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Background: It is common clinical experience that, after structured withdrawal, some patients with chronic migraine and medication overuse headache (CM with MOH) are more prone than others to relapse and to be in need of further structured treatments. Our aim was to explore similarities and differences between frequent relapsers (FRs) and non-frequent relapsers (NFRs) by considering their point of view, perceptions, and perspective of their subjective experience with relapse into CM with MOH., Methods: Patients were consecutively recruited on occasion of a structured withdrawal treatment and were interviewed individually about their headache experience and their perspectives on relapse into CM with MOH. We considered FR those patients requiring 2 or more structured withdrawals for MOH within 3 years. A narrative approach with no preconceived coding schemes was employed. To facilitate coding, categorization and organization of data the software QRS NVivo 11.0 was used: themes were defined as common to FR and NFR, or peculiar (by frequency or content) to one of the 2 groups., Results: Sixteen patients (13 women; mean age of 53) were interviewed: 7 were classified as FRs. A total of 22 themes emerged from 552 single quotations (the 10 most relevant covered 82% of the entire body of quotations). Four themes were commonly reported by both FR and NFR patients, and 6 were peculiar to one group only. Common aspects included issues connected to the dilemma between disclosing, concealing and the feelings of isolation around MOH, the idea of being addicted to medication, presence of anxiety, and the attempt to use non-pharmacological therapies as an alternative to medication. Peculiar aspects included causal attribution (FRs attributed headache to uncontrollable factors); future expectations at the time point of withdrawal (FRs were generally resigned); high-performance functioning (FRs believed they are "forced" to reach high levels of performance as a consequence of others' inability); coping strategies (FRs tended to "passively accept" problems and showed avoidance-related behaviors). Moreover, FRs were less frequently aware of their problems and described more frequently depressive symptoms., Conclusions: Our results highlight that some differences between FR and NFR patients with CM and MOH exist. Frequent relapsers among patients with CM and MOH reported some important peculiarities of the lived experience of having chronic migraine; clinicians should recognize these psychosocial aspects such as social relationships, future expectations, the experience of illness, medication management, and how the withdrawal experience is regarded, as they may be associated with frequent relapse into MOH., (© 2018 American Headache Society.)

Background: The degree to which work-related difficulties are recognized in headache research is poor and often carried out with inadequate information such as "reduced ability to work as usual", which do not capture at all the variety of difficulties and the factors that impact over them. The aim of this paper is to present the validation of the HEADWORK questionnaire, which addresses the amount and severity of difficulties in work-related tasks and the factors that impact over them., Methods: We developed a set of items based on a previous literature review and patients' focus groups and tested it on a wide set of patients with episodic and chronic migraine attending eight different Italian headache centers. HEADWORK factor structure was assessed with exploratory and confirmatory factor analysis; internal consistency and construct validity were addressed as well., Results: The validation sample (N = 373) was mostly composed of patients with episodic migraine without aura (64.3%) and of females (81%). Factor analysis retrieved two different scales: "Work-related difficulties", composed of eleven items which explain 67.1% of the total variance, and "Factors contributing to work difficulties", composed of six items which explain 52.1% of the total variance. Both HEADWORK subscales have good measurement properties, with higher scores being associated to higher disability, lower quality of life, lower productivity, higher headache frequency and pain intensity., Conclusions: HEADWORK is a 17-item, two-scale questionnaire addressing the impact of migraine on work-related difficulties in terms of difficulties in general or specific skills, and the factors contributing to these difficulties, defined as negative impact on work tasks. It can be used to address disability weights for the purpose of calculating the burden of migraine, and to assess the balance between therapeutic and side effects of medication on productivity.

To explore the relationships between psychosocial difficulties (PSDs), quality of life (QoL), and disability and to explore the degree to which PSDs can be predicted by demographic variables, clinical variables, and risk and protective factors. Patients with episodic migraine completed a protocol inclusive of PARADISE 24 questionnaire (the 24-item Psychosocial Difficulties Relevant to Brain Disorders questionnaire), a new questionnaire that captures PSDs relevant to brain disorders, and assessments of disability, QoL, disease severity, presence of comorbidities, social support, and clinical and risk factors (i.e., smoking and body mass index). Spearman's correlation was used to address the relationship between PARADISE 24, and the assessments of disability and QoL; multivariable linear regression analysis was carried out to address PARADISE 24 predictors. Eighty patients were enrolled (86.3 % females, mean age 44.5). PARADISE 24 was well correlated with disability (ρ = 0.787) and moderately with QoL (ρ = -0.526). The regression analysis shows that younger age, higher migraine frequency, higher comorbidities index and being a smoker were predictors of PARADISE 24 (R 2 : 0.470). Addressing the burden associated with PSDs in migraineurs is important as these might be the reason why patients look for specialists in headache disorders. PARADISE 24 represents a viable way to address patients' difficulties in daily practice.

