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.

Is kinesiophobia related to fear of falling, dizziness disability, and migraine disability in patients with migraine?

INTRODUCTION: Kinesiophobia is a common symptom associated with high disability, and has been observed in patients with migraine. However, the association between kinesiophobia and clinical factors in this population is unknown. OBJECTIVE: To assess the fear of falling, dizziness disability, and migraine disability in patients with migraine, considering the presence of kinesiophobia. METHODS: Eighty patients with migraine completed the Tampa Scale for Kinesiophobia and were divided into two groups according to the questionnaire cutoff point: migraine without kinesiophobia (MoK, n = 39) and migraine with kinesiophobia (MK, n = 41). Fear of falling, dizziness disability, and migraine disability were assessed in both groups using validated questionnaires. RESULTS: The MK group presented higher scores on dizziness disability, fear of falling, and migraine disability compared to the MoK (p < .05). Kinesiophobia can explain 29% of the variance in dizziness disability and 18% of migraine disability. Both kinesiophobia and the presence of dizziness can explain 14% of fear of falling variability. Also, kinesiophobia is associated with the risk of presenting fear of falling (Prevalence Ratio = 2.4, p = .012), and migraine disability (Prevalence Ratio = 2.6, p = .01). CONCLUSION: The presence of kinesiophobia should be considered in clinical practice when evaluating migraine, as it is associated with increased levels of fear of falling, dizziness disability, and migraine disability.

Migraine With Aura Is Related to Delayed Motor Control Reaction and Imbalance Following External Perturbations.

Background: It is evidenced that migraineurs present balance deficits. However, the balance recovery following unexpected ground perturbations, which reflect conditions of everyday activities, has not been investigated in this population. Aim: We aimed to assess the reactive postural responses among patients with migraine with and without aura, chronic migraine, and controls. We further aimed to assess the factors associated with greater self-report of falls. Methods: Ninety patients diagnosed by headache specialists were equally classified into three migraine subgroups according to the presence of aura and chronic migraine. Thirty controls were also recruited. All participants underwent the motor control test (MCT) and adaptation test (ADT) protocols of dynamic posturography tests (EquiTest®, NeuroCom, USA). Clinical and headache features and information on falls in the previous year, fear of falling, and vestibular symptoms were also assessed. Results: Patients with aura presented a greater sway area in most of the MCT conditions than the other three groups (p = 0.001). The aura group also presented delayed latency responses after perturbations compared with controls and patients without aura (p < 0.03). In the ADT, a greater sway area was observed in patients with aura than in groups without aura, chronic migraine, and controls (p < 0.0001). The MCT and ADT sway area, the frequency of aura, and the fear of falling explained 46% of the falls in the previous 12 months. Conclusion: Patients with aura exhibited greater delay and sway area after unexpected ground perturbations than controls and other migraine subgroups, which are related to the reported number of falls.

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.

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.

Impact of chronic migraine attacks and their severity on the endogenous µ-opioid neurotransmission in the limbic system.

OBJECTIVE: To evaluate, in vivo, the impact of ongoing chronic migraine (CM) attacks on the endogenous µ-opioid neurotransmission. BACKGROUND: CM is associated with cognitive-emotional dysfunction. CM is commonly associated with frequent acute medication use, including opioids. METHODS: We scanned 15 migraine patients during the spontaneous headache attack (ictal phase): 7 individuals with CM and 8 with episodic migraine (EM), as well as 7 healthy controls (HC), using positron emission tomography (PET) with the selective µ-opioid receptor (µOR) radiotracer [11C]carfentanil. Migraineurs were scanned in two paradigms, one with thermal pain threshold challenge applied to the site of the headache, and one without thermal challenge. Multivariable analysis was performed between the µ-opioid receptor availability and the clinical data. RESULTS: µOR availability, measured with [11C]carfentanil nondisplaceable binding potential (BPND), in the left thalamus (P-value = 0.005) and left caudate (P-value = 0.003) were decreased in CM patients with thermal pain threshold during the ictal phase relative to HC. Lower µOR BPND in the right parahippocampal region (P-value = 0.001) and right amygdala (P-value = 0.002) were seen in CM relative to EM patients. Lower µOR BPND values indicate either a decrease in µOR concentration or an increase in endogenous µ-opioid release in CM patients. In the right amygdala, 71% of the overall variance in µOR BPND levels was explained by the type of migraine (CM vs. EM: partial-R2 = 0.47, P-value<0.001, Cohen's effect size d = 2.6SD), the severity of the attack (pain area and intensity number summation [P.A.I.N.S.]: partial-R2 = 0.16, P-value = 0.031), and the thermal pain threshold (allodynia: partial-R2 = 0.08). CONCLUSIONS: Increased endogenous µ-opioid receptor-mediated neurotransmission is seen in the limbic system of CM patients, especially in right amygdala, which is highly modulated by the attack frequency, pain severity, and sensitivity. This study demonstrates for the first time the negative impact of chronification and exacerbation of headache attacks on the endogenous µ-opioid mechanisms of migraine patients. ClinicalTrials.gov identifier: NCT03004313.

