Migraine and balance impairment: Influence of subdiagnosis, otoneurological function, falls, and psychosocial factors.

OBJECTIVE: To assess the balance sensory organization among patients with migraine, considering the influence of migraine subdiagnosis, otoneurological function, falls, and psychosocial factors. BACKGROUND: Migraine has been associated with vestibular symptoms and balance dysfunction; however, neither comprehensive balance assessment nor associated factors for greater impairment have been addressed thus far. METHODS: Patients from a tertiary headache clinic with a diagnosis of episodic migraine with aura (MWA), without aura (MWoA), and chronic migraine (CM) were included for this cross-sectional study (30 patients per group). Thirty headache-free controls (CG) were recruited. Participants underwent a comprehensive evaluation protocol, including the Sensory Organization Test (SOT) and otoneurological examination. Questionnaires about fear of falls, dizziness disability, and kinesiophobia were administered. RESULTS: All migraine groups presented lower composite SOT scores than controls (CG: 82.4 [95% confidence interval (CI): 79.5-85.3], MWoA: 76.5 [95% CI: 73.6-79.3], MWA: 66.5 [95% CI: 63.6-69.3], CM: 69.1 [95% CI: 66.3-72.0]; p < 0.0001). Compared to controls and to MWoA, MWA and CM groups exhibited greater vestibular (CG: 75.9 [95% CI: 71.3-80.4], MWoA: 67.3 [95% CI: 62.7-71.8], MWA: 55.7 [95% CI: 51.2-60.3], CM: 58.4 [95% CI: 53.8-63.0]; p < 0.0001) and visual functional impairment (CG: 89.6 [95% CI: 84.2-94.9], MWoA: 83.2 [95% CI: 77.9-88.6], MWA: 68.6 [95% CI: 63.3-74.0], CM: 71.9 [95% CI: 66.5-77.2], p < 0.0001). Fall events during the assessment were documented more often among patients with migraine (CG: 0.0, interquartile range [IQR], 0.0, 0.0); MWoA: 1.0 [IQR: 1.0, 1.0], MWA: 2.0 [IQR: 1.8, 4.3], CM: 1.0 [IQR: 1.0, 2.0]; p = 0.001). The SOT scores correlated with fear of falls (r = -0.44), dizziness disability (r = -0.37), kinesiophobia (r = -0.38), and migraine frequency (r = -0.38). There was no significant influence of the vestibular migraine diagnosis in the study outcomes when used as a covariate in the analysis (composite score [F = 3.33, p = 0.070], visual score [F = 2.11, p = 0.149], vestibular score [F = 1.88, p = 0.172], somatosensory score [F = 0.00, p = 0.993]). CONCLUSIONS: Aura and greater migraine frequency were related to falls and balance impairment with sensory input manipulation, although no otoneurological alterations were detected. The diagnosis of vestibular migraine does not influence the balance performance. The vestibular/visual systems should be considered in the clinical examination and treatment of patients with migraine.

Effects of fremanezumab in patients with chronic migraine and comorbid depression: Subgroup analysis of the randomized HALO CM study.

OBJECTIVE: To evaluate the efficacy of fremanezumab in patients with chronic migraine (CM) and moderate to severe depression. BACKGROUND: Fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, has been approved for the preventive treatment of migraine in adults. CM and depression are highly comorbid. METHODS: The 12-week, Phase 3 HALO trial randomized patients with CM to fremanezumab quarterly (675 mg/placebo/placebo), fremanezumab monthly (675/225/225 mg), or placebo. Post hoc analyses evaluated the effects of fremanezumab in patients with moderate to severe depression (baseline 9-item Patient Health Questionnaire sum score ≥10) on monthly number of headache days of at least moderate severity; monthly migraine days; Patient Global Impression of Change (PGIC); 6-item Headache Impact Test (HIT-6) scores; and depression. RESULTS: For the 219/1121 (19.5%) patients with moderate to severe depression at baseline, fremanezumab was associated with a significant reduction in monthly number of headache days of at least moderate severity for active treatment versus placebo (least-squares mean change ± standard error for quarterly dosing: -5.3 ± 0.77; for monthly dosing: -5.5 ± 0.72; and for placebo: -2.2 ± 0.81; both p < 0.001). More patients achieved a ≥50% reduction in headache days of at least moderate severity with fremanezumab (quarterly: 31/78 [39.7%]; monthly: 39/96 [40.6%]) than placebo (9/67 [13.4%]; both p < 0.001). Compared with placebo, fremanezumab improved PGIC and HIT-6 scores. CONCLUSIONS: Fremanezumab demonstrated efficacy in the preventive treatment of CM and reduced headache impact in patients with comorbid depression.

