Publications by authors named "Giuseppe Nappi"

180 Publications

Clinical Subtypes of Medication Overuse Headache - Findings From a Large Cohort.

Headache 2019 10 3;59(9):1481-1491. Epub 2019 Oct 3.

Headache Science Center, IRCCS Mondino Foundation, Pavia, Italy.

Background: The International Classification of Headache Disorders lists different subtypes of medication overuse headache (MOH), according to the medication overused. The aim of this study is to evaluate whether the different subtypes correspond to clinically distinguishable phenotypes in a large population.

Method: This descriptive cross-sectional observational study included 660 patients with MOH referred to headache centers in Europe and Latin America as a part of the COMOESTAS project. Information about clinical features was collected with structured patient interviews and with self-administered questionnaires for measuring disability, anxiety, and depression.

Results: Female/male ratio, body mass index, marital status, and level of education were similar among in subjects enrolled in the 5 centers. The mean age was higher among subjects overusing triptans (T-MOH) with respect to subjects overusing simple analgesic (A-MOH). Duration of headache before chronification was longer in T-MOH (19.2 ± 11.9 years) and in subjects overusing ergotamines (E-MOH, 17.8 ± 11.7 years) with respect to the A-MOH group (13.1 ± 10.9; P < .001 and P = .017, respectively) and in T-MOH with respect multiple drug classes (M-MOH, 14.9 ± 11.7; P = .030). Migraine Disability Assessment (MIDAS) score was significantly lower in E-MOH group (33.6 ± 41.6), while T-MOH group (56.8 ± 40.6) had a significant lower MIDAS score with respect to M-MOH (67.2 ± 62.5; P = .016 and P = .037, respectively). Prevalence of depression and anxiety was lower in patients overusing T with respect to other groups of patients (χ  = 10.953, P = .027 and χ  = 25.725, P < .001, respectively).

Conclusion: In this study on a large and very well characterized population of MOH, we describe the distinctive clinical characteristics of MOH subtypes. These findings contribute to more clearly define the clinical picture of a poorly delineated headache disorder. They also provide some insights in the possible trajectories leading to this highly disabling chronic headache, that is classified as a secondary form, but whose occurrence is entirely dependent on an underlying primary headache.
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http://dx.doi.org/10.1111/head.13641DOI Listing
October 2019

Prevalence and pathophysiology of post-prandial migraine in patients with functional dyspepsia.

Cephalalgia 2019 Oct 15;39(12):1560-1568. Epub 2019 Jun 15.

1 Department of Medicine, University of Pavia, Foundation IRCCS "S.Matteo" Hospital, Pavia, Italy.

Background: Migraine is a condition frequently associated with gastrointestinal disorders. Previous reports have shown the relationship between irritable bowel syndrome and migraine, but no data are yet available in patients with functional dyspepsia. We therefore evaluated whether alteration of gastric sensorimotor activity may be related to migraine.

Methods: Sixty patients affected by functional dyspepsia, 38 with postprandial distress syndrome and 22 with epigastric pain syndrome were enrolled in a cohort study. Presence and severity of dyspeptic symptoms, migraine presence and severity, gastric sensitivity thresholds during fasting and postprandial period, gastric accommodation and gastric emptying time were evaluated.

Results: In epigastric pain syndrome, 12/22 (54%) patients suffered from migraine and this condition was never correlated with meal ingestion. In postprandial distress syndrome patients, 29/38 (76%) suffered from migraine, in 26/29 (89%) its onset was considered as meal-related, and migraine severity was significantly correlated with postprandial modification of the gastric discomfort threshold (r = -0.73;  < 0.001). In patients with postprandial distress syndrome, in the subgroup with moderate to severe migraine, the severity of fullness and early satiation was significantly higher than in patients with mild or absent migraine. In patients with moderate to severe migraine, gastric accommodation, sensitivity thresholds and gastric emptying time were similar to patients with mild or no migraine.

Conclusions: In patients with functional dyspepsia and postprandial symptoms, migraine is a very frequent comorbidity. On clinical grounds, it is associated with an increased severity of fullness and early satiation and, on pathophysiological grounds, it seems correlated with postprandial hypersensitivity.
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http://dx.doi.org/10.1177/0333102419857596DOI Listing
October 2019

Prolonged migraine aura: new insights from a prospective diary-aided study.

J Headache Pain 2018 Aug 31;19(1):77. Epub 2018 Aug 31.

Headache Science Center, IRCCS Mondino Foundation, Pavia, Italy.

Background: There is limited literature on prolonged aura (PA - defined as an aura including at least one symptom for > 1 h and < 7d), and there are no prospective studies. The aim of this study is to characterize prospectively the phenotype and prevalence of PA.

