Recent animal studies on the mechanism of migraine show that intracranial pain is accompanied by increased periorbital skin sensitivity. These findings suggest that the pathophysiology of migraine involves not only irritation of meningeal perivascular pain fibers but also a transient increase in the responsiveness (ie, sensitization) of central pain neurons that process information arising from intracranial structures and skin. The purpose of this study was to determine whether the increased skin sensitivity observed in animal also develops in humans during migraine attacks. Repeated measurements of mechanical and thermal pain thresholds of periorbital and forearm skin areas in the absence of, and during, migraine attacks enabled us to determine the occurrence of cutaneous allodynia during migraine. Cutaneous allodynia is pain resulting from a nonnoxious stimulus to normal skin. In 79% of the patients, migraine was associated with cutaneous allodynia as defined, and in 21% of the patients it was not. The cutaneous allodynia occurred either solely within the referred pain area on the ipsilateral head, or within and outside the ipsilateral head. Cutaneous allodynia in certain well‐defined regions of the skin during migraine is an as yet unreported neurological finding that points to hyperexcitability of a specific central pain pathway that subserves intracranial sensation. Ann Neurol 2000;47:614–624

Summary:Purpose: On the basis of the neuroactive properties of estradiol and progesterone and the menstrually related cyclic variations of their serum concentrations, we propose the existence of three hormonally based patterns of seizure exacerbation. Because previous reports both support and refute the concept of catamenial epilepsy, we test the hypothesis by charting seizures and menses and measuring midluteal serum progesterone levels to estimate the frequency of epileptic women with catamenial seizure exacerbation.Methods: One hundred eighty-four women with intractable complex partial seizures (CPS) charted their seizure occurrence and onset of menstruation on a calendar for one cycle during which they had a midluteal blood sample taken for serum progesterone determination on day 22. Levels >5 ng/ml were considered ovulatory. The cycle was divided into four phases with onset of menstruation being day 1: menstrual (M) = -3 to +3, follicular (F) = 4 to 9, ovulatory (0) = 10 to -13, and luteal (L) = -12 to -4. Average daily seizure frequency for each phase was calculated and compared among phases by repeatedmeasures analysis of variance (ANOVA) and the StudentNewman-Keul's test, separately for ovulatory and anovulatory cycles.Results We propose the existence of three hormonally based patterns of seizure exacerbation in epilepsy (1). Seizures do not occur randomly in most men and women with epilepsy (2). They tend to cluster in >50% of cases (2). Seizure clusters in turn may occur with temporal rhythmicity in a significant proportion of men (29%) and women (35%) with epilepsy (3). In women, seizures may cluster in relation to the menstrual cycle; such seizures are commonly termed catamenial epilepsy (4) and may be attributable to (a) the neuroactive properties of steroid hormones and (b) the cyclic variation in serum levels.Estradiol inhibits y-aminobutyric acid (GABA) and potentiates glutamatergic transmission (5). It increases neuronal metabolism and discharge rates (5,6). It pro-

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A variety of seemingly diverse pain syndromes are characterized by movement-induced pain radiating in the distribution of a peripheral nerve or nerve root. This could be explained by the induction of ectopic mechanical sensitivity in intact sensory axons. Here we show that inflammation led to mechanical sensitivity of the axons of a subset of mechanically sensitive primary sensory neurons. Dorsal root recordings were made from 194 mechanically sensitive neurons that innervated deep and cutaneous structures and had C, Adelta, and Aalphabeta conduction velocities. No axons of any category were mechanically sensitive in control experiments. However, the axons of neurons innervating deep structures and having C- or Adelta-conduction velocities became mechanically sensitive during the neuritis, and also exhibited an increased incidence of spontaneous discharge. The incidence of mechanical sensitivity followed a distinct time course. In some cases, paw withdrawal thresholds were obtained after neuritis induction. The time course of the resultant hypersensitivity was not directly related to the time course of the axonal mechanical sensitivity. Ectopic axonal mechanical sensitivity could explain some types of radiating, nerve-related pain coexisting with diseases of seemingly diverse etiologies.