Fremanezumab for the Preventive Treatment of Chronic Migraine.

BACKGROUND: Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being investigated as a preventive treatment for migraine. We compared two fremanezumab dose regimens with placebo for the prevention of chronic migraine. METHODS: In this phase 3 trial, we randomly assigned patients with chronic migraine (defined as headache of any duration or severity on ≥15 days per month and migraine on ≥8 days per month) in a 1:1:1 ratio to receive fremanezumab quarterly (a single dose of 675 mg at baseline and placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), or matching placebo. Both fremanezumab and placebo were administered by means of subcutaneous injection. The primary end point was the mean change from baseline in the average number of headache days (defined as days in which headache pain lasted ≥4 consecutive hours and had a peak severity of at least a moderate level or days in which acute migraine-specific medication [triptans or ergots] was used to treat a headache of any severity or duration) per month during the 12 weeks after the first dose. RESULTS: Of 1130 patients enrolled, 376 were randomly assigned to fremanezumab quarterly, 379 to fremanezumab monthly, and 375 to placebo. The mean number of baseline headache days (as defined above) per month was 13.2, 12.8, and 13.3, respectively. The least-squares mean (±SE) reduction in the average number of headache days per month was 4.3±0.3 with fremanezumab quarterly, 4.6±0.3 with fremanezumab monthly, and 2.5±0.3 with placebo (P<0.001 for both comparisons with placebo). The percentage of patients with a reduction of at least 50% in the average number of headache days per month was 38% in the fremanezumab-quarterly group, 41% in the fremanezumab-monthly group, and 18% in the placebo group (P<0.001 for both comparisons with placebo). Abnormalities of hepatic function occurred in 5 patients in each fremanezumab group (1%) and 3 patients in the placebo group (<1%). CONCLUSIONS: Fremanezumab as a preventive treatment for chronic migraine resulted in a lower frequency of headache than placebo in this 12-week trial. Injection-site reactions to the drug were common. The long-term durability and safety of fremanezumab require further study. (Funded by Teva Pharmaceuticals; ClinicalTrials.gov number, NCT02621931 .).

The Influence of Photophobia on Postural Control in Patients With Migraine.

BACKGROUND: People with migraine exhibit postural control impairments. These patients also have an increased light sensitivity due to the disease, and it remains during the headache-free period. It is currently unknown if increased lighting levels can alter the balance control, especially in individuals with visual hypersensitivity, such as migraineurs. This study aimed to assess the balance and photophobia of women with migraine and non-headache controls under different light conditions. METHODS: This cross-sectional study consisted of 14 women with migraine (mean ± SD 30.6 ± 8.1 years old) and 14 women without any kind of headache (mean ± SD 27.2 ± 2.8 years old) screened from a tertiary headache clinical hospital and the local community. Quiet standing balance was evaluated during bipodal and unipodal support, under 3 light conditions: ambient (AMB) - 270 lx, visual discomfort threshold (VDT) - 400 lx, and intense visual discomfort (IVD) - 2000 lx. Sway area of the center of pressure was processed and compared between groups. The association of migraine with the risk of presenting a greater imbalance in the discomfort lighting conditions was verified. RESULTS: Compared to the non-headache controls, the migraine group presented greater sway area in bipodal stance under the 3 light conditions (mean difference (95% CI)): AMB 0.81 cm2 (0.19 to 1.43), P = .011; VDT 3.17 cm2 (0.74 to 5.60), P = .001; IVD 5.56 cm2 (2.75 to 8.37), P < .0001. Within-subject analysis showed increased sway area in bipodal stance among all lighting conditions for the migraine group only (mean difference (95% CI)): VDT-AMB 2.20 cm2 (0.23 to 4.18), P = .024; IVD-AMB 4.50 cm2 (2.38 to 6.62), P < .0001, IVD-VDT 2.29 cm2 (0.57 to 4.01), P = .005. The Prevalence Ratio (PR) analysis showed that migraine was associated with the risk of presenting greater imbalance in both bipodal and unipodal standing conditions for both VDT (PR value (95% CI) - bipodal: PR = 4.00 (1.02 to 15.59), P = .045; unipodal: PR = 4.00 (1.43 to 11.15), P = .008), and the IVD (bipodal: PR = 3.33 (1.13 to 9.58), P = .025; unipodal: PR = 5.50 (1.48 to 20.42), P = .010) lighting conditions. CONCLUSION: Photophobia might be a disturbing factor that worsens the balance of patients with migraine during the quiet standing posture.

Presence of vestibular symptoms and related disability in migraine with and without aura and chronic migraine.