Findings: Two hundred and twenty-four patients suffering from migraine with aura were recruited from the Headache Centers of Pavia and Trondheim. Patients prospectively described, on an ad hoc diary, each aura symptom (AS), the duration of AS and headache, and headache features. Seventy-two patients recorded three consecutive auras in their diaries. 19 (26.4%) of patients suffered at least one PA. Out of 216 recorded auras, 38 (17.6%) were PAs. We compared PAs with non-PAs with respect to 20 features; PAs were characterized by a higher number of non-visual symptoms (non-VS) (p < 0.001). No other differences were found. We obtained similar results when we compared auras with at least one symptom with a duration of > 2 h (n = 23) or > 4 h (n = 14) with the the others (n = 193 and n = 202 respectively).

Conclusion: PAs are quite common. They do not differ from the other auras (even when their duration extends to 2 and/or 4 h) with the exception of a higher number of non-VS.
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http://dx.doi.org/10.1186/s10194-018-0910-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119171PMC
August 2018

Economic benefits of treating medication-overuse headache - results from the multicenter COMOESTAS project.

Cephalalgia 2019 02 8;39(2):274-285. Epub 2018 Jul 8.

7 Headache Science Centre, C. Mondino National Neurological Institute, Pavia, Italy.

Background: Medication-overuse headache is a costly disease for individuals and society.

Objective: To estimate the impact of medication-overuse headache treatment on direct and indirect headache-related health care costs.

Methods: This prospective longitudinal study was part of the COMOESTAS project (COntinuous MOnitoring of Medication Overuse Headache in Europe and Latin America: development and STAndardization of an Alert and decision support System). Patients with medication-overuse headache were included from four European and two Latin American headache centers. Costs of acute medication, costs of health care services, and measurements of productivity were calculated at baseline and at 6-month follow-up Treatment consisted of overused drug withdrawal with optional preventive medication.

Results: A total of 475 patients (71%) completed treatment and were followed up for 6 months. Direct health care costs were on average reduced significantly by 52% ( p < 0.001) for the total study population. Significant reductions were seen in both number of consumed tablets (-71%, p < 0.001) and number of visits to physicians (-43%, p < 0.001). Fifty percent of patients reduced their number of consumed tablets ≥ 80%. Headache-related productivity loss, calculated either as absence from work or ≥ 50% reduction of productivity during the workday, were reduced by 21% and 34%, respectively ( p < 0.001).

Conclusion: Standardized treatment of medication-overuse headache in six countries significantly reduced direct health care costs and increased productivity. This emphasizes the importance of increasing awareness of the value of treating medication-overuse headache.

Trial Registration: The trial was registered at ClinicalTrials.gov (no. NCT02435056).
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http://dx.doi.org/10.1177/0333102418786265DOI Listing
February 2019

Psychological, clinical, and therapeutic predictors of the outcome of detoxification in a large clinical population of medication-overuse headache: A six-month follow-up of the COMOESTAS Project.

Cephalalgia 2019 01 27;39(1):135-147. Epub 2018 Jun 27.

1 Headache Science Centre, IRCCS Mondino Foundation, Pavia, Italy.

Aim: To identify factors that may be predictors of the outcome of a detoxification treatment in medication-overuse headache.

Methods: Consecutive patients entering a detoxification program in six centres in Europe and Latin America were evaluated and followed up for 6 months. We evaluated anxious and depressive symptomatology (though patients with severe psychiatric comorbidity were excluded), quality of life, headache-related disability, headache characteristics, and prophylaxis upon discharge.

Results: Of the 492 patients who completed the six-month follow up, 407 ceased overuse following the detoxification (non overusers), another 23 ceased overuse following detoxification but relapsed during the follow-up. In the 407 non-overusers, headache acquired an episodic pattern in 287 subjects (responders). At the multivariate analyses, lower depression scores (odds ratio = 0.891; p = 0.001) predicted ceasing overuse. The primary headache diagnosis - migraine with respect to tension-type headache (odds ratio = 0.224; p = 0.001) or migraine plus tension-type headache (odds ratio = 0.467; p = 0.002) - and the preventive treatment with flunarizine (compared to no such treatment) (odds ratio = 0.891; p = 0.001) predicted being a responder. A longer duration of chronic headache (odds ratio = 1.053; p = 0.032) predicted relapse into overuse. Quality of life and disability were not associated with any of the outcomes.

Conclusions: Though exploratory in nature, these findings point to specific factors that are associated with a positive outcome of medication-overuse headache management, while identifying others that may be associated with a negative outcome. Evaluation of the presence/absence of these factors may help to optimize the management of this challenging groups of chronic headache sufferers.
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http://dx.doi.org/10.1177/0333102418783317DOI Listing
January 2019

Factors associated to chronic migraine with medication overuse: A cross-sectional study.

