Urine 5-Hydroxyindoleacetic Acid Negatively Correlates with Migraine Occurrence and Characteristics in the Interictal Phase of Episodic Migraine.

Although migraine belongs to the main causes of disability worldwide, the mechanisms of its pathogenesis are poorly known. As migraine diagnosis is based on the subjective assessment of symptoms, there is a need to establish objective auxiliary markers to support clinical diagnosis. Tryptophan (TRP) metabolism has been associated with the pathogenesis of neurological and psychiatric disorders. In the present work, we investigated an association between migraine and the urine concentration of TRP and its metabolites 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QA) in 21 low-frequency episodic migraine patients and 32 controls. We chose the interictal phase as the episodic migraine patients were recruited from the outpatient clinic and had monthly migraine days as low as 1-2 in many cases. Migraine patients displayed lower urinary levels of 5-HIAA (p < 0.01) and KYNA (p < 0.05), but KYN and QA were enhanced, as compared with the controls (p < 0.05 and 0.001, respectively). Consequently, the patients were characterized by different values of the 5-HIAA/TRP, KYN/TRP, KYNA/KYN, and KYNA/QA ratios (p < 0.001 for all). Furthermore, urinary concentration of 5-HIAA was negatively correlated with Migraine Disability Assessment score and monthly migraine and monthly headache days. There was a negative correlation between Patient Health Questionnaire 9 scores assessing depression. In conclusion, the urinary 5-HIAA level may be further explored to assess its suitability as an easy-to-determine marker of migraine.

Endogenous Melatonin Levels and Therapeutic Use of Exogenous Melatonin in Migraine: Systematic Review and Meta-Analysis.

BACKGROUND: Sleep disorders and circadian dysregulation appear to be associated with primary headache disorders. OBJECTIVE: The aim of this study was to review the existing evidence for the deployment of melatonin in migraine prophylaxis. Initially, case-control studies investigating nocturnal melatonin and 6-sulphatoxymelatonin (aMT6s, melatonin metabolite discarded by the urine) levels in patients with migraine and healthy controls (HC) would be reviewed and meta-analyzed. Second, results from randomized controlled trials (RCTs) and non-randomized studies evaluating the use of melatonin in migraine would be synthesized. METHODS: MEDLINE EMBASE, CENTRAL, PsycINFO, trial registries, Google Scholar, and OpenGrey were comprehensively searched. The quality of studies was assessed according to the Newcastle-Ottawa Scale (case-control studies) and the Risk-of-Bias Cochrane tool (RCTs). Random-effects (RE) or fixed-effects (FE) model was used based on heterogeneity among studies (homogeneity assumed when PQ > 0.1 and I2  < 30%). Publication bias was assessed by funnel plots. RESULTS: Literature search provided 11 case-control studies. Evidence was compatible with lower nocturnal serum [5 of 6 studies were synthesized due to deficient reporting of 1 abstract, migraine n = 197, HC n = 132, RE MD = -12.29 pg/ml, 95%CI = (-21.10, -3.49)] and urinary melatonin [3 studies, migraine n = 30, HC n = 29, RE MD = -0.12 nmol/nocturnal (12 hours) urinary collection, 95%CI = (-0.22, -0.03)], as well as urine aMT6s levels [1 study, migraine n = 146, HC n = 74, MD = -11.90 µg/nocturnal (12 hours) urine collection, 95%CI = (-19.23, -4.57)] in adult migraine patients compared to HC [1 study involving children did not reveal any difference regarding nocturnal urine aMT6s, n = 18 per group, MD = -6.00 µg/nocturnal (12 hours) urine collection, 95%CI = (-21.19, 9.19)]. Regarding the treatment-prevention of migraine, 7 RCTs and 9 non-randomized studies were retrieved. Data synthesis was not feasible for the comparison of melatonin and placebo due to the existing clinical and methodological heterogeneity of the 5 relevant RCTs. Overall, melatonin was more efficacious and equally safe with placebo in the prevention of migraine in adults (3 of 4 RCTs provided superior efficacy results for melatonin, 1 RCT revealed no difference regarding Headache Frequency -HF-), while there are limited data for children (1 RCT revealed no difference against placebo regarding HF). Additionally, no difference was revealed between melatonin and amitriptyline (1 RCT), sodium valproate (1 RCT) or propranolol (1 non-randomized study) with respect to their efficacy in adults with migraine, while melatonin was more effective than pizotifen (1 RCT). In children with migraine, amitriptyline is more efficacious regarding most assessed parameters (2 studies, n = 85 per group, HF: RE MD = 4.03, 95%CI = (2.64, 5.42), Headache Duration: RE MD = 0.72, 95%CI = (0.41, 1.03), Headache Severity: FE MD = 1.57, 95%CI = (1.13, 2.00), Response to Treatment: FE MD = 0.33, 95%CI = (0.16, 0.69), Headache Induced Disability Severity: RE MD = 6.07, 95%CI = (-11.87, 24.01 ), Analgesic Consumption - assessed in 1 study, n = 40 per group - MD = 1.11, 95%CI = (-0.10, 2.32)), although melatonin presents a superior safety profile than amitriptyline both in adults and in children. CONCLUSIONS: Melatonin may be of potential benefit in the treatment-prevention of migraine in adults, but complementary evidence from high-quality RCTs is required.