OBJECTIVE: To assess the presence and handicap due to vestibular symptoms in three subgroups of patients with migraine and controls. METHODS: Women between 18-55 years old were diagnosed by headache specialists and stratified as migraine with aura (n = 60), migraine without aura (n = 60), chronic migraine (n = 60) and controls (n = 60). Information regarding demographics, headache and vestibular symptoms were collected in this cross-sectional study. The self-perceived handicap related to vestibular symptoms was assessed through the Dizziness Handicap Inventory questionnaire. RESULTS: A total of 85% of women with migraine with aura and chronic migraine had vestibular symptoms contrasted to 70% of the migraine without aura group ( p < 0.05), and 12% of the control group reported symptoms ( p < 0.0001). Patients with migraine exhibited greater Dizziness Handicap Inventory scores than controls ( p < 0.001); and migraine with aura and chronic migraine groups reached greater scores than migraine without aura ( p < 0.01). Presence of migraine is associated with a greater risk of vestibular symptoms (migraine without aura: 5.20, migraine with aura: 6.60, chronic migraine:6.20, p < 0.0003) and with a greater risk of moderate-to-severe handicap (migraine without aura: 20.0, migraine with aura: 40.0, chronic migraine: 40.0, p < 0.0003). The presence of aura and greater migraine frequency adds to the risk of any handicap (migraine with aura: 1.9, chronic migraine: 1.7, p < 0.04) and to the risk of moderate-to-severe handicap (migraine with aura: 2.0, chronic migraine: 2.0, p < 0.0003). Migraine aura, intensity and frequency predict 36% of the dizziness handicap. CONCLUSION: The prevalence of vestibular symptoms is increased in migraine during and between headache attacks, particularly in migraine with aura and chronic migraine along with an increased handicap due to those symptoms. Vestibular symptoms among subgroups of migraine should be considered when evaluating the functional impact of migraine.

Sustained reductions in migraine days, moderate-to-severe headache days and days with acute medication use for HFEM and CM patients taking fremanezumab: Post-hoc analyses from phase 2 trials.

BACKGROUND: In phase 2 and 3 studies, fremanezumab, a monoclonal CGRP antibody, was an effective preventive treatment for high-frequency episodic migraine (HFEM) and chronic migraine (CM). OBJECTIVE: Post-hoc analyses evaluated population-wise 50%, 75% and 100% responder rates, and the extent to which individual responders sustained a 50%, 75% and 100% reduction in migraine days, moderate-to-severe (M/S) headache days and days of acute medication use during all three treatment months of the fremanezumab phase 2 studies. DESIGN/METHODS: HFEM patients received either placebo or three once-monthly injections of 225 mg or 675 mg. CM patients received either placebo or three once-monthly injections of 900 mg, or an initial loading dose of 675 mg and subsequent injections of 225 mg. Patients reported headache-related data daily using an electronic diary. RESULTS: In the HFEM study, the percent of patients on fremanezumab doses 225 mg and 675 mg were greater compared to the percent of placebo patients with sustained 50% reduction in migraine days (39% and 35% vs. 10% for placebo, both p < 0.0001), M/S headache days (36% and 38% vs. 16% placebo, p = 0.0017 and p = 0.0007 respectively), and acute medication use days (36% and 27% vs. 8% placebo, p < 0.0001 and p = 0.0003). Likewise, although there were fewer patients with sustained 75% reduction, there were increases in the percent of patients on fremanezumab 225 mg and 675 mg in the HFEM study relative to placebo patients in migraine days (19% and 11% vs. 3% placebo, p = 0.0002 and p = 0.0176), M/S headache days (19% and 15% vs. 2% placebo, p = 0.0001 and p = 0.0011) and days of acute medication use (16% and 8% vs. 2% placebo, p = 0.0005 and p = 0.0377). In the CM study, there were increases in the percent of patients on fremanezumab 675/225 mg and 900 mg with 50% sustained reduction in M/S headache days (32% and 40% vs. 15% placebo, p = 0.0058 and p = 0.0002) and days of acute medication use (26% and 22% vs. 11% placebo, p = 0.0098 and p = 0.0492). There were also increases in the percent of patients on fremanezumab 675/225 mg and 900 mg compared to patients on placebo with 75% sustained reduction in M/S headache days (10% and 13% vs. 3%, p = 0.0665 and p = 0.0203). Few patients had 100% sustained reductions in these parameters in either study. CONCLUSIONS: Post-hoc results must be interpreted with caution; nonetheless, a statistically significant percentage of patients who initially responded to fremanezumab within 1 month sustained this response over the subsequent 2 months. Sustained reduction in individual patients may provide a novel patient-centric, clinically meaningful endpoint for future trials assessing the effectiveness of preventive migraine treatments. Trials are registered as http://clinical trials.gov as NCT02025556 and NCT02021773.