Cephalalgia 2018 12 10;38(14):2045-2057. Epub 2018 Apr 10.

1 Headache Science Center, IRCCS Mondino Foundation, Pavia, Italy.

Background And Aim: Factors implicated in the evolution of episodic migraine into chronic migraine are largely elusive. Medication overuse is considered to be one of the main determinants, but other possible clinical and psychological factors can play a role. The aim of this study is to identify factors that are associated with chronic migraine with medication overuse.

Method: We enrolled consecutive migraine patients, subdividing them in two groups: Subjects with a long history of episodic migraine and subjects with chronic migraine and medication overuse. We then compared their clinical and psychological variables in a cross-sectional study.

Results: Three hundred and eighteen patients were enrolled, of which 156 were episodic migraine and 162 were chronic migraine and medication overuse patients. The mean age was 42.1 ± 10.3, 80.8% were female. The duration of migraine was 24.6 years in episodic migraine and 24.0 years in chronic migraine and medication overuse ( p = 0.57). After the multivariate analysis, the factors associated to chronic migraine and medication overuse were: Marital status (married vs. unmarried, OR 3.65, 95% CI 1.63-8.19, p = 0.002; separated/divorced/widowed vs. unmarried, OR 4.19, 95% CI 1.13-15.47, p = 0.031), physical activity (OR 0.42, 95% CI 0.19-0.91, p = 0.029), age at onset of migraine (OR 0.94, 95% CI 0.89-0.98, p = 0.016), use of at least one migraine preventive medication (OR 2.36, 95% CI 1.18-4.71, p = 0.014), history of depression (OR 2.91, 95% CI 1.25-6.73, p = 0.012), insomnia associated with the use of hypnotics (OR 5.59, 95% CI 1.65-18.93, p = 0.006), traumatic head injuries (OR 3.54, 95% CI 1.57-7.99, p = 0.002), snoring (OR 2.24, 95% CI 1.05-4.79, p = 0.036), previous and/or actual use of combined oral contraceptives (OR 3.38, 95% CI 1.10-10.3, p = 0.031) and higher scores in the Childhood Trauma questionnaire (OR 1.48, 95% CI 1.09-2.02, p = 0.012).

Conclusion: We considered several aspects that may be involved in the development of chronic migraine and medication overuse. A multivariate analysis identified 10 factors belonging to five different areas, to suggest that chronic migraine and medication overuse onset is likely influenced by a complex mixture of factors. This information is useful when planning strategies to prevent and manage chronic migraine and medication overuse.
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http://dx.doi.org/10.1177/0333102418761047DOI Listing
December 2018

Botulinum toxin for chronic migraine: Clinical trials and technical aspects.

Toxicon 2018 Jun 4;147:111-115. Epub 2017 Sep 4.

Headache Science Center and Headache Unit, National Neurological Institute C. Mondino Foundation, Pavia, Italy; Dept of Brain and Behavioral Sciences, University of Pavia, Italy.

OnabotulinumtoxinA has been approved for the prophylaxis of chronic migraine following the demonstration of efficacy in two large controlled trials. Data collected from pragmatic studies in the real-life setting have contributed important additional information useful for the management of this group of extremely disabled and challenging patients. The main findings from these studies are presented and discussed.
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http://dx.doi.org/10.1016/j.toxicon.2017.08.026DOI Listing
June 2018

De novo exonic duplication of ATP1A2 in Italian patient with hemiplegic migraine: a case report.

J Headache Pain 2017 Dec 7;18(1):63. Epub 2017 Jun 7.

Genomic and Post-Genomic Center, "C. Mondino" National Neurological Institute, Mondino 2, 27100, Pavia, Italy.

Background: Sporadic Hemiplegic Migraine is a rare form of migraine headache. Mutations in three different genes, two ion-channel genes and one encoding an ATP exchanger, CACNA1A, ATP1A2 and SCN1A are all responsible for the FHM phenotype, thus indicating a genetic heterogeneity for this disorder. Here, we described a de novo exonic duplication of ATP1A2 in an Italian patient with Hemiplegic Migraine.

Case Presentation: We describe the case of a young woman (33 year old) who suffered from the age of 8 years of episodic weakness of the limbs, associated to other subjective and objective features. From aged 25, she developed neurological symptoms, like dizziness, blurred vision and an MRI scan revealed aspecific peritrigonal white matter hyperintensities. Aged 32 she suffered of right hemisomatic sudden-onset paresthesias, hypoesthesia and hyposthenia and the patient was genetically investigated for sporadic hemiplegic migraine.