Preliminary Evidence that Melatonin Is not a Biomarker in Children and Adolescents With Episodic Migraine.

BACKGROUND: To date, there have not been reliable biomarkers to identify impending migraine episodes. A prior study in adults with migraine demonstrated a reduction in the urinary metabolic substrate of melatonin (urinary 6-sulfatoxymelatonin; aMT6s) during a migraine. The aim of this study was to examine whether evening urinary melatonin metabolite levels could predict migraine the next day in children and adolescents with migraine. METHODS: Twenty-one children and adolescents with migraine (aged 5-17 years) were recruited to this observational study conducted at UC San Francisco to provide urine samples for 10 days and maintain a prospective headache diary during the same period. Nightly melatonin metabolite 6-sulfatoxymelatonin in urine was assayed and results from nights preceding migraine were compared to nights preceding a non-headache day. RESULTS: Mean (±SD) aMT6s levels the night prior to a migraine attack were 56.2 ± 39.0 vs 55.4 ± 46.6 ng/mL (P = .915), and mean melatonin metabolite levels the night following migraine were 55.5 ± 46.9 vs 57.0 ± 37.7 ng/mL (P = .841). However, in post hoc exploratory analyses, aMT6s levels were lower the night before a migraine in those who experienced aura or premonitory symptoms. CONCLUSION: While urinary melatonin metabolites do not predict migraine attacks in children and adolescents overall, they may be predictive in those who experience premonitory phase symptoms as part of their migraine attacks.

Ovarian hormones, age and pubertal development and their association with days of headache onset in girls with migraine: An observational cohort study.

Background Fifty-three percent of adolescent girls report headaches at the onset of menses, suggesting fluctuations of ovarian hormones trigger migraine during puberty. Aims To determine if urinary metabolites of estrogen and progesterone are associated with days of headache onset (HO) or severity in girls with migraine. Methods This was a pilot study and included 34 girls with migraine balanced across three age strata (pre-pubertal (8-11), pubertal (12-15), and post-pubertal (16-17) years of age). They collected daily urine samples and recorded the occurrence and severity of headache in a daily diary. Urine samples were assayed for estrone glucuronide (E1G) and pregnandiol glucuronide (PdG) and the daily change was calculated (ΔE1G, ΔPdG). Pubertal development was assessed by age, pubertal development score (PDS), and menstrual cycle variance. The primary outcome measures were HO days and headache severity. Generalized linear mixed models were used, and included the hormonal variables and three different representations of pubertal development as covariates. Results Models of HO days demonstrate a significant age*PdG interaction (OR 0.85 [95% CI 0.75, 0.97]) for a 1 standard deviation increase in PdG and three-year increase in age. A separate model showed a significant PDS*PdG interaction (OR -0.85 [95% CI; 0.76, 0.95]). ΔPDG was associated with headache severity in unadjusted models ( p < 0.017). Conclusion Age and pubertal development could moderate the effect of ovarian hormones on days of headache onset in girls with migraine.