The Effect of Beginning Treatment With Fremanezumab on Headache and Associated Symptoms in the Randomized Phase 2 Study of High Frequency Episodic Migraine: Post-Hoc Analyses on the First 3 Weeks of Treatment.

BACKGROUND: Migraine has a substantial impact on daily living, affecting productivity and quality of life for patients and their families. Patients frequently discontinue preventive medications in part because of a delay in headache and symptom relief due to the long dose titration procedures necessary for some migraine preventives. OBJECTIVE: To evaluate the efficacy of fremanezumab, a selective monoclonal CGRP ligand antibody, during the first 3 weeks of therapy in patients with high-frequency episodic migraine (HFEM) to relieve migraine headaches and associated symptoms and to reduce use of acute migraine medications. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, phase 2 study, patients with HFEM who met inclusion criteria and were 80% compliant with daily headache diary entry were randomized and treated once every 28 days for 3 months with either placebo or fremanezumab 225 or 675 mg. Compared to placebo, both doses of fremanezumab significantly reduced the primary endpoint of the HFEM study, change in the number of migraine days in month 3 relative to baseline. Herein, we performed post-hoc analyses to assess the efficacy of each dose during the first 3 weeks of treatment to reduce migraine headache parameters, associated migraine symptoms, and the consumption of acute migraine medications. RESULTS: The sample consisted of 297 study participants. Compared to placebo, decreases in migraine days were seen during the first week of therapy for both fremanezumab doses with least square mean (LSM) differences between fremanezumab 225 mg and placebo of -0.93 (95% CI: -1.36, -0.49) and between 675 mg dose and placebo of -1.02 (95% CI: -1.46, -0.58), both P < .0001. This benefit was maintained through the second week of therapy for the 225 and 675 mg doses, respectively, (-0.76 (95% CI: -1.11, -0.40) P < .0001, -.79 (95% CI: -1.15, -0.44) P < .0001) and the third week of therapy (-0.64 (95% CI: -0.97, -0.30) P = .0003 and -0.64 (95% CI: -0.98, -0.30) P = .0003). Likewise in the first week, patients recorded reductions in associated migraine symptoms such as nausea, vomiting, photophobia, and phonophobia, which continued through weeks 2 and 3. There were also reductions in days with acute medication use to treat migraine for the 225 and 675 mg fremanezumab doses compared to placebo. In the first week, LSM differences between 225 mg and placebo were -1.02 (95% CI: -1.39, -0.64) and between 675 mg and placebo were -1.06 (95% CI: -1.39, -0.64) P < .0001); for the second and third weeks (-1.01 (95% CI: -1.14, -0.55) P < .0001; -.90 (95% CI: -1.04, -0.44) P < .0001; -.91 (95% CI: -0.92, -0.34) P < .0001; and -.83 (95% CI: -0.84, -0.26) P = .0002), respectively. CONCLUSION: Fremanezumab treatment resulted in a rapid preventive response in patients with HFEM, with reductions seen in several headache parameters and migraine symptoms within the first week after therapy initiation and continuing during the second and third weeks. Patients also were able to rapidly reduce their use of acute medications to treat migraine attacks. The trial is registered at Clinicaltrials.gov as NCT02025556.

Effect of Fremanezumab Compared With Placebo for Prevention of Episodic Migraine: A Randomized Clinical Trial.

Importance: Fremanezumab, a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, may be effective for treating episodic migraine. Objective: To assess the efficacy of fremanezumab compared with placebo for prevention of episodic migraine with a monthly dosing regimen or a single higher dose. Design and Setting: Randomized, double-blind, placebo-controlled, parallel-group trial conducted at 123 sites in 9 countries from March 23, 2016 (first patient randomized), to April 10, 2017, consisting of a screening visit, 28-day pretreatment period, 12-week treatment period, and final evaluation at week 12. Participants: Study participants were aged 18 to 70 years with episodic migraine (6-14 headache days, with at least 4 migraine days, during 28-day pretreatment period). Patients who had previous treatment failure with 2 classes of migraine-preventive medication were excluded. Interventions: Patients were randomized 1:1:1 to receive subcutaneous monthly dosing of fremanezumab (n = 290; 225 mg at baseline, week 4, and week 8); a single higher dose of fremanezumab, as intended to support a quarterly dose regimen (n = 291; 675 mg of fremanezumab at baseline; placebo at weeks 4 and 8); or placebo (n = 294; at baseline, week 4, and week 8). Main Outcomes and Measures: The primary end point was mean change in mean number of monthly migraine days during the 12-week period after the first dose. Results: Among 875 patients who were randomized (mean age, 41.8 [SD, 12.1] years; 742 women [85%]), 791 (90.4%) completed the trial. From baseline to 12 weeks, mean migraine days per month decreased from 8.9 days to 4.9 days in the fremanezumab monthly dosing group, from 9.2 days to 5.3 days in the fremanezumab single-higher-dose group, and from 9.1 days to 6.5 days in the placebo group. This resulted in a difference with monthly dosing vs placebo of -1.5 days (95% CI, -2.01 to -0.93 days; P < .001) and with single higher dosing vs placebo of -1.3 days (95% CI, -1.79 to -0.72 days; P < .001). The most common adverse events that led to discontinuation were injection site erythema (n = 3), injection site induration (n = 2), diarrhea (n = 2), anxiety (n = 2), and depression (n = 2). Conclusions and Relevance: Among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3- to 1.5-day reduction in the mean number of monthly migraine days over a 12-week period. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy. Trial Registration: clinicaltrials.gov Identifier: NCT02629861.

