Matteo Paolucci

1-Hz Repetitive Transcranial Magnetic Stimulation Increases Cerebral Vasomotor Reactivity: A Possible Autonomic Nervous System Modulation

BACKGROUND Neuromodulation techniques, i.e. repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), can modify cerebral hemodynamics. High frequency rTMS appeared to decrease cerebral vasomotor reactivity (VMR), while there is still poor evidence about the effect of low frequency (LF) rTMS on cerebral blood flow (CBF) and VMR. HYPOTHESIS The present study aimed to test if LF rTMS decreases CBF and increases cerebral VMR. Monolateral or bilateral hemispheric involvement and duration of the effect were considered. A possible role of autonomic nervous system in CBF and VMR modulation was also investigated. METHODS Twenty-four right-handed healthy subjects underwent randomly real (12) or sham (12) 20-min 1-Hz rTMS on left primary motor cortex. Mean flow velocity and VMR of middle cerebral arteries were evaluated by means of transcranial Doppler before (T0), after 10 min (T1) and after 2 (T2), 5 (T3) and 24 h (T4) from rTMS. Heart rate variability (HRV) was studied within the same timing interval, assessing low frequency/high frequency (LF/HF) ratio as index of autonomic balance. RESULTS After real rTMS compared with sham stimulation, MFV decreased bilaterally at T1 (F = 3.240, P = .030) while VMR increased bilaterally (F = 5.116, P = .002) for at least 5 h (T3). LF/HF ratio decreased early after real rTMS (F = 2.881, P = .040). CONCLUSION 1-Hz rTMS may induce a bilateral long-lasting increase of VMR, while its effect on MFV is short-lasting. Moreover, HRV changes induced by rTMS suggest a possible autonomic nervous system modulation.

P038. Effects of non-invasive vagus nerve stimulation on cerebral vasomotor reactivity in patients with chronic migraine during intercritical phase: a pilot study

Different strategies of neurostimulation have been developed as treatment tools for migraine. Among them, vagus nerve stimulation (VNS) can be performed both invasively and non-invasively. Recently, “Gammacore” has been approved as a non-pharmacological and non-invasive tool for headache, and a recent study demonstrated its efficacy in 22% of patients with acute migraine attacks[1]. Although the pathophysiology of migraine is not yet fully understood, many studies have shown a role of sterile inflammation of cerebral vessels and of the change in diameter of the intracranial arteries. Blood flow velocities and vasomotor reactivity (VMR) in patients suffering from migraine without aura in the intercritical phase were found either increased or normal compared to non-migraineurs healthy controls[2, 3]. Since the vagus nerve is the largest parasympathetic nerve of the body, it is probable that its neuromodulation can affect cerebral hemodynamics. The purpose of the study was to evaluate the effects of external vagus nerve stimulation on VMR of patients suffering from chronic migraine.

Patent foramen ovale and migraine with aura in a retrospective analysis: age matters