Conclusions: Here we report, for the first time, an exonic duplication in the ATP1A2 associated with hemiplegic migraine. The variation identified involves exon 21 of the ATP1A2 and is expected to alter the function of the alpha(2) subunit of the Na(+)/K(+) pump; the de novo nature of the duplication further supports its pathogenic role. To date, no other CNVs have been described in the ATP1A2 but only point mutations are reported. The novel mutation may result impaired M9 transmembrane domain, in a loss-of-function of the alpha(2) Na(+)/K(+)-ATPase with glutamate accumulation, alteration of synaptic function and neurotransmission.
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http://dx.doi.org/10.1186/s10194-017-0770-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462664PMC
December 2017

Changes in anxiety and depression symptoms associated to the outcome of MOH: A post-hoc analysis of the Comoestas Project.

Cephalalgia 2018 04 11;38(4):646-654. Epub 2017 Apr 11.

1 Headache Science Centre, C. Mondino National Neurological Institute, Pavia, Italy.

Aims To evaluate the impact of treatment success on depression and anxiety symptoms in medication-overuse headache (MOH) and whether depression and anxiety can be predictors of treatment outcome. Methods All consecutive patients entering the detoxification program were analysed in a prospective, non-randomised fashion over a six-month period. Depression and anxiety were assessed using the Hospital Anxiety and Depression Scale. Results A total of 663 MOH patients were evaluated, and 492 completed the entire protocol. Of these, 287 ceased overuse and reverted to an episodic pattern (responders) and 23 relapsed into overuse. At the final evaluation, the number of patients with depressive symptoms was reduced by 63.2% among responders ( p < 0.001) and did not change in relapsers ( p = 0.13). Anxious symptomatology was reduced by 43.1% in responders ( ps < 0.001) and did not change in relapsers ( p = 0.69). At the multivariate analysis, intake of a prophylactic drug and absence of symptoms of depression at six months emerged as prognostic factors for being a responder (OR 2.406; p = 0.002 and OR 1.989; p = 0.019 respectively), while lack of antidepressant drugs and presence of symptoms of depression at six months were prognostic factors for relapse into overuse (OR 3.745; p = 0.004 and OR 3.439; p = 0.031 respectively). Conclusions Symptomatology referred to affective state and anxiety can be significantly reduced by the treatment of MOH. Baseline levels of depression and anxiety do not generally predict the outcome at six months. Their persistence may represent a trait of patients with a negative outcome, rather than the consequence of a treatment failure.
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http://dx.doi.org/10.1177/0333102417704415DOI Listing
April 2018

Rehabilitation from symptomatic drugs overuse: yes, no, may be.

J Headache Pain 2015 Dec;16(Suppl 1):A34

Headache Science Centre, C. Mondino National Neurological Institute, Pavia, Italy.

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http://dx.doi.org/10.1186/1129-2377-16-S1-A34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759053PMC
December 2015

P007. Inhibition of monoacylglycerol lipase activity modulates the activation of brain structures relevant for migraine pathogenesis.

J Headache Pain 2015 Dec;16(Suppl 1):A165

Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Centre, "C. Mondino" National Neurological Institute, Pavia, Italy.

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http://dx.doi.org/10.1186/1129-2377-16-S1-A165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759149PMC
December 2015

When cervical pain is actually migraine: An observational study in 207 patients.

Cephalalgia 2018 02 7;38(2):383-388. Epub 2016 Dec 7.

1 Headache Science Center, C. Mondino National Neurological Institute, Pavia, Italy.

Introduction A large proportion of migraine patients remain undiagnosed or misdiagnosed in Italy. In our experience, many migraineurs self-diagnose their condition as "cervical pain attack" or "cervical pain syndrome" (CP), assuming cervical spine pathology as the cause. We aimed to phenotype and classify the headache of patients with self-diagnosed CP, and to describe this sample of patients. Methods Consecutive patients aged 18 to 75 years, referred to the Headache Center of the Mondino Institute (Pavia, Italy) for a first visit for headache, completed a questionnaire about CP and were subsequently examined by an experienced clinician. Results Out of 207 patients, 132 (64%) believed they suffered from CP. According to ICHD-IIIβ criteria, these patients suffered from migraine or probable migraine in 91% of cases. The great majority of patients who believed that they suffered from CP underwent unnecessary medical exams (including radiation exposure in 40% of cases) and used treatments that were inadequate for their real diagnosis. Conclusion The majority of patients with CP suffer from typical migraine. The misdiagnosis produces an economic burden (for patients and the health care system) and leads to impaired quality of life of patients.
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http://dx.doi.org/10.1177/0333102416683917DOI Listing
February 2018

Effects of kynurenic acid analogue 1 (KYNA-A1) in nitroglycerin-induced hyperalgesia: Targets and anti-migraine mechanisms.