Primary Headaches in an Elderly Population Seeking Medical Care for Cognitive Decline.

OBJECTIVES: To assess the prevalence of specific headache disorders in a population older than 65 years seeking consultation due to memory problems or cognitive impairment. METHODS: We verified the occurrence of headache symptoms and the impact of headaches on daily life. Headaches were classified as per the International Classification of Headache Disorders, 2nd edition (ICHD-2). All patients were screened with the Mini-Mental State Examination (MMSE), followed by the Selective Reminding Test and neuroimaging. Participants with severe cognitive impairment or dementia were excluded. RESULTS: A total of 1,237 patients (51.6% women), with mean age of 75.6 years (SD = 6.9) were screened from January 2006 to December 2014. Of them, 302 (24.4%) patients suffered from headaches. Most common individual diagnoses were probable migraine (13.8%), episodic tension-type headache (3.4%), and episodic migraine (3.0%). Chronic migraine or probable chronic migraine happened in 3.5%, while chronic tension-type headache affected 0.6%. Most patients with headaches routinely used symptomatic medications (55.6%). Mean MMSE scores were similar in patients with or without headaches, or with different headache diagnoses. CONCLUSIONS: Headache disorders overall, frequent headaches, and headaches requiring treatment are commonly seen in the elderly seeking care for cognitive decline and should be properly assessed and managed.

Fremanezumab as Add-On Treatment for Patients Treated With Other Migraine Preventive Medicines.

BACKGROUND: Fremanezumab (formerly TEV-48125) is a monoclonal antibody directed against calcitonin-gene-related peptide (CGRP), a validated target for migraine preventive therapy. In two previous phase 2 studies, fremanezumab administered once every 28 days for 12 weeks was found to be effective and safe as a preventive treatment for patients suffering from episodic migraine (EM) and chronic migraine (CM). OBJECTIVE: To evaluate the efficacy and safety of fremanezumab as an add-on preventive therapy in individuals with EM and CM who are on stable doses of preventive migraine medications. METHODS: Two randomized placebo-controlled studies tested once-monthly subcutaneous injections of various dosing regimens of fremanezumab versus placebo in EM and CM. Headache information was captured daily using an electronic headache diary. For these post hoc analyses, data were pooled from patients who were on stable preventive medications and taking fremanezumab doses of 225 mg or 675/225 mg, or placebo. RESULTS: The sample consisted of 133 patients, (67 fremanezumab and 66 placebo). Total reduction in migraine days for the duration of the study was 12.4 for fremanezumab and 7.4 for placebo (P = .0321). There were also decreases in moderate/severe headache days (12.5 vs 7.1, P = .0058), and days using acute medication for headaches relative to placebo (11.6 vs 7.5, P = .0414). Treatment emergent adverse events were generally mild and transient, and no serious adverse events were considered to be treatment-related by the site investigators. CONCLUSIONS: The findings from these post hoc analyses suggest that fremanezumab is a safe and effective add-on treatment for migraine patients being concomitantly treated with other migraine preventive medications. Trials are registered at Clinicaltrials.gov NCT02025556 and NCT02021773.

Balance Impairments in Different Subgroups of Patients With Migraine.