Sex hormones in women with and without migraine: Evidence of migraine-specific hormone profiles.

OBJECTIVE: To compare daily sex hormone levels and rates of change between women with history of migraine and controls. METHODS: History of migraine, daily headache diaries, and daily hormone data were collected in ovulatory cycles of pre- and early perimenopausal women in the Study of Women's Health Across the Nation. Peak hormone levels, average daily levels, and within-woman day-to-day rates of decline over the 5 days following each hormone peak were calculated in ovulatory cycles for conjugated urinary estrogens (E1c), pregnanediol-3-glucuronide, luteinizing hormone, and follicle-stimulating hormone. Comparisons were made between migraineurs and controls using 2-sample t tests on the log scale with results reported as geometric means. RESULTS: The sample included 114 women with history of migraine and 223 controls. Analyses of within-woman rates of decline showed that E1c decline over the 2 days following the luteal peak was greater in migraineurs for both absolute rate of decline (33.8 [95% confidence interval 28.0-40.8] pg/mgCr vs 23.1 [95% confidence interval 20.1-26.6] pg/mgCr, p = 0.002) and percent change (40% vs 30%, p < 0.001). There was no significant difference between migraineurs and controls in absolute peak or daily E1c, pregnanediol-3-glucuronide, luteinizing hormone, and follicle-stimulating hormone levels. Secondary analyses demonstrated that, among migraineurs, the rate of E1c decline did not differ according to whether a headache occurred during the cycle studied. CONCLUSIONS: Migraineurs are characterized by faster late luteal phase E1c decline compared to controls. The timing and rate of estrogen withdrawal before menses may be a marker of neuroendocrine vulnerability in women with migraine.

Urinary leukotriene E4 and prostaglandin F2a concentrations in children with migraine: a randomized study.

OBJECTIVES: Pro-inflammatory mediators are thought to play both peripheral and central roles in migraine pathophysiology. Prostaglandins and leukotrienes, known as the eicosanoids, are degradation products of arachidonic acid and constitute signalization components of inflammatory pathways. This study was designed to assess concentrations of leukotriene E4 (LT-E4) and prostaglandin F2a (PG-F2a) in children with migraine. MATERIALS AND METHODS: This study involved patients aged ≤18 years who presented to the Ondokuz Mayis University Children's Hospital with migrainous headache between January and October 2011. Urinary LT-E4 and PG-F2a concentrations were measured in patients during a headache episode and at a headache-free time and in a control group. RESULTS: The patient group consisted of 38 girls and 26 boys aged 5-18 years diagnosed with migraine and having at least 6 months of headache, whereas the control group consisted of 21 girls and 29 boys. Mean ± standard deviation (SD) urinary LT-E4 concentrations were significantly higher in patients during a migraine episode than in controls (1466.8±1052.5 pg/ml vs 811.6±460.0 pg/ml, P<0.001). In patients with migraine, both urinary LT-E4 (P<0.001) and PG-F2a (P=0.021) levels were significantly higher during headache than during non-headache periods. CONCLUSION: Urinary LT-E4 and PG-F2a were both significantly higher in children with migraine during headache than during non-headache periods. The elevation in the levels of these inflammatory mediators was compatible with the hypothesis relating neuroinflammation in trigeminal vascular blood vessels with migraine pathophysiology. Leukotriene antagonists may be effective in the prophylaxis of migraine attacks.

Urinary 6-sulphatoxymelatonin levels and sleep disorders in children with migraine.

We conducted the present study to assess melatonin secretion in a sample of children with migraine, to describe their sleep patterns and problems, and to examine the impact of sleep problems on migraine disability. The parents of 18 children with migraine completed the Children's Sleep Habits Questionnaire and Pediatric Migraine Disability Assessment Score in Arabic. The parents of 18 healthy controls also completed the Children's Sleep Habits Questionnaire. Urinary 6-sulphatoxymelatonin levels were determined with the enzyme-linked immunosorbent assay method. There was no significant difference in urinary 6-sulphatoxymelatonin between the migraine and control groups (Z = -0.127, P = .889). There were no significant differences between groups in Children's Sleep Habits Questionnaire subscales or total scores. There were significant correlations between bedtime resistance, parasomnias subscales, and migraine disability. Our findings indicate that nocturnal production of melatonin is not reduced in children with migraine, and sleep disturbances impact the degree of migraine disability.

