Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:Trigeminal neuralgia (TN) and trigeminal autonomic cephalalgias (TACs) are both painful diseases which directly impact the branches of the trigeminal nerve, which supply the face. Patients who have experienced adverse effects, have not responded to mainstream treatments, or have a personal preference for nonmedication options, often turn to complementary and integrative medicine (CIM). The aim of this review is to discuss the efficacy and safety of CIM therapies available for the treatment of TN and TACs. RECENT FINDINGS/RESULTS:Not only are there limited therapeutic options for TN and TAC patients, but also is there a proportion of patients who are intolerant to standard medical treatments. Recent findings have illustrated that 86% of patients with headache disorders utilize CIM modalities in combination with mainstream medical therapy. CIM modalities can be helpful for these diseases and have primarily been studied in combination with standard medical therapy. There is limited evidence for CIM and behavioral therapies in managing these conditions, and more research is needed to confirm which therapies are safe and effective.

BACKGROUND:Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, including the fully humanized monoclonal antibody (IgG2Δa) fremanezumab, have demonstrated safety and efficacy for migraine prevention. Clinical trials include responders and nonresponders; efficacy outcomes describe mean values across both groups and thus provide little insight into the clinical benefit in responders. Clinicians and their patients want to understand the extent of clinical improvement in patients who respond. This post hoc analysis of fremanezumab treatment attempts to answer this question: what is the benefit in subjects who responded to treatment during the two, phase 3 HALO clinical trials? METHODS:We included subjects with episodic migraine (EM) or chronic migraine (CM) who received fremanezumab quarterly (675 mg/placebo/placebo) or monthly (EM: 225 mg/225 mg/225 mg; CM: 675 mg/225 mg/225 mg) during the 12-week randomized, double-blind, placebo-controlled HALO EM and HALO CM clinical trials. EM and CM responders were defined as participants with a reduction of ≥ 2 or ≥ 4 monthly migraine days, respectively. Treatment benefits evaluated included reductions in monthly migraine days, acute headache medication use, and headache-related disability, and changes in health-related quality of life (HRQoL). RESULTS:Overall, 857 participants from the HALO trials were identified as responders (EM: 429 [73.8%]; CM: 428 [56.7%]). Reductions in the monthly average number of migraine days were greater among EM (quarterly: 5.4 days; monthly: 5.5 days) and CM (quarterly: 8.7 days; monthly: 9.1 days) responders compared with the overall population. The proportion of participants achieving ≥ 50% reduction in the average monthly number of migraine days was also greater in responders (EM: quarterly, 59.8%; monthly, 63.7%; CM: quarterly, 52.8%; monthly, 59.0%) than in the overall population. Greater reductions in the average number of days of acute headache medication use, greater reductions in headache-related disability scores, and larger improvements in HRQoL were observed among EM and CM responders compared with the overall populations. CONCLUSIONS:Fremanezumab responders achieved clinically meaningful improvements in all outcomes. The magnitude of improvements with fremanezumab across efficacy outcomes was far greater in responders than in the overall trial population, providing insight into expected treatment benefits in participants who respond to fremanezumab in clinical practice. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov identifiers: NCT02629861 (HALO EM) and NCT02621931 (HALO CM).

Introduction: The FOCUS study of fremanezumab, a fullyhumanized monoclonal antibody (IgG2DELTAa) that selectively targets calcitonin gene-related peptide (CGRP), was the first and largest study of a migraine preventive treatment in adults with both chronic and episodic migraine (CM and EM) and documented inadequate response to 2-4 classes of migraine preventive medications. Efficacy in a subgroup of patients with medication overuse (use of any acute medication on >=15 days/month or triptans/ergots/combination medications on >=10 days/month) at baseline was evaluated.
Method(s): Patients were randomized (1:1:1) to quarterly fremanezumab (Month 1: 675mg; Month 2 and 3: placebo), monthly fremanezumab (Month 1: CM, 675mg; EM, 225mg; Month 2 and 3: 225mg), or matched monthly placebo for 12 weeks. Changes from baseline in monthly migraine days and headache days of at least moderate severity at 4 weeks and during 12 weeks of treatment were compared using a mixed-effect model for repeated measures.
Result(s): Of 838 randomized patients, 427 had medication overuse. Treatment with quarterly and monthly fremanezumab versus placebo resulted in significantly greater reductions from baseline in the monthly average number of migraine days at 4 weeks (least-squares mean [SE] change from baseline, -3.7 [0.62] and -4.5 [0.57] vs -0.0 [0.62]; P<0.0001) and over 12 weeks (-3.3 [0.62] and -4.5 [0.57] vs -0.5 (0.62); P<0.0001). With quarterly and monthly fremanezumab versus placebo, significant reductions from baseline were also observed in the monthly average number of headache days of at least moderate severity at 4 weeks (-4.3 [0.62] and -5.1 [0.56] vs -0.2 [0.62]; P<0.0001) and over 12 weeks (-4.0 [0.62] and -5.0 [0.56] vs -0.8 [0.62]; P<0.0001).
Conclusion(s): Quarterly and monthly fremanezumab provided early and sustained reductions in migraine and headache days vs placebo in patients with medication overuse and documented inadequate response to 2-4 classes of migraine preventive medications

Purpose Patients who overuse acute medicationsfor migraine generally experience more migraine days, greater disability, and more severe pain intensity. The FOCUS study of fremanezumab, a fully-humanized monoclonal antibody (IgG2DELTAa) that selectively targets calcitonin gene-related peptide (CGRP), was the first and largest study of a migraine preventive treatment in adults with both chronic migraine (CM) and episodic migraine (EM) and documented inadequate response to 2 to 4 classes of migraine preventive medications.This subgroup analysis of the FOCUS study evaluated the efficacy of fremanezumab in patients with baseline medication overuse (use of any acute medication on >=15 days/month or use of triptans, ergots, or combination medications on >=10 days/month). Methods In the randomized, double-blind, placebo-controlled period of the phase 3b FOCUS study, patients were randomized (1:1:1) to quarterly fremanezumab (month 1: 675 mg; months 2 and 3: placebo), monthly fremanezumab (month 1: CM, 675 mg; EM, 225 mg; months 2 and 3: 225 mg), or matched monthly placebo for 12 weeks. Changes from baseline in the monthly average number of migraine days and monthly average number of headache days of at least moderate severity at 4 weeks and during 12 weeks of treatment were compared using a mixed-effect model for repeated measures. Results Of 838 randomