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Abstract

Mechanisms underlying migraine precipitation are largely unknown. A role of the immune system in migraine precipitation is a matter of debate because of the association of atopic disorders and migraine. Recently, it was demonstrated that migraineurs benefit from eradication of a Helicobacter pylori infection, which substantiates a possible role for (sub-clinical) infections in precipitation of migraine. Since 1966, about 45 clinical investigations have reported on alterations of immune function in migraine patients, which we present in this review. Changes of serum levels of complement and immunoglobulins, histamine, cytokines and immune cells were found in some of these studies but in most cases not corroborated by others. Migraineurs suffering from comorbid atopic disorders show elevated plasma IgE levels but not patients without a type I hypersensitivity. Histamine plasma levels are chronically elevated in migraineurs, and interictally decreased lymphocyte phagocytotic function and increased plasma tumor necrosis factor alpha (TNFα) levels were found, and may be related to increased infection susceptibility. The cause of this increased susceptibility is unclear but most likely is a result of chronic stress, a well-known suppressor of the immune system. Stress relief enhances immune activity and triggers a burst of circulating vasoactive compounds that function as mediators of inflammation and potential precipitators of a migraine attack in vulnerable subjects. In conclusion, in the clinical literature of the past decades, there is no clear-cut evidence of an immune dysfunction in migraineurs, but we cannot totally exclude the possibility of an altered immune function in migraineurs. Discrepancies in the literature most likely are caused by the divergent patterns of sample collection relative to the time of the attack. We propose stringent definition of sample collection times for future studies of immune function in migraine patients.

Keywords

Infection cytokines vasoactive compounds neurogenic inflammation stress

Introduction

Migraine is the most common neurological disorder and affects 6% of the male and 15–17% of the female Western population (1). The pathogenesis of migraine is still largely unknown. Various factors such as foods, drinks, stress, or stress relieve, menses, environmental changes, smoking or exercise have been associated with migraine precipitation (2, 3). The migraine attack usually is characterized by a severe, unilateral headache accompanied by nausea, vomiting and photo- and/or phono-phobia. Some patients have prodromes, which may be changes of mood, alertness, appetite and fluid balance (4, 5) that announce the attack about 24 h before the actual start of the headache. About 30% of the migraineurs have an aura: visual, sensor and/or speech disturbances occurring between 15 and 30 min before the headache starts.

Why certain precipitators cause migraine in some but not in other patients is unknown but most likely it is determined by a genetic vulnerability for selective physiological alterations. Here we will review the available data on a possible role of the immune system and mediators of inflammation in migraine precipitation.

Migraine: hypersensitivity and infections

Comorbidity of migraine and atopic diseases such as eczema and asthma is an important argument for a suspected immune system dysfunction in migraineurs. In 1985, Nelson reviewed this issue and found evidence for a close association between migraine and atopic diseases (6). Recent studies have confirmed this association. One study, examining more than 1000 children, found a significantly increased prevalence of migraine in children with atopic diseases (7). Another study reported that the prevalence of asthma was about twice as high in children of mothers with migraine but without asthma or allergies (8). Both migraine and allergy appear in a paroxysmal and recurrent fashion and a hypersensitive response would fit well with both the duration of the migraine attack and the fact that selective foods can precipitate migraine. Based on these similarities it is understandable that in 1913 migraine was already linked to a hypersensitive immune system (9).

Four different types of hypersensitivity are distinguished and so-called types I and III hypersensitivity may be of special relevance for migraine precipitation. The production of immunoglubulin-E (IgE) by plasma cells plays a central role in allergy, or type I hypersensitivity. IgE stimulates the release of mediators of inflammation such as histamine and cytokines from mast cells and leucocytes. These mediators are a cause of vasodilatation and plasma protein extravasation in small blood vessels, platelet aggregation, and irritation of sensory nerve terminals (10). Type III hypersensitivity is characterized by expression of large amounts of immune complexes formed, for example, in response to circulating bacterial products. These immune complexes stimulate the release of vasoactive amines from platelets and basophilic granulocytes, and result in platelet aggregation and neutrophilic granulocyte recruitment that cause local inflammation and vascular wall damage.