The physiopathological relationship between patent foramen ovale (PFO) and migraine with aura (MA) is the matter of a long-standing debate. MA patients have twice the prevalence of PFO and right-to-left shunt (RLS) than non-migraine controls [1]. Moreover, among subjects with PFO, those with MA show a larger RLS size. Conflicting results failed to draw a definite conclusion on PFO pathogenic role at least in a subset of MA patients. In this line, the last European consensus does not advice investigation for PFO detection in MA patients, although in some unspecified cases, it is recommended [2]. On the other hand, MA patients display an increased risk for stroke at least in part explained by paradoxical embolism. The aim of our study was to explore if there are peculiar attack clinical features and family history related to the presence of PFO in patients withMA.With this aim, we retrospectively searched the clinical electronic dossiers of our Headache Center for patients with MA referring those who had also undergone transcranial Doppler (TCD) with microbubbles for the detection of PFO. Diagnosis of migraine with aura was made accordingly with IHCD-3β. We collected MA clinical features (number of attacks per year, aura duration, family history of MA, trigger factors, age onset, aura type) and the presence of vascular risk factors at MA onset (diabetes, hypertension, smoking, estrogen hormones, or pregnancy/puerperium). When available, we also recorded echocardiography findings for the detection of atrial septal aneurysm (ASA), and the results for thrombophilia screening (Factor II, Factor V, MTHFR genotype, homocysteinemia, lupus anticoagulant). We enrolled 86 patients (73% female, mean age 40.6 years SD 11 [min 20–max 71]). TCD examination had been performed with insonation of the middle cerebral artery bilaterally according to guidelines at rest and after Valsalva maneuver [3]. Results were stratified for severity: 0, no detection of hyperintense transient signals (HITS); 1, ≤ 10 HITS/side; 2, 10–20/side at rest or Bshower^ effect after Valsalva maneuver; 3, Bshower^ effect at rest or Bcurtain^ effect after Valsalva maneuver; 4, Bcurtain^ effect at rest. Non-parametric tests and contingency table were run to determine if there were differences in attack frequency, duration of aura, and aura type (visual, sensitive, aphasic, or complex) and aura onset age, trigger factor types, the presence of thrombophilia, and vascular factors at onset between patients with and without PFO and/or ASA. Table 1 summarizes baseline characteristics. Our results showed that patients with PFO presented the first MA attack at a younger age (Mann-Whitney test, p < .0001; mean age onset: patients with PFO + 17.6 years SD 8.2; patients without PFO 29.8 years SD 10.4). Besides, PFO severity was associated with younger age MA onset (Spearman Rho − 481, p < .0001). Similarly, patients with ASA presented younger age compared than patients without ASA (Mann-Whitney test, p = .023). Aura duration and frequency were not associated with PFO. PFO was not associatedwith the presence or kind of trigger factors neither with aura type. On the other hand, family history for MAwas associated with the presence of PFO (chi-squared p = .02). Age onset was not influenced by the presence of thrombophilia or other vascular factor at onset. Only Bhormones^ (estrogen hormones or pregnancy/puerperium) were related to older age at MA onset (Mann-Whitney test, p = .009), reflecting a clear bias. Thrombophilia and other vascular risks at onset were not associated with PFO. MA pathophysiology is a very complicated scenario where vascular, neuronal, and metabolic factors interplay. To our knowledge, this is the first study reporting that age of MA * Claudia Altamura c.altamura@unicampus.it

Psychopathological profile of medication overuse headache patients, drug assumption and degree of disability

Patients with medication overuse headache (MOH) show a complex psychopathological profile characterized by high rate of mood, anxiety, and obsessive-compulsive disorders and dependence-related behavior. Several studies suggested a negative prognostic value for psychiatric comorbidities and reported that these represent a risk factor for the transformation of episodic into chronic headaches. Moreover, the presence of psychopathological disturbances seems to be a predictor of relapse and poor response to the treatment, complicating headache management and promoting the maintenance of MOH [1]. Several studies have suggested that psychiatric disorders and chronic headaches are comorbid, but only few studies assessed the presence of psychiatric disorders in MOH patients [2]. Moreover, studies assessed only the rate of psychiatric symptoms as depression, anxiety, or obsessive-compulsive behavior; so far, the presence and the role of the recognition and regulation abilities of their behavior and emotions have not been investigated. These skills are essential to psychological well-being and functional relationships with others. Our study aimed at evaluating the prevalence of psychopathological profiles in MOH patients utilizing a comprehensive psychopathological tool assessing not only depression and anxiety disorders but also recognition and elaboration of emotions, and impulsiveness. Moreover, we investigated potential correlations between psychopathological profile and other clinical variables, such as headache frequency, drug consumption, and the impact of headaches on abilities of daily living. We arranged a set of questionnaires to assess psychological profile of MOH patients followed by our headache center. This set is composed by Beck Depression Inventory II Edition (BDI-2), trait subtest of State-Trait Anxiety Inventory (STAI-Y), Difficulties in Emotion Regulation Scale (DERS), Barratt Impulsiveness Scale (BIS-11), and Toronto Alexithymia Scale (TAS-20). We extracted headache frequency and drug consumption in the previous month from personal headache diaries, and asked patients to fill in HIT-6 and MIDAS scores, two questionnaires designed to measure headache-related disability. From November 2015 to May 2017, we recruited 48 consecutive patients affected by MOH according to ICHD 3-beta (F = 79%). Patients presented a mean of 24.1 days (± 6.4) of headache per month and a median of 40 symptomatic medications taken for month (IQR, 36; min 12 and maximum 315 drug for month), without significant difference between men and women. Mean of total HIT-6 score was 67.4 (± 5.6), and mean of MIDASA score was 61.2 (± 28.3), showing high disability on activity of daily living. No significant differences between sexes were observed. The percentage of MOH patients showing pathological score on questionnaires was 68.8% for DERS, 47.9% for * Simone Migliore sim.migliore@gmail.com

