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Migraine and immunoglobulin E-mediated hypersensitivity/Migren ve immunoglobulin E aracili hipersensitivite.


Migraine is a complex neurological disease with a genetic background of unknown origin (1). In recent years, immunological mechanisms are considered to exist in the occurrence of the pain, and it is thought to be some form of sterile neurogenic inflammation. In experimental studies, platelet aggregation, mastocyte degranulation and histamine secretion have been shown to occur after trigeminal ganglion stimulation (2).

Epidemiological studies suggest an association between migraine and mast cell-related diseases such as asthma and allergies (3). It seems possible that substances which degranulate mast cells are capable of inducing migraine attacks without clear experimental evidence (1). An increase in local blood flow and vascular permeability has been observed with histamine secretion, and they have caused a fast activation of other proteins, including antibodies. Histamine has been shown to trigger migraine attacks in patients with migraine and in healthy controls (2). Plasma levels of histamine have been found to be elevated in migraineurs both during and between attacks (1). As histamine is a potent vasoactive amine, it is thought to precipitate a migraine attack as a result of its vascular effects (2).

An increase in IgA and IgG levels have been shown during and between attacks in patients with migraine in some studies, whereas in others a simultaneous increase in both IgA, IgM and IgE levels have been shown (4,5). Four different types of hypersensitivity have been defined, and type 1 and type 3 hypersensitivity reactions were thought to play a special role in migraine. IgE production by plasma cells plays a central role in allergy and type 1 hypersensitivity. IgE induces release of inflammatory mediators such as histamine and cytokine from mastocytes and leukocytes. These mediators cause vasodilatation of small blood vessels and plasma extravasation, platelet aggregation and irritation of the sensory nerve terminals. Migraine has been investigated as type 1 hypersensitivity in studies in which high levels of total IgE and food-associated IgE in serums of patients with migraine have been found (6). Elevated serum levels of IgE found in migraine patients could alone play a role in migraine even in the absence of antigen (3).

Our aim was to detect if there has been any changes in IgE levels in a small population of Turkish patients with migraine during attacks and between attacks, and thus to determine if IgE-mediated hypersensitivity and allergic background are important factors in the etiology of migraine.


In this study, we included 43 female and 3 male patients, aged 17-51 years, admitted to the neurology outpatient clinic of Ankara Numune Education and Research Hospital and diagnosed as migraine according to the criteria of the International Headache Society (IHS) (7), and 41 (38 females and 3 males) age- and gender-matched healthy controls. Patients in whom a specific etiology was detected on cranial imaging and controls with a history of allergy were excluded from the study. The study was approved by the local ethics committee of Ankara Numune Education and Research Hospital and written informed consent was obtained from both patients and controls.

IgE levels of the patients were measured during migraine attack and in the interictal period, and were compared with IgE levels of controls. IgE levels were measured by a Beckmann-Coulter Access 2 device, using commercial kits. The patients were questioned for the presence of hypertension, heart disease, diabetes, epilepsy, allergic diseases (allergic asthma, allergic rhinitis, atopic dermatitis, contact dermatitis, urticaria, etc.), and for long-term drug use, treatment for migraine, family history of migraine, family history of allergic diseases and presence of autoimmune diseases.

SPSS 11.5 Software the data. Descriptive statistics of continuous variables were shown as mean [+ or -] standard deviation or median (min-max) values. Nominal variables were presented as the number of observations (%). Student's t test or Mann-Whitney U test was used in determining the significance of a difference between the measurements in the two groups. The significance of the difference of IgE levels measured during attack and in the interictal period was assessed with Wilcoxon test with Bonferroni correction. Chi-square test or Fisher's exact test was used for categorical comparisons. P<0.05 was considered as statistically significant.


The patient group consisted of 43 females and 3 males with a median age of 29 (17-51) years, while the median age of the controls (38 females and 3 males) was 31 years (16-44). There was no statistical difference between the groups in terms of age and gender (p = 1.00). The accompanying diseases in the patient group are shown in Table 1. History of allergic disease was found in 16 patients (34.8%), and 7 patients with allergic diseases had family history of allergic disease (15.2%); all were first-degree relatives. History of allergic asthma, heart disease or autoimmune disease was not reported in any patients.

In Table 2, characteristics of migraine are summarized. There was no statistically significant difference in terms of type of migraine and monthly number of attacks (p = 0.575). Twenty-one patients reported family history of migraine (45.7%), and 19 of the relatives with migraine were of the first degree (90.5%), whereas 2 were second-degree relatives (9.5%).