Cephalalgia 2017 Nov 16;37(13):1272-1284. Epub 2016 Nov 16.

1 Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Center, C. Mondino National Neurological Institute, Pavia, Italy.

Background Trigeminal sensitization represents a major mechanism underlying migraine attacks and their recurrence. Nitroglycerin (NTG) administration provokes spontaneous migraine-like headaches and in rat, an increased sensitivity to the formalin test. Kynurenic acid (KYNA), an endogenous regulator of glutamate activity and its analogues attenuate NTG-induced neuronal activation in the nucleus trigeminalis caudalis (NTC). The anti-hyperalgesic effect of KYNA analogue 1 (KYNA-A1) was investigated on animal models specific for migraine pain. Aim Rats made hyperalgesic by NTG administration underwent the plantar or orofacial formalin tests. The effect of KYNA-A1 was evaluated in terms of nocifensive behavior and of neuronal nitric oxide synthase (nNOS), calcitonin gene-related peptide (CGRP) and cytokines expression in areas involved in trigeminal nociception. Results KYNA-A1 abolished NTG-induced hyperalgesia in both pain models; NTG alone or associated to formalin injection induced an increased mRNA expression of CGRP, nNOS and cytokines in the trigeminal ganglia and central areas, which was reduced by KYNA-A1. Additionally, NTG caused a significant increase in nNOS immunoreactivity in the NTC, which was prevented by KYNA-A1. Conclusion Glutamate activity is likely involved in mediating hyperalgesia in an animal model specific for migraine. Its inhibition by means of a KYNA analogue modulates nNOS, CGRP and cytokines expression at peripheral and central levels.
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http://dx.doi.org/10.1177/0333102416678000DOI Listing
November 2017

Clinical features of migraine aura: Results from a prospective diary-aided study.

Cephalalgia 2017 Sep 29;37(10):979-989. Epub 2016 Aug 29.

1 Headache Science Center, C. Mondino National Neurological Institute, Pavia, Italy.

Background A detailed evaluation of migraine aura symptoms is crucial for classification issues and pathophysiological discussion. Few studies have focused on the detailed clinical aspects of migraine aura. Methods We conducted a prospective diary-based study of migraine aura features including presence, quality, laterality, duration of each aura symptom, their temporal succession; presence of headache and its temporal succession with aura. Results Seventy-two patients completed the study recording the characteristics of three consecutive auras ( n = 216 auras). Visual symptoms occurred in 212 (98%), sensory symptoms in 77 (36%) and dysphasic symptoms in 22 (10%). Most auras had more than one visual symptom (median 2, IQR 1-3, range 1-4). The majority of patients (56%) did not report a stereotyped aura on the three attacks with respect to visual features, the combination and/or temporal succession of the three aura symptoms. Fifty-seven percent of patients also reported a different scenario of temporal succession between aura and headache in the three attacks. Five per cent of aura symptoms were longer than four hours. Conclusion These findings show a high inter- and intravariability of migraine with aura attacks. Furthermore, they provide reliable data to enrich and clarify the spectrum of the aura phenotype.
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http://dx.doi.org/10.1177/0333102416657147DOI Listing
September 2017

Modulation of nociceptive threshold by combined hormonal contraceptives in women with oestrogen-withdrawal migraine attacks: a pilot study.

J Headache Pain 2016 Dec 4;17(1):70. Epub 2016 Aug 4.

Research Centre for Reproductive Medicine, Gynaecological Endocrinology and Menopause, IRCCS San Matteo Foundation, Pavia, Italy.

Background: Menstrually-related headache and headaches associated with oestrogen withdrawal are common conditions, whose pathophysiology has not been completely elucidated. In this study we evaluated the influence of combined hormonal contraceptives (CHC) on pain threshold in women presenting migraine attacks during hormone-free interval.

Findings: Eleven women with migraine attacks recurring exclusively during the oestrogen-withdrawal period were studied with the nociceptive flexion reflex, a neurophysiological assessment of the pain control systems, during the third week of active treatment and during the hormone-free interval. During the hormone-free interval, nociceptive withdrawal reflex threshold was significantly lower (12.8 ± 8.0 mA) as compared to the third week of hormonal treatment (15.6 ± 6.6 mA) (p = 0.02). No change was observed in the pain perceived and in the temporal summation.

Conclusions: Oestrogen withdrawal may mediate an increased sensitivity to somatosensory stimuli in women with migraine attacks recurring during the hormone-free interval.
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http://dx.doi.org/10.1186/s10194-016-0661-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972742PMC
December 2016

The added value of an electronic monitoring and alerting system in the management of medication-overuse headache: A controlled multicentre study.

