Long-Term Treatment Over 52 Weeks with Monthly Fremanezumab in Drug-Resistant Migraine: A Prospective Multicenter Cohort Study.

BACKGROUND: Real-world studies on fremanezumab, an anti-calcitonin gene-related peptide monoclonal antibody for migraine prevention, are few and with limited follow-up. OBJECTIVE: We aimed to evaluate the long-term (up to 52 weeks) effectiveness and tolerability of fremanezumab in high-frequency episodic migraine and chronic migraine. METHODS: This s an independent, prospective, multicenter cohort study enrolling outpatients in 17 Italian Headache Centers with high-frequency episodic migraine or chronic migraine and multiple preventive treatment failures. Patients were treated with fremanezumab 225 mg monthly. The primary outcomes included changes from baseline (1 month before treatment) in monthly headache days, response rates (reduction in monthly headache days from baseline), and persistence in medication overuse at months 3, 6, and 12 (all outcome timeframes refer to the stated month). Secondary outcomes included changes from baseline in acute medication intake and disability questionnaires scores at the same timepoints. A last observation carried forward analysis was also performed. RESULTS: A total of 90 patients who received at least one dose of fremanezumab and with a potential 12-month follow-up were included. Among them, 15 (18.0%) patients discontinued treatment for the entire population, a reduction in monthly headache days compared with baseline was reported at month 3, with a significant median [interquartile range] reduction in monthly headache days (- 9.0 [11.5], p < 0.001). A statistically different reduction was also reported at month 6 compared with baseline (- 10.0 [12.0]; p < 0.001) and at 12 months of treatment (- 10.0 [14.0]; p < 0.001). The percentage of patients with medication overuse was significantly reduced compared with baseline from 68.7% (57/83) to 29.6% (24/81), 25.3% (19/75), and 14.7% (10/68) at 3, 6, and 12 months of treatment, respectively (p < 0.001). Acute medication use (days and total number) and disability scores were also significantly reduced (p < 0.001). A ≥ 50% response rate was achieved for 51.9, 67.9, and 76.5% of all patients at 3, 6, and 12 months, respectively. Last observation carried forward analyses confirmed these findings. Fremanezumab was well tolerated, with just one patient discontinuing treatment because of adverse events. CONCLUSIONS: This study provides evidence for the real-world effectiveness of fremanezumab in treating both high-frequency episodic migraine and chronic migraine, with meaningful and sustained improvements in multiple migraine-related variables. No new safety issue was identified.

Cathodal tDCS Guided by Thermography as Adjunctive Therapy in Chronic Migraine Patients: A Sham-Controlled Pilot Study.

Objective: To explore the efficacy of cathodal tDCS applied ipsilateral to the cold patch, as determined by thermographic evaluation, in the treatment of chronic migraine. Background: Transcranial direct current stimulation (tDCS) is a non-invasive and safe technique that modulates the activity of the underlying cerebral cortex. tDCS has been extensively tested as a possible treatment for chronic pain and migraine with controversial results mainly due to the different setting procedure and location of electrodes. Since the presence of a hypothermic patch region detected through thermography has been suggested as a possible support for headache diagnosis, this "cold patch" could considered as possible effective location for tDCS application. Methods: Forty-five patients with chronic migraine were randomized to receive either cathodal (25 patients) or sham tDCS, for 5 consecutive daily sessions plus a recall session after 1 month. Cathodal tDCS was delivered at 1.5 mA for 15 min in each session. Subjects were evaluated before treatment (baseline, T0), and after 10 (T10), 60 (T60), and 120 (T120) days after treatment. The number of attacks, duration of attacks, pain intensity, number of days with headache, and number of analgesics were collected at each time evaluation. Results: Patients in the tDCS group showed a significant improvement compared to the sham group, during the whole study period in the frequency of migraine attacks (tDCS vs. sham: -47.8 ± 50.1% vs. -14.2 ± 16.5%, p = 0.004), number of days with headache (tDCS vs. sham: -42.7 ± 65.4% vs. -11.3 ± 18.0%, p = 0.015), duration of attacks (tDCS vs. sham: -29.1 ± 43.4% vs. -7.5 ± 17.6%, p = 0.016), intensity of the pain during an attack (tDCS vs. sham -31.1 ± 36.9% vs. 8.3 ± 13.5%, p = 0.004), and number of analgesics (tDCS vs. sham -54.3 ± 37.4% vs. -16.0 ± 19.6%, p < 0.0001). Conclusion: Our results suggest that cathodal tDCS is an effective adjuvant technique in migraine provided that an individual correct montage of the electrodes is applied, according to thermographic investigation.

Frontal infrared thermography in healthy individuals and chronic migraine patients: Reliability of the method.