More recently, occurrence of migraine has been associated with infection. Migraineurs reported not only that infections precipitate migraine attacks but also that they increase the headache intensity (11). An elevated frequency of (sub-clinical) herpes labialis, pharyngitis, cystitis, vaginitis and mycosis infections has been found in migraine patients (12). A study investigating 31 children with migraine reported that 29 suffered from a gastrointestinal inflammation such as oesophagitis, gastritis and/or duodenitis (13). Moreover, recently it was shown that 19 out of 81 migraineurs with a Helicobacter pylori (H. pylori) infection became migraine-free (during a half-year follow-up period) after successful eradication of the H. pylori infection. The remaining 62 migraine patients reported a significant reduction of the migraine intensity, duration and frequency compared with 13 unsuccessfully treated H. pylori-infected migraine patients (14). This report awaits replication but is an indication for a potential role of infectious diseases in migraine precipitation.

The aforementioned studies mainly provide indirect evidence for involvement of the immune system in migraine precipitation. We have conducted a meta-analysis of the clinical literature investigating selective expression changes of mediators of inflammation during headache, migraine and the interictal phase in order to obtain information about physiological evidence of immune system dysfunction in migraine. The results will be summarized here.

Methods

Using Silverplatter Medline as the search engine, we have identified all articles published between 1966 and 1999 that combine migraine/headache with relevant immunological keywords, in which one or various immune factors were measured in the blood, cerebrospinal fluid or urine. Table 1 gives an overview of the results of this search in the literature.

TABLE 1

Non-controversial alterations of immune function in migraine

During spontaneous attacks	During the interictal phase
Increased	Increased
Serum Histamine levels [47, 48]	Serum Histamine levels [47, 48]
Leucocyte Spontaneous Histamine Release [53]	Leucocyte Spontaneous Histamine Release [51, 52]
Monocyte chemotaxis, respiratory burst, and	Lymphocyte D5-receptor expression [80]
TNFα, IL-1β production at 2 h [74]	Serum TNFα levels [93]
Decreased	Decreased
Serum monocyte counts [73]	Lymphocyte β-endorphin levels and β-adrenergic sensitivity [78, 79]
PMN phagocytosis [73]	Monocyte chemotaxis [74]
Serum IL-4 levels [98]	Serum IL-2 levels [99]

Immunoglobulin E

Migraine as a type I hypersensitivity reaction was investigated in 10 clinical studies, measuring total IgE and food-related IgE levels in the serum of migraine patients. Six of these studies reported the personal history of the patients with respect to comorbid atopic diseases, which is an important IgE-inducing condition. One study, excluding the atopic patients, did not find a rise of IgE levels in migraineurs (15) and is corroborated by three other studies (16–18). Increased serum IgE levels in migraineurs were reported in six studies that correlated this rise with comorbid atopy (19–22) or did not mention atopic disease histories of the patients (23, 24).

A selective food-related IgE expression was reported in two studies (22, 24). Monro (24) found a high correlation between the provoking food and pattern of serum IgE expression. In this study, 23 out of 26 patients showed improvement of the migraine symptoms after the IgE-provoking food components were eliminated from the diet. However, Pradalier (22) could not induce a migraine attack when he challenged patients with the IgE-provoking food. Moreover, two other studies did not find a food-related IgE expression pattern in migraine patients (15, 16).

In conclusion, in the atopic patients, increased IgE serum levels could be associated with migraine precipitation but there is no evidence for an association of serum IgE levels and migraine in non-atopic patients. The literature about relationships between diet, IgE expression pattern and migraine is controversial, but we would conclude that the pattern of IgE expression is not relevant for migraine precipitation since Pradalier's challenge study (22) has produced negative results.

Histamine

There is substantial evidence in the clinical literature that histamine may be associated with migraine precipitation. Histamine challenge in migraine patients and healthy volunteers, respectively, induced a migraine attack and headache (25–27). Histamine is a potent vasoactive compound (28–35), and since the headache of a migraine attack has been attributed to cerebrovascular vasodilation (36–39), histamine may be a candidate mediator for vascular changes observed during a migraine attack. There is evidence that the vascular effects of histamine are at least partially mediated by nitric oxide (NO) (40), a gaseous molecule with a potential important role in development of migraine. NO-inhibitors may provide headache relief (41).

Both reports of ictally and interictally changed blood (42) and urine (43, 44) histamine levels in migraineurs were identified and mainly produced in the early 1970s. Loisy reported that interictally the histamine metabolite 104MIA was elevated in the urine of migraineurs (45). In recent studies, however, these observations could not be confirmed with whole blood (46–48) and urine (46, 49, 50) samples of migraine patients. Two studies reported slightly elevated plasma histamine levels in migraine patients, both ictally and interictally, compared with the plasma histamine levels of non-migraineurs (47, 48). Three studies showed a higher spontaneous histamine release (SHR) by leucocytes from migraineurs, both interictally (51, 52) and ictally (53). Thus, the slightly elevated plasma levels of histamine in migraine patients may be associated with increased SHR of leucocytes but there is no evidence for a direct correlation of plasma histamine levels and attack precipitation.

