.5 ± 2.9 (4.3–16.0)	0.74
Duration of headache since onset at baseline (years)	2.3 ± 2.5 (0.0–10.0)	2.8 ± 2.8 (0.0–11.0)	0.35
Duration of follow-up (years)	3.0 ± 0.6 (1.6–4.3)	3.2 ± 1.0 (0.9–4.6)	0.56
Photophobia	12 (32.4%)	14 (26.4%)	0.54
Phonophobia	15 (40.5%)	21 (39.6)	0.93
Nausea	2 (5.4%)	0 (0.0%)	0.09
Vomiting	0	0	-
Family history for migraine	28 (75.7%)	33 (62.3%)	0.18

Descriptive statistics: for quantitative variables, mean ± standard deviation (range); for qualitative variables, count (%).

There was no relationship between the predictive role of osmophobia for migraine and the characteristics of migrainous pattern: duration (p = 0.45), intensity (p = 0.68), quality of pain (p = 0.46), location of pain (p = 0.47), aggravation of or causing avoidance of routine physical activity (p = 0.74) (data not shown).

Analysis of the prognostic role of osmophobia

We analysed the diagnosis of headache at baseline (T0) and follow-up (T1) and we found that, at the end of follow-up, 35 (39%) cases were diagnosed as having migraine instead of TTH.

In fact, at T1, 23 participants in group A were diagnosed as having migraine (19 MO, one migraine with aura (MA) and three chronic migraine (CM)); and eight had TTH (six ETTH, two CTTH), two had both MO and ETTH, two had headache remission and two had headache not elsewhere classified (NEC) (1). In group B, 12 participants were diagnosed as having migraine (12 MO), 30 had TTH (28 ETTH, two CTTH), six had both MO and ETTH and five had headache remission.

Therefore, at the end of follow-up, the rate of diagnosis transformation from TTH to migraine was greater in group A (62.2%) than in group B (22.6%) (p < 0.005) (Figure 1).

Figure 1.

Comparison between diagnosis of first level in group A (with osmophobia) and group B (without osmophobia) at follow-up. M: migraine, TTH: tension type headache, R: remission, NEC: not elsewhere classified in ICHD-II. Mixed: pattern of mixed M and TTH.

We also evaluated the stability during time of osmophobia and we found that in 28 (85%) cases of group A, who complained the symptom at T0, osmophobia was still present at T1, whereas 40 (83%) participants of group B, in which osmophobia was absent at T0, did not report the symptom even at T1 (p < 0.0001). Therefore, osmophobia was found to be persistent during the follow-up in the majority of our cases (85%).

Among the participants of group A, the probability of changing the diagnosis from TTH to migraine was greater if osmophobia was still present at T1 than in cases without osmophobia at T1 (respectively 71% vs 28%; p = 0.0002). Therefore the persistence at follow-up of osmophobia was correlated with a greater likelihood of evolution from TTH to migraine.

Other predictors of evolution to migraine

We compared the characteristics of the headache pattern in the participants who become migraineurs at T1 with those of participants who continued to have a TTH or NEC. We found that in the first group the persistence of osmophobia at follow-up, the presence of odour as trigger and the presence of phonophobia were significantly more frequent (Table 2). Moreover, participants with a probable diagnosis of TTH at T0 can more easily become migraineurs at T1 than those with a certain diagnosis of TTH at T0 (Table 2).

Table 2.

Analysis of risk factors for evolution from tension type headache to migraine during follow-up

Clinical characteristics	Migraine at follow-up (N = 35)	TTH and others* at follow-up (N = 55)	p
Gender (male)	17 (48.6%)	29 (52.7%)	0.70
Age at diagnosis (years)	11.6 ± 2.8 (7.0–16.5)	11.5 ± 3.0 (4.3–17.3)	0.94
Duration of headache since onset at T0 (years)	3.0 ± 2.6 (0.0–10.0)	2.3 ± 2.7 (0.0–11.0)	0.23
Osmophobia at baseline	23 (65.7%)	14 (25.5%)	0.0002
Osmophobia at follow-up	26 (74.3%)	10 (21.7%)	<0.0001
Olfactory triggers at baseline	12 (34.3%)	7 (12.7%)	0.01
Diagnosis of TTH (certain vs probable) at baseline	23 (65.7%)	47 (85.4%)	0.03
ETTH/CTTH	30/5	49/6	0.63
Photophobia at baseline	12 (34.3%)	14 (25.5%)	0.37
Phonophobia at baseline	19 (54.3%)	17 (30.9%)	0.03
Nausea at baseline	2 (5.7%)	0 (0.0%)	0.07
Vomiting at baseline	0	0	-
Family history for migraine	33 (62.3%)	28 (75.7%)	0.18

CTTH: chronic tension type headache, ETTH: episodic tension type headache, TTH: tension type headache. Bold indicates significance.

