A Propensity Score Matching Study on the Effect of OnabotulinumtoxinA Alone versus Short-Term Psychodynamic Psychotherapy Plus Drug-of-Choice as Preventive Therapy in Chronic Migraine: Effects and Predictive Factors.

OBJECTIVE: The objective of this study was to test the superiority of multidisciplinary approach, that is, Short-Term Psychodynamic Psychotherapy (STPP) plus drug of choice, versus monotherapy, that is, OnabotulinumtoxinA (OnaBoNT-A). METHOD: We consecutively recorded data from chronic migraine (CM) patients, with or without medication overuse headache (MOH), who underwent STPP or OnaBoNT-A, with a 3-month follow-up schedule. Headache days and analgesics intake were monitored as primary outcome measures. Propensity score matching (PSM) was used to eliminate discrepancies between groups. Discriminant function analysis (DFA) was used to pinpoint predictive factors associated with the clinical response. RESULTS: 96 patients with CM (64% with MOH) were treated with STPP and 54 (59% with MOH) with OnaBoNT-A. At baseline, OnaBoNT-A patients had more failed preventive therapies, more years of illness and chronicity, and were older; STPP patients were more depressed and had a higher HIT-6. Both STPP and OnaBoNT-A patients showed a significant reduction of headache days (STPP: -14 vs. OnaBoNT-A:-14.3) and analgesics intake (STPP: -12,3 vs. OnaBoNT-A -13.5 pills/month), respectively. MOH diminished more in STPP, adherence was higher in OnaBoNT-A. Results were confirmed after PSM balancing of the groups for those variables that resulted as different (but age). CONCLUSION: OnaBoNT-A monotherapy produced similar results to psychotherapy plus medication, after correcting for baseline differences.

Prevalence and characteristics of Alice in Wonderland Syndrome in adult migraineurs: Perspectives from a tertiary referral headache unit.

BACKGROUND: Migraine affects how the brain processes sensory information at multiple levels. The aberrant integration of visual and somatosensory stimuli is thought to underlie Alice in Wonderland Syndrome, a disorder often reported as being associated with migraine. However, there is still a lack of knowledge about the epidemiology of this syndrome in migraineurs and the association between Alice in Wonderland Syndrome episodes and migraine attacks. Therefore, we conducted a prospective cohort study to systematically evaluate the prevalence and the clinical features of Alice in Wonderland Syndrome in a large sample of patients with migraine. METHODS: All the patients attending for the first time a tertiary-level headache clinic were consecutively screened for Alice in Wonderland Syndrome symptoms by means of an ad hoc questionnaire and detailed clinical interview, over a period of 1.5 years. Patients experiencing Alice in Wonderland Syndrome symptoms were contacted for a follow-up after 8-12 months. RESULTS: Two hundred and ten patients were recruited: 40 patients (19%) reported lifetime occurrence of Alice in Wonderland Syndrome, 90% of whom (38/40) had migraine with aura. Thirty-one patients experienced episodes of Alice in Wonderland Syndrome within 1 h from the start of migraine headache. Patients reported either visual or visual and somatosensory symptoms (i.e. somatosensory symptoms never presented alone). We collected the follow-up details of 30 patients with Alice in Wonderland Syndrome, 18 of whom had been prescribed a preventive treatment for migraine. After 8-12 months, 5 of the treated patients reported a decrease, while 13 reported no episodes of Alice in Wonderland Syndrome. CONCLUSION: Alice in Wonderland Syndrome prevalence in migraineurs was found to be higher than expected. Alice in Wonderland Syndrome was mostly associated with migraine with aura and tended to occur close to the migraine attack, suggesting the existence of a common pathophysiological mechanism. Patients treated with migraine preventive treatments had a higher chance of decreasing or even resolving Alice in Wonderland Syndrome episodes.

Thalamo-cortical networks in subtypes of migraine with aura patients.

BACKGROUND: We searched for differences in resting-state functional connectivity (FC) between brain networks and its relationship with the microstructure of the thalamus between migraine with pure visual auras (MA), and migraine with complex neurological auras (MA+), i.e. with the addition of at least one of sensory or language symptom. METHODS: 3T MRI data were obtained from 20 patients with MA and 15 with MA + and compared with those from 19 healthy controls (HCs). We collected resting state data among independent component networks. Diffusivity metrics of bilateral thalami were calculated and correlated with resting state ICs-Z-scores. RESULTS: As compared to HCs, both patients with MA and MA + disclosed disrupted FC between the default mode network (DMN) and the right dorsal attention system (DAS). The MA + subgroup had lower microstructural metrics than both HCs and the MA subgroup, which correlated negatively with the strength of DMN connectivity. Although the microstructural metrics of MA patients did not differ from those of HCs, these patients lacked the correlation with the strength of DAS connectivity found in HCs. CONCLUSIONS: The present findings suggest that, as far as MRI profiles are concerned, the two clinical phenotypes of migraine with aura have both common and distinct morpho-functional features of nodes in the thalamo-cortical network.