Migraine affects work productivity in terms of missed workdays and days with reduced productivity. In this literature review, we looked for papers addressing specific difficulties in work-related activities. Twenty-three papers were included in the review, reporting data on 51,135 patients. Results showed that there is some evidence for limitations in skills such as problem solving, and activities such as speaking and driving. However, the way in which problems with remunerative employment are addressed is limited to concepts such as reduced performance or inability to work as usual. Given the paucity of data, a return to patient-derived data will be needed to develop an assessment instrument that is able to collect information on headache-related problems in work activities.

Nervous and immune systems mutually cooperate via release of mediators of both neurological and immunological derivation. Adrenocorticotropin hormone (ACTH) is a product of the hypothalamus-pituitary adrenal axis (HPAA) which stimulates secretion of corticosteroids from adrenals. In turn, corticosteroids modulate the immune response in virtue of their anti-inflammatory activity. On the other hand, catecholamines, products of the sympathetic nervous system (SNS), regulate immune function by acting on specific beta-adrenergic receptors. Conversely, cytokines released by monocytes/macrophages and lymphocytes, upon antigenic stimulation, are able to cross the blood-brain-barrier, thus modulating nervous functions (e.g., thermoregulation, sleep, and appetite). However, cytokines are locally produced in the brain, especially in the hypothalamus, thus contributing to the development of anorexic, pyrogenic, somnogenic and behavioural effects. Besides pathogens and/or their products, the so-called stressors are able to activate both HPAA and SNS, thus influencing immune responses. In this respect, many studies conducted in medical students taking exams have evidenced an array of stress-induced immune alterations. Phobic disorders and migraine without aura (MWA) represent examples of stress-related disorders in which phagocytic immune deficits, endotoxemia and exaggerated levels of proinflammatory cytokines [Tumor Necrosis Factor-alpha (TNF- alpha), and interleukin- 1 beta] have been detected. Quite interestingly, administration of a thymic hormone could ameliorate clinical symptoms in phobic patients. In MWA patients, a beta-blocker, propranolol, could mitigate migraine, whose cessation coincided with a drop of TNF-alpha serum concentration. In phobic disorders and in MWA, benzodiazepines are very often administered and, in this respect, some of them, such as diazepam, inhibit immune functions, while others, e.g., alprazolam, enhance immune responses. Alprazolam could improve clinical symptoms in MWA patients. Chronic Fatigue Syndrome (CFS) is a disorder whose etiology and pathogenesis are still unknown. In this syndrome both abnormalities of nervous and immune systems have been reported. Despite many immune parameters evaluated in CFS no specific biomarkers of disease have been found. Our own data are in agreement with current literature in that we found decreased levels of serum (IFN)-gamma in these patients, thus indicating a predominance of T helper (h)1 response in CFS. Also leptin, a hormone which regulates food intake, fluctuates within normal ranges in CFS individuals. Quite interestingly, in depressed patients, used as controls, leptinaemia was more elevated than in CFS. Finally, in a series of recent therapeutic trials several immunomodulating agents have been used, such as staphypan Berna, lactic acid bacteria, kuibitang and intravenous immunoglobulin. In conclusion, it seems that major drug targets in stress-related disorders are immune cells in terms of inhibition of proinflammatory cytokines and modulation of Th responses. In particular, according to recent evidences, antidepressants seem to exert beneficial effects in experimental autoimmune neuritis in rats by decreasing IFN- beta release or augmenting NK activity in depressed patients.

Patients with migraine headaches show significantly lower prevalence of malignant neoplasms when compared with the general control group or the age-matched control group. Conversely, no significant difference concerning the family history for neoplasms has been found between the two groups. Nevertheless, headache and cancer in a family member in migraneous are not coexistent. Although more extensive, epidemiological studies are necessary to confirm our data, it is suggested that some particular biochemical or psychologic aspects involved in the pathogenesis of migraine might represent the presence of a protective factor against neoplasm development.

The hypothesis that alpha-adrenergic receptor blockade accounts for the ability of ergotamine to stop migraine attacks was tested, in migraine patients, in an experimental migraine model based on nitroderivative- induced attacks. In a preliminary single blind, placebo controlled study, thymoxamine, a prevalently post-synaptic alpha adrenergic receptor antagonist, was able to abort migraine attack in 9 out of 10 patients, as opposed to 2 out of 10 by placebo (p < 0.005 Fisher's exact test). In a subsequent randomized, crossover, placebo controlled double blind study, the ability of a selective alpha-1 adrenergic receptor agonist, methoxamine, to block ergotamine antimigraine effect was studied. In 26 patients migraine was induced in two separate tests and then ergotamine was administered once after methoxamine pretreatment and once after placebo; methoxamine was significantly more effective than placebo in blocking antimigraine effect of ergotamine (p = 0.0055 Fisher's exact test). These results support the hypothesis that ergotamine alpha-1 adrenolytic properties may account for its antimigraine effect suggesting that this action takes place outside the blood-brain barrier, since methoxamine can cross it very poorly. Ergotamine target structure could be the trigeminal innervation of the extracranial and/or dural vessels.