BACKGROUND: The use of frontal infrared thermography in the diagnosis of primary headaches provided scattering results due to measurement fluctuations and different types of headaches or research protocols. OBJECTIVE: This study aims to assess the reliability of frontal infrared thermography in healthy individuals and provide a preliminary evaluation in chronic migraine patients using a commercial infrared thermal camera. METHODS: Thermographic images were acquired in 20 controls and 15 patients at three consecutive time-points in two daily sessions. The Side Difference and Asymmetry Index parameters were defined. The reproducibility of the measurements, the correlation of Asymmetry Index and Side Difference with clinical evaluations and patient perceptions, and the ability of the parameters to discriminate between patients and controls were investigated. RESULTS: We reported a good reproducibility of the measurements (Inter-class Correlation Coefficient > 0.75 and Coefficient of Variation < 13.4%), independent from external factors. The Side Difference was significantly different between patients and controls ( p < 0.001). The Asymmetry Index showed good correlation with the side of unilateral pain ( p = 0.0056). CONCLUSIONS: Frontal infrared thermography can be used to quantify the difference between the right and the left side of frontal vascular changes in chronic migraine patients, provided that standardized conditions are satisfied.

KCNK18 (TRESK) genetic variants in Italian patients with migraine.

OBJECTIVES: To evaluate the prevalence of KCNK18 gene mutations in a dataset of Italian migraineurs, with and without aura, and in healthy controls, and to investigate in silico the functional effects of the mutations. BACKGROUND: A role for the KCNK18 gene encoding for TRESK, a member of the family of potassium channel, has been recently suggested in migraine with aura. METHODS: We sequenced the KCNK18 gene in 425 migraineurs (255 with aura and 170 without aura) and 247 healthy controls. RESULTS: Five genetic variants (R10G, C110R, Y163Y, S231P, and F372L) were found in 13 (5.1%) out of 255 migraine with aura patients, and 6 variants (R10G, D46D, C110R, Y163Y, S178T, and S231P) were identified in 12 (7.1%) out of 170 migraine without aura patients. In 2.8% of controls, the R10G and L20V substitutions were found. In silico analysis suggested that C110R, S178T, S231P, and F372L mutations may have potential damaging effect on channel function, whereas the remaining mutations may have low damaging effect. CONCLUSIONS: Our study shows the presence of several KCNK18 gene mutations in both migraine with aura and migraine without aura. However, the precise role of this gene in migraine predisposition deserves further studies.

Interaction between proatherosclerotic factors and right-to-left shunt on the risk of cryptogenic stroke: the Italian Project on Stroke in Young Adults.

OBJECTIVE: To explore the interaction effects between cardiac interatrial right-to-left shunt (RLS) and proatherosclerotic factors on the risk of brain ischaemia. DESIGN: Multicentre Italian case-control study. SETTING: University hospitals. PARTICIPANTS: 588 patients with cryptogenic stroke (CS) aged ≤45 years and 585 control subjects consecutively enrolled as part of the Italian Project on Stroke in Young Adults. METHODS: Interaction effects between RLS and an individual proatherosclerotic score computed from the number of conventional vascular risk factors for the risk of CS were investigated. Data were examined by logistic regression models and expressed as interaction OR or interaction risk difference (RD). RESULTS: CS risk increased with increasing number of proatherosclerotic factors in subjects without RLS (OR 2.73; 95% CI 1.98 to 3.76; RD +0.246; 95% CI +0.17 to +0.32; for subjects with one or more factors), but was higher in subjects with RLS and no additional proatherosclerotic factors (OR 5.14; 95% CI 3.49 to 7.58; RD +0.388; 95% CI +0.31 to +0.47) compared with subjects without RLS and no risk factors. Negative interaction and antagonistic effects between RLS and proatherosclerotic factors were observed (interaction OR 0.52; 95% CI 0.31 to 0.91; interaction RD -0.17; 95% CI -0.29 to -0.05). CONCLUSIONS: The influence of RLS on the risk of CS decreases with increasing number of atherosclerotic factors, and is highest when such factors are absent. Individual proatherosclerotic profiles may help to identify patients with CS whose patent foramen ovale is probably pathogenic.

Is frontotemporal lobar degeneration a rare disorder? Evidence from a preliminary study in Brescia county, Italy.

Frontotemporal Lobar Degeneration (FTLD) has always been considered a rare disorder, but only a few epidemiologic studies are available. The aim of the present work was to ascertain all FTLD patients in a Northern Italy area from January 2001 to December 2008, and to estimate the disease prevalence. On the census day, 213 FTD patients were still alive, resulting in an overall prevalence of 17.6 per 100,000 inhabitants. The prevalence of FTLD in patients aged 45-65 years was 22 per 100,000 inhabitants (95% CI=17-27). The prevalence of FTLD was the highest in patients aged 66-75 (78 per 100,000 inhabitants, 95% CI=56-100), and it was still high over 75 years (54 per 100,000 inhabitants, 95% CI=36-69). FTLD is a more common form of dementia than previously recognized. Our results claimed that FTLD is not only an early-onset disorder, but it is frequent in advanced age as well.