Reduced urinary glutamate levels are associated with the frequency of migraine attacks in females.

BACKGROUND AND PURPOSE: Recent evidences indicate that glutamatergic homeostasis disorders are implicated in the pathogenesis of migraine. In particular, plasma and cerebrospinal fluid glutamate levels seem to be altered in migraine patients. However, the impacts of glutamate on migraine and especially on aura symptoms, alterations in the frequency of migraine attacks as well as investigations on glutamate on migraine-related metabolic dysfunctions, like hyperinsulinaemia, and an atherogenic lipid profile remain elusive to date. The aim of the present study was to investigate the impact of glutamate on migraine and related metabolic dysfunctions. METHODS: We investigated the urinary glutamate levels of female migraineurs (n = 48) in the interictal phase and healthy controls (n = 48). Parameters of the insulin- and lipid metabolism, inflammatory parameters and anthropometric parameters were additionally determined. RESULTS: Urinary glutamate levels of female migraineurs were significantly decreased with respect to the control group. Logistic regression revealed an odds ratio of 4.04 for migraine. We found a significant correlation with the time-period of patients' last attack and a significant inverse correlation with the annual frequency of migraine attacks. Other parameters of the insulin- and lipid metabolism, anthropometric and inflammatory parameters showed no significant correlation with glutamate levels. CONCLUSION: We show here that female migraineurs exhibit decreased urinary glutamate levels which are associated with a 4.04-fold higher risk for migraine and correlated with patients' frequency of migraine attacks.

Urinary 6-sulphatoxymelatonin levels are depressed in chronic migraine and several comorbidities.

OBJECTIVE: To assess urinary 6-sulphatoxymelatonin levels in a large consecutive series of patients with migraine and several comorbidities (chronic fatigue, fibromyalgia, insomnia, anxiety, and depression) as compared with controls. BACKGROUND: Urine analysis is widely used as a measure of melatonin secretion, as it is correlated with the nocturnal profile of plasma melatonin secretion. Melatonin has critical functions in human physiology and substantial evidence points to its importance in the regulation of circadian rhythms, sleep, and headache disorders. METHODS: Urine samples were collected into a single plastic container over a 12-hour period from 8:00 pm to 8:00 am of the next day, and 6-sulphatoxymelatonin was measured by quantitative ELISA. All of the patients were given a detailed questionnaire about headaches and additionally answered the following questionnaires: Chalder fatigue questionnaire, Epworth somnolence questionnaire, State-Trait Anxiety Inventory, and the Beck Depression Inventory. RESULTS: A total of 220 subjects were evaluated - 73 (33%) had episodic migraine, 73 (33%) had chronic migraine, and 74 (34%) were enrolled as control subjects. There was a strong correlation between the concentration of 6-sulphatoxymelatonin detected and chronic migraine. Regarding the comorbidities, this study objectively demonstrates an inverse relationship between 6-sulphatoxymelatonin levels and depression, anxiety, and fatigue. CONCLUSIONS: To our knowledge, this is the first study to evaluate the relationship between the urinary concentration of melatonin and migraine comorbidities. These results support hypothalamic involvement in migraine pathophysiology.

Low urinary 6-sulphatoxymelatonin concentrations in acute migraine.