Median IgE level of the patients during an attack was 31.40 IU/ml (1.40-3000.00 IU/ml) and median IgE level of patients in interictal period was 29.25 IU/ml (1.30-3000.00 IU/ml). There was a statistical difference between the patients' median IgE levels during and between attacks (p = 0.005), as IgE levels presented higher during attack than in the interictal period. The median IgE level of the control group was 30.80 IU/ml (1.40-1078.20) and there was no statistical difference between median IgE level of the patients and controls, during or between attacks (p = 0.472 and p = 0.772, respectively) (Table 3). During attack, the median IgE level of the patients who had 2 or less attacks per month was 14.70 IU/ml (1.40-3000.00) and the median IgE level of the patients who had more than 2 attacks in a month was 49.00 IU/ml (7.50996.50), and there was a statistical difference between these two groups (p = 0.011). The median IgE levels during interictal period of patients who experienced 2 or less attacks per month was 13.70 IU/ml (1.30-3000.00) and the ones' who experienced more than 2 attacks per month was 48.60 IU/ml (6.60-985.40), and these values were statistically significant (p = 0.009). The median IgE level of the 16 patients with migraine and allergic diseases was 45.80 IU/ml (1.40-996.00 IU/ml) during attack, while the median IgE level of these patients during the interictal period was 34.45 IU/ml (1.30-894.20) and this difference was also statistically significant (p = 0.023) (p<0.025 after Bonferroni correction). The median IgE level of 30 patients with migraine who did not have any allergic diseases was 30.70 IU/ml (2.80-3000.00) during attack and the median IgE level was 29.25 IU/ml (2.50-3000.00) during the interictal period and there was no statistical difference between these two values (p = 0.094) (Table 4).


Migraine is a complex neurological disorder and affects approximately 15% of the general population. Its pathophysiology is still mostly unknown, although there are many studies investigating its mechanism (8). Although its etiology and pathogenesis are not completely known, allergic processes are among many other factors that precipitate migraine attack. The best evidence for the role played by immunological mechanisms has been reported in the study by Lord et al., which showed the activation of complement system during migraine headache (9). The interaction between allergy and migraine has been discussed for many years. The association between migraine and allergy may be based on IgE mediation, and histamine release also plays an important role. Many studies have been made in order to lighten the association between allergy, especially food allergy, and migraine. Additionally, Alpay et al. showed that diet restriction based on IgG antibodies has been an effective strategy in reducing the frequency of migraine attacks (10). Migraine induced by food has not been shown to be mediated by IgE, but histamine by leading to vasodilatation can cause migraine headache. There is evidence especially in children that diets not containing histamine and avoidance of inhaled or environmental allergens may abolish episodes of headache (8). In the present study, IgE levels of patients during and between attacks were compared with IgE levels of age- and gender-matched controls. Female patients were obviously more than males in the patient group, which was randomly assigned (F/M ratio = 43/3). This finding was in accordance with the study by Stewart et al., in which the frequency of migraine was higher in females than in males, and also in accordance with the findings of Waters (11,12). As the coexistence of migraine and allergic diseases (5,13,14,15), and a family history of migraine (16) and family history of allergic diseases (14,16) are well known, the patients were questioned about presence of allergic diseases and presence of a family history of migraine and allergic diseases. History of allergic diseases was positive in 34.8% of the patients and the fact that more than a third of the patient group reported a history of allergic diseases remind us to be aware of the co-existence of migraine and allergic diseases, and allergens as a triggering cause of migraine attacks. Ozge et al. also found 41.4% of migraine patients reporting at least one atopic disease and showed that even in headache-free periods, the migraineurs with atopic diseases had increased IgE levels (17).There was a family history of allergic diseases in 15.2% of the patients. The study by Mortimer et al., showing an association between maternal migraine and allergic diseases in their children, is another evidence for the relationship between migraine and presence of allergic diseases (16). Additional support for a possible involvement of allergy in migraine comes from clinical studies reporting migraine-like symptoms that are associated with allergy season and allergy-related nasal and ocular symptoms that frequently accompany migraine. Other allergic-like symptoms including nausea, vomiting, diarrhea, malaise, and fatigue also accompany migraine attacks.

In a large study, Eross et al. confirms that migraine and other headaches are associated with respiratory and allergic disorders (18). In this study, 54% of the patients with IHS-defined migraine reported a medical history of allergic rhinitis, and 76% claimed to have had at least one episode of prior acute sinusitis, which are numbers higher than expected in the general population.