A Study of Clinical Features and Risk Factors of Self-Referring Emergency Department Headache Patients: A Comparison with Headache Center Outpatients.

BACKGROUND: Nonlife-threatening headaches account for 3% of emergency department (ED) admissions, with social and economic negative consequences. We aim to investigate clinical features and risk factors of nonlife-threatening headache patients referring to ED versus those referring to headache outpatient clinics. METHODS: During 6 months, we promptly reevaluated in our headache unit (HU) patients discharged from ED. We compared the clinical characteristics of patients who referred to ED with those of HU outpatients visited in the same time interval. Discriminant Function Analysis and Correspondence Analysis were used to determine risk factors for ED referral. RESULTS: We recruited 49 post-ED patients and 126 outpatients. The main reasons for ED admission were poor response to acute treatment and aura-related symptoms. Headache diagnoses made in ED were generally not confirmed later (overall concordance of 47%), except for cluster headache (CH) and migraine with aura (MA). ED patients complained higher headache intensity, longer duration, and prolonged aura compared to outpatients. Aura was the main risk factor associated with ED admission on statistical models, while less prominent risk factors were sex, age, and years from migraine onset. CONCLUSIONS: ED patients presented a more severe headache clinical phenotype compared with outpatients. Headache diagnosis remains difficult in the emergency setting and is more easily achieved for the headache forms with standout features, such as MA or CH. According to statistical models, the aura is the most important risk factor for ED admissions.

Patients with chronic migraine without history of medication overuse are characterized by a peculiar white matter fiber bundle profile.

BACKGROUND: We investigated intracerebral fiber bundles using a tract-based spatial statistics (TBSS) analysis of diffusion tensor imaging (DTI) data to verify microstructural integrity in patients with episodic (MO) and chronic migraine (CM). METHODS: We performed DTI in 19 patients with MO within interictal periods, 18 patients with CM without any history of drug abuse, and 18 healthy controls (HCs) using a 3 T magnetic resonance imaging scanner. We calculated diffusion metrics, including fractional anisotropy (FA), axial diffusion (AD), radial diffusion (RD), and mean diffusion (MD). RESULTS: TBSS revealed no significant differences in the FA, MD, RD, and AD maps between the MO and HC groups. In comparison to the HC group, the CM group exhibited widespread increased RD (bilateral superior [SCR] and posterior corona radiata [PCR], bilateral genu of the corpus callosum [CC], bilateral posterior limb of internal capsule [IC], bilateral superior longitudinal fasciculus [LF]) and MD values (tracts of the right SCR and PCR, right superior LF, and right splenium of the CC). In comparison to the MO group, the CM group showed decreased FA (bilateral SCR and PCR, bilateral body of CC, right superior LF, right forceps minor) and increased MD values (bilateral SCR and right PCR, right body of CC, right superior LF, right splenium of CC, and right posterior limb of IC). CONCLUSION: Our results suggest that chronic migraine can be associated with the widespread disruption of normal white matter integrity in the brain.

Migrainous Infarction in a Patient With Sporadic Hemiplegic Migraine and Cystic Fibrosis: A 99mTc-HMPAO Brain SPECT Study.

Genetic mutations of sporadic hemiplegic migraine (SHM) are mostly unknown. SHM pathophysiology relies on cortical spreading depression (CSD), which might be responsible for ischemic brain infarction. Cystic fibrosis (CF) is caused by a monogenic mutation of the chlorine transmembrane conductance regulator (CFTR), possibly altering brain excitability. We describe the case of a patient with CF, who had a migrainous stroke during an SHM attack. A 32-year-old Caucasian male was diagnosed with CF, with heterozygotic delta F508/unknown CFTR mutation. The patient experiences bouts of coughing sometimes triggering SHM attacks with visual phosphenes, aphasia, right-sided paresthesia, and hemiparesis. He had a 48-hour hemiparesis triggered by a bout of coughing with hemoptysis, loss of consciousness, and severe hypoxia-hypercapnia. MRI demonstrated transient diffusion hyperintensity in the left frontal-parietal-occipital regions resulting in a permanent infarction in the primary motor area. Later, a brain perfusion SPECT showed persistent diffuse hypoperfusion in the territories involved in diffusion-weighted imaging alteration. Migrainous infarction, depending on the co-occurrence of 2 strictly related phenomena, CSD and hypoxia, appears to be the most plausible explanation. Brain SPECT hypoperfusion suggests a more extensive permanent neuronal loss in territories affected by aura. CF may be then a risk factor for hemiplegic migraine and stroke since bouts of coughing can facilitate brain hypoxia, triggering auras.