Substantial evidence points to melatonin as playing a role in the regulation of circadian rhythms, sleep, and headache disorders. The objective of the study was to assess 6-sulphatoxymelatonin (aMT6s) levels in a large consecutive series of patients with migraine, comparing with controls. A total of 220 subjects were evaluated-146 had migraine and 74 were control subjects. Urinary samples were collected into the same plastic container since 8:00 p.m. to 8:00 a.m. of the next day (12-h period) and aMT6s was measured with quantitative ELISA technique. Among patients with migraine, 53% presented pain on the day of the urine samples collection. Their urinary aMT6s concentration was significantly lower than in the urine of patients without pain [14.0 +/- 7.3 vs. 49.4 +/- 19.0; t(143) = -15.1; 95% CI = -40.0 to -30.8; P < 0.001]. There was no significant difference in the aMT6s concentration of patients with migraine without pain on the day of their urine samples collection and controls [49.4 +/- 19.0 vs. 42.5 +/- 27.9; t(140) = 1.7; 95% CI = -1.2 to 14.8; P = 0.094]. To our knowledge, this is the first study to demonstrate reduction in melatonin levels during attacks in episodic and chronic migraine.

Increased urinary excretion of nitric oxide metabolites in longitudinally monitored migraine patients.

This study evaluated a relationship between nitric oxide (NO) and migraine attacks in order to gain insight into migraine pathomechanism. The study groups consisted of 12 migraineurs and eight controls. All subjects collected morning urine samples for 40 consecutive days. Urinary NO metabolites, nitrite/nitrate (NO(x)) levels were measured with the vanadium-based assay, whilst creatinine (Cr) and neopterin were determined with high-performance liquid chromatography. The mean urinary NO(x)/Cr ratio and number of NO(x) peaks was significantly greater in the migraine group compared with controls (P = 0.01 and P = 0.007, respectively). In the second approach, high NO(x) values were re-assessed in relation to raised neopterin, a marker of systemic infection or inflammation, and were excluded. The excretion of NO(x) persisted being pulsatile, and migraineurs had more peaks compared with controls (P = 0.01). In seven patients, NO(x) peaks coincided with headache days. This was more frequent than expected by random association in four patients (Monte-Carlo simulation; odds ratios: 2.16-7.77; no overlap of 95% CI). In four patients, NO(x) peaks preceded or followed headache days. Although there is a difference in the pattern of urinary NO(x) excretion between control and migraine populations, the variable temporal association of NO(x) peaks and headaches suggests a complex role of NO in this condition.

Incidence of migraine relative to menstrual cycle phases of rising and falling estrogen.

OBJECTIVE: To investigate the association between urinary hormone levels and migraine, with particular reference to rising and falling levels of estrogen across the menstrual cycle in women with menstrual and menstrually related migraine. METHODS: Women with regular menstrual cycles, who were not using hormonal contraception or treatments and who experienced between one and four migraine attacks per month, one of which regularly occurred on or between days 1 +/- 2 of menstruation, were studied for three cycles. Women used a fertility monitor to identify ovulation, conducting a test each day as requested by the monitor, using a sample of early morning urine. Urine samples were collected daily for assay of estrone-3-glucuronide, pregnanediol 3-glucuronide, follicle-stimulating hormone, and luteinizing hormone. All women kept a daily migraine diary and continued their usual treatment for migraine. RESULTS: Of 40 women recruited, data from 38 women were available for analysis. Compared with the expected number of attacks, there was a significantly higher number of migraine attacks during the late luteal/early follicular phase of falling estrogen and lower number of attacks during rising phases of estrogen. CONCLUSION: These findings confirm a relationship between migraine and changing levels of estrogen, supporting the hypothesis of perimenstrual but not postovulatory estrogen "withdrawal" migraine. In addition, rising levels of estrogen appear to offer some protection against migraine.

Defining the relationship between ovarian hormones and migraine headache.