Migraineurs with aura present an increased cerebral hemodynamics in the anterior and posterior circulation compared with stroke patients and controls

Patients affected by migraine with aura (MA) present an increased risk for stroke, especially if they present some specific conditions (patent foramen ovale—PFO, thrombophilia, cervical artery dissection) [1] or vascular risk factors (smoking, estrogen therapy). Vasomotor reactivity (VMR) is a marker of efficiency of the cerebral hemodynamics: it reflects the arterial capability to dilate in response to vasodilatory stimuli, such as hypercapnia. Previous studies reported that migraineurs present a preserved or indeed increased VMR in the anterior circulation [2] but possibly a poor hemodynamics in the posterior circulation [3]. In this line, some studies reported also an increased vascular burden in migraine patients mainly in cerebral posterior territory. We aimed at comparing VMR in patients with MA, patients with stroke, and controls. Based on previous reports, we hypothesized that VMR in MA patients is comparable to healthy controls in the anterior circulation and to stroke patients in the posterior circulation. We consecutively enrolled 39 MA patients (35.8 years SD 9, 87% female), 15 young (younger than 60 years) patients with cryptogenetic stroke (47.9 years SD 7, 53% F) and 16 controls age matched (38.5 years SD 9, 50% F) with MA patients referred to our neurosonology lab to undergo transcranial Doppler with bubble test for PFO detection. To assess VMR, we performed a breath-holding test. Middle (MCA) and posterior (PCA) cerebral arteries were continuously and simultaneously insonated at rest and during at least a 30-s apnea in all subjects. The breath-holding index (BHI) was quantified as the percent increase of cerebral mean blood flow velocity—MBFv—after the apnea test with respect to baseline corrected by the length of apnea expressed in seconds. A neurosonologist blind to subjects’ diagnosis computed BHI off-line. The hemodynamic evaluation preceded TCD microbubble test in all subjects. BH test was performed within 7 days and at least 48 h from symptom onset in stroke patients and always in the inter-ictal period in MA patients. In stroke patients, PCA and MCAwere insonated in the unaffected territory/side, while in MA patients and controls, PCAwas insonated at the right side andMCA on the left. Vascular risk factors and, when present, the results of thrombophilia screening (gene mutations of Factor II, Factor V, lupus anticoagulant antibodies, homocysteine blood levels) were recorded in all subjects. To compare variables across groups, parametric (t test) and non-parametric tests (MannWhitney test, chi-squared test) were used according to data distribution. Patients with stroke were significantly older and presented higher prevalence (100%) of PFO compared to MA patients (77%) and controls (23%) (p < .001). MA patients were more frequently female (p < .001). Stroke patients more frequently (p < .01) presented dyslipidemia (50 vs 3% MA patients and 8% controls). No difference was observed for the other vascular risk factors, prevalence of thrombophilia (stroke 41% vs migraine patients 37%), and homocysteinemia (mean values within the reference range in all groups). Stroke patients presented reduced mean MBFv compared with MA patients and controls (p < .05) in both MCA (stroke patients 53.2 cm/s, SD 8; controls 66.3 cm/s, SD 12 and MA patients 68.7 cm/s, SD 12) and PCA (38.7 cm/s, SD 11 vs 43.7 cm/s, SD 11 vs 47.3 cm/s, SD 12). Cerebral hemodynamics was preserved in all groups as average BHI was consistently above the pathological cutoff in the MCA (0.69%/s) as well as in the PCA. * Claudia Altamura c.altamura@unicampus.it

Frequency and clinical implications of hypercoagulability states in a cohort of patients with migraine with aura