Fremanezumab as a preventive treatment for episodic and chronic migraine.

Introduction: The importance of calcitonin gene-related peptide (CGRP) in migraine pathogenesis is well established. Fremanezumab is a humanized IgG2a monoclonal antibody that binds to CGRP. Areas covered: In this paper, we review the development of fremanezumab, from early development into approval. The authors focus on the efficacy and safety of fremanezumab in both migraine stages. The authors highlight studies conducted in special populations and focus on unique aspects of its development, as well as on clinical pearls supported by the data. Expert opinion: Fremanezumab was shown to be effective in episodic and chronic migraine, with a monthly and quarterly dose of administration, as monotherapy and add-on therapy. As with other monoclonal antibodies, the anti-CGRP onset of action was remarkably quick, and the effect seems to be maintained over time. No overt safety concerns emerged from the clinical studies, although long-term surveillance is necessary.

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.

From LBR-101 to Fremanezumab for Migraine.

Calcitonin gene-related peptide (CGRP) is a neuropeptide of importance in migraine pathogenesis. Its central role in migraine was proven pharmacologically by the development of CGRP receptor antagonists. Monoclonal antibodies targeting CGRP or its receptor are effective in the preventive treatment of episodic and chronic migraine and are considered potential breakthroughs in their treatment. Fremanezumab (previously known as TEV-48125, LBR-101, or RN-307) is a humanized IgG2a monoclonal antibody that binds to CGRP. The development of this antibody validated the role of CGRP in chronic migraine and the drug has been recently approved in the US by the FDA, while it continues to be reviewed by other regulatory agencies. Herein we provide an in-depth review of its development. We start by summarizing its in vitro and in vivo pharmacology, and the phase I studies. We then review the late-stage clinical development, with a focus on its efficacy, safety, similarities, and uniqueness relative to other CGRP antibodies. We close by discussing lessons learned on the mechanisms of migraine and areas for future development and exploration.

Fremanezumab for preventive treatment of migraine: Functional status on headache-free days.

OBJECTIVE: To evaluate the effect of fremanezumab on the functional status on headache-free days in phase 2 episodic migraine (EM) and chronic migraine (CM) studies. METHODS: Functional status data were collected prospectively via the electronic headache diary on all headache-free days by patients answering questions regarding work/school/household chore performance, speed of work completion, concentration, and feeling of fatigue. Individuals with EM receiving monthly doses of fremanezumab 225 mg (n = 96) or 675 mg (n = 97) or placebo (n = 104) were compared. Individuals with CM receiving fremanezumab 675 mg followed by monthly 225 mg (n = 88) and 900 mg (n = 86) were also independently compared to those receiving placebo (n = 89). RESULTS: In patients with EM, compared to patients receiving placebo, those receiving fremanezumab experienced an increased number of headache-free days with normal function in work/school/household chore performance and concentration/mental fatigue measures compared to their baseline over the entire treatment period (all p < 0.005). An increased number of headache-free days with normal functional performance for some measures was also found in the CM group in those treated with fremanezumab. CONCLUSION: There was an increased number of headache-free days with normal functional performance on all measures for the patients with EM and some measures for patients with CM in the fremanezumab-treated groups. Further research is required to confirm these findings in a prospective study and to clarify the underlying mechanism(s). CLINICALTRIALSGOV IDENTIFIER: NCT02025556 and NCT02021773. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with migraine, fremanezumab increases normal functional performance on headache-free days.

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.

Functional Balance Deterioration on Daily Activities in Patients With Migraine: A Controlled Study.

OBJECTIVE: This study aimed to assess functional activities in different subgroups of patients with migraine. DESIGN: One-hundred forty subjects were uniformly divided into the following four groups: headache-free controls, migraine with aura, without aura, and chronic migraine. Subjects performed the tests walk across, tandem walk, sit to stand, and step up and over at the Balance Master system (Neurocom). RESULTS: All migraine groups had slower velocity and shorter step length at the walk across test (P < 0.0009). The step width was wider in migraine with aura and chronic migraine groups (P < 0.03). At the tandem walk test, patients with migraine exhibited slower velocity and wider step width (P < 0.03). All migraine groups were different than controls at weight transfer and rising index of the sit-to-stand test (P < 0.002). At the step-up-and-over test, there were differences in all outcomes of both legs between headache-free controls versus migraine groups (P < 0.02) and at one outcome between without aura versus migraine with aura (P < 0.01). Moderate to high effect sizes were found for all tests on at least two outcomes assessed, mostly between controls compared with migraine groups. CONCLUSIONS: Migraine is related to changes in the performance of functional tasks, suggesting early motor control deterioration. Proper balance assessment and rehabilitation strategies should be considered for these patients.

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 .).

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.

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.

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.