The migraine-ischemic stroke relation in young adults.

In spite of the strong epidemiologic evidence linking migraine and ischemic stroke in young adults, the mechanisms explaining this association remain poorly understood. The observation that stroke occurs more frequently during the interictal phase of migraine prompts to speculation that an indirect relation between the two diseases might exist. In this regard, four major issues might be considered which may be summarized as follows: (1) the migraine-ischemic stroke relation is influenced by specific risk factors such as patent foramen ovale or endothelial dysfunction and more frequent in particular conditions like spontaneous cervical artery dissection; (2) migraine is associated with an increased prevalence of cardiovascular risk factors; (3) the link is caused by migraine-specific drugs; (4) migraine and ischemic vascular events are linked via a genetic component. In the present paper, we will review epidemiological studies, discuss potential mechanisms of migraine-induced stroke and comorbid ischemic stroke, and pose new research questions.

Topiramate weight loss in migraine patients.

Topiramate (TPM) is generally recognized efficacious and safe in migraine prevention. A significant proportion of patients undergoing TPM administration may show weight loss. In epileptic subjects, high body mass index (BMI) was found to be predictive of weight loss under TPM therapy. We therefore aimed to study whether common clinical determinants may be associated to TPM weigh loss in migraine patients. In our clinical series, high BMI was not found a predictor of weight loss under TPM treatment. Unknown genetic and environmental factors that may determine the courses of weight loss under TPM therapy are still do be identified.

Migraine mediates the influence of C677T MTHFR genotypes on ischemic stroke risk with a stroke-subtype effect.

BACKGROUND AND PURPOSE: The objective was to investigate the role of C677T MTHFR polymorphism in migraine pathogenesis and in the migraine-ischemic stroke pathway. METHODS: A first genotype-migraine association study was conducted on 100 patients with migraine with aura (MA), 106 with migraine without aura (MO), and 105 subjects without migraine, which provided evidence in favor of association of the TT677 MTHFR genotype with increased risk of MA compared with both control subjects (OR, 2.48; 95% CI, 1.11 to 5.58) and patients with MO (OR, 2.21; 95% CI, 1.01 to 4.82). Based on these findings, mediational models of the genotype-migraine-stroke pathway were fitted on a group of 106 patients with spontaneous cervical artery dissection, 227 young patients whose ischemic stroke was unrelated to a spontaneous cervical artery dissection (noncervical artery dissection), and 187 control subjects, and a genotype-migraine partial mediation model was selected. RESULTS: Both migraine and the TT genotype were more strongly associated to the subgroup of patients with spontaneous cervical artery dissection (OR, 4.06; 95% CI, 1.63 to 10.02 for MA; OR, 5.45; 95% CI, 3.03 to 9.79 for MO; OR, 2.87; 95% CI, 1.45 to 5.68 for TT genotype) than to the subgroup of patients with noncervical artery dissection ischemic stroke (OR, 2.22; 95% CI, 1.00 to 4.96 for MA; OR, 1.81; 95% CI, 1.02 to 3.22 for TT genotype) as compared with controls. CONCLUSIONS: Migraine may act as mediator in the methylenetetrahydrofolate reductase-ischemic stroke pathway with a more prominent effect in the subgroup of patients with spontaneous artery dissection.

Prevalence of patent foramen ovale in a large series of patients with migraine with aura, migraine without aura and cluster headache, and relationship with clinical phenotype.

A relationship between migraine and patent foramen ovale (PFO) has been observed in relatively small series of patients so far. Furthermore, the exact mechanism underlying such an association remains unknown. In the present study we determined the prevalence of PFO by contrast-enhanced transcranial Doppler (TCD) in a group of 260 patients with migraine with aura (MA+), 74 patients with migraine without aura (MA-), and 38 patients with cluster headache (CH). One-hundred-sixty-one MA+subjects (61.9%), 12 MA-subjects (16.2%), and 14 CH-subjects (36.8%) were PFO-carriers. The association was independent on the frequency of migraine attacks and complexity of aura. Finally, among the 15 patients who had a history of at least one migraine attack occurring during a Valsalva maneuver only one subject turned out to be PFO-carrier. Our findings confirm previous observations of a link between MA+, CH, and PFO. They also suggest that such an association is independent on migraine clinical phenotype and is probably unrelated to the pathogenic mechanism of paradoxical embolism.