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Objective: To evaluate the long-term effectiveness, safety, and tolerability of erenumab in a real-world migraine population, looking for putative predictors of responsiveness. Background: Erenumab proved to be effective, safe, and well tolerated in the prevention of episodic migraine (EM) and chronic migraine (CM) in long-term extension studies of double-blind, placebo-controlled trials in patients with no more than two (EM) or three (CM) prior preventive treatment failures. Methods: A 48-week, multicenter, longitudinal cohort real-life study was conducted at 15headache centers across eight Italian regions between December 20, 2018 and July 31, 2020. We considered all consecutive patients with high-frequency episodic migraine (HFEM) or CM aged 18–65years. Each patient was treated with erenumab 70mg, administered monthly. The dose was switched to 140mg in nonresponders and in responders who had become nonresponders for at least 4weeks. Change in monthly migraine days (MMDs) or monthly headache days (MHDs) at Weeks 45–48 compared with baseline was the primary efficacy endpoint. Secondary endpoints encompassed variation in monthly analgesic intake, achievement of a ≥50%, ≥75%, or 100% reduction in migraine or headache days, and any change in the Visual Analogue Scale (VAS) and Headache Impact Test-6 scores (HIT-6) during the same time interval. Results: A total of 242 patients with migraine received at least one dose of erenumab 70mg and were considered for safety analysis, whereas 221 received a monthly erenumab dose for ≥48weeks and were included in the effectiveness and safety analysis set. All patients had previously been treated unsuccessfully with ≥3migraine-preventive medication classes. From baseline to Weeks 45–48, erenumab treatment reduced MMD by 4.3±5.3(mean±SD) in patients with HFEM, and MHD by 12.8±8.9 (mean±SD) in subjects with CM. VAS and HIT-6scores were decreased by 1.8±1.9 (mean±SD) and 12.3±11 (mean±SD) in HFEM, and by 3.0±2.2 (mean±SD) and 13.1±11.2 (mean±SD) in CM. Median monthly analgesic intake passed from 11.0 (interquartile range [IQR] 10.0–13.0) to 5 (IQR 2.0–8.0) in HFEM and from 20.0 (IQR 15.0–30.0) to 6.0 (IQR 3.8–10.0) in CM. The ≥50% responders were 56.1% (32/57) in HFEM and 75.6% (124/164) in CM; ≥75% responders were 31.6% (18/57) and 44.5% (73/164); and 100% responders were 8.8% (5/57) and 1.2% (2/164), respectively. At Week 48, 83.6% (137/164) of patients with CM had reverted to EM. Erenumab was safe and well tolerated. Responsiveness to erenumab was positively associated with cutaneous allodynia (OR: 5.44, 95% CI: 1.52–19.41; p=0.009) in HFEM. In patients with CM, ≥50% responsiveness was positively associated with male sex (OR: 2.99, 95% CI: 1.03–8.7; p=0.044) and baseline migraine frequency (OR: 1.12, 95% CI: 1.05–1.20; p=0.001) and negatively associated with psychiatric comorbidities (OR: 0.37, 95% CI: 0.15–0.87; p=0.023) and prior treatment failures (OR: 0.77, 95% CI: 0.64–0.92; p=0.004). Conclusions: Long-term (48-week) erenumab treatment provides sustained effectiveness, safety, and tolerability in real-life patients with HFEM or CM with ≥3 prior preventive treatment failures. The dose of 140mg was required in most patients along the study and should be taken into consideration as the starting dose. Allodynia (in HFEM), male sex, and baseline migraine frequency (in CM) might represent positive responsiveness predictors. Conversely, psychiatric comorbidities and multiple prior preventive treatment failures could be negative predictors in patients with CM.

Objective: This article reviews current headache disability measures and clinical need, as well as presenting the rationale for a new measure addressing work-related disability in migraine patients and the steps devoted to this aim. Background: Episodic and chronic migraine (EM and CM) constitute an enormous economic burden to societies, and the vast majority of this burden is attributable to indirect costs, ie those associated with productivity loss. A measure of work-related disability is therefore needed to quantify the impact of EM and CM on patients' ability to carry out work tasks. Methods: We briefly present the advantages and disadvantages of the disability measures that have been most commonly used for this purpose and the rationale for developing a new measure. Results: The entire process of development of HEADWORK, a questionnaire designed to assess work-related disability, is presented together with short-term sensitivity to change. Conclusions: Current headache disability measures need improvement. HEADWORK is a valid, reliable, and sensitive questionnaire to address the amount and severity of work-related difficulties and of the factors contributing to such difficulties. HEADWORK is suitable for daily clinical practice, epidemiological research and for clinical trials, and potentially to define work-related disability weights for the calculation of migraine indirect costs.

Objective The Bologna motor and non-motor prospective study on parkinsonism at onset (BoProPark) was designed to prospectively characterize motor and non-motor features in patients with a progressive neurodegenerative disease starting with parkinsonism since early disease stage and to investigate their diagnostic and prognostic role in the differential diagnosis of Parkinson’s disease from atypical parkinsonisms. The aim of this paper is to describe the method and population of the BoProPark study. Methods Patients referred to our Department with parkinsonism within 3 years from motor onset were recruited. Secondary causes of parkinsonism were excluded. Each patient underwent a comprehensive evaluation of motor and non-motor symptoms, assessed by means of quantitative, objective instrumental tests in addition to scales and questionnaires. The evaluations were performed at enrolment (T0), after 16 months (T1) and after 5 years (T2). Diagnoses were made according to consensus criteria. Results We recruited 150 patients, with mean age 61.5 ± 9.8 years and mean disease duration 20 ± 9 months. H&Y stage was 1 in 47.3% and 2 in 46.7% of cases. Mean UPDRS-III was 17.7 ± 9.2. Fifty-four patients were on dopaminergic treatment with median levodopa equivalent daily dose (LEDD) of 200 mg. Conclusions We expect that the prospective nature of the BoProPark study as well as the comprehensive, instrumental evaluation of motor and non-motor symptoms in patients with parkinsonism will provide important new insights for both clinical practice and research. Our data could be used for comparison with other cohorts and shared with national and international collaborators to develop new innovative projects.

Background The PRESTO study of non-invasive vagus nerve stimulation (nVNS; gammaCore®) featured key primary and secondary end points recommended by the International Headache Society to provide Class I evidence that for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 h post stimulation. Here, we examined additional data from PRESTO to provide further insights into the practical utility of nVNS by evaluating its ability to consistently deliver clinically meaningful improvements in pain intensity while reducing the need for rescue medication. Methods Patients recorded pain intensity for treated migraine attacks on a 4-point scale. Data were examined to compare nVNS and sham with regard to the percentage of patients who benefited by at least 1 point in pain intensity. We also assessed the percentage of attacks that required rescue medication and pain-free rates stratified by pain intensity at treatment initiation. Results A significantly higher percentage of patients who used acute nVNS treatment (n = 120) vs sham (n = 123) reported a ≥ 1-point decrease in pain intensity at 30 min (nVNS, 32.2%; sham, 18.5%; P = 0.020), 60 min (nVNS, 38.8%; sham, 24.0%; P = 0.017), and 120 min (nVNS, 46.8%; sham, 26.2%; P = 0.002) after the first attack. Similar significant results were seen when assessing the benefit in all attacks. The proportion of patients who did not require rescue medication was significantly higher with nVNS than with sham for the first attack (nVNS, 59.3%; sham, 41.9%; P = 0.013) and all attacks (nVNS, 52.3%; sham, 37.3%; P = 0.008). When initial pain intensity was mild, the percentage of patients with no pain after treatment was significantly higher with nVNS than with sham at 60 min (all attacks: nVNS, 37.0%; sham, 21.2%; P = 0.025) and 120 min (first attack: nVNS, 50.0%; sham, 25.0%; P = 0.018; all attacks: nVNS, 46.7%; sham, 30.1%; P = 0.037). Conclusions This post hoc analysis demonstrated that acute nVNS treatment quickly and consistently reduced pain intensity while decreasing rescue medication use. These clinical benefits provide guidance in the optimal use of nVNS in everyday practice, which can potentially reduce use of acute pharmacologic medications and their associated adverse events. Trial registration ClinicalTrials.gov identifier: NCT02686034.