Cephalalgia 2017 Oct 20;37(12):1115-1125. Epub 2016 Jul 20.

1 Headache Science Centre, C. Mondino National Neurological Institute, Pavia, Italy.

Background Medication-overuse headache (MOH) is a chronic disabling condition associated with a high rate of relapse. Methods We evaluated whether the adoption of electronic-assisted monitoring, advice and communication would improve the outcome over a follow-up of 6 months in a controlled, multicentre, multinational study conducted in six headache centres located in Europe and Latin America. A total of 663 MOH subjects were enrolled and divided into two groups: the Comoestas group was monitored with an electronic diary associated with an alert system and a facilitated communication option, and the Classic group with a paper headache diary. Results We observed a significantly higher percentage of overuse-free subjects in the Comoestas group compared with the Classic group: 73.1 vs 64.1% (odds ratio 1.45, 95% confidence interval 1.07-2.09, p = 0.046). The Comoestas group performed better also regarding the number of days/month with intake of acute drugs and the level of disability [Migraine Disability Assessment Score: Comoestas group - 42.5 ± 53.6 (35.5-49.3) and Classic group - 27.5 ± 56.1 (20.6-34.3) ( p < 0.003)]. Conclusion The adoption of the electronic tool improved the outcome of patients suffering from MOH after withdrawal from overused drugs. Information and communication technology represents a valid aid for optimizing the management of chronic conditions at risk of worsening or of relapsing. Trial registration The trial was registered at ClinicalTrials.gov (no. NCT02435056).
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http://dx.doi.org/10.1177/0333102416660549DOI Listing
October 2017

Andrographis Paniculata shows anti-nociceptive effects in an animal model of sensory hypersensitivity associated with migraine.

Funct Neurol 2016 Jan-Mar;31(1):53-60

Administration of nitroglycerin (NTG) to rats induces a hyperalgesic condition and neuronal activation of central structures involved in migraine pain. In order to identify therapeutic strategies for migraine pain, we evaluated the anti-nociceptive activity of Andrographis Paniculata (AP), a herbaceous plant, in the hyperalgesia induced by NTG administration in the formalin test. We also analyzed mRNA expression of cytokines in specific brain areas after AP treatment. Male Sprague-Dawley rats were pre-treated with AP extract 30 minutes before NTG or vehicle injection. The data show that AP extract significantly reduced NTG-induced hyperalgesia in phase II of the test, 4 hours after NTG injection. In addition, AP extract reduced IL-6 mRNA expression in the medulla and mesencephalon and also mRNA levels of TNFalpha in the mesencephalic region. These findings suggest that AP extract may be a potential therapeutic approach in the treatment of general pain, and possibly of migraine.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819820PMC
http://dx.doi.org/10.11138/fneur/2016.31.1.053DOI Listing
December 2016

Medication overuse headache in Europe and Latin America: general demographic and clinical characteristics, referral pathways and national distribution of painkillers in a descriptive, multinational, multicenter study.

J Headache Pain 2015 8;17:20. Epub 2016 Mar 8.

Danish Headache Center, Neurological Department, Glostrup Hospital, Glostrup, Denmark.

Background: Medication overuse headache (MOH) is a very disabling and costly disorder due to indirect costs, medication and healthcare utilization. The aim of the study was to describe general demographic and clinical characteristics of MOH, along with the national referral pathways and national painkillers distribution in several European and Latin American (LA) Countries.

Methods: This descriptive cross-sectional observational study included 669 patients with MOH referred to headache-centers in Europe and LA as a part of the COMOESTAS project. Information about acute medication and healthcare utilization were collected by extensive questionnaires, supplemented with structured patient interviews.

Results: Triptans were overused by 31 % European patients and by 6 % in LA (p < 0.001), whereas ergotamines were overused by 4 % in Europe and 72 % in LA (p < 0.001). Simple analgesics were overused by 54 % in Europe and by 33 % in LA (p < 0.001), while combination-analgesics were more equally overused (24 % in Europe and 29 % in LA). More European patients (57 %) compared with LA patients (27 %) visited general practitioners (p < 0.001), and 83 % of European patients compared to 38 % in LA consulted headache specialists (p < 0.001). A total of 20 % in Europe and 30 % in LA visited emergency rooms (p = 0.007).

Conclusion: There are marked variations between LA and Europe in healthcare pathways and in acute medication overuse regarding patients with MOH. This should be considered when planning prevention campaigns against MOH.
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http://dx.doi.org/10.1186/s10194-016-0612-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783306PMC
September 2016

Alexithymia in chronic and episodic migraine: a comparative study.

J Ment Health 2017 Jun 6;26(3):192-196. Epub 2016 Jan 6.

b Headache Science Center, National Neurological Institute C. Mondino , Pavia , Italy.