The absence of any history of allergic asthma in the patient group was not in accordance with the reports that both migraine and allergic asthma have been associated with specific HLAs (14,16). The IgE levels of patients with allergic diseases during an attack being statistically higher than the IgE levels during the interictal period is supported by the suggestion that IgE is a mediator of histamine release from mastocytes and, histamine, as a potent vasoactive agent, may play a role in the induction of migraine attacks. The fact that IgE levels during and between attacks were higher in the patients with more than 2 migraine attacks per month than in the patients reporting less than 2 attacks a month, and that most of the patients with an allergic disease experienced more than 2 attacks per month suggests an IgE-mediated immunity in the etiology of migraine headache. The absence of a difference between the two periods in patients without an allergic disease took us away from IgE-mediated immunity in the etiology of migraine in patients without atopy. In a study, IgE levels of patients with migraine have been investigated and found to be increased, and atopy has been determined in some of these cases (6). Kemper et al. conducted a meta-analysis of the clinical literature on migraine and the immune system in 2001, and had indeed found evidence of increased levels of IgE in patients with atopic migraine, but could not show the same in patients without type I hypersensitivity (19).

Moreover in a recent study done by Martin et al., it has been shown that lower "degrees of atopy" were associated with less frequent and disabling migraine headaches, especially in younger subjects, while higher degrees were associated with more frequent migraines. Finally, the administration of immunotherapy has been associated with a decreased prevalence, frequency, and disability of migraine headache in younger subjects (20).

Although our study has a limitation of having a small sample size of patients and controls, the following conclusions have been made: in patients with migraine who also had an allergic disease, the IgE levels during attack were higher than the levels measured in the interictal period. Atopic diseases are seen somewhat more frequently in patients with migraine and IgE levels during attack increase more in patients with both migraine and allergic diseases than in patients with migraine who are not allergic, and the frequency of attacks is higher in atopic patients. Thus, questioning patients with diagnosis of migraine about allergic diseases and avoidance of allergic conditions that may cause an increase in Ig E levels may be beneficial for decreasing the frequency of attacks.

Conflict of Interest

The authors reported no conflict of interest related to this article

Cikar catismasi:

Yazarlar bu makale ile ilgili olarak herhangi bir cikar catismasi bildirmemislerdir.

DOI: 10.4274/npa.y6142


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Mesut CAKICI [1], Sule BILEN [1], Sedat MOTOR [2], Fikri AK

[1] Ankara Numune Training and Research Hospital, Department of Neurology, Ankara, Turkey

[2] Ankara Numune Training and Research Hospital Department of Biochemistry, Ankara, Turkey

Address for Correspondence/Yazism a Adresi: Sule Bilen MD, Ankara Numune Training and Research Hospital, Department of Neurology, Ankara, Turkey

Gsm: +90 505 390 48 09 E-mail: Received/Gelis tarihi: 29.05.2011 Accepted/Kabul tarihi: 04.09.2011
Table 1. Coexisting diseases in migraine patients

Disease N %

Hypertension 6 13
Diabetes Mellitus 1 2.2
Heart disease 0 0
Epilepsy 1 2.2
Eczema/atopic dermatitis 2 4.3
Allergic rhinitis 4 8.7
Drug allergy 2 4.3
Contact dermatitis/urticaria 9 19.6
Allergic asthma 0 0
Autoimmune disease 0 0

N: Number of the patients, %: Percent of the patients

Table 2. Characteristics of migraine in patients

 N %

Migraine with aura 18 39.1
Migraine without aura 28 60.9
>2 attacks per month 31 67.4
[less than or equal 15 32.6
 to]2 attacks per
Positive family history 21 45.7
 of migraine

N: Number of the patients, %: Percent of the patients

Table 3. Comparison of median IgE levels of patients
and controls

 Median IgE levels
 (range) (IU/ml)

Patients During attack 31.40 (1.40-3000.00) *
 Interictal period 29.25 (1.30-3000.00) *
Controls 30.80 (1.40-1078.20)

* There was a statistically significant difference
between median IgE levels of patients
during attacks and interictal period (p = 0.005)

Table 4. Comparison of median IgE levels of patients

 Median IgE levels (range) (IU/ml)

 During In interictal
 attacks period

Pts with attack 14.70 (1.40-3000.00) * 13.70 (1.30-3000.00) **
 frequency [less
 than or equal
Pts with attack 49.00 (7.50-996.50) * 48.60 (6.60-985.40) **
Pts with 45.80 (1.40-996.00) *** 34.45 (1.30-894.20) ***
Pts without 30.70 (2.80-3000.00) 29.25 (2.50-3000.00)

Pts: Patients

* There was a statistically significant difference between IgE levels
during attack of patients with attack frequency >2/months and
[less than or equal to] 2/month (p = 0.011)

** There was a statistically significant difference between IgE
levels in the interictal period of patients with attack frequency
>2/months and [less than or equal to] 2/month (p = 0.009)

*** There was a statistically significant difference between IgE
levels of patients with allergic disease during attack and in the
interictal period (p = 0.023)
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Title Annotation:Research Article/Arastirma Makalesi
Author:Cakici, Mesut; Bilen, Sule; Motor, Sedat; Ak, Fikri
Publication:Archives of Neuropsychiatry
Article Type:Report
Date:Jun 1, 2012
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