Migraine as a complex disease:heterogeneity, comorbidity and genotype-phenotype interactions.

Migraine is a chronic illness interspersed with acute signs and symptoms which is currently defined, according to IHS criteria, in terms of "attacks". However, this should not lead us to ignore a critical point emerging from the simple observation of patients, i.e. the variability of the combinations in which the disease manifests itself in the same individual and especially in different individuals. This heterogeneity underpins both migraine "as attacks" (e.g. presence/absence of aura, different pain severity) and migraine "as a disease" (e.g. different onset, occurrence, association with other diseases, evolution, outcome). Genetic determinants are certainly at the basis of some migraine forms, and the role of genetics is now increasing due to the better phenotypical characterization rendered possible by the 1988 criteria. In most cases, however, migraine occurs as multifactorial inherited character. The level of complexity is further increased by the effect of "modifying" genes (such as those encoding for dopamine receptors), by comorbidity (the non coincidental association with other neurological diseases), and by the fact that the expression of comorbidity varies over time (phenotypical heterochronia). The clinical-descriptive approach allows only a partial understanding of migraine, the nature of which is more complex and heterogeneous than previously thought.