Background: Alexithymia is a term used to describe a disorder where patients have difficulty in expressing their own feelings in words.

Aims: The analysis of alexithymia in patients suffering from chronic migraine (CM) or episodic migraine (EM) compared to healthy controls.

Methods: Two clinical samples formed by 80 CM patients (21 males and 59 females, mean age: 44.65) and 44 EM patients (8 males and 36 females, mean age: 42.18) were enrolled. A group of 67 healthy subjects served as controls (26 males and 41 females, mean age: 41.21). All subjects were requested to fill in the 20-item version of the Toronto Alexithymia Scale (TAS-20).

Results: We found a statistically significant difference between groups in Factor 1 (difficulty in describing feelings), F(2, 191) = 7.96, p < 0.001, and in TAS total, F(2, 191) = 5.37, p = 0.005. Post-hoc analyses revealed that CM patients had higher scores in TAS factor 1 and in TAS total than healthy controls. There were no significant differences between CM and EM patients, even if CM sufferers reported a trend towards higher scores in each TAS factor as well as in TAS total.

Conclusions: Alexithymia emerges as a potential characteristic trait of migraine, regardless of disease severity.
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http://dx.doi.org/10.3109/09638237.2015.1124404DOI Listing
June 2017

The Neuropharmacology of Cluster Headache and other Trigeminal Autonomic Cephalalgias.

Curr Neuropharmacol 2015 ;13(3):304-23

National Institute of Neurology IRCCS C. Mondino Foundation, University of Pavia, via Mondino 2, 27100 Pavia, Italy.

Trigeminal autonomic cephalalgias (TACs) are a group of primary headaches including cluster headache (CH), paroxysmal hemicrania (PH) and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT). Another form, hemicrania continua (HC), is also included this group due to its clinical and pathophysiological similarities. CH is the most common of these syndromes, the others being infrequent in the general population. The pathophysiology of the TACs has been partly elucidated by a number of recent neuroimaging studies, which implicate brain regions associated with nociception (pain matrix). In addition, the hypothalamic activation observed in the course of TAC attacks and the observed efficacy of hypothalamic neurostimulation in CH patients suggest that the hypothalamus is another key structure. Hypothalamic activation may indeed be involved in attack initiation, but it may also lead to a condition of central facilitation underlying the recurrence of pain episodes. The TACs share many pathophysiological features, but are characterised by differences in attack duration and frequency, and to some extent treatment response. Although alternative strategies for the TACs, especially CH, are now emerging (such as neurostimulation techniques), this review focuses on the available pharmacological treatments complying with the most recent guidelines. We discuss the clinical efficacy and tolerability of the currently used drugs. Due to the low frequency of most TACs, few randomised controlled trials have been conducted. The therapies of choice in CH continue to be the triptans and oxygen for acute treatment, and verapamil and lithium for prevention, but promising results have recently been obtained with novel modes of administration of the triptans and other agents, and several other treatments are currently under study. Indomethacin is extremely effective in PH and HC, while antiepileptic drugs (especially lamotrigine) appear to be increasingly useful in SUNCT. We highlight the need for appropriate studies investigating treatments for these rare, but lifelong and disabling conditions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812802PMC
http://dx.doi.org/10.2174/1570159x13666150309233556DOI Listing
August 2016

Clinical and Demographical Characteristics of Patients with Medication Overuse Headache in Argentina and Chile: Analysis of the Latin American Section of COMOESTAS Project.

J Headache Pain 2015 18;16:83. Epub 2015 Sep 18.

Headache Science Centre, C. Mondino National Neurological Institute, Pavia, Italy.

Background: Data on the characteristics of Medication Overuse Headache (MOH) in Latin American (LA) are scarce. Here we report the demographic and clinical features of the MOH patients from Argentina and Chile enrolled in the multinational COMOESTAS project in the period 2008-2010.

Methods: The LA population was formed by 240 MOH subjects, 110 from Chile and 130 from Argentina, consecutively attending the local headache centres. In each centre, specifically trained neurologist interviewed and confirmed the diagnosis according to the ICHD-II criteria. A detailed history was collected on an electronic patient record form.

Results: The mean patient age was 38.6 years, with a female/male ratio of 8:2. The mean time since onset of the primary headache was 21 years, whereas duration of MOH was 3.9 years. The primary headache was migraine without aura in 77.5 % and migraine with aura in 18.8 %. Forty two % of the patients self-reported emotional stress associated with the chronification of headache; 43.8 % reported insomnia. The most overused medications were acute drug combinations containing ergotamine (70 %), NSAIDs (33.8 %) and triptans (5.4 %).