ObjectiveTo evaluate the efficacy, safety, and tolerability of noninvasive vagus nerve stimulation (nVNS; gammaCore; electroCore, LLC, Basking Ridge, NJ) for the acute treatment of migraine in a multicenter, double-blind, randomized, sham-controlled trial.MethodsA total of 248 participants with episodic migraine with/without aura were randomized to receive nVNS or sham within 20 minutes from pain onset. Participants were to repeat treatment if pain had not improved in 15 minutes.ResultsnVNS (n = 120) was superior to sham (n = 123) for pain freedom at 30 minutes (12.7% vs 4.2%; p = 0.012) and 60 minutes (21.0% vs 10.0%; p = 0.023) but not at 120 minutes (30.4% vs 19.7%; p = 0.067; primary endpoint; logistic regression) after the first treated attack. A post hoc repeated-measures test provided further insight into the therapeutic benefit of nVNS through 30, 60, and 120 minutes (odds ratio 2.3; 95% confidence interval 1.2, 4.4; p = 0.012). nVNS demonstrated benefits across other endpoints including pain relief at 120 minutes and was safe and well-tolerated.ConclusionThis randomized sham-controlled trial supports the abortive efficacy of nVNS as early as 30 minutes and up to 60 minutes after an attack. Findings also suggest effective pain relief, tolerability, and practicality of nVNS for the acute treatment of episodic migraine.ClinicalTrials.gov identifierNCT02686034.Classification of evidenceThis study provides Class I evidence that for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 hours poststimulation (absolute difference 13.2%).

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.

Objectives: Maladaptive cognitive strategies and reduced autonomic flexibility have been reported in chronic pain conditions. No study to date addressed the effects of maladaptive coping and reduced autonomic flexibility, as indexed by heart rate variability (HRV), in chronic headaches. The present study aimed to assess the mediating role of pain catastrophizing and HRV on pain outcomes in patients with chronic headache. Methods: Thirty-two chronic headache patients and 28 healthy controls were recruited. Self-reported pain severity, pain interference on daily activity, and pain catastrophizing were assessed through the Multidimensional Pain Inventory and the Pain-Related Self Statements Scale. HRV was recorded at rest. Correlations and mediation analysis between self-report, HRV, and pain outcomes were run. Results: Patients with chronic headache reported significantly higher pain severity (p

The authors used 1H-MRS to investigate hypothalamic metabolism in 26 patients with cluster headache (CH) and 12 healthy subjects. Hypothalamic N-acetylaspartate/creatine was reduced in patients with CH vs controls (p < 0.01). Dividing the patients into episodic CH outside- and in-cluster periods and chronic CH, the hypothalamic N-acetylaspartate/creatine in all three subgroups of patients was reduced. The reduction of the neuronal marker N-acetylaspartate is consistent with hypothalamic neuronal dysfunction in patients with CH.

Cold-induced sweating syndrome type 1 (CISS1) is a rare disorder characterized by profuse sweating in a cold environment, determined by mutations in cytokine receptor–like factor 1 ( CRLF1 ).1 Its pathogenesis is not fully understood. It has been demonstrated in vitro that CRLF1 may be involved in inducing differentiation from a noradrenergic to a cholinergic transmitter phenotype. During development, catecholaminergic and cholinergic neurotransmission is required for the induction of secretory function, whereas cholinergic transmission becomes crucial for the maintenance of the secretory responsiveness.2 The abnormal sweat response in CISS1 could be also related to alterations in temperature signals acting on hypothalamus and preoptic areas.1 We report clinical, molecular, skin biopsy, and temperature monitoring data of an Italian boy with CISS1. ### Case report. A 16-year-old boy had come to our observation at 1 year of age. His parents were healthy and unrelated. A brother, with facial dysmorphisms and hypotonia, had died at age 3 months from bronchopulmonary infection. Our patient was hypotonic at birth and experienced severe feeding difficulties. He had elongated face, high-arched palate, weak cry, large pinnae, short hands, tapering fingers, clinodactyly, and reduced tendon reflexes. Concentric needle EMG, nerve conduction velocity (NCV) studies (ulnar, median, peroneal, tibial, and sural nerves), and repetitive nerve stimulation testing excluded a …

Background Sleep disorders are increasingly recognized in the symptomatology of many neurodegenerative diseases. Gerstmann-Straussler-Scheinker (GSS) disease is a hereditary prion disease featuring cerebellar ataxia, akinetic parkinsonism, pyramidal signs and cognitive decline. Methods We performed a polysomnographic study (PSG) of sleep and body core temperature (BcT°) in two sisters with GSS. Results Our study showed protracted nocturnal awakenings, reduced sleep efficiency and brief daytime naps but also qualitatively preserved slow-wave and REM sleep and substantially normal arousal and periodic limb movements in sleep indices and BcT° rhythm. Conclusions These findings conflict with those in multiple system atrophy and other prion diseases such as fatal familial insomnia, which enter the differential diagnosis of GSS and are characterized by prominently disrupted sleep-wake and BcT° cycles.

Objectives: The COVID-19 pandemic and the consequent lockdown came as a storm disrupting people’s everyday life. This study aimed at observing whether the COVID-19 related lockdown influenced migraine frequency and disability in migraine patients on therapy with monoclonal antibodies inhibiting the CGRP pathway. Methods: In this longitudinal observational cohort study, 147 consecutive patients receiving monthly administration of erenumab or galcanezumab were enrolled in four Italian headache centers. All patients filled a questionnaire concerning working and household settings, recent flu symptoms or COVID-19 diagnosis, and family loss due to COVID-19 infection. Monthly migraine days (MMDs), monthly painkiller intake (MPI), and HIT-6 disability relative to the first month of lockdown imposition (T-lock) and the month before (T-free) were also collected. Results: From T-free to T-lock, the cohort displayed a reduction in MMDs (from 10.5 ± 7.6 to 9.8 ± 7.6, p =.024) and HIT-6 scores (from 59.3 ± 8.3 men reduced MPI more frequently than women (p =.005). Conclusions: Our study observed that the lockdown impact to 57.8 ± 8.8, p=.009), while MPI resulted unchanged (from 11.6 ± 11.5 to 11.1 ± 11.7; p =.114). MMDs, MPI, and HIT-6 variations from T-free to T-lock did not differ according to work settings or household. Patients beyond the first 3 months of therapy presented less often a reduction in MMDs (p =.006) and on everyday life did not affect the migraine load in patients receiving monoclonal antibodies inhibiting the CGRP pathway. Patients in the first months of therapy experienced a greater improvement according to drug pharmacokinetics, while women more frequently needed rescue medications, possibly indicating presenteeism or cephalalgophobia.