The factor(s) that are responsible for increased SHR or plasma histamine levels in general in migraineurs have not been identified. In an attempt to isolate a possible trigger from serum, Selmaj stimulated leucocytes from healthy volunteers with serum from migraineurs in vitro and initially showed an increased SHR (52) but failed when he wanted to replicate this in a larger follow-up study (53). An explanation for the increased plasma histamine levels may be a chronic (sub-clinical) infection, for example with Helicobacter pylori, eradication of which has ameliorated migraine intensity and attack frequency (14), that can produce histamine (54) or stimulate its release from gastric mucosa cells (55–58). The literature showed little pharmacological evidence for a role of histamine in migraine pathophysiology. Studies applying H1 and H2 receptor selective drugs in migraine patients gave disappointing results but the histamine-3 receptor may be an interesting novel target in the treatment of migraine (59). The H3 receptor agonist R(–)-α-methyl-histamine, like most antimigraine drugs (60–63), effectively inhibited plasma protein extravasation (PPE) (64) in the dura mater, a pathophysiological phenomenon of migraine.

Immunoglobulins and complement

In the available literature, we have not found any evidence for a major role of immunoglobulin and/or complement-mediated type II or III hypersensitivity in migraine. Circulating immunoglobulins and complement are important for lysis and opsonization of bacteria. In 1977, Lord reported decreased complement 4 (C4) and C5 in the early headache phase of nine migraine patients without aura (65). In 20 classic migraineurs, increased levels of IgA were found ictally and interictally, and 35 non-prodromal (common) migraineurs showed increased IgA and IgG levels during both periods (66). IgA, IgG and also IgM were reported to be increased during the headache-free phase (67), but the interictal IgA levels were decreased in another study (68). However, by far the majority of the clinical studies could not find changes in IgA, IgG and IgM levels (17, 18, 48, 69–71) or complement factors (18, 71, 72) in migraineurs, neither during the headache nor the interictal phase (18, 48, 71, 72). Therefore, the conclusion seems justified that there is no change of serum immunoglobulin or complement levels in migraineurs and that these factors are not involved in migraine precipitation.

Immune cells

Basophilic and eosinophilic granulocytes (polymorphonuclear cells), monocytes, mast cells, natural killer cells and macrophages are members of the innate or non-specific immune system, and essential for infectious and hypersensitive immunological responses.

The number of eosinophilic and basophilic granulocytes was not found to be different in migraineurs, neither in the headache or headache-free phase (48), but another study described that the phagocytotic capacity of these polymorphonuclear cells was decreased in migraineurs during the headache phase (73). Gallai, however, could not confirm a monocyte dysfunction in 110 migraine patients. Ictally, the chemotactic response, phagocytotic capacity, TNF-α/interleukin-1β production and respiratory burst of monocytes were all increased when compared with the attack-free phase (74). Interictally, the monocyte chemotactic response was decreased in migraine patients (74). The time of blood sampling may be the main reason for the differential findings. Gallai measured levels and function of the immune cells 2 h after the start of the migraine attack, whereas irrespective of the phase of the attack, Covelli (66) sampled all patients between 09.00 and 10.00. Based on these observations, we conclude that increased monocyte phagocytotic capacity is a transient condition at the start (after 2 h) of the migraine attack, but monocyte function overall (phagocytosis/chemotaxis) appears to be decreased in migraineurs. A decreased phagocytotic capacity of monocytes and polymorphonuclear cells may explain reports of increased infection risks of migraine patients (12). Reports of lower interictal β-endorphin levels of monocytes may be additional evidence for aberrant monocyte function in migraineurs (75).

Studies investigating natural killer cell levels in migraineurs have not found significant changes (69, 73, 76). One study reported a decreased natural killer cell number (77) and another found increased numbers in milk-induced migraine (70). Various types of T-lymphocytes were found to be increased in the headache-free phase of six patients suffering from milk-induced migraine (70). Increased total T-lymphocyte counts after isosorbide dinitrate-induced migraine (76) confirm these results. However, in blood samples collected after a spontaneous attack, the total number of T-lymphocytes was not altered (69, 73, 77). Cytotoxic/suppressor T-lymphocyte counts were either unaltered (73) or slightly decreased (69, 77).

Data concerning B-lymphocytes, albeit not conclusive, do not yield evidence for B-cell involvement in migraine pathophysiology. B-lymphocyte counts were found increased interictally in one study (69) but decreased in another (77). Moreover, three other reports did not find changes in B-lymphocytes in spontaneous (73) and milk-induced (70) or isosorbide dinitrate-induced (76) migraine.