In 22 migraine patients and 5 healthy controls an investigation has been performed on lymphocyte subsets in basal conditions and 90 minutes after sublingual isosorbide dinitrate (IDN) administration. In all patients the drug assumption induced a typical migraine attack with increase in all examined lymphocyte subsets with except of NK cells. A statistically significant increase (p < 0.05) in T lymphocyte subsets we found during the crisis, whereas in healthy controls neither a migraine attack nor any modification in lymphocyte subsets could be observed. These results seem to confirm the immune alteration we have previously found in migraineous patients and suggest the possible role of IDN-stimulated endothelium not only in vasodilatation but also in production of substances responsible of the observed immune modifications.

Over the past few years, the immunomodulating role of benzodiazepines (BDZ) has been reported in literature. In particular, diazepam is an inhibitory BDZ with regard to its effects on the phagocytic and metabolic activities of polymorphonuclear cells (PMN) and monocytes, while triazolobenzodiazepines (alprazolam and triazolam) upregulate normal human peripheral blood T lymphocyte function. On these grounds, the administration of alprazolam (1 mg/per day for 1 month) in 13 patients with migraine without aura (MWA) and of lorazepam (2 mg/per day for 1 month) in 10 matched MWA subjects has been evaluated in terms of immune response. Results show that before administration of BDZ in both groups of patients phagocytosis and killing of PMN and monocytes were profoundly depressed and the same was true for the lymphocyte-dependent antibacterial activity. After one month treatment lorazepam further decreased lymphocyte function without modifying phagocytic capabilities. On the contrary, alprazolam increased PMN phagocytosis and killing and monocyte phagocytosis without modifying antibacterial activity values. Taken together, these results further support the existence of different classes of BDZ in terms of their immunomodulating capacities. Moreover, alprazolam seems to be a more appropriate BDZ for treating immunocompromised patients, even including MWA patients.

Patients with migraine without aura (MWA) display elevated amounts of Tumor Necrosis Factor (TNF)-alpha in their sera. In this study in 18 patients with MWA the in vivo effect of propranolol, a beta blocker agent, was evaluated with regard to the TNF serum levels before and after treatment. Results show that in 9 out 11 patients exaggerated serum concentrations of TNF reverted to normality after three months of therapy. Some hypotheses on the mechanisms of action of propranolol in terms of modulation of the immune response are formulated.

Migraine without aura (MWA) is a clinical condition characterized by multiple immune deficits, which may play an important role in the pathogenesis of the disease. In this respect, previous studies have demonstrated that patients with MWA exhibit profound dysfunctions of phagocytosis and killing exerted by polymorphonuclear cells (PMN) and monocytes. This may correlate with the increased frequency of infectious processes observed in these patients. The overall results suggested to evaluate the presence of circulating cytokines (CKs) in subjects affected by MWA. In particular, the present data point out an exaggerated spontaneous release of tumor necrosis factor (TNF)-alpha in a group of MWA individuals, which correlates with detectable levels of bacterial lipopolysaccharides (LPS) in their plasma. In view of the different biological activities displayed by TNF-alpha in the host, such as effects on the nervous and vascular systems, hemodynamics modifications and demyelinating properties, the intervention of this CK in the pathogenesis of MWA will be discussed.

Serum levels of tumor necrosis factor (TNF)-alpha/cachectin have been evaluated in 20 patients with Migraine without Aura (MwA) versus 17 patients with Chronic Type Tension Headache (CTTH). Results show an exaggerated release of TNF-alpha/cachectin in sera of patients affected by MwA, while in CTTH patients TNF serum concentration is comparable to that observed in normal donors. Some hypotheses are formulated in order to clarify the TNF-alpha/cachectin spontaneous production and its biological significance in patients with MwA.

In 23 patients with common migraine (CM), immune responsiveness and frequency of immunocompetent cells were investigated. In particular, phagocytosis and killing of Candida albicans by polymorphs (PMNs) and monocytes were analyzed. Also, the percentages of CD3+, CD4+, CD8+, natural killer, and CD15+ cells were evaluated by direct immunofluorescence using specific monoclonal antibodies. The results showed deficits of phagocytosis or killing exhibited by PMNs and monocytes. These immunological findings are discussed in terms of perturbation of immune status in CM patients during migraine attacks.