Neurophysiological correlates of clinical improvement after greater occipital nerve (GON) block in chronic migraine: relevance for chronic migraine pathophysiology.

BACKGROUND: Therapeutic management of Chronic Migraine (CM), often associated with Medication Overuse Headache (MOH), is chiefly empirical, as no biomarker predicting or correlating with clinical efficacy is available to address therapeutic choices. The present study searched for neurophysiological correlates of Greater Occipital Nerve Block (GON-B) effects in CM. METHODS: We recruited 17 CM women, of whom 12 with MOH, and 19 healthy volunteers (HV). Patients had no preventive treatment since at least 3 months. After a 30-day baseline, they received a bilateral betamethasone-lidocaine GON-B of which the therapeutic effect was assessed 1 month later. Habituation of visual evoked potentials (VEP) and intensity dependence of auditory evoked potentials (IDAP) were recorded before and 1 week after the GON-B. RESULTS: At baseline, CM patients had a VEP habituation not different from HV, but a steeper IDAP value than HV (p = 0.01), suggestive of a lower serotonergic tone. GON-B significantly reduced the number of total headache days per month (- 34.9%; p = 0.003). Eight out 17CM patients reversed to episodic migraine and medication overuse resolved in 11 out of 12 patients. One week after the GON-B VEP habituation became lacking respect to baseline (p = 0.01) and to that of HV (p = 0.02) like in episodic migraine, while the IDAP slope significantly flattened (p < 0.0001). GON-B-induced reduction in headache days positively correlated with IDAP slope decrease (rho = 0.51, p = 0.03). CONCLUSIONS: GON-B may be effective in the treatment of CM, with or without MOH. The pre-treatment IDAP increase is compatible with a weak central serotonergic tone, which is strengthened after GON-B, suggesting that serotonergic mechanisms may play a role in CM and its reversion to episodic migraine. Since the degree of post-treatment IDAP decrease is correlated with clinical improvement, IDAP might be potentially useful as an early predictor of GON-B efficacy.

Cerebral gray matter volume in patients with chronic migraine: correlations with clinical features.

BACKGROUND: To date, few MRI studies have been performed in patients affected by chronic migraine (CM), especially in those without medication overuse. Here, we performed magnetic resonance imaging (MRI) voxel-based morphometry (VBM) analyses to investigate the gray matter (GM) volume of the whole brain in patients affected by CM. Our aim was to investigate whether fluctuations in the GM volumes were related to the clinical features of CM. METHODS: Twenty untreated patients with CM without a past medical history of medication overuse underwent 3-Tesla MRI scans and were compared to a group of 20 healthy controls (HCs). We used SPM12 and the CAT12 toolbox to process the MRI data and to perform VBM analyses of the structural T1-weighted MRI scans. The GM volume of patients was compared to that of HCs with various corrected and uncorrected thresholds. To check for possible correlations, patients' clinical features and GM maps were regressed. RESULTS: Initially, we did not find significant differences in the GM volume between patients with CM and HCs (p < 0.05 corrected for multiple comparisons). However, using more-liberal uncorrected statistical thresholds, we noted that compared to HCs, patients with CM exhibited clusters of regions with lower GM volumes including the cerebellum, left middle temporal gyrus, left temporal pole/amygdala/hippocampus/pallidum/orbitofrontal cortex, and left occipital areas (Brodmann areas 17/18). The GM volume of the cerebellar hemispheres was negatively correlated with the disease duration and positively correlated with the number of tablets taken per month. CONCLUSION: No gross morphometric changes were observed in patients with CM when compared with HCs. However, using more-liberal uncorrected statistical thresholds, we observed that CM is associated with subtle GM volume changes in several brain areas known to be involved in nociception/antinociception, multisensory integration, and analgesic dependence. We speculate that these slight morphometric impairments could lead, at least in a subgroup of patients, to the development and continuation of maladaptive acute medication usage.