OBJECTIVE: (1) To determine whether the attack characteristics of migraine differ between different intervals of the menstrual cycle; (2) To ascertain whether the "rate of change,""magnitude of change," or "total burden" of urinary hormone metabolites correlates with headaches outcome measures during different intervals of the menstrual cycle. BACKGROUND: The mechanisms through which migraines are influenced by ovarian hormones remain unclear. No previous studies until now have identified "hormonally defined" time intervals within the female menstrual cycle and compared headache outcome measures among these intervals in female migraineurs. METHOD: Daily headache diary data were obtained from 21 female migraineurs during three native menstrual cycles. Daily urine samples were collected and later assayed for estrogen and progesterone metabolites. Seven 3-day time intervals were identified within each menstrual cycle based on urine hormone measurements. Primary (headache index) and secondary (disability index, headache severity, and headache frequency) outcome measures were compared between intervals using the mixed model approach. "Rates of change,""magnitude of change," and the "total burden" of ovarian hormones were estimated from urine hormone metabolites and correlated with headache outcome measures. RESULTS: The headache index was significantly different across different intervals of the menstrual cycle (P values <.001) and was higher during menstrual intervals (first 6 days of the menstrual cycle) than during mid-cycle and mid-luteal intervals (P < .002). Similarly, secondary outcome measures were highest during the menstrual intervals. "Higher burdens" of urinary progesterone metabolites were positively correlated with headache outcome measures during the luteal intervals of the menstrual cycle. "Rates of change" and the "magnitude of change" of urinary hormone metabolites did not correlate with headache outcome measures. CONCLUSIONS: Migraine headache is more severe, disabling, and frequent during the menstrual intervals of the female reproductive cycle than during mid-luteal or mid-cycle intervals. Progesterone metabolites may play a role in modulating migraine headaches during luteal intervals of the menstrual cycle.

Urinary nitric oxide metabolites and lipid peroxidation by-products in migraine.

Enhanced endothelium nitric oxide (NO) and superoxide anion release may cause migraine through related cerebral blood flow changes. Thirty subjects suffering from migraine with and without aura and 20 healthy controls were investigated. Urine samples collected for 24 h during and after the migraine attack, and during the headache-free period, were assayed for urinary NO stable metabolites (NOx) and thiobarbituric acid reactive substances (TBARS). During the headache-free period urinary NOx and TBARS levels were higher in migraine sufferers than in controls (NOx 0.77 +/- 0.14 vs. 0.28 +/- 0.15 mmol/mmol creatinine, P < 0.05; TBARS 0.40 +/- 0.19 vs. 0.26 +/- 0.13 micro mol/mol creatinine, P < 0.05). Also, NOx excretion was higher during the headache-free period than during or after the migraine attack (P < 0.05). Urinary TBARS were increased during the attack with respect to the headache-free period (P < 0.05). No differences were observed in the same parameters between sufferers of migraine with and without aura. Urinary NOx and TBARS might be promising as markers of their systemic levels to evaluate the increased vulnerability to oxidative stress in migraine sufferers.

Prostaglandin F(2alpha) metabolite and F(2)-isoprostane excretion rates in migraine.

The pathophysiology theory of migraine postulates a local, neurogenic inflammation and the possible involvement of oxidative stress. We analysed the levels of 15-oxo-dihydro-prostaglandin F(2alpha) (a metabolite of prostaglandin F(2alpha)) and 8-iso-prostaglandin F(2alpha) (a major isoprostane), which are biomarkers for inflammation and oxidative stress respectively, in urine from 21 patients with migraine, with and without aura. Urine samples from migraine patients were collected during a migraine attack, and control samples were collected from the same subjects on a migraine-free morning. The mean basal levels of 15-oxo-dihydro-prostaglandin F(2alpha) and 8-iso-prostaglandin F(2alpha) in the morning control urine samples were 0.54+/-0.11 and 0.31+/-0.13 nmol/mmol of creatinine respectively. The mean levels of 15-oxo-dihydro-prostaglandin F(2alpha) and 8-iso-prostaglandin F(2alpha) in the urine samples collected during the migraine attack in the 21 patients were 0.53+/-0.13 and 0.32+/-0.11 nmol/mmol of creatinine respectively. Thus there were no differences in the 15-oxo-dihydro-prostaglandin F(2alpha) and 8-iso-prostaglandin F(2alpha) excretion rates during the migraine attack compared with on the migraine-free day. However, the basal 8-iso-prostaglandin F(2alpha) excretion levels on the migraine-free day were significantly lower in pre-menopausal women (0.24+/-0.08 nmol/mmol of creatinine, n=11) compared with post-menopausal women (0.39+/-0.14 nmol/mmol of creatinine; n=7; P=0.009). In conclusion, in this study we found no support for the involvement of inflammation and oxidative stress in migraine pathophysiology. Our results indicate, however, a lower level of oxidative stress in pre-menopausal compared with post-menopausal women.