BACKGROUND: Patients with migraine often experience balance impairments. However, the relationship between clinical features - like aura and chronicity - and the severity of balance impairments is not well established. The objective of this study was to assess balance impairments in different subgroups of migraine patients. METHOD: One hundred five subjects diagnosed according to the ICHD-III were recruited in the study. They were uniformly distributed among three groups: migraine with aura, migraine without aura, and chronic migraine. Thirty-five controls were also recruited in the study. Balance impairments were assessed in all subjects via the modified Sensory Organization test and the Limits of Stability test. The results in the four groups were compared using ANCOVA tests with age, BMI, presence of dizziness, level of physical activity, time of migraine onset, and medication intake as covariates. RESULTS: Subjects in the migraine with aura and the chronic migraine groups showed poorer balance control than control subjects in three of the four conditions tested using the modified Sensory Organization test: FirmCE: CG: 1.5 cm2 , 95%CI 1.3 to 1.7; M: 2.1 cm2 , 95%CI 1.6 to 2.6; MA: 4.5 cm2 , 95%CI 3.2 to 5.8; CM: 4.5 cm2 , 95%CI 3.0 to 6.0; P < .027; FoamOE: CG: 5.1 cm2 , 95%CI 4.6 to 5.6; M: 5.6 cm2 , 95%CI 5.0 to 6.1; MA: 8.8 cm2 , 95%CI 7.3 to 10.2; CM: 8.8 cm2 , 95%CI 7.7 to 10.0; P < .018; FoamCE: CG: 14.8 cm2 , 95%CI 13.7 to 15.9 cm2; M: 17.3 cm2 , 95%CI 15.4 to 19.1; MA: 21.9 cm2 , 95%CI 19.1 to 24.7; CM: 22.4 cm2 , 95%CI 19.9 to 24.9; P < .0001. In the FoamOE and FoamCE conditions, both groups also showed poorer postural control than subjects in the migraine without aura group (P < .01). Differences between control subjects and subjects in all the migraine groups were found in the reaction time, movement velocity, endpoint excursion, and maximal excursion parameters (P < .04) in all the directions tested during the Limits of Stability test. None of the covariates appeared to affect the balance parameters (P > .05). CONCLUSION: There is evidence of balance control impairments in subjects with all subtypes of migraine compared to control subjects. The presence of aura and frequent migraine attacks reflect negatively in the postural control performance and may have a significant clinical impact in patients with migraine that should be addressed with appropriate clinical interventions.

A Phase I, Open-Label, Single-Dose Safety, Pharmacokinetic, and Tolerability Study of the Sumatriptan Iontophoretic Transdermal System in Adolescent Migraine Patients.

OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetics of sumatriptan delivered by the iontophoretic transdermal system (TDS) in adolescent patients. BACKGROUND: Since nausea can be a prominent and early symptom of migraine, nonoral treatment options are often required. Sumatriptan iontophoretic TDS is approved for the acute treatment of migraine in adults. The present study evaluates the pharmacokinetics of sumatriptan administered via the iontophoretic TDS in adolescents, contrasting the findings with historical data from adults. DESIGN: Patients aged 12-17 years (inclusive) with acute migraine were treated with sumatriptan iontophoretic TDS for 4 hours. Blood samples for pharmacokinetic profiling of sumatriptan were obtained prior to dosing and at predetermined time points covering the 12 hours postonset of treatment. Key pharmacokinetic endpoints included Cmax (peak plasma drug concentration), tmax (time to Cmax ), AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and t½ (terminal elimination half-life). Safety was evaluated by monitoring of adverse events in addition to laboratory and clinical assessments. RESULTS: The sample consisted of 37 patients, and 36 were included in the PK evaluable population. Cmax , tmax , AUC0-∞ , and t½ values were all similar between male and female patients and between younger (12-14 years) and older (15-17 years) adolescents. When compared with historical adult data, adolescent patients demonstrated similar systemic exposures to those observed in adults (mean Cmax 20.20 (±6.43) ng/mL in adolescents vs 21.89 (±6.15) ng/mL in adults; mean AUC0-∞ 98.1 (±28.1) ng·h/mL in adolescents vs 109.7 (±26.1) ng·h/mL in adults). All adverse events were mild or moderate, with application-site paresthesia being the most common (32%). No clinically relevant changes in laboratory values, vital signs, or electrocardiogram findings were observed. CONCLUSIONS: The iontophoretic TDS produced mean systemic exposures to sumatriptan in younger and older adolescents, in line with what was seen in adult subjects. It was generally well tolerated.

Therapeutic antibodies against CGRP or its receptor.

CGRP is an extensively studied neuropeptide that has been implicated in the pathophysiology of migraine. While a number of small molecule antagonists against the CGRP receptor have demonstrated that targeting this pathway is a valid and effective way of treating migraine, off-target hepatoxicity and formulation issues have hampered the development for regulatory approval of any therapeutic in this class. The development of monoclonal antibodies to CGRP or its receptor as therapeutic agents has allowed this pathway to be re-investigated. Herein we review why CGRP is an ideal target for the prevention of migraine and describe four monoclonal antibodies against either CGRP or its receptor that are in clinical development for the treatment of both episodic and chronic migraine. We describe what has been publically disclosed about their clinical trials and future clinical development plans.

