Læknablaðið : fylgirit - 01.05.2002, Blaðsíða 24

ABSTRACTS / 33RD SNC & 2ND SCNN
ratus in the head on which these mechanisms play. In migraine with
aura evidence continues to increase in favor of cortical spreading
depression as the underlying mechanism. Thus, recent MR-BOLD
studies have confirmed the previously observed slowly spreading
oligemia and reversible, slowly spreading inhibition of cortical
activation. Cortical spreading depression phenomenon probably
triggers the painful migraine attack via leakage of neurotrans-
mitters and ions from cortical cellular element and subsequent
depolarization of perivascular sensory nerve terminals. In migraine
without aura there is no evidence of blood flow changes or cortical
spreading depression. Here it has been hypothesized that the attack
may start in the brain stem where a so-called migraine generator
area has been shown. Whether or not these findings hold up, there
is little doubt that subsequent nociception (pain triggering) takes
place in sensory nerve endings around cranial arteries. These nerve
endings are sensitized and there may be sensitization also at higher
levels of the neuraxis. The peripheral changes may lead to release of
calcitonin gene-related peptide and other peptides and mono-
amines. CGRP occurs in increased quantity in the external jugular
venous blood during a migraine attack. Other messenger molecules
that are important include nitric oxide (NO) and 5-hydroxytrypta-
mine (5-HT). The migraine attack can be induced by nitroglycerin,
which is a prodrug for NO. Furthermore, an inhibitor of nitric oxide
syntase is effective in reducing or curing pain during a spontaneous
migraine attack. Infusion of CGRP can cause a migraine attack.
The most efficient drugs for migraine are interacting with the 5-HT
receptors. The triptans are 5-HTlb/d agonists and highly effective in
the treatment of acute migraine attack, while certain prophylactic
drugs are 5-HT antagonists probably mainly at the 5-HT2 receptor.
Further studies have clarified the neurobiology of the headache
pain pathway. Thus, stimulation of vascular structures such as the
superior saggital sinus induces activity in nucleus caudalis of the
trigeminal nerve as reflected in C-fos expression. The pharmaco-
logy of this first synapse in the trigeminal vascular pain pathway has
been extensively described. In recent years, it has also been clearly
demonstrated that the sensory affective components of pain may be
discriminated at a cortical level. Here PET studies and MR-activa-
tion studies have contributed significantly but a more detailed
understanding of the role of the hemispheres in headache percep-
tion is still to come.
Tlie neurobiological understanding of migraine has thus pro-
gressed tremendously. Even more exciting is that: this research has
lead to the identification of several new targets for drug develop-
ment for migraine. The likelihood is overwhelming that our already
good therapeutic possibilities will be further enhanced in the near
future.
18 - Genetics of migraine
Kallela M, Wessman M
Historical perspective: It has been known for centuries that mig-
raine runs in families and many studies have addressed the inheri-
tance of migraine. Still there is no consensus on the mode of inheri-
tance of the common types of migraine, migraine with and without
aura. There are various reasons for this. Firstly, migraine is so pre-
valent that it might easily occur in several family members just by
chance. Secondly, variable definitions of migraine have been used
and the diagnostic criteria have changed from time to time. In
addition, the family studies are also demanding: all family members
should be interviewed directly, migraine with and without aura
should be accurately differentiated and population based cohorts
should be used instead of clinical patients.
Family studies: Two population based studies have addressed the
heredity of migraine using the IHS criteria and making a distinction
between migraine with and without aura. Based on these studies,
Russell and colleagues concluded that migraine is a hereditary
disease, migraine with and without aura are distinct entities, and
that migraine with aura is largely or exclusively determined by
genetic factors while in migraine without aura also environmental
factors are important. It is very likely that a syndrome as diverse as
migraine is not inherited in any simple way, and, indeed, segrega-
tion studies of migraine have suggested for multifactorial inheri-
tance.
Twin studies: Several twin studies have supported a strong genetic
component for migraine. Merikangas reviewed twin studies com-
paring monozygotic (MZ) and dizygotic (DZ) twins and concluded
that about 50% of the predisposition to migraine can be considered
heredilary. Table 1 summarises probandwise concordance rates and
heritability figures from seven large population based twin studies.
In a recent twin study involving MZ and DZ twins raised together
and apart Ziegler came up to an estimate of 52%, which is probably
the best heritability estimate of migraine to date.
Molecular genetic studies: Recent molecular genetic studies have
provided new and important information on migraine pathophysio-
logy. Several chromosomal gene loci relevant to migraine have
been identified. Mitochondrial DNA has also been studied.
In 1993 a gene for familial hemiplegic migraine (FHM) was
linked to chromosome 19 and in 1996 the first gene for FHM was
found. The gene, CACNAl A, codes for a subunit (alfa 1A subunit)
of a calcium channel (P/Q type voltage sensitive Ca2+ channel) and
this discovery has evolved theories of migraine as a “chanello-
pathy”. Additional linkage of FHM to chromosome 1 has been
found by two groups. The gene (or genes) has not yet been identi-
Table 1. Population-based Twin Studies of Migraine.
Migraine Probandwise concordance
Population sample Author IHS type MZ DZ Heritability
USA Corey et al. (1991) - Migraine 0.35 0.17 0.36
Norway Corey et al. (1991) - Migraine 0.32 0.18 0.28
Sweden Larsson (1995) + Migraine 0.48 0.31 0.39-0.58
Australia Merikangas et al (1994) + Migraine 0.44 0.24 0.36
Finland Honkasalo et al. (1995) - Migraine 0.28 0.12 0.34-0.51
Denmark Gervil et al. (1999) + MwoA 0.43 0.31 0.61
Denmark Ulrich et al. (1999) + MwA 0.34 0.12 0.65
MwoA = migraine without aura, MwA = migraine with aura, IHS+ = a study using the IHS criteria for migraine, IHS- = a study using other criteria, MZ ! = monozygotic, DZ = dizygotic
24 Læknablaðið/Fylgirit 43 2002/88