Deficiency of tumor necrosis factor α in a subclass of menstrual migraineurs

Objective. - The objective of this study was to determine whether differences in urinary proinflammatory cytokines, interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α), exist between migraineurs and nonheadache control subjects, and between nonhormonal migraine and menstrual migraine. Any differences noted would expand and clarify a neuroimmune hypothesis of migraine pathogenesis and lead to future diagnostic markers or therapeutic options or both for the disorder. Background. - Current theories of migraine pathogenesis focus on biochemical abnormalities in the central nervous system resulting in sterile inflammation of meningeal blood vessels. Vasoactive substances involved in this process may include substance P, calcitonin gene-related peptide, neurokinin A, serotonin, and nitric oxide. Immune cell products, such as histamine, leukotrienes, and cytokines, also have vascular inflammatory properties. Methods. - A study of proinflammatory cytokines, IL-1β, IL-6, and TNF-α, was undertaken in menstrual migraineurs. During and outside of menses, 24-hour urine samples of 19 women with migraine were taken during a menstrual migraine, a nonmenstrual migraine, and a headache-free day, and compared with 24-hour urine samples taken of 10 nonheadache controls during and outside of menses. Results. - A neuroimmune mechanism for migraine was tested with expected increases in proinflammatory cytokines tested during a migraine. This hypothesis was not validated. Mean IL-6 levels were increased in all three samples of migraineurs versus controls, but did not achieve statistical significance. No differences were found in IL-1β levels between samples. Interestingly, marked differences were found in TNF-α values in menstrual migraineurs. Twelve (63%) of 19 migraineurs had at least one urine sample with undetectable TNF-α levels, whereas none of the 20 samples given by the 10 nonheadache controls in this study had undetectable levels. Thirty-two samples from men with cluster headache and nonheadache control subjects in prior studies had detectable levels. Conclusions. - This deficiency of TNF-α levels in women with migraine may signal a disordered neuroimmune communication network and predisposition to migraine.