Quantitive studies of T- and B-lymphocyte numbers in migraineurs do not provide evidence for a role of these cells in precipitation of migraine; however, three reports examining lymphocyte biochemistry in migraineurs suggest otherwise, showing decreased β-adrenergic receptor sensitivity (78), decreased β-endorphin levels (79) and increased dopamine D5-receptor expression (80). These changes are not necessarily related to the cerebrovascular disease but may be a result of pathology elsewhere in the body, as all three studies have suggested. The biochemical changes can alter lymphocyte function, dopamine has immunosuppressive activity (81), β-endorphin and adrenaline stimulate T-cell proliferation (82–84), and adrenalin can alter natural killer cell activity (85). Reduced lymphocyte proliferations and enhanced sensitivity for dopamine-mediated immune suppression may, in combination with a higher stress sensitivity of migraineurs that also is a cause of immune suppression, create conditions for an increased infection susceptibility or recurrence. Stress reduction, a condition associated with reduced cortisol release and occurrence of weekend migraine, would enhance immune activity and lead to a burst of circulating vasoactive compounds that function as mediators of inflammation.

Mediators of inflammation: the cytokines

Cytokines not only mediate the communication between the different cells of the immune system but also between the immune system and the brain. Cytokines have been shown to induce headache (86–92), but few studies examined cytokine levels in migraine patients. Migraine patients without aura showed higher serum levels of TNF-α (93) and IL-1β (94) interictally (the latter only in three patients) but during the attack the plasma levels of IL-1α, IL-1β and TNF-α were not increased. One study suggests that they may be decreased during the attack (95). Mean body temperatures of migraine patients were significantly higher in the headache-free phase than in the headache phase (95). TNF-α plays a role in regulation of body temperature and induces fever (96). Accordingly, higher mean body temperatures of migraineurs could be caused by increased plasma levels of TNF-α in the headache-free phase. Plasma IL-4 and IL-6 levels were decreased and plasma GM-CSF and IFN-γ were increased ictally in patients with food-induced common migraine (97). IL-6, like TNF-α, can induce fever, and since both appear to be reduced during the headache phase, this could explain the lower body temperature during the attack. Moreover, the vasodilatation that is characteristic of the headache phase, contributes to a reduction of body temperature during the attack. Serum IL-4 levels were reduced in isosorbide dinitrate-induced attacks as well as in spontaneous migraine (98). One study reported decreased levels of IL-2 in migraineurs in the headache-free phase (99).

Discussion

All studies specifying the time of the measurements with respect to the occurrence of the headache somehow found a change in immunological parameter(s) (47, 53, 66, 74, 76, 97). Most of the studies analysed only included one sample from the headache phase (47, 74, 76, 97). However, a few longitudinal studies of the headache phase (53, 66) found transient effects, and illustrate the importance of an accurate definition of the time of the measurements. This also raises the question of whether the lack of changes reported in many studies was due to the ‘large’ variation in measurement times, not only with respect to the phase of the attack but also between the time of the day that the samples of the included subjects were obtained. It is well known that various hormones exhibit a clear diurnal rhythm, in particular the diurnal cortisol rhythm should be considered in determination of immune status in migraine patients.

Systemic changes of selective immune parameters were mostly used for establishing a possible immune dysfunction in migraine patients. However, a meningeal or other local sub-clinical infection that is too small for induction of systemic changes may be characteristic for migraineurs. A typical example of a local inflammatory response in migraineurs that has been associated with migraine pathogenesis is neurogenic inflammation (NI) of the meningeal vasculature. NI is a process involving vasodilatation and plasma protein extravasation (PPE) and is generated by release of neuropeptides such as calcitonin gene related peptide (CGRP) and substance P (SP) from the trigeminal afferent nerves (100). Stimulation of the trigeminal afferents in rats is a cause of mast cell degranulation in the dura mater (101) and although it is not likely that mast cell degranulation is involved in PPE (102), it is a part of the windup of the local inflammatory process. Anti-migraine drugs like sumatriptan (60), classic ergot alkaloids (63) and naratriptan (103) all can inhibit PPE in the dura mater when it is elicited by trigeminal afferent stimulation in animal models. Moreover, the efficacy of non-steroidal-anti-inflammatory-drugs (NSAIDs) in inhibition of dural PPE (61) and migraine relief (104, 105) are additional arguments for a pathogenic role of meningeal NI in migraine as well as the elevated CGRP levels that were found in plasma samples obtained from the jugular vein during a migraine attack (106). However, elevated plasma SP levels, that weaken the importance of meningeal NI for migraine pathogenesis, were not found in these patients (106). Accordingly, evidence of a meningeal inflammation has not been reported in migraineurs. Most anti-migraine drugs not only ameliorate PPE but also induce vasoconstriction. Bosentan for example, blocks PPE but has no vasoconstrictive effects, and cannot alleviate migraine when administered during the headache phase (107), which implies that NI is not a drive for mechanisms underlying the headache. However, meningeal NI may be a process that occurs in the period before the headache. Treatments with drugs such as Bosentan in the prodromal phase of the attack may provide evidence for occurrence of local inflammatory processes in the meninges of migraine patients.