Migraine is the most common neurological disorder, affecting 12% of the adult population. Migraine with aura (MA) accounts for 15% of all migraines and its typical symptoms include temporary visual or sensory of aphasic disturbances that usually strike before clinical migraine symptoms. Migraine auras can be confused with transient ischemic attack (TIA), where there are stroke symptoms passing in a short time. However, patients affected by MA present a higher cerebrovascular risk with respect to general population, in particular for cardioembolic or criptogenetic stroke. This was pointed out by a study [1] with 1.622 migraineurs compared to nonheadache participants: there was a significant association between migraine with visual aura and ischemic stroke (hazard ratio 1.7, 95% confidence interval 1.2–2.6, p = 0.008). This incidence of stroke in patients with MA may be only in part linked to the higher prevalence of patent foramen ovale (PFO) in these patients [2]. Few studies reported controversial findings about the association of MAwith hypercoagulability states (HS), but a study [3] on 154 patients with stroke, of whom 59 with a history of migraine, showed that HS were more frequent in the migraine than in the non-migraine group (38.6 vs. 16.4%, p < 0.01). In the current study, we aim at evaluating the frequency of hypercoagulability state in patients with MA in our Headache Center; moreover, we look at evidencing if there are differences in PFO frequency in patients with MAwith or without HS and, finally, if there are differences in the characteristics of aura between MA patients with or without HS. We retrospectively screened our Center patient files and included MA patients who underwent medical examination at our Headache Center between January 2012 and July 2017 with a complete thrombophilic screening (MTHR C677T and A1298C mutations, factor V mutation, factor II mutation, lupus anticoagulant (LAC) panel, protein C and S dosage). A headache questionnaire was administered to all participants. International Classification of Headache Disorders (ICHD III beta) diagnostic criteria were used to characterize migraine with visual, visual, paresthesic, or aphasic aura. Individuals with non-migraine headaches according to ICHD-3 were excluded from analysis. In a subgroup of these patients, we performed transcranial Doppler (TCD) for PFO screening; we then compared the rate of PFO in patients with and without hypercoagulability states. Further, we examined if a hypercoagulability state could influence frequency, type, and duration of aura. We found 45 MA patients with complete thrombophilic screening: there was only a male subject. The mean age of the study participants was 36 years (range 16–75 years). Of these, 26 patients (57.8%) presented at least one hypercoagulability state; six patients presented 2 contemporary procoagulant factors. The distribution of procoagulant factors was 14 patients with homozygosis for MTHFR C667T (31.1%), 3 patients with heterozygosis for MTHFR A1298C (6.7%), 2 patients with heterozygosis for factor V mutation (4.4%), 1 patient with heterozygosis for factor II mutation (2.2%), 5 patients with LAC positivity (11.1%), and 6 patients with protein C or S deficiency (13.3%). The incidence of MTHFR C677Hom and LAC positivity in our patients looked like the incidence of the same mutation in patient with stroke [3] (MTHFR C677T Hom 21% and LAC positivity 9.7–12.5%). The deficiency of protein C or S in our patients was present in 13.3%, compared with 1% of similar adult population with inherited deficiencies. Out of the 26 patients with procoagulant factors, 19 underwent TCD, and 11 present a PFO (57.9%); of the remaining 19 patients without procoagulant factors, 13 underwent TCD, and 7 present a PFO (53.8%). Both groups * Gianluca Cecchi g.cecchi@unicampus.it

Promoting healthy eating can help preventing migraine: a real-life preliminary study