Cerebral Venous Thrombosis and Headache--A Case-Series.

BACKGROUND: Headache happens in the majority of patients with Cerebral Venous Thrombosis (CVT) being sometimes the sole manifestation of the disease. Herein we report a case-series of CVT, focusing on headache characteristics. METHODS: Etiological, clinical, and radiological features of 25 consecutive adult patients with CVT were compiled from August 2005 to December 2013. Diagnosis of CVT was confirmed by brain magnetic resonance imaging and magnetic resonance venography. All patients underwent extensive systematic etiological and genetic work-up at admission. A structured questionnaire about the characteristics of headache was responded by all participants. RESULTS: Headache was reported by 23 out of 25 (92%) of participants, being by far the most frequent symptom. It was the sole manifestation in nearly one third of the patients (8/25, 32.0%). Headache was typically severe (19/23, 82.6%) and throbbing (16/23, 69.5%), with sudden onset (13/23, 56.5%) and non-remitting (20/23, 86.9%) characteristics. The sinus most frequently involved was the transverse sinus (24/25, 96.0%), either alone or in association with other sinuses. CONCLUSION: Headache is the most frequent symptom and sometimes the sole presentation of CVT.

Psychosocial adjustment of children with migraine and tension-type headache - a nationwide study.

OBJECTIVE: To describe patterns of psychosocial adjustment and psychological attributes in preadolescent children as a function of headache status in univariate and adjusted analyses. METHODS: Target sample of children (n = 8599) was representative of Brazil by demographics. Parents were interviewed using validated headache questionnaires and the "Strengths and Difficulties Questionnaire," which measures behavior in 5 domains. One-year prevalence estimates of headaches were derived by demographics. Relative risk of abnormal Strengths and Difficulties Questionnaire scores were separately modeled in children with episodic migraine and episodic tension-type headache using logistic regression. RESULTS: Sample consisted of 5671 children (65.9% of the target sample), from 5 to 12 years old (49.3% girls). Prevalence estimates in children were 20.6% for "no headache," 9% for episodic migraine, and 12.8% for episodic tension-type headache. Abnormal scores in psychosocial adjustment were significantly more likely in children with episodic migraine, relative to children without headaches and children with episodic tension-type headache, and was significantly influenced by frequency of headache attacks, nausea, school performance, prenatal exposure to tobacco, as well as by phonophobia and photophobia. CONCLUSIONS: Children with migraine are at an increased risk of having impairment in psychosocial adjustment, and the factors associated with this impairment have been mapped. Future studies should address the directionality of the association and putative mechanisms to explain it.

Sumatriptan Iontophoretic Transdermal System Reduces Treatment-Emergent Nausea and Is Effective in Patients With and Without Nausea at Baseline - Results From a Randomized Controlled Trial.

OBJECTIVES: To test the hypothesis that sumatriptan iontophoretic transdermal system (TDS) is associated with lower rates of treatment-emergent nausea (TEN) relative to placebo, as well as to compare the efficacy of sumatriptan TDS in migraineurs with or without nausea at baseline. METHODS: Participants of a double-blind, randomized, parallel-group, single-attack, placebo-controlled study conducted at 38 sites in the United States were analyzed. Participants who treated their migraine attacks while nausea-free were identified. The primary endpoint was TEN over 24 hours post-treatment contrasting both treatment groups and it was assessed by regression analyses using generalized estimating equations. Secondary endpoint was headache response as a function of presence of nausea, assessed by generalized linear model. RESULTS: A total of 130 participants free of nausea at baseline were treated with sumatriptan TDS, while 109 participants free of nausea at baseline were treated with placebo TDS. The occurrence of TEN over 24 hours post-treatment was significantly lower with the sumatriptan TDS than with placebo (P = .0011). These differences were statistically significant at 1 hour (13.8% vs 9.2%, P < .01), 2 hours (13.8% vs 4.6% P < .001) and 3 hours (13.8% vs 8.5% P < .01). The efficacy of sumatriptan TDS was similar regardless of the presence or absence of nausea at baseline for all clinical parameters. CONCLUSION: Sumatriptan TDS is not associated with the emergence of nausea in migraineurs without nausea. It is equally effective in participants with or without nausea at the time of treatment.

TEV-48125: a review of a monoclonal CGRP antibody in development for the preventive treatment of migraine.