Headaches are among the most prevalent and disabling neurologic disorders and there are several unmet needs as current pharmacological options are inadequate in treating patients with chronic headache, and a growing interest focuses on nutritional approaches as non-pharmacological treatments. Among these, the largest body of evidence supports the use of the ketogenic diet (KD). Exactly 100 years ago, KD was first used to treat drug-resistant epilepsy, but subsequent applications of this diet also involved other neurological disorders. Evidence of KD effectiveness in migraine emerged in 1928, but in the last several year’s different groups of researchers and clinicians began utilizing this therapeutic option to treat patients with drug-resistant migraine, cluster headache, and/or headache comorbid with metabolic syndrome. Here we describe the existing evidence supporting the potential benefits of KDs in the management of headaches, explore the potential mechanisms of action involved in the efficacy in-depth, and synthesize results of working meetings of an Italian panel of experts on this topic. The aim of the working group was to create a clinical recommendation on indications and optimal clinical practice to treat patients with headaches using KDs. The results we present here are designed to advance the knowledge and application of KDs in the treatment of headaches.

Background Although migraine is a disabling neurological condition that causes important disability, it remains an area of underdiagnosis and undertreatment worldwide. The aim of this study was to depict the burden of the unmet medical needs in migraine treated with triptans in a large Italian population. Methods A 2-year longitudinal analysis of migraineurs with unmet medical needs on treatment with triptans was performed. The studied cohort consisted of subjects with ≥4 triptan dose units per month, selected from the general population These patients were stratified into: possible Low-Frequency Episodic Migraine (pLF-EM: 4–9 triptan dose units per month), possible High-Frequency Episodic Migraine (pHF-EM: 10–14 triptan dose units per month) and possible Chronic Migraine (pCM:> 14 triptan dose units per month). The first follow-up year was analysed to describe the use of preventive therapies, the second year to describe the ≥50% reduction in triptan use. Results Of 10,270,683 adults, 8.0 per 1000 were triptan users and, of these, 38.2% were migraineurs with unmet medical needs, corresponding to 3.1 per 1000 adults. By stratifying for the number of triptan dose units per month, 72.3% were affected by pLF-EM, 17.4% by pHF-EM, and 10.3% by pCM. In this cohort, 19.1% of individuals used oral preventive drugs and 0.1% botulinum toxin. Triptan use reduction was found in 22.3% individuals of the cohort, decreasing with the intensification of need levels (25.8% pLF-EM, 13.6% pHF-EM, 12.0% pCM). Conclusions This real-life analysis underlined that the unmet medical needs concern a large part of patients treated with triptans and there is an undertreatment with preventive therapies whose benefit is insufficient, which may be due to the lack of effective preventive strategies, probably still reserved to severe patients. This study allows forecasting the actual impact of newest therapeutic strategies aimed to fill this gap.

Objective: This study aimed at estimating the treated cluster headache (CH) prevalence and describing prescription patterns and direct costs paid by the Italian National-Health-System. Methods: Through the ReS database (healthcare administrative data collection of a large sample of the Italian population), adults in treatment for CH (acute therapy with sumatriptan/subcutaneous or oxygen, associated with preventive therapy with verapamil or lithium) were selected. A cross-sectional analysis described the prevalence of CH-treated subjects repeated annually in 2013–2017. A longitudinal analysis of patients selected in 2013–2015 and followed for 2 years provided the prescription patterns. Results: The annual prevalence of CH-treated patients increased from 6.4×100,000 adults in 2013 to 6.7 in 2017. In 2013–2015, 570 patients (80.7% M; mean age 46) treated for CH were found. In 50.4%, the identifying CH treatment was sumatriptan/subcutaneous+verapamil. During follow-up, >1/3 changed the preventive drug and interruption was the most frequent modification, although acute treatments were still prescribed. The mean annual cost/patient ranged from €2,956 to €2,267; pharmaceuticals expenditure represented the 56.4% and 57.3%, respectively. Conclusions: This study showed an important unmet need among CH patients, carrying a high economic burden that should be considered in the evaluation of the impact of incoming therapies (e.g. Calcitonin-Gene-Related-Peptide antibodies).

Introduction: A large corpus of evidence has reported encouraging results for acupuncture as a prophylaxis therapy for migraine. However, trials that investigated the efficacy of acupuncture in comparison with pharmacological treatment in episodic migraine showed conflicting results. The study aimed to evaluate if acupuncture is as effective as evidence-based pharmacological drugs in episodic migraine prophylaxis.Methods: This is a randomized controlled clinical study. Patients suffering from migraine without preventive treatment in the past 3 months were recruited. After the run-in period, episodic migraineurs were assigned randomly to two groups: the acupuncture group (A) was treated with 12 sessions of acupuncture, and the pharmacological group (B) was treated with the most appropriate medication for each patient. Headache frequency was compared at baseline and at the end of treatment. Both groups were evaluated 3 and 6 months after treatment.Results: A total of 148 patients (24 males and 124 females) were enrolled in the study. Out of these, 69 were randomized to A and 66 to B. At baseline, no significant differences were found between the two groups. Of the patients, 15.5% (21/135) interrupted the treatment, especially those randomized to B. After 4 months, migraine frequency decreased from 8.58 ± 3.21 to 6.43 ± 3.45 in A and from 8.29 ± 2.72 to 6.27 ± 4.01 in B. Headache frequency decreased significantly after treatment without differences between the two groups (time-effect: p < 0.001; group effect: p = 0.332; interaction time-group effects: p = 0.556). Approximately 34% of patients showed a reduction of headache days by at least 50% after the treatment. The improvements observed at the end of treatment persisted in 57.3% (59/103) after 3 months and 38.8% (40/103) after 6 months, especially in patients randomized to A.Conclusions: Our trial is the first one comparing acupuncture with the more appropriate pharmacological treatment for migraine prophylaxis. Data suggested that acupuncture could be adopted as migraine prophylaxis and seem to be slightly superior to pharmacological treatment in compliance and rate of adverse events.

Background Finding an intracranial aneurysm (IA) during a thunderclap headache (TCH) attack, represents a problem because it is necessary to distinguish whether the aneurysm is responsible for the headache as a warning leak or as an incidental finding. High-Resolution Vessel-Wall (HRVW) MRI sequences have been proposed to assess the stability of the wall, as it permits to detect the presence of aneurysmal wall enhancement (AWE). In fact, AWE has been confirmed due to inflammation, recognizable preceding rupture. Case 1: A 37-year-old woman with a migraine more intense than her usual. A CTA revealed a 10 mm AComA aneurysm without subarachnoid hemorrhage (SAH) and HRVW-MRI excluded AWE. The patient’s headache improved, and therefore, the aneurysm was considered an incidental finding, and the headache diagnosed as TCH attack. Subsequently, the aneurysm was surgically clipped, and typical migraine relapsed was reported at follow-up (FU). Case 2: A 67-year-old woman with no history of headaches underwent CTA for an abrupt onset of headache. A 7 mm right carotid-ophthalmic aneurysm with no sign of SAH was discovered. HRVW-MRI demonstrated AWE and thus, a TCH attack for a warning leak of an unstable wall was suspected. Endovascular coiling was immediately performed and at FU any further headache attack was reported. Conclusions HRVW-MRI is useful in case of finding aneurysm as the cause of headaches, particularly the TCH attack. In fact, HRVW-MRI could assess the stability of the aneurysms wall, allowing different patient management and eventually the aneurysmal treatment.

