Environmental manganese (Mn) toxicity causes an extrapyramidal, parkinsonian-type movement disorder with characteristic magnetic resonance images of Mn accumulation in the basal ganglia. We have recently reported a suspected autosomal recessively inherited syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia in cases without environmental Mn exposure. Whole-genome mapping of two consanguineous families identified SLC30A10 as the affected gene in this inherited type of hypermanganesemia. This gene was subsequently sequenced in eight families, and homozygous sequence changes were identified in all affected individuals. The function of the wild-type protein and the effect of sequence changes were studied in the manganese-sensitive yeast strain Δpmr1. Expressing human wild-type SLC30A10 in the Δpmr1 yeast strain rescued growth in high Mn conditions, confirming its role in Mn transport. The presence of missense (c.266T>C [p.Leu89Pro]) and nonsense (c.585del [p.Thr196Profs(∗)17]) mutations in SLC30A10 failed to restore Mn resistance. Previously, SLC30A10 had been presumed to be a zinc transporter. However, this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain. This is an important step toward understanding Mn transport and its role in neurodegenerative processes.

IntroductionMelatonin has been studied in headache disorders. Amitriptyline is efficacious for migraine prevention, but its unfavourable side effect profile limits its use.MethodsA randomised, double-blind, placebo-controlled study was carried out. Men and women, aged 18–65 years, with migraine with or without aura, experiencing 2–8 attacks per month, were enrolled. After a 4-week baseline phase, 196 participants were randomised to placebo, amitriptyline 25 mg or melatonin 3 mg, and 178 took a study medication and were followed for 3 months (12 weeks). The primary outcome was the number of migraine headache days per month at baseline versus last month. Secondary end points were responder rate, migraine intensity, duration and analgesic use. Tolerability was also compared between groups.ResultsMean headache frequency reduction was 2.7 migraine headache days in the melatonin group, 2.2 for amitriptyline and 1.1 for placebo. Melatonin significantly reduced headache frequency compared with placebo (p=0.009), but not to amitriptyline (p=0.19). Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency. Melatonin was better tolerated than amitriptyline. Weight loss was found in the melatonin group, a slight weight gain in placebo and significantly for amitriptyline users.ConclusionsMelatonin 3 mg is better than placebo for migraine prevention, more tolerable than amitriptyline and as effective as amitriptyline 25 mg.

Increased plasma pro-inflammatory and decreased anti-inflammatory cytokines have been implicated in physiological and behavioural aspects of mood- and pain-related disorders, including migraine. In this case-control study, we assessed mood scores, cardiorespiratory fitness (VO), and plasma concentrations of TNF-α, IL-1β, IL-6, IL-8, IL-10, and IL-12p70 interictally in women with episodic migraine with/without aura (ICHD-II), taking no preventive medicine, and in healthy women recruited from São Paulo Hospital and local community, respectively. Thirty-seven participants (mean±SD age=34±10 and BMI=26.5±4.9) were assessed. Groups (Control, n=17; Migraine, n=20) showed no differences in age, BMI, and VO. Migraine patients showed higher tension (p=0.019) and anxiety scores (p=0.046), TNF-α (p<0.01), and IL-12p70 (p=0.01), while IL-6 (p<0.01), IL-8 (p<0.01), and IL-10 (p<0.01) were decreased compared to control group. Multiple linear regression models showed that migraine was positively associated with TNF-α and IL-12p70, and negatively associated with IL-6, IL-8, and IL-10. Anxiety scores were positively associated with IL-12p70, and VO was negatively associated with TNF-α. In conclusion, an exaggeratedly skewed cytokine profile, in particular the TNF-α and 12p70/IL-10 balance may be related to migraine pathomechanisms, and its psychiatric comorbidities and functional capacity. Additional studies are needed to confirm these results.

Objective: To conduct a randomized controlled trial to evaluate the effect of a 12-week aerobic exercise program for migraine prevention, plasma cytokines concentrations (TNF-α, interleukin [IL]-1β, IL-6, IL-8, IL-10, and IL-12p70), and anxiety in women with migraine. Methods: Women with episodic migraine (ICHD-II), aged between 20 and 50 years, who had never taken any prophylactic medication, and were physically inactive in the past 12 months were recruited from the university’s hospital and a tertiary headache clinic between March 2012 and March 2015. Migraine attacks were recorded in headache diaries, cytokines were quantified by flow cytometry, and anxiety was assessed by the 7-item General Anxiety Disorder (GAD-7) scale. Blood sampling and psychometric interviews were undertaken on headache-free days. Results: Twenty participants ([mean ± SD] age 33.8 ± 10.5; BMI 26 ± 5.2) were randomly assigned and received intervention (“trained”: n = 10) or entered on a waitlist (“inactive”: n = 10). There were no differences between groups regarding patients’ characteristics and baseline data. Days with migraine (p = 0.001), IL-12p70 levels (p = 0.036), and GAD-7 score (p = 0.034) were significantly reduced in the trained group after the intervention period, but there were no significant changes in these variables in the inactive group. There was no change in the levels of the other cytokines in either group. There were positive correlations between a reduction in IL-12p70 level and a reduction in the number of days with migraine (R² = 0.19, p = 0.045), and GAD-7 score (R² = 0.53, p < 0.001). Conclusion: The clinical and psychological therapeutic effects of aerobic exercise in treatment-naïve women with migraine may involve the downregulation of IL-12p70.

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Recurrent painful ophthalmoplegic neuropathy, previously known as ophthalmoplegic migraine, is a rare condition that affects children and young adults. Its cause and classification are still controversial and, consequently, there are no published treatment guidelines or consensus. Glucocorticoids seem to be beneficial for some patients, but there is no established treatment when failure of this therapy occurs. The aim of this study was to report a case where pregabalin was successfully used after failure of glucocorticoid therapy in a patient with recurrent painful ophthalmoplegic neuropathy.