Deficiency of tumor necrosis factor alpha in a subclass of menstrual migraineurs.

OBJECTIVE: The objective of this study was to determine whether differences in urinary proinflammatory cytokines, interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha), 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-1beta, IL-6, and TNF-alpha, 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-1beta levels between samples. Interestingly, marked differences were found in TNF-alpha values in menstrual migraineurs. Twelve (63%) of 19 migraineurs had at least one urine sample with undetectable TNF-alpha 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-alpha levels in women with migraine may signal a disordered neuroimmune communication network and predisposition to migraine.

Plasma and urinary serotonin and 5-hydroxyindol-3-acetic acid in adults with migraine and tension-type headache.

Each headache can be a complex diagnostic, therapeutic, prognostic and social problem. The pain in the head can be connected with many organic and non-organic causes. In this work, the levels of plasma and urinary free 5-HT and 5-HIAA were investigated in eight migraine (aged 23-59 years) and ten tension-type headache suffers (aged 38-61 years). Based on the data obtained and their correlation with clinical features and in comparison with a control group, the following can be stated: (1) there is involvement of serotonin in migraine and tension-type headache during the attacks, although the positive 5-HT values from plasma were small; (2) urinary 5-HT values in migraine and tension-type headache were normal in comparison to the control group; (3) significantly decreased values of 5-HIAA in urine were found both in migraine and tension-type headache groups. These findings show that catabolism of 5-HT is probably decreased during headache periods; (4) visual aura was found in five out of ten subjects with tension-type headache.

Mast cell activation in children with migraine before and after training in self-regulation.

Migraine may affect as many as 9% of all schoolchildren and often presents with abdominal symptoms of pain, nausea, and vomiting. Even though the pathophysiology of migraine remains unknown, self-regulation techniques appear to be more effective in prevention of childhood migraine than conventional pharmacotherapy which is often associated with adverse effects. Mast cells have been implicated in the pathogenesis of migraine in adults, but have not been previously studied in children with migraine. Mast cells are found close to the vessels and nerves in the meninges where they can release multiple vasoactive, neurosensitizing, and pro-inflammatory mediators. Therefore, we investigated whether children with migraine may have increased urinary levels of mast cell mediators and whether practicing relaxation imagery exercises has an effect on the frequency of headache, as well as on mast cell activation. Urine was collected for 24 hours from children with and without migraine after a 5-day amine-restricted diet. Children with migraine also collected urine during migraine episodes. The mean levels of urinary histamine, its main metabolite, methylhistamine, and the mast cell enzyme, tryptase, were higher in children than generally found in adults, but they did not differ statistically in any of the categories studied. However, in 8 of 10 children who practiced relaxation imagery techniques and successfully reduced the number of migraines, the urine tryptase levels were also significantly lower. There was no relationship between successful practice and sex or age of the child. These results suggest that stress may activate mast cells which could be involved in the pathophysiology of migraine.

Nocturnal melatonin excretion is decreased in patients with migraine without aura attacks associated with menses.

Nocturnal melatonin excretion was studied throughout a complete menstrual cycle in 10 women with migraine without aura attacks associated with menses and 9 women controls. Urine melatonin was determined by radioimmunoassay. The mean nocturnal melatonin excretion throughout the cycle was significantly lower in the migraine patients than in controls. In the control group, melatonin excretion increased significantly from the follicular to the luteal phase, whereas no difference was observed in the migraine group. Results are discussed in view of the role of the pineal gland in the organization of biological rhythms and homeostasis in relation to environmental conditions.

Urinary melatonin excretion throughout the ovarian cycle in menstrually related migraine.

Nocturnal urinary melatonin excretion was significantly decreased throughout an ovarian cycle in 12 migraine without aura patients compared to 8 healthy controls. Normal increases in urinary melatonin excretion during the luteal phase was less pronounced in the migraine patients. Melatonin excretion was further decreased during headache. The data indicate impaired pineal function in migraine.