Chronic pain prevalence is high worldwide and increases at older ages. Signs of premature aging have been associated with chronic pain, but few studies have investigated aging biomarkers in pain-related conditions. A set of DNA methylation (DNAm)-based estimates of age, called “epigenetic clocks,” has been proposed as biological measures of age-related adverse processes, morbidity, and mortality. The aim of this study is to assess if different pain-related phenotypes show alterations in DNAm age. In our analysis, we considered three cohorts for which whole-blood DNAm data were available: heat pain sensitivity (HPS), including 20 monozygotic twin pairs discordant for heat pain temperature threshold; fibromyalgia (FM), including 24 cases and 20 controls; and headache, including 22 chronic migraine and medication overuse headache patients (MOH), 18 episodic migraineurs (EM), and 13 healthy subjects. We used the Horvath's epigenetic age calculator to obtain DNAm-based estimates of epigenetic age, telomere length, levels of 7 proteins in plasma, number of smoked packs of cigarettes per year, and blood cell counts. We did not find differences in epigenetic age acceleration, calculated using five different epigenetic clocks, between subjects discordant for pain-related phenotypes. Twins with high HPS had increased CD8+ T cell counts (nominal p = 0.028). HPS thresholds were negatively associated with estimated levels of GDF15 (nominal p = 0.008). FM patients showed decreased naive CD4+ T cell counts compared with controls (nominal p = 0.015). The severity of FM manifestations expressed through various evaluation tests was associated with decreased levels of leptin, shorter length of telomeres, and reduced CD8+ T and natural killer cell counts (nominal p < 0.05), while the duration of painful symptoms was positively associated with telomere length (nominal p = 0.034). No differences in DNAm-based estimates were detected for MOH or EM compared with controls. In summary, our study suggests that HPS, FM, and MOH/EM do not show signs of epigenetic age acceleration in whole blood, while HPS and FM are associated with DNAm-based estimates of immunological parameters, plasma proteins, and telomere length. Future studies should extend these observations in larger cohorts.

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Background: Transverse sinus stenosis is a common brain MRI finding in chronic migraine (CM) and chronic tension-type headache (CTTH) patients in clinical practice; however, its clinical and diagnostic role is unclear. The aim of the study is to determine the frequency of transverse sinus stenosis in these headache patients resistant to preventive treatments and to verify whether this is a useful finding for identifying patients with intracranial hypertension. Methods: This is an observational study. Patients with refractory CM and CTTH underwent a 3T-magnetic resonance venography (MRV) before cerebrospinal fluid (CSF) opening pressure measurement. Transverse sinus stenosis was determined using the combined conduit score. Patients with opening pressure >200 repeated MRV study 1 month after CSF withdrawal to evaluate changes in neuroimaging findings. Results: We analyzed MRV studies of 40 patients (32 F, 8 M; mean age, 49.4 ± 10.8; mean body mass index, 26.7 ± 6.4; 39 CM and 1 CTTH with concomitant episodic migraine). Nineteen cases (47.5%) had evidence of transverse sinus stenosis: bilateral in seven patients (17.5%) and unilateral in 12 cases (30%). No statistically significant differences in transverse sinus stenosis distribution were found between patients with opening pressure 200 mmH2O. On Spearman bivariate test, there was no correlation between opening pressure and combined conduit score. No changes in neuroimaging findings were found 1 month after CSF withdrawal. Conclusion: Transverse sinus stenosis is a frequent radiological finding (47.5%) in CM and CTTH patients refractory to preventive treatments. However, this finding is not suggestive of intracranial hypertension. Whether transverse sinus stenosis may be a possible risk factor for chronic headache or a comorbidity needs to be evaluated in larger epidemiological studies.

This study aimed to quantify 24 h body core temperature (BcT°) and sleep-wake cycle rhythm alterations in craniopharyngioma (CP) patients and to identify markers related to the postsurgical outcomes. Ten consecutive CP patients underwent neuroradiological, endocrinological and ophthalmological evaluations, 24 h BcT° and sleep-wake cycle recordings before and after endoscopic endonasal surgery. The sample included four women and six men. Nocturnal sleep efficiency was pathologically reduced in eight patients before surgery. Seven out of ten patients presented one to three daytime naps. 24 h BcT° rhythm was pathological in six out of ten cases. Post-surgery sleep efficiency normalized in four out of eight patients, whereas nine out of ten patients presented with two to six longer daytime naps. Diurnal naps were mainly present in patients showing pre-operative involvement of the third ventricle floor. 24 h BcT° remained pathological in only one out of six cases, returned to normal in two and improved in three. 24 h BcT° rhythm improved more in papillary CPs than in adamantomatous CPs. Our data confirmed that both CP and surgery frequently disrupt the sleep-wake cycle and BcT° rhythms. Tumour location and histotype may be related to a worse postsurgical outcome. Therefore, in-depth investigation including circadian monitoring is crucial for surgical outcome.

Aim: To validate the Composite Autonomic Symptom Score (COMPASS) 31, in its Italian version, for the diagnosis of diabetic cardiovascular autonomic neuropathy in a clinic-based, single-centre study. Methods: A total of 73 participants with diabetes (age 55 ± 14 years) completed the COMPASS 31 questionnaire before undergoing cardiovascular autonomic neuropathy and diabetic polyneuropathy assessment according to cardiovascular reflex tests, neuropathic symptoms and signs, and vibration and thermal thresholds. Results: The COMPASS 31 total weighted score differed between participants with and without cardiovascular autonomic neuropathy (29.9 ± 19.5 vs 16.1 ± 14.7; P = 0.003) and with and without diabetic polyneuropathy (28.9 ± 19.1 vs 12.7 ± 11.3; P < 0.0001). It was related to cardiovascular reflex tests score (rho = 0.38, P = 0.0013) as well as diabetic polyneuropathy symptoms (rho=0.61, P < 0.0001) and signs scores (rho = 0.49, P < 0.0001). Receiver-operating curve analysis showed a fair diagnostic accuracy of total score for cardiovascular autonomic neuropathy (area under the curve 0.748 ± 0.068, 95% CI 0.599-0.861) and diabetic polyneuropathy (area under the curve 0.742 ± 0.061, 95% CI 0.611-0.845). The best score thresholds were 16 for early cardiovascular autonomic neuropathy (sensitivity 75.0%, specificity 64.9%, positive predictive value 37.5% and negative predictive value 90.2%), and 17 for both confirmed cardiovascular autonomic neuropathy and diabetic polyneuropathy (sensitivity 70.0% and 65.5%, respectively; specificity 66.7% and 79.5%, respectively; positive predictive value 25.0% and 67.9%, respectively; and negative predictive value 93.0% and 77.8%, respectively). COMPASS 31 had a good internal consistency according to Cronbach's α coefficient of 0.73. Conclusions: COMPASS 31 can represent a valid, easy-to-use, quantitative assessment tool for autonomic symptoms in diabetic neuropathy, with a fair diagnostic accuracy for both cardiovascular autonomic neuropathy and diabetic polyneuropathy.