Local expression of TNF-α in the meningeal vasculature, induced by a process called spreading depression (a proposed pathophysiological mechanism occurring during the aura phase of migraine (108)), is a possible other local immune system mechanism for pathogenesis of migraine (109). TNF-α, like cortical spreading depression (110, 111), triggers the release of nitric oxide (112), a vasoactive agent (111) and inducer of migraineous headache in migraineurs (113, 114). Worrall showed that systemic TNF-α injections induce PPE in vascular beds of various organs, including the brain (112). Meningeal TNF-α expression also may be a local response to a peripheral inflammation, since it has been demonstrated that LPS is able to induce cytokine expression inside the blood brain barrier (BBB), which can act as relays of peripheral immune signals to the brain parenchyma (115). Glucocorticoids enhanced this process of cytokine expression (116) and it seems that the severity and nature of a stressor are important factors in the glucocorticoid mediated cytokine expression after stress. The timing of the sample collection relative to the end of the stress was found be important for the detection of this effect, which corroborates our conclusions about the need for accurately defining the timing of the sample collection in studies of migraine patients.

Finally, we should consider the possibility of an inflammation-induced trigeminal hyperalgesia as a mechanism of increased migraine vulnerability in genetically predisposed individuals. Hypersensitivity of nociceptive nerve fibres after immune activation has been reported for the extracranial nerves (117), the skin (118) and the hind paw of rats (119, 120). We have demonstrated in a model of intracranial trigeminal stimulation in conscious rats (121) that also the intracranial trigeminal nociceptive fibres show sensitization after lipopolysaccharide administration (122). Inflammation-induced hyperalgesia thus could explain why migraineurs report the highest headache intensity after an infection (11) and why certain precipitators generate migraine in some conditions but not in others.

Conclusion

There is no evidence in the literature of a clear-cut, well-defined immunological disorder in migraineurs. Available results usually were obtained with a limited number of patients who were studied in different phases of the attack that do not allow conclusions about immune dysfunction in migraineurs.

IgE and other immunoglobulin levels are not altered in migraineurs and when such changes were found they could be related to comorbid atopic disorders. Plasma histamine levels most likely are chronically elevated in migraineurs. Therefore, it is unlikely that a recurrent atopic/hypersensitive disorder underlies the migraine pathogenesis.

From the available literature, we can draw the conclusion that migraineurs have an increased susceptibility for various infections and benefit from eradication of Helicobacter pylori. The decreased interictal lymphocyte phagocytotic capacity and increased plasma levels of TNF-α and histamine are additional evidence for increased infection susceptibility of migraineurs. It is well known that stress and glucocorticoids suppress the function of the immune system and cause increased vulnerability for infections (123). Stress relief and associated reduction of plasma levels of cortisol improve the immune function and the response to infections (123, 124). Vasoactive compounds functioning as mediators of inflammation could be precipitators of a migraine attack in the vulnerable subjects. Moreover, it has been demonstrated that oestrogens enhance and androgens suppress the immune response (125), implicating selective periods in the monthly female cycle as important factors for migraine precipitation after infection. A differential role of the sex hormones in immune system function may explain the higher migraine prevalence in females (1).

Footnotes

Acknowledgements

The authors would like to thank Glaxo-Wellcome, Zeist, the Netherlands for sponsoring the project and Dr I. Molema for critical reading of the manuscript and commenting on clarity of fundamental immunological aspects.

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Migraine and Function of the Immune System: A Meta-Analysis of Clinical Literature Published Between 1966 and 1999

Abstract

Keywords

Introduction

Migraine: hypersensitivity and infections

Methods

Immunoglobulin E

Histamine

Immunoglobulins and complement

Immune cells

Mediators of inflammation: the cytokines

Discussion

Conclusion

Footnotes

Acknowledgements

References