Diet has been often implied in migraine pathophysiology. Many patients report certain foods or fasting as trigger factors; besides, inflammatory mediator release from adipose tissue can explain why obese migraine patients are at higher risk for headache chronicization. An increased interest is also widespread in general population on the potential therapeutic effects of specific dietary styles for different diseases. Unfortunately, these common believes are not always supported by scientific data. On the other hand, recent studies showed that the ketogenic diet produces significant results onmigraine frequency explained by the possible role of ketones as neurotransmitter regulator [1]. Nevertheless, this diet forces the patients to reduce carbohydrates to a very low daily intake, strongly limiting food variety consumptions including vegetables (e.g., carrots, beans). Despite its efficacy, patients may have a scarce compliance to this strict alimentary regimen especially for longer periods. Besides, since it produces a significant weight loss, it may not be advisable for skinny patients. In 2012, the Agricultural Department of United States published a renewed version of food pyramid proposed by Harvard School of Public Health: the Healthy Eating Plate [2]. Dietary advices are no longer based on food frequency recommendations as represented by the pyramid, but as a suggestion of proportion of aliment consumption for each meal. The Healthy Eating Plate is divided in four parts, promoting primary vegetable intake (over 30% of the plate), whole cereals, and healthy protein. Our study aimed at evaluating (a) retrospectively the relationship between dietary habit and migraine frequency and disability and (b) the effect of the education on the Healthy Eating Plate on migraine frequency and disability. We enrolled 101 consecutive migraine patients (mean age 44 years, SD 14.2, 89% female) referring to our headache center. Patients affected by severe obesity (BMI > 30), cancer, inflammatory bowel disease, celiac disease, type 1 diabetes, and chronic renal insufficiency were excluded. At baseline, all patients underwent anthropometric (weight, height, abdominal circumference) assessment and filled a Frequency Food Questionnaire (FFQ) to assess their dietary habit in the previous 3 months and clinical scales addressing pain evaluation, migraine frequency, and related disability (BS11, PPI, BRS6, SF-MPQ–S, SF-MPQ-A, MIDAS e HIT6). All patients received pharmacological abortive or prophylactic treatment indications as appropriate. All patients were educated about the Healthy Eating Plate advices, and they were also asked to complete a food diary in a week for the coming control visit. To note, the patients did not receive any specific recommendations about weight food amount or specific menus, and they were provided with the written indication downloaded by the Healthy Eating Plate website [2]. After 3 months, 30 out of the 101 enrolled patients returned for the control visit and underwent again the anthropometric assessment and filled all the questionnaires completed at the baseline visit. Patients were also asked if they believed that the diet influenced their headaches. All data were analyzed with SPSS 24.0. We used parametric and non-parametric tests to evaluate differences between observations according to data distribution. The analysis of baseline data showed an average BMI 25.3 ± 5.45 and waist circumference 88.5 cm; mean headache days per month 9.9 ± 7.3, abortive drugs per month 9 ± 8.2, MIDAS TOT 29.91 ± 31.44, HIT6 TOT 63.46 ± 11.69. The analysis carried out on FFQ at the baseline showed that the consumptions of whole grain bread (inversely) and seasoned cheese were related to headache frequency and abortive drugs per month (respectively p = 0.04 and p = 0.013). * Claudia Altamura c.altamura@unicampus.it

OnabotulinumtoxinA for chronic migraine: a real-life Italian multicenter experience

Chronic migraine (CM) is a disabling neurological disorder affecting about 2% of the population [1]. It occurs on 15 or more days per month for more than 3 months, having the features of migraine headache on at least 8 days per month. People with CM have impaired quality of life, more severe disability, and greater economic burden than patients with episodic migraine (EM). Furthermore, patients with CM are often poor responders to prophylactic treatments. Recently, onabotulinumtoxinA (OBT-A) was proposed as a preventive treatment option for CM. Its efficacy for the CM prophylaxis has been demonstrated in two well-designed phase III clinical trials, PREEMPT 1 and 2 trials [2, 3]. A pooled analysis of these trials showed that OBT-Awas significantly more effective than placebo in reducing the mean frequency of days with headache and headache episodes. The use of OBT-A for the prophylaxis of CM has also been endorsed by several international societies, usually as secondline treatment. In Italy, onabotulinumtoxinAwas approved for the treatment of CM in 2013 in patients who have failed, or do not tolerate, oral prophylactic treatments. Recent studies demonstrated that the treatment is effective and safe for CM, even if complicated with medication overuse headache (MOH), in the short and long term. However, the management of OBT-A in clinical practice remains to be fully defined. In particular, it remains to be clarified how long the treatment has to be continued either if clinically effective or not, and, if effective, whether and when it has to be discontinued and for how long. Current literature have not addressed these and other questions and currently different centers may administer OBT-A in different ways. The aim of the present study was to answer these questions from the real-life clinical practice by three third level Italian headache centers in order to help finding the best management of OBT-A in CM patients. First, we compared data from two different centers (Roma, Campus Bio-Medico andMilano, Istituto Neurologico Besta). Both centers performed treatment with OBT-A in patients with CM, following the PREEMPT protocol, for at least four injections, with a 12-week span. We retrospectively reviewed medical records of consecutive patients treated in these centers from November 2013 to November 2017. Our analysis proceeded in order to answer three questions: (a) if there is consistency in patient selection between the centers, (b) if there is consistency in the treatment efficacy between centers, and (c) if, halfway during the treatment, it is possible to identify a subset of patients who will not benefit from the continuation of the treatment. For this latter purpose, we defined as responders patients experiencing 30% or more reduction in headache frequency at an intermediate time point (3 months after the second injection). We then compared both centers with a third one (Bologna, IRCCS Istituto delle Scienze Neurologiche, Ospedale Bellaria). This center performed the PREEMPT protocol evaluating patients at 6 months, and continued the treatment only in responder patients (patients with 30% or more reduction in headache frequency or a significant reduction in disability). Set time points were T0 (baseline, before the first injection), T2 (6 months, 3 months after the second injection and just before the third injection), T4 (1 year, 3 months after the fourth—and last—injection). * Fabrizio Vernieri f.vernieri@unicampus.it