A study of migraine characteristics in joint hypermobility syndrome a.k.a. Ehlers-Danlos syndrome, hypermobility type.

Joint hypermobility syndrome (JHS) and Ehlers-Danlos syndrome, hypermobility type (EDS-HT) are two clinically overlapping heritable connective tissue disorders strongly associated with musculoskeletal pain, fatigue and headache. Migraine with or without aura is considered the most common form of headache in JHS/EDS-HT. In this population of chronically ill patients, we investigated whether migraine characteristics were different from those of a control population of migraine patients. The study was carried out on 33 selected JHS/EDS-HT patients, diagnosed according to current criteria. Sixty-six migraine subjects matching age and gender were consecutively selected as controls (MO group) among patients attending our Headache Clinic. JHS/EDS-HT and MO were screened for a series of headache characteristics, such as frequency, intensity, age of onset, level of disability, use of rescue and prophylactic medications. Differences between the two groups were tested by using independent group comparisons. Results showed that in JHS/EDS-HT: (1) migraine has an earlier onset (12.6 vs 17 years of age; p = 0.005); (2) the rate of migraine days/month is higher (15 vs 9.3 days/month; p = 0.01); (3) accompanying symptoms are usually more frequent; (4) HIT-6 and MIDAS scores are higher (p = 0.04 and p = 0.03); (5) efficacy of rescue medication is almost identical, although, total drug consumption is significantly lower (p < 0.04). Joint hypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type patients have a more severe headache syndrome with respect to the MO group, therefore demonstrating that migraine has a very high impact on quality of life in this disease.

Neuroanatomical, Clinical and Cognitive Correlates of Post-Stroke Dysphagia.

BACKGROUND AND PURPOSE: About half of the dysphagic stroke patients have persistent swallowing dysfunction after 7 days from symptom onset. The aim of the study was to evaluate incidence, prognosis, clinical and neuroradiological correlates of post-stroke dysphagia. METHODS: We prospectively examined consecutive patients with acute ischemic or hemorrhagic stroke. Patients' clinical and neuroradiological data were collected. Swallowing function was assessed by the water swallow test upon admission and after 14 days; patients were then classified as persistent dysphagic, non-persistent dysphagic or non-dysphagic. RESULTS: We recruited 275 patients, 121 of whom were dysphagic upon admission and 254 patients attended follow-up at 14 days; 141 never presented dysphagia, 21 had a non-persistent pattern of dysphagia and 92 had a persistent one. Stroke type, leukoaraiosis degree, previous cognitive impairment and stroke severity upon admission independently predicted the occurrence of dysphagia after stroke and its persistence as well. At receiver operating characteristic (ROC) analysis, the National Institutes of Health Stroke Scale (NIHSS) score of 11.5 was the best predictive value of persistent dysphagia, with a specificity of 90.1% and a sensitivity of 72.4%. CONCLUSION: Stroke severity is an important predictor of a persistent pattern of dysphagia, with a suggested NIHSS cutoff value of ≥12. An independent correlation was observed with leukoaraiosis and with previous cognitive impairment.

Chronic Migraine Preventive Treatment by Prefrontal-Occipital Transcranial Direct Current Stimulation (tDCS): A Proof-of-Concept Study on the Effect of Psychiatric Comorbidities.

Chronic migraine (CM) is often complicated by medication overuse headache (MOH) and psychiatric comorbidities that may influence the clinical outcome. This study aimed to investigate the relationship between psychiatric comorbidities and the effect of transcranial direct current stimulation (tDCS) in patients with CM with or without MOH. We recruited 16 consecutive CM patients who had an unsatisfactory response to at least three pharmacological preventive therapies. They were treated with anodal right-prefrontal and cathodal occipital tDCS (intensity: 2 mA, time: 20 min) three times per week for 4 weeks. All patients underwent a psychopathological assessment before and after treatment, and five of them were diagnosed with bipolar disorder (BD). After treatment, all the patients showed a significant decrease of severe and overall headache days per month. Despite having a higher migraine burden at baseline, patients with CM and BD showed a significantly greater reduction of severe headaches and psychiatric symptoms. Overall, tDCS seems to be effective in the treatment of CM patients with a poor response to different classes of pharmacological therapies, whereas BD status positively influences the response of migraineurs to tDCS.

Corrigendum: A Case of Post-traumatic Persistent Nasal Pain.

[This corrects the article DOI: 10.3389/fneur.2019.01409.].

Increased neural connectivity between the hypothalamus and cortical resting-state functional networks in chronic migraine.