Calcitonin gene-related peptide (CGRP) is a 37-amino-acid neuropeptide whose involvement in migraine pathophysiology is well established. Originally migraine was believed to be a disease of the vasculature, but research has highlighted this to be a disease of the brain with CGRP playing an important role. While targeting CGRP using small molecule antagonists against the receptor has been effective, long-term use of these agents has not been possible due to safety concerns and/or formulation challenges. Recent advances in therapeutic antibodies have opened up new possibilities for treatment of migraine. TEV-48125 is one of four monoclonal antibodies targeting CGRP or its receptors, currently in development for the preventive treatment of migraine. This article discusses the in vitro and in vivo pharmacology of TEV-48125 as well as highlighting its safety profile through the six Phase 1 studies that have been conducted. Finally, the current state of development and future studies for TEV-48125 will be reviewed.

Cardiovascular and hemodynamic parameters in women following prolonged CGRP inhibition using LBR-101, a monoclonal antibody against CGRP.

BACKGROUND: The vascular effects of acute calcitonin gene-related peptide (CGRP) inhibition are well described, but the effects of sustained inhibition warrant further exploration in humans. OBJECTIVES: The objective of this article is to assess the effects of sustained CGRP inhibition on blood pressure, heart rate, and ECGs in healthy women ≥ 40 years of age. METHODS: In this double-blind, placebo-controlled study, 31 women (mean age = 56) were randomized to receive placebo or an anti-CGRP monoclonal antibody at doses up to 2000 mg. Participants were confined for seven days and followed for 168 days. Cardiac telemetry was conducted for eight hours after infusion completion. Hemodynamic assessments and ECGs were conducted six times during Day 1 and periodically for three months. RESULTS: No clinically relevant changes in systolic or diastolic blood pressure, heart rate, or ECG parameters (RR, PR, QRS, or QTcF) were observed when comparing baseline vs. post-dose time-points or in-between groups. No significant changes were seen for adjusted QTcF (baseline subtracted and placebo and baseline subtracted). No significant differences or relevant abnormalities were seen when comparing parameters obtained at Tmax vs. any other time-point. CONCLUSION: Sustained CGRP inhibition was not associated with hemodynamic or ECG changes in a population at an increased age risk for cardiovascular events.

Safety and tolerability of LBR-101, a humanized monoclonal antibody that blocks the binding of CGRP to its receptor: Results of the Phase 1 program.

BACKGROUND: LBR-101 is a fully humanized monoclonal antibody that binds to calcitonin gene-related peptide. OBJECTIVE: The objective of this article is to characterize the safety and tolerability of LBR-101 when administered intravenously to healthy volunteers, by presenting the pooled results of the Phase 1 program. METHODS: LBR-101 was administered to 94 subjects, while 45 received placebo. Doses ranged from 0.2 mg to 2000 mg given once (Day 1), as a single IV infusion, or up to 300 mg given twice (Day 1 and Day 14). RESULTS: Subjects receiving placebo reported an average of 1.3 treatment-emerging adverse events vs 1.4 per subject among those receiving any dose of LBR-101, and 1.6 in those receiving 1000 mg or higher. Treatment-related adverse events occurred in 21.2% of subjects receiving LBR-101, compared to 17.7% in those receiving placebo. LBR-101 was not associated with any clinically relevant patterns of change in vital signs, ECG parameters, or laboratory findings. The only serious adverse event consisted of "thoracic aortic aneurysm" in a participant later found to have an unreported history of Ehlers-Danlos syndrome. CONCLUSION: Single IV doses of LBR-101 ranging from 0.2 mg up to 2000 mg and multiple IV doses up to 300 mg were well tolerated. Overt safety concerns have not emerged. A maximally tolerated dose has not been identified.

Association between tension-type headache and migraine with sleep bruxism: a systematic review.

AIM: To evaluate the association between tension-type headache and migraine with sleep bruxism (SB). BACKGROUND: The association between SB and headaches has been discussed in both children and adults. Although several studies suggested a possible association, no systematic analysis of the available published studies exists to evaluate the quantity, quality, and risk of bias among those studies. METHODS: A systematic review was undertaken, including articles that classified the headaches according to the International Classification of Headache Disorders and SB according to the criteria of the American Association of Sleep Medicine. Only articles in which the objective was to investigate the association between primary headaches (tension-type and migraine) and SB were selected. Detailed individual search strategies for The Cochrane Library, MEDLINE, EMBASE, PubMed, and LILACS were developed. The reference lists from selected articles were also checked. A partial grey literature search was taken by using Google Scholar. The methodology of selected studies was evaluated using the quality in prognosis studies tool. RESULTS: Of 449 identified citations, only 2 studies, both studying adults, fulfilled the inclusion criteria. The presence of SB significantly increased the odds (study 1: odds ratio [OR] 3.12 [1.25-7.7] and study 2: OR 3.8; 1.83-7.84) for headaches, although studies reported different headache type. CONCLUSION: There is not enough scientific evidence to either support or refute the association between tension-type headache and migraine with SB in children. Adults with SB appear to be more likely to have headache.