Provocation of migraine by dietary components has been clearly described in
the medical literature for over 100 years. Competing immunologic and metabolic
concepts of pathogenesis have been proposed. The metabolic concept inroducted
by Alex Russell1,2,3 was based upon inherited enzyme deficiencies,
in some apparently increasing the sensitivity of migraineurs to vasoactive substances
consumed in food. Deficient activity of monoamine- and diamine-oxidases and
of phenolsulphotransferase have been described. Phenolic amines have been suggested
as triggers. The failure of tyramine administered alone to provoke migraine
in children has dampened enthusiasm for this hypothesis, although Russell’s
concept of a specifically metabolic and X-linked genetically determined form
of hyperammonemic migraine has not been refuted. The immunologic concept assumes
a delayed allergic mechanism. Egger proposed a two-stage process in migraine
provocation: allergic reaction to foods increases intestinal permeability to
vasoactive substances derived from food or gut flora.
Marteletti and his colleagues have found evidence of altered immune activation
in pediatric and adult migraine. Following food challenge their subjects demonstrate
an increase in circulating immune complexes and in total and activated T-cells.
Egger et al have published the only double-flind placebo-controlled trials
of food intolerance in childhood migraine, confirming specific food sensitivities
in 52% of children with severe, frequent migraine. An average delay of two days
between exposure and symptom supports the thesis that provocation occurs in
stages. Egger, McEwen and Stolla subsequently demonstrated that children with
food-induced migraine could be desensitized to their food triggers by an immunologic
hyposensitization procedure. At the study'’ end, 80% of children receiving active
treatment and 25% of children receiving placebo were able to resume a full normal
diet without experiencing migraine attacks (p=0.001).
These studies support a role of immunologic hypersensitivity in the genesis
of migraine in food-intolerant children.
Migraine headache and food intolerance are ancient phenomena, each mentioned
in the Hippocratic texts. Pediatric migraine as a distinct disorder received
relatively little attention until the middle of this century when Vahlquist
established strict criteria for its definition. These were paroxysmal headache
separated by pain-free intervals, associated with two fo the following four
features; nausea or vomiting, visual aura, positive family history of migraine,
unilateral distribution of throbbing pain.4 In studies conducted
twenty years apart in different countries, Bille5 and Silanpaa6
found the prevalence of migraine among schoolchildren to be approximately 4%,
using Valquist’s criteria.
A role for dietary components in provoking attacks of migraine was first clearly
described in Living’s classic monograph of 1873, which included four cases of
food-induced migraine7. During the first half of this century, numerous
reports of an association between migraine and food appeared, most attributing
headache to allergy8-13. The weak association between food-induced
migraine and total IgE levels or the results of cutaneous prick tests, however,
led some authors to doubt the existence of allergic headache14-17.
BIOCHEMICAL PROVOCATION OF MIGRAINE
Over the past three decades, competition between immunologic and pharmacologic
mechanisms for food-induced migraine has received considerable attention. The
pharmacologic concept was initiated by Hannington in 1967, when she proposed
that food-borne tyramine, not anti- genic protein, was the trigger18.
In subsequent reports, Hannington and her colleagues suggested that migraineurs
are sensitive to tyramine because of a deficiency of monoamine oxidase in plateletsl19,20.
The defect in monoamine oxidase proved to be transitory, however, a result rather
than a cause of the migraine state21, and the group's attention turned
to a persisting deficiency of platelet phenolsulphotransferase as the underlying
biochemical defect in migraine22. Phenolsulphatransferase not only
inactivates phenylethylamines23 but also metabolizes other foodderived
phenols such as the flavonoids which may act as triggers for red wine headache24.
Additional candidates for the chief biochemical trigger of migraine have been
advanced by researchers in Sweden, Canada and Germany, based upon response to
exclusion diets. These include tryptophan, the precursor of serotonin25,
phenylalanine, the precursor of norepinephrine (which stimulates platelet serotonin
release)26 and histamine (which allegedly accumulates because of
a deficiency of diamine oxidase)27. The notion that food chemicals
provoke migraine because of enzymatic deficiency implies an inborn error of
metabolism, yet very few children with migraine have been studied biochemically.