OBJECTIVE: The findings of resting-state functional MRI studies have suggested that abnormal functional integration between interconnected cortical networks characterises the brain of patients with migraine. The aim of this study was to investigate the functional connectivity between the hypothalamus, brainstem, considered as the migraine generator, and the following areas/networks that are reportedly involved in the pathophysiology of migraine: default mode network (DMN), executive control network, dorsal attention system, and primary and dorsoventral visual networks. METHODS: Twenty patients with chronic migraine (CM) without medication overuse and 20 healthy controls (HCs) were prospectively recruited. All study participants underwent 3-T MRI scans using a 7.5-min resting-state protocol. Using a seed-based approach, we performed a ROI-to-ROI analysis selecting the hypothalamus as the seed. RESULTS: Compared to HCs, patients with CM showed significantly increased neural connectivity between the hypothalamus and brain areas belonging to the DMN and dorsal visual network. We did not detect any connectivity abnormalities between the hypothalamus and the brainstem. The correlation analysis showed that the severity of the migraine headache was positively correlated with the connectivity strength of the hypothalamus and negatively with the connectivity strength of the medial prefrontal cortex, which belongs to the DMN. CONCLUSION: These data provide evidence for hypothalamic involvement in large-scale reorganisation at the functional-network level in CM and in proportion with the perceived severity of the migraine pain.

A Case of Post-traumatic Persistent Nasal Pain.

Nasal pain is a complex and misdiagnosed entity with various peripheral and central etiologies. It is often a bothersome, treatment-resistant condition and could be spontaneous or post-traumatic. Although pain usually occurs immediately after injury, rarely it may occur long after the nasal trauma. Due to its rarity, successful treatment is difficult because of the lack of standardized options. According to our experience, an effective therapeutic approach should take into account both local inflammatory factors and aberrant nerve modulations. We describe the case of a young woman complaining of a delayed onset persistent nasal pain occurring 1 month after facial trauma and who has improved with the addition of intranasal steroids to first-line neuropathic pain treatment.

Aberrant interactions of cortical networks in chronic migraine: A resting-state fMRI study.

OBJECTIVE: We investigated resting-state (RS)-fMRI using independent component analysis (ICA) to determine the functional connectivity (FC) between networks in chronic migraine (CM) patients and their correlation with clinical features. METHODS: Twenty CM patients without preventive therapy or acute medication overuse underwent 3T MRI scans and were compared to a group of 20 healthy controls (HC). We used MRI to collect RS data in 3 selected networks, identified using group ICA: the default mode network (DMN), the executive control network (ECN), and the dorsal attention system (DAS). RESULTS: Compared to HC, CM patients had significantly reduced functional connectivity between the DMN and the ECN. Moreover, in patients, the DAS showed significantly stronger FC with the DMN and weaker FC with the ECN. The higher the severity of headache, the increased the strength of DAS connectivity, and the lower the strength of ECN connectivity. CONCLUSION: These results provide evidence for large-scale reorganization of functional cortical networks in chronic migraine. They suggest that the severity of headache is associated with opposite connectivity patterns in frontal executive and dorsal attentional networks.

The effects of a sensitisation campaign on unrecognised migraine: the Casilino study.

A striking feature of migraine is the difference between the estimated migraine prevalence and the actual number of migraineurs consulting their general practitioners (GPs). We investigated the impact of a sensitisation campaign on migraine in a large cohort of patients, living in a district of Rome. The study involved 10 GPs and a population of about 12 000 people, contacted by mail and posters located in GP clinics. Both the letter and poster stressed the impact of headache on quality of life and included the Italian version of the three-item Identification of Migraine (ID Migraine) screening test, consisting of questions on disability, nausea and photophobia. If the subjects suffered from headaches, they were invited to contact their GPs for a visit and a free consultation with a headache expert. By means of this sensitisation campaign, 195 headache patients consulted their GPs. Ninety-two percent of them (n=179) were migraineurs; 73% of them had never consulted a physician for headache. The ID Migraine test had a sensitivity of 0.92 (95% CI 0.86-0.95), a specificity of 0.75 (95% CI 0.47-0.91) and a positive predictive value (PPV) of 0.97 (95% CI 0.93-0.99) for a clinical diagnosis of migraine, according to the International Headache Society (IHS) criteria. This study confirms that a large number of migraine patients never see a doctor for their headache. This awareness campaign is likely to identify the severest cases of undiagnosed migraineurs. However, mailing campaigns do not seem to be so effective in bringing undiagnosed migraine patients into the primary care setting, and more efficient strategies have to be planned.