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Objective To clarify whether the clinical response after the first 2 cycles with Onabotulinumtoxin A can accurately predict the long-term response. Background Onabotulinumtoxin-A (OBT-A) is an approved preventive treatment option for chronic migraine (CM). Nowadays, it remains to be clarified if the treatment has to be prolonged for at least an entire year (4 injections every 3 months - ie, quarterly, as proposed in the PREEMPT trials) or it can be halted after the second or third injection if not clinically effective. Design and Methods We conducted a multicenter observational cohort study based on real-life data on the usage of OBT-A in CM patients from 2 Italian headache centers, Roma Campus Bio-Medico and Milano Besta, adopting the whole 4-injections protocol. We performed a retrospective analysis of medical records of consecutive patients treated in the 2 centers. The main statistical analysis aimed to evaluate longitudinal measures related to headache (monthly headache frequency, monthly number of analgesic drugs, MIDAS). We hypothesized from our clinical practice with OBT-A that only 2 cycles of treatment were not enough to actually define the non-responder status to botulinum toxin A and that probably a longer time of treatment is needed to get the condition of long-term (delayed) responder. Results We considered 115 patients from the 2 centers: 53 in Roma and 62 in Milano. Regarding the main analysis, a clear improvement in each measure was obtained at the 6 months assessment and maintained up to 12 months. Comparing patients with = 30% reduction in headache frequency between T0 and T2 or T4 (respectively, "Non-Responders" and "Responders"), we found that the agreement between the classification Responders/Non-Responders at T2 and T4 was not very high (79/104 = 76.0%, with a "moderate" Cohen's Kappa of 0.51), suggesting that the status at T4 is not fully predictable by the status at T2 (lambda = 0.47). Responders for headache frequency at T4 were 54.8%. Among Responders at T2, Responders at T4 were 47/62 = 75.8% (95% CI: 64.5%, 85.5%), while among Non-Responders at T2, Responders at T4 were 10/42 = 23.8% (95% CI: 11.9%, 38.1%). Similarly, even when considering the 50% reduction in painkillers consumption or in MIDAS total score between T0 and T2 as possible prognostic factors, the changes occurring at T4 are not strongly predictable by those at T2. Conclusions A >= 30% reduction in headache frequency at T2 cut-off is not adequate in predicting a late response to treatment: more than a quarter of excluded patients would miss a clinical improvement with an ongoing treatment, while in a similar percentage of Responders the treatment would lose efficacy. Results from our real-life study suggest that we possibly have to postpone the definition of Responder/Non-Responder to OBT-A at least after 1 year of treatment (4 cycles).

Background Case-finding tools, such as the Identify Chronic Migraine (ID-CM) questionnaire, can improve detection of CM and alleviate its significant societal burden. We aimed to develop and validate the Italian version of the ID-CM (ID-EC) in paper and as a smart app version in a headache clinic-based setting. Methods The study investigators translated and adapted to the Italian language the original ID-CM questionnaire (ID-EC) and further implemented it as a smart app. The ID-EC was tested in its paper and electronic version in consecutive patients referring to 9 Italian tertiary headache centers for their first in-person visit. The scoring algorithm of the ID-EC paper version was applied by the study investigators (case-finding) and by patients (self-diagnosis), while the smart app provided to patients automatically the diagnosis. Diagnostic accuracy of the ID-EC was assessed by matching the questionnaire results with the interview-based diagnoses performed by the headache specialists during the visit according to the criteria of International Classification of Headache Disorders, III edition, beta version. Results We enrolled 531 patients in the test of the paper version of ID-EC and 427 in the validation study of the smart app. According to the clinical diagnosis 209 patients had CM in the paper version study and 202 had CM in the smart app study. 79.5% of patients returned valid paper questionnaires, while 100% of patients returned valid and complete smart app questionnaires. The paper questionnaire had a 81.5% sensitivity and a 81.1% specificity for case-finding and a 30.7% sensitivity and 90.7% specificity for self-diagnosis, while the smart app had a 64.9% sensitivity and 90.2% specificity. Conclusions Our data suggest that the ID-EC, developed and validated in tertiary headache centers, is a valid case-finding tool for CM, with sensitivity and specificity values above 80% in paper form, while the ID-EC smart app is more useful to exclude CM diagnosis in case of a negative result. Further studies are warranted to assess the diagnostic accuracy of the ID-EC in general practice and population-based settings.

Disorders of arousal include confusional arousals, sleepwalking and sleep terrors. The diagnosis of disorders of arousal is based on the clinical criteria established in the International Classification of Sleep Disorders, third edition, although the interobserver reliability of these criteria has never been investigated. The aim of this study was to estimate the inter-rater reliability of the diagnostic criteria for disorders of arousal throughout the whole life in order to understand their feasibility in clinical daily activity and in multicenter observational studies. Three raters interviewed 126 subjects (patients complaining of sleep disorders, headache, and healthy subjects), aged 18–80 years, with a standardized questionnaire created by applying the International Diagnostic Criteria for Disorders of Arousal. An “almost perfect” inter-rater reliability for disorders of arousal criteria and the final diagnosis was found among the raters (kappa 0.89 for confusional arousals, 0.87 for sleepwalking, and 0.87 for sleep terrors). The International Classification of Sleep Disorders, Third Edition criteria are adequate for a reliable diagnosis of disorders of arousal. Further validation studies, confirming DOA diagnosis with video polysomnography, are needed to investigate the predictive value of ICSD-3 criteria.

Background: Anger is involved in the emotional experience of pain. Individuals with migraine are more likely to hold their anger-in than controls. However, only one study evaluated anger in cluster headache (CH). The objective is to compare anger between migraine and CH patients. Methods: One hundred thirty-five migraine and 108 CH patients completed the State Trait Anger Expression Inventory (STAXI-2), composed of 7 subscales. State Anger measures the intensity of the individual’s angry feelings at the time of testing. Trait Anger evaluates general predisposition to become angry. Anger Expression Out and Anger Expression In measure the extent to which anger could be overtly expressed or suppressed. Anger Control Out and Anger Control In evaluate how individual try to control the outward or inward expression of anger. Anger Expression Index is a general index. Results: CH patients have higher median scores than migraine patients in State Anger (46 vs 44, p = 0.012). CH patients have lower scores in Anger Control Out (44 vs 50, p = 0.016). In subgroup analysis, CH patients during the cluster period have higher scores than chronic migraine patients in State Anger (47 vs 44, p = 0.035), while CH patients in headache-free period did not differ from migraine patients. Conclusions: Migraine and CH patients differ in state anger, indicating that CH patients experienced higher intensity of anger during the time of testing. These data add new information about emotional regulation in headache patients and could support the hypothesis of different emotional and behavioral responses to pain in migraine and CH patients.

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The burden of migraine strongly increases, considering its linkage with sleep disorders. Migraine is positively associated with many sleep-complaint disorders; some are confirmed by several studies, such as restless leg syndrome, whereas others still remain uncertain or controversial, e.g. narcolepsy. Many studies have investigated the association between headache and other sleep disturbances such as daytime sleepiness, insomnia, snoring and/or apnea, but only a few have focused on migraine. Highlighting the comorbidity between migraine and sleep disorders is important to improve treatment strategies and to extend the knowledge of migraine pathophysiology.