Conclusion: Though little described, MOH is present also in LA, where it affects mostly women, in the most active decades of life. Some differences emerge as regards the demographic and clinical characteristics of MOH in this population as compared to Europe or Northern America. What seems more worrying about MOH in Argentina and Chile is that most patients overuse ergotamine, a drug that may cause serious adverse events when used chronically. These findings once more underscore the importance of properly diagnose and treat MOH.
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http://dx.doi.org/10.1186/s10194-015-0561-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573742PMC
May 2016

Evaluation of ADMA-DDAH-NOS axis in specific brain areas following nitroglycerin administration: study in an animal model of migraine.

J Headache Pain 2015 13;16:560. Epub 2015 Aug 13.

Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Centre, "C. Mondino" National Neurological Institute, Pavia, Italy,

Background: Nitric oxide (NO) is known to play a key role in migraine pathogenesis, but modulation of NO synthesis has failed so far to show efficacy in migraine treatment. Asymmetric dimethylarginine (ADMA) is a NO synthase (NOS) inhibitor, whose levels are regulated by dimethylarginine dimethylaminohydrolase (DDAH). Systemic administration of nitroglycerin (or glyceryl trinitrate, GTN) is a NO donor that consistently induces spontaneous-like headache attacks in migraneurs. GTN administration induces an increase in neuronal NOS (nNOS) that is simultaneous with a hyperalgesic condition. GTN administration has been used for years as an experimental animal model of migraine. In order to gain further insights in the precise mechanisms involved in the relationships between NO synthesis and migraine, we analyzed changes induced by GTN administration in ADMA levels, DDHA-1 mRNA expression and the expression of neuronal and endothelial NOS (nNOS and eNOS) in the brain. We also evaluated ADMA levels in the serum.

Methods: Male Sprague-Dawley rats were injected with GTN (10 mg/kg, i.p.) or vehicle and sacrificed 4 h later. Brain areas known to be activated by GTN administration were dissected out and utilized for the evaluation of nNOS and eNOS expression by means of western blotting. Cerebral and serum ADMA levels were measured by means of ELISA immunoassay. Cerebral DDAH-1 mRNA expression was measured by means of RT-PCR. Comparisons between experimental groups were performed using the Mann Whitney test.

Results: ADMA levels and nNOS expression increased in the hypothalamus and medulla following GTN administration. Conversely, a significant decrease in DDAH-1 mRNA expression was observed in the same areas. By contrast, no significant change was reported in eNOS expression. GTN administration did not induce any significant change in serum levels of ADMA.

Conclusion: The present data suggest that ADMA accumulates in the brain after GTN administration via the inhibition of DDAH-1. This latter may represent a compensatory response to the excessive local availability of NO, released directly by GTN or synthetized by nNOS. These findings prompt an additional mediator (ADMA) in the modulation of NO axis following GTN administration and offer new insights in the pathophysiology of migraine.
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http://dx.doi.org/10.1186/s10194-015-0560-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536246PMC
February 2016

Migraine aura symptoms: Duration, succession and temporal relationship to headache.

Cephalalgia 2016 Apr 8;36(5):413-21. Epub 2015 Jul 8.

Headache Science Center, C. Mondino National Neurological Institute, Italy Department of Brain and Behavioural Sciences, University of Pavia, Italy.

Background: As there are no biological markers, a detailed description of symptoms, particularly temporal characteristics, is crucial when diagnosing migraine aura. Hitherto these temporal aspects have not been studied in detail.

Methods: We conducted a prospective diary-aided study of the duration and the succession of aura symptoms and their temporal relationship with headache.

Results: Fifty-four patients completed the study recording in a diary the characteristics of three consecutive auras ( ITALIC! n = 162 auras). The median duration of visual, sensory and dysphasic symptoms were 30, 20 and 20 minutes, respectively. Visual symptoms lasted for more than one hour in 14% of auras ( ITALIC! n = 158), sensory symptoms in 21% of auras ( ITALIC! n = 52), and dysphasic symptoms in 17% of auras ( ITALIC! n = 18). Twenty-six percent of patients had at least one aura out of three with one symptom lasting for more than one hour. In aura with multiple symptoms the subsequent symptom, second versus first one or third versus second, might either start simultaneously (34 and 18%), during (37 and 55%), with the end (5 and 9%), or after (24 and 18%) the previous aura symptom. The headache phase started before the aura (9%), simultaneously with the onset of aura (14%), during the aura (26%), simultaneously with the end of aura (15%) or after the end of aura (36%).

Conclusion: We provide data to suggest that symptoms may last longer than one hour in a relevant proportion of auras or migraine with aura patients, and that there is a high variability of scenarios in terms of time relationship among aura symptoms and between aura and headache.
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http://dx.doi.org/10.1177/0333102415593089DOI Listing
April 2016