Daith Piercing in a Case of Chronic Migraine: A Possible Vagal Modulation

Daith piercing is an ear piercing located at the crus of the helix, bilaterally. It is getting great consent on social media as alternative treatment in chronic migraine. No data about its efficacy and action are available in scientific literature so far. We present the case of a 54-year-old male patient suffering from refractory chronic migraine with medication-overuse, who substantially improved after bilateral ear daith piercing. His migraine was refractory to symptomatic as well as prophylactic therapies. He used to treat headaches with up to five symptomatic drugs per attack and had attempted several pharmacological preventive therapies, including Onabotulinumtoxin A. He also underwent detoxification treatments with intravenous steroids and diazepam, without durable benefit. At the time of daith piercing, the headache-related disability measures showed a HIT-6 score of 64, a MIDAS-score of 70, and a 11-point Box scale of 5. On his own free will, he decided to get a “daith piercing.” After that, he experienced a reduction of migraine attacks, which became very rare, and infrequent, less disabling episodes of tension-type headache (HIT-6 score of 56; MIDAS score of 27, 11-point Box scale of 3). Painkiller assumption has much decreased: he takes only one tablet of indomethacin 50 mg to treat tensive headaches, about four times per month. Beyond a placebo effect, we can speculate a vagal modulation as the action mechanism of daith piercing: a nociceptive sensory stimulus applied to trigeminal and vagal areas of the ear can activate ear vagal afferents, which can modulate pain pathways by means of projections to the caudal trigeminal nucleus, to the locus coeruleus and to the nucleus raphe magnus. Currently, daith piercing cannot be recommended as migraine treatment because of the lack of scientific evidence, the unquantified rate of failure and the associated risks with insertion. However, given the increasing but anecdotal evidence, we think that the mechanism needs testing by means of a controlled clinical trial in a population of chronic migraineurs.

The Role of White Matter Damage in the Risk of Periprocedural Diffusion-Weighted Lesions after Carotid Artery Stenting

Background: White matter hyperintensities (WMH) are a common finding in aged individuals affected by carotid artery disease and are a risk factor for first-ever and recurrent stroke. We investigated if white matter damage increases the risk of brain microembolism during carotid artery stenting (CAS), as evaluated by the appearance of new areas of restricted diffusion on diffusion-weighted images (DWI). Methods: We evaluated 47 patients with severe internal carotid artery (ICA) stenosis undergoing CAS, comparing preprocedural clinical, ultrasound and radiological characteristics. WMH volume was computed on FLAIR images before CAS. After CAS, the DWI scan was looked over for areas of restricted diffusion (DWI lesions). A first univariate analysis was adopted to compare groups according to the occurrence of DWI lesions. Then, the variable DWI lesion was modelled by means of a logistic regression model. Results: Seventeen patients developed at least 1 DWI lesion after CAS. Compared with non-DWI, DWI patients were more commonly treated in the left ICA (p = 0.007) and had a more severe WMH damage (p = 0.027). Indeed, the risk of a DWI lesion was higher in left versus right stenosis (OR = 9.0, 95% CI 1.9-42.7, p = 0.005) and increased for each log-unit of WMH lesion load (OR = 7.05, 95% CI 1.07-46.49, p = 0.042). A WMH lesion load of at least 5.25 cm3 had a 50% probability of occurrence of a new DWI lesion. Conclusions: Treated side and preexisting white matter damage are risk conditions for brain microembolism during CAS. This should be taken into account to optimize severe carotid artery disease management.