Study objective Narcolepsy with cataplexy (NC) is associated with loss of hypocretin neurons in the lateral hypothalamus involved in the circadian timing of sleep and wakefulness, and many biologic functions including autonomic control. The authors investigated whether chronic lack of hypocretin signaling alters cardiovascular control during sleep in humans. Design Comparison of 24-hr circadian rhythms, day-night, time- and state-dependent changes of blood pressure (BP) and heart rate (HR) in drug-free patients with NC and control subjects. Setting University hospital. Patients or participants Ten drug-free patients with NC (9 men, 1 woman) and 12 control subjects (9 men, 3 women). Interventions N/A. Measurements and results Daytime BP was comparable in patients with NC and controls, but patients with NC displayed a nighttime nondipping BP pattern. The 24-hr circadian rhythmicity of BP and HR was normal in both groups. Systolic BP during nighttime rapid eye movement sleep was significantly increased in the NC group. The 24-hr HR was significantly higher in the NC group but the day-night and state-dependent HR modulations were intact. The nighttime BP pattern coupled in the NC group with increased sleep fragmentation and a higher prevalence of arousals, periodic limb movements in sleep (PLMS), and PLMS arousals. In an analysis of the sleep/cardiovascular interaction in the periods after sleep onset and preceding morning awakening, only PLMS were consistently associated with the blunted nighttime decrease in BP in the NC group. Conclusions Hypocretin deficiency in humans may couple with an altered nighttime BP regulation that can be associated with an increased cardiovascular risk. This finding may be the result not only of the hypocretinergic deficiency per se but also of the altered sleep/wake regulation characterizing NC.

(Headache 2010;50:273-289) Objective.— The objective of this study is to present a view of the primary headaches as genetically determined behavioral responses consistent with sickness behavior and defense reaction, respectively. Background and Design.— A review of the literature bearing on the behavioral, humoral, and functional imaging aspects of the primary headaches shows that migraine and cluster headache (CH) are pain conditions characterized by different behaviors during the attacks. Here it is postulated that the behavioral responses to migraine and CH are evolutionary conserved reactions consistent with sickness behavior and defense reaction. Results.— The sickness behavior observed during migraine attacks is a pan-mammalian adaptive response to internal and external stressors, characterized by withdrawal and motor quiescence, sympatho-inhibition and lethargy, in which visceral pain signals a homeostatic imbalance of the body and/or brain. In contrast, the defense reaction in CH consists of a fight-or-flight reaction, with motor restlessness and agitation, in which pain is exteroceptive in kind. Conclusion.— These different behavioral responses are thus specific to different kinds of pain, distinguished by the behavioral significance of the pain (visceral pain in migraine vs exteroceptive pain in CH), and imply brain matrices involving different networks in the brainstem, hypothalamus, and forebrain regions that engender evolutionarily conserved adaptive genetic responses. Cytokines play an important role in their development. Predictions and limitations of the hypothesis are discussed together with implications for genetic studies on headaches.

The intra vitam diagnosis of prion disease is challenging and a definite diagnosis still requires neuropathological examination in non-familial cases. Magnetic resonance imaging has gained increasing importance in the diagnosis of prion disease. The aim of this study was to compare the usefulness of different magnetic resonance imaging sequences and proton magnetic resonance spectroscopy in the differential diagnosis of patients with rapidly progressive neurological signs compatible with the clinical diagnosis of sporadic prion disease. Twenty-nine consecutive patients with an initial diagnosis of possible or probable sporadic prion disease, on the basis of clinical and electroencephalography features, were recruited. The magnetic resonance protocol included axial fluid-attenuated inversion recovery-T2- and diffusion-weighted images, and proton magnetic resonance spectroscopy of the thalamus, striatum, cerebellum and occipital cortex. Based on the clinical follow-up, genetic studies and neuropathology, the final diagnosis was of prion disease in 14 patients out of 29. The percentage of correctly diagnosed cases was 86% for diffusion-weighted imaging (hyperintensity in the striatum/cerebral cortex), 86% for thalamic N-acetyl-aspartate to creatine ratio (cutoff ≤1.21), 90% for thalamic N-acetyl-aspartate to myo-inositol (mI) ratio (cutoff ≤1.05) and 86% for cerebral spinal fluid 14-3-3 protein. All the prion disease patients had N-acetyl-aspartate to creatine ratios ≤1.21 (100% sensitivity and 100% negative predictive value) and all the non-prion patients had N-acetyl-aspartate to myo-inositol ratios >1.05 (100% specificity and 100% positive predictive value). Univariate logistic regression analysis showed that the combination of thalamic N-acetyl-aspartate to creatine ratio and diffusion-weighted imaging correctly classified 93% of the patients. The combination of thalamic proton magnetic resonance spectroscopy (10 min acquisition duration) and brain diffusion-weighted imaging (2 min acquisition duration) may increase the diagnostic accuracy of the magnetic resonance scan. Both sequences should be routinely included in the clinical work-up of patients with suspected prion disease.

The objective of this study was to determine the cardiovascular effects of chronic stimulation of the posterior hypothalamic area (PHA) in cluster headache (CH) patients. Systolic and diastolic blood pressure (SBP, DBP), cardiac output, total peripheral resistance (TPR), heart rate (HR) and breathing were monitored at supine rest and during head-up tilt test (HUTT), Valsalva manoeuvre, deep breathing, cold face test and isometric handgrip in eight drug-resistant chronic CH patients who underwent monolateral electrode implantation in the PHA for therapeutic purposes. Autoregressive power spectral analysis (PSA) of HR variability (HRV) was calculated at rest and during HUTT. Each subject was studied before surgery (condition A) and after chronic deep brain stimulation (DBS) of PHA (condition B). Baseline SBP, DBP, HR and cardiovascular reflexes were normal and similar in both conditions. With respect to condition A, DBP, TPR and the LF/HF obtained from the PSA of HRV were significantly (P < 0.05) increased during HUTT in condition B. In conclusion, chronic DBS of the PHA in chronic CH patients is associated with an enhanced sympathoexcitatory drive on the cardiovascular system during HUTT.

The hypothalamus forms part of the central autonomic network, regulating body homeostasis and controlling pain. To this effect, it is strongly wired to more rostral and caudal areas, in particular the brainstem periaqueductal grey, the locus coeruleus and the median raphe nuclei, all involved in autonomic and sleep mechanisms and also in the descending control of pain perception. The hypothalamus, especially its posterior regions, becomes activated during attacks of the trigeminal autonomic cephalalgias (TACs), while brainstem, especially dorsal pontine, activity shows up during migraine attacks. The hypothalamus and interconnected brainstem areas likely represent the neural sites responsible for the chronobiological features of some headaches, in particular the sleep-related attacks typical of the TACs, migraines and the hypnic headaches.