During two double-blind placebo-controlled trials of tyramine feeding, Forsyth
and Redmond were unable to induce migraine headache in children28.
A similar study in adults also yielded negative results29. It seams
unlikely that monoamines alone are the principal. food triggers for pediatric
migraine, although Russell's concept of a specifically metabolic and X-linked
genetically determined form of hyperamnionemic migraine has not been refuted.
Indeed, the vindication of its X-linked transmission supports its analogy as
one form of classical migraine1.
IMMUNOLOGIC EVENTS IN THE GENESIS OF MIGRAINE
Marteletti and his colleagues have found evidence of immunologic disturbance
following food challenges in patients with ostensibly food-related migraine,
specifically an increase in circulating immune complexes and activated T-cells30,31
and a decline in circulating levels of IL-4 and IL-6 accompanied by an increase
in gamma-IFN and GM-CSF32. They have also demonstrated protection
against precipitation of migraine attacks by oral administration of sodium cromoglycate,
a stabilizer of mast cell membranes33. Prophylactic benefits of sodium
cromoglycate in adult migraine have been demonstrated by Mansfield et al in
a double-blind placebo-controlled trial34 and by Monro et al35,36.
Paganelli found that ingestion of allergenic foods by atopic individuals produces
an increase in circulating immune complexes containing food protein, which can
be attenuated by pretreatment with cromolyn sodium37. Doering has
proposed that failure of migraineurs to clear food-containing circulating immune
complexes may precipitate an immunologically mediated headache and that susceptibility
to immunecomplex phenomena cannot be detected by prick tests or IgE measurements38.
Egger has attempted to weld together immunologic and pharmacologic mechanisms
in migraine with his proposal that food allergic reactions cause an increase
in small intestinal mucosal permeability which allows excessive absorption of
vasoactive substances from the gut, derived either from food or from the endogenous
flora39. His theory receives indirect support from the work of Andre
and of Dupont in Paris. Each has demonstrated that ingestion of food allergens
by atopic children causes an increase in para-cellular permeability of the small
intestine to biochemical substances such as the disaccharide lactulose, which
are ordinarily not absorbed from the intestinal tract. Dupont found a weak correlation
between prick test results and increased permeability in response to food challenge,
but a strong clinical correlation between provocation of allergic symptoms and
an increase in permeability on challenge40,41. Andre was able to
show that pre-treatment with cromolyn attenuated the permeability increase42
and concluded that the increase in permeability in response to food is more
sensitive and specific than prick tests or RAST and by itself constitutes an
accurate diagnostic test of food allergy43. If food-induced eczema
is considered a model for immunologic food allergy, then the inconsistent relationship
between prick test or RAST results and clinical response to food challenge is
found in atopic eczema as well as migraine and does not constitute evidence
against an immunologic basis for migraine. In contrast the protective effect
of sodium cromoglycate in both conditions suggests a pathogenetic role for gut
OLIGOANTIGENIC DIETS FOR MIGRAINE
In 1970, McEwen and Constantinopoulos published the results of a prospective
trial of diet in so-called "intrinsic" asthma44. Three years later,
Professor Soothill of the Hospital for Sick Children, Great Ormond Street, London,
began investigating the role of non-atopic dietary hypersensitivity in a number
of common diseases of childhood, including migraine. Soothill accepted six principles
for dietary trials of nonatopic food sensitivity which had been set down by
McEwen. These are:
(1) The essential baseline for further investigation is a symptom-free patient
on a formal diagnostic diet.
(2) Because food intolerances are often multiple, the diagnostic diet must
be limited to a small number of foods which are unlikely to provoke intolerance
(3) Because non-atopic sensitivity often provokes prolonged and fluctuating
symptoms, the diagnostic diet must be administered for sufficient time to allow
remission to occur and b_~ clearly recognized, usually two to three weeks.
(4) Because the symptoms of food intolerance are often delayed, testing by
dietary reintroduction of foods which have been avoided must be restricted to
one new food per week, which is eaten daily during the challenge period.
(5) As the dose-response curve of food intolerance is bell-shaped, challenge
with Virget foods should be done using normal quantities, not excessive quantities.
Foods provoking migraine
in 76 children
(Egger et al, Lancet 1983)