Others include patients with headache remission, a mixed headache pattern (both MO and ETTH) and headache not elsewhere classified in ICHD-II.

It is noteworthy that among these five predictors of evolution to migraine, three are related to osmophobia (osmophobia a T0, osmophobia persistent at T1 and olfactory triggers).

We also evaluated the individual probability for a young patient with TTH to become a migraineur over 3 years considering the presence of these predictors individually or together (Figure 2). We found that the probability of evolution to migraine was 39% independently from these predictors, 63% in cases with osmophobia, 78% in cases with osmophobia and phonophobia, 79% in cases with osmophobia and a probable diagnosis of TTH, and 100% in cases with osmophobia, phonophobia and a probable diagnosis of TTH (Figure 2). Therefore the risk of becoming migraineur after 3 years is significantly increased by the presence of osmophobia and even more if this symptom is associated to other predictors, such as phonophobia and/or a probable diagnosis of TTH.

Figure 2.

Individual probability for a young patient with TTH to become migrainous at follow-up by presence of predictors (individually or associated). M: migraine, TTH: tension type headache.

Discussion

Osmophobia is an accompanying symptom of primary headaches, significantly associated with MO at any age. In fact, studies on adults show that this symptom is present in 24–35% of cases with primary headaches (3,4,7,8) and in up to 63% of migraineurs (3–9), more in MA (71%) than in MO (57%) (9); in children, 18–27% of cases with primary headaches (10–13) and up to 34% of migraineurs (10) can report osmophobia.

In adults osmophobia was complained only by migraineurs and not by participants affected by TTH, showing a specificity of 100% for the diagnosis of migraine (6–8); only one study in adults has found the presence of osmophobia even in patients with TTH (20). In children osmophobia has been found in 8–14% of cases of TTH (10,11).

Recent studies have validated the proposed criteria of the Appendix 1.1 (1), documenting an agreement with the current criteria for the diagnosis of MO in 98% of adults (2) and in 96% of children (10); moreover, using as diagnostic criterion the presence of osmophobia, 54% of previously unclassifiable patients received a definite diagnosis among primary headaches (10).

In children and adolescents the diagnosis of primary headache can change over time and the transformation from TTH to migraine is relatively frequent, ranging from 11% to 42% of cases (14–19).

There are few studies in the literature focusing on osmophobia in children with primary headache (10–12), and its prognostic role has not yet been considered.

The presence of osmophobia as a diagnostic feature specific for migraine is important also because if we used the current ICHD-II criteria, the accompanying symptoms of a headache attack could sometimes be confounding factors (such as the inclusion of either photophobia or phonophobia for TTH, or mild nausea for CTTH), creating a possible overlap between migraine and TTH.

In the current prospective longitudinal study, we found that in 39% of cases with TTH the diagnosis changed to migraine after a 3-year follow-up, similarly to the rate of diagnosis transformation previously reported by others (14–19). The detection of osmophobia in children affected by TTH correlated with a greater likelihood (OR = 5.6) of evolution to migraine compared with children with TTH without osmophobia (p = 0.001), supporting the hypothesis that osmophobia could predict the diagnosis of migraine.

Our data confirm that osmophobia is stable over time, accordingly to Zanchin et al. (8) who describe osmophobia as an early and constant characteristic in the patient's medical history. Moreover we found that the persistence of osmophobia at the end of follow-up greatly increases the probability of evolution from TTH to migraine (71% if present at T1 vs 28% if absent at T1; p = 0.0002).

In our study the main predictors of evolution from TTH to migraine were, other than the presence of osmophobia at T0, the presence of odour as trigger, the persistence of osmophobia at T1, a probable diagnosis of TTH and the presence of phonophobia. It is noteworthy that among these five main predictors, which were statistically significant, three were related to osmophobia. The presence of odour as a trigger of the headache attack occurs in about 25% of migrainous adults (8), mainly affected by MA (9), and in 16% of children (10) with migraine. All patients who reported odour as a trigger also reported osmophobia during attacks (8). Therefore odour as a trigger for headache and osmophobia as a symptom should always be sought for in headache history.

In TTH patients the individual probability of evolution to migraine at follow-up increased from 39% to 63% in presence of osmophobia, to 78% if osmophobia was associated with phonophobia, to 79% if osmophobia was associated with a probable diagnosis of TTH, and to 100% if all these three factors are present.

Conclusions

Osmophobia is an important clinical feature of the headache pattern closely associated with migraine, not only because it is significantly more frequent in migraineurs but also because it has an important prognostic value; in fact, if present, it is one of the most relevant predictors of evolution from TTH to migraine at a 3-year follow-up.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflicts of interest

The authors declare that there are no conflicts of interest.

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