The aim of our study was to translate and to do a linguistic validation of the Composite Autonomic Symptom Score COMPASS 31. COMPASS 31 is a self-assessment instrument including 31 items assessing six domains of autonomic functions: orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor functions. This questionnaire has been created by the Autonomic group of the Mayo Clinic from two previous versions: the Autonomic Symptom Profile (ASP) composed of 169 items and the following COMPASS with 72 items selected from the ASP. We translated the questionnaire by means of a standardized forward and back-translation procedure. Thirty-six subjects, 25 patients with autonomic failure of different aethiologies and 11 healthy controls filled in the COMPASS 31 twice, 4 ± 1 weeks apart, once in Italian and once in English in a randomized order. The test-retest showed a significant correlation between the Italian and the English versions as total score. The evaluation of single domains by means of Pearson correlation when applicable or by means of Spearman test showed a significant correlation between the English and the Italian COMPASS 31 version for all clinical domains except the vasomotor one for the lack of scoring. The comparison between the patients with autonomic failure and healthy control groups showed significantly higher total scores in patients with respect to controls confirming the high sensitivity of COMPASS 31 in revealing autonomic symptoms.

Objective : The reciprocal relation between breathing, heart and motor system abnormalities during sleep was studied in multiple system atrophy (MSA) by means of video-polysomnographic recordings (VPSG). Patients and Methods : Nineteen consecutive MSA patients underwent VPSG with scoring for sleep, respiratory abnormalities, heart (HR) and breathing (BR) rates, and abnormal motor activities. A comparative analysis was performed versus 10 patients with obstructive sleep apnoea syndrome (OSAS). Results : All MSA patients displayed snoring, 42% stridor, and 37% OSAS. Mean sleep SaO 2 was 92.7%, and lowest SaO 2 86%. Patients with stridor had a significant increase in BR from Wake to NREM and REM sleep, and higher HR during sleep. Respiratory muscles and tibialis anterior EMG tonic activity was frequently found, more often in patients with stridor. All patients had REM sleep behaviour disorders (RBD) and 88% periodic limb movements during sleep (PLMS). No OSAS patient had RBD or respiratory muscles and tibialis anterior tonic activity. Conclusions : MSA patients, especially those with associated stridor, commonly display impaired breathing and abnormal control of respiratory and limb muscles during sleep. Breathing and motor abnormalities are often concomitant in the same patient, indicating a diffuse impairment of sleep homeostatic integration that should be included within the diagnostic features of MSA.

Introduction Morvan chorea is an antibody-mediated limbic encephalopathy characterized by severe insomnia, mental confusion, hallucinations, enacted dreams, hyperhidrosis, and neuromyotonia. Case description In a 78 years old man presenting with progressive insomnia apathy and depression, a video-polysomnogram documented enacted dreams mimicking daily life activity (oneiric stupor). This finding led us to perform a search for serum antibodies to voltage-gated K+ channels, which was positive. A diagnosis of Morvan chorea was done. The patient underwent plasma exchange with complete resolution of the clinical picture. Conclusions Oneiric stupor may represent a useful precocious diagnostic marker in Morvan chorea.

Migraine is a neurologic disorder characterized by head pain jointed by hypersensitivities to normal environmental stimuli such as light, sound, and odor during and, at a lower degree, outside attacks. Understanding of the migraine brain has advanced through neurophysiological and functional imaging studies. Different techniques have emphasized as migraineurs show an increased cortical responsiveness, an altered brainstem processing of peripheral stressors, and an impaired energy metabolism. The involvement of multiple brain networks is not confined to the pain pathway indicating migraine as a complex maladaptive coping state.

The aim of this study was to evaluate the prevalence of mood and eating disorders in patients with menstrual migraine. Quality of life and disability were also assessed. The study confirmed the presence of significant disability and poor quality of life due to migraine even in a selected subgroup of patients affected with menstrual migraine. In contrast with the previous literature we did not find any difference in the prevalence of mood and eating disorders.

Headache is generally regarded as a symptom of high blood pressure in spite of conflicting opinions on the association of headache and arterial hypertension. Most studies have shown that mild chronic hypertension and headache are not associated and this demonstration needs to be implemented in clinical practice. Whether moderate hypertension predisposes to headache remains controversial, but there is little evidence that it does. Headaches caused by significant disturbances in arterial pressure are included in the section "Headache attributed to a disorders of homeostasis" (code 10.3) of the 2nd edition of the International Classification of Headache disorders.

Several case-control and cohort studies have suggested an association between migraine and stroke. A significantly higher risk for stroke was found in women under the age of 45 years and for the subgroup with migraine with aura, the posterior circulation being significantly more frequently involved. The link between cardiac diseases and the comorbidity migraine-stroke has been evaluated considering both possible relationships: a higher prevalence of a vascular disease involving both heart and brain in migraineurs, or a cardiac disorder, more prevalent in migraineurs, with a possible aetiological role in migraine attacks.

Lack of nighttime blood pressure (BP) reduction by 10-20% from the mean daytime values (dipping) has been described as a distinguishing feature of essential hypertension and associated, also in normotensive subjects, with increased cardiovascular (CV) risk. Mechanisms involved in the loss of the nocturnal dip are still unclear, but involvement of autonomic nervous system (ANS) activity probably plays a crucial role. Sleep is fundamental in modulating ANS activity to maintain the physiological BP circadian rhythm, and for this reason its integrity has been widely investigated in hypertension. We investigated, under controlled conditions, the autonomic control of the CV system through an autonomic reflex screen in the awake condition and by assessment of circadian rhythm-, day-night-, time-, and state-dependent changes of BP and heart rate (HR) and associated sleep parameters in patients with a recent (≤1 yr) diagnosis of essential grade I hypertension naïve of therapy. Fourteen hypertensive patients (6 males, age: 43 ± 11 yrs; body mass index [BMI]: 24 ± 3 kg/m(2)) were compared with 28 healthy controls matched for sex, age, BMI (2 controls/patient) for cardiovascular reflex and to 8 different subjects from previous controls (6 males), comparable for age and BMI, for the day-night and nighttime CV profiles during two consecutive nights. The cardiovascular reflex screen data showed increased sympathetic effect in hypertensive patients, represented by higher overshoot of BP after Valsalva maneuver. Nighttime sleep architecture during the dark period in terms of duration, representation of sleep stages, sleep fragmentation, and incidence of arousals-periodic limb movements in sleep (PLMS) and PLMS arousals-was similar in patients and controls. Hypertensive patients displayed higher 24-h BP and HR values, but their sleep-related BP decrease was significantly reduced compared with controls. The circadian rhythms of BP and HR were intact and similar in patients and controls, coupling with the expected physiological peak time. BP and HR showed normal state-dependent modulation in hypertensive patients that, however, was higher in all sleep stages compared with controls. The lowering of systolic blood pressure (SBP) during non-rapid eye movement (NREM) sleep stages 1 and 2 and REM sleep, relative to daytime wake values, was significantly attenuated in the hypertensive group, whereas it was comparable to controls during slow-wave sleep. In hypertensive patients, analysis of sleep and CV parameters in the 90 min following sleep onset and preceding morning awakening showed normal depressor effect during the first part of the night after sleep onset and significantly higher BP rise in the hours preceding morning awakening. These findings were associated with comparable sleep architecture, sleep fragmentation, incidence of arousals, and PLMS and PLMS arousals in patients and controls. Our data suggest that drug-naïve essential grade I hypertension is associated with signs of increased vascular sympathetic response to standardized stress of the Valsalva maneuver during the awake condition, and during sleep with a non-dipping BP profile plus higher BP surge preceding morning awakening, assessable only by around-the-clock ambulatory BP monitoring, both representing additional CV risk already in early-stage hypertension and, therefore, requiring proper selection of pharmacological treatment.

Despite the burden of chronic daily headache (CDH), general practitioners’ (GPs) ability to recognize it is unknown. This work is a sub-study of a population-based study investigating GPs’ knowledge on their CDH patients. Patients diagnosed with CDH through the screening questionnaire were interviewed by their GPs who indicated if subjects were known as patients suffering from CDH with medication overuse (MO), CDH without MO, episodic headache (EH) or non-headache sufferers. Our study showed that 64.37 % of CDH sufferers are misdiagnosed by their GPs. However, overusers are better known to GPs.

Migraine has complex relationships with cerebrovascular and cardiovascular disorders but also with cardiac anomalies. Patients affected by migraine with aura have an increased prevalence of right-to-left shunt due to patent foramen ovale or pulmonary arteriovenous malformations. The association between ischemic heart disease, cardiovascular mortality and migraine remains unsettled. The debate focuses on a physiopathological link between migraine and cardiovascular diseases or a higher prevalence of risk factors in migraineurs.

OBJECTIVES: To describe wake-sleep and body core temperature (t degrees ) rhythm abnormalities in two patients with bilateral paramedian thalamic calcifications. METHODS: Patients underwent (18F)FDG PET scans and 24 hour polygraphic recordings of wake-sleep and t degrees. RESULTS: PET showed bilateral thalamic hypometabolism in both patients with additional basal ganglia or mesiolateral frontal and cingular hypometabolism. Wake-sleep studies showed abnormal sleep organisation and in the case with frontal and limbic PET hypometabolism, pre-sleep behaviour associated with "subwakefulness" EEG activities, lack of EEG spindles and K complexes, and features of status dissociatus. The t degrees rhythms showed increased mesor in both (37.4 degrees C and 37.75 degrees C) and inverted rhythm in one patient. CONCLUSIONS: Paramedian thalamic structures and interconnected, especially frontal and cingular, areas play a part in the organisation of the wake-sleep cycle and attendant autonomic functions.

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According to the diagnostic criteria of International Headache Society classification, hemicrania continua is a strictly unilateral continuous headache of moderate intensity with painful exacerbations associated with ipsilateral autonomic signs without pain-free periods. We report a case of a 42-year-old woman suffered of a remitting form of hemicrania continua evolved from a strictly unilateral migraine without aura.

Background: Hypocretins (orexins) are hypothalamic neuropeptides which are involved in a wide range of physiological processes in mammals including central pain processing. Genetic studies in humans evidenced a role for the hypocretinergic system in cluster headache (CH). Patients and methods: We tested cerebrospinal fluid (CSF) hypocretin-1 (orexin-A) levels in 10 CH patients during an active cluster period. CSF hypocretin-1 levels were measured by radioimmunoassay. Results: CSF hypocretin-1 levels were within the normal range (mean 457.3 ± 104.98 pg/ml, range 304–639) in our 10 patients, with a slight reduction in one case (304 pg/ml). There were no associations between CSF hypocretin-1 levels and the clinical features of CH. A trend towards higher hypocretin-1 levels was disclosed in patients with chronic CH compared to episodic CH. Conclusions: CSF hypocretin-1 levels seem not to influence the clinical course of CH, but our results cannot completely exclude a functional involvement of the hypothalamic hypocretinergic system in the pathogenesis of CH.

Migraine is associated with stroke-like episodes in mitochondrial encephalomyopathy, lactic acidosis, stroke-like syndrome (MELAS). Moreover, abnormalities of oxidative phosphorylation are also reported in migraine. We studied two maternal lineages with MELAS and chronic progressive external ophthalmoplegia (CPEO) affected probands carrying the 3243 A>G tRNALeu (MELAS) mutation, remarkable for a high frequency of subjects suffering only migraine. Thus, migraine could be a monosymptomatic expression of the MELAS mutation. We assessed the 3243 A>G tRNALeu mutational load in skeletal muscle and other somatic tissues from the migraine-only subjects, as well as lactic acid levels after exercise. All migraine-only subjects did not carry the MELAS mutation. Muscle biopsy showed mild mitochondrial abnormalities in the non-mutant, migraine-only subjects and, occasionally, abnormal lactic acid. Clear features of mitochondrial myopathy and pathological lactic acid characterised the subjects carrying the MELAS mutation. Our study demonstrates that migraine-only subjects lacked the MELAS mutation, but still had a possible mtDNA-associated genetic predisposition, being maternally related and having some evidence of impaired mitochondrial oxidative phosphorylation.

Objectives.— The aim of our study was to investigate the prevalence of sleep disorders in chronic headache patients and to evaluate the role of psychiatric comorbidity in the association between chronic headache and sleep complaints. Background.— The prevalence of sleep disorders in chronic headache has been seldom investigated, although from the earliest description chronic headache has been associated with sleep disturbances. On the contrary, mood disorders are commonly associated with both sleep disturbances and chronic headache – each of which are, in turn, core features of mood disorders. Therefore, it may be important to discriminate between sleep problems that can be attributed to a comorbid psychiatric disorder, and those specifically associated with headache. Only a few studies investigating the association of chronic headache with sleep difficulties have also taken into account to consider the possible role of anxiety and depression. Patients and Methods.— A total of 105 consecutive patients with daily or nearly daily headache and 102 patients with episodic headache, matched by age, sex, and type of headache at onset, underwent a structured direct interview about their sleep habits and psychiatric diseases. Results.— In total, 80 out of 105 patients with chronic headache received a diagnosis of medication overuse headache, 21 patients were classified as chronic migraine and 4 as chronic tension-type headache without drug overuse. Patients.— Patients with chronic headache showed a high prevalence of insomnia, daytime sleepiness, and snoring with respect to controls (67.7% vs 39.2%, 36.2% vs 23.5%, and 48.6% vs 37.2%, respectively). Forty-five patients with chronic headache (42.9%) had psychiatric comorbidity (anxiety and/or depressive disorders), vs 27 episodic headache patients (26.5%). Multivariate analysis disclosed that low educational level, lower mean age at headache onset, and insomnia are independently associated with chronic headache. Conclusions.— Patients with chronic headache had a high prevalence of sleep complaints. Insomnia may thus represent an independent risk factor for headache chronification. Recognition of sleep disorders, alone or in association with depression or anxiety, may be useful in episodic headache patients to prevent chronification.

The migraine attack is a reversible brain dysfunction characterized by pain autonomic symptoms and passive coping strategies consistent with sickness behavior. The migraine attack may be interpreted as an example of genetically determined adaptive behavioral response to internal or external stressors that it is orchestrated by a threatened brain. In this view, the migraine attack itself may not be categorized as a disease, i.e., a deviation from or interruption of the normal structure or function of the brain but it may turn into a disease in an allostatic perspective, when the repeated migraine attacks start maladaptive mechanisms (inefficient turning on or shutting off of the mechanisms underlying the migraine attack) that resulted in a chronic pain of the brain. In future, we should recognize and treat early all the conditions able to transform a normal response of the brain into a morbid state, i.e., we have to categorize migraine not only as a type of headache attack but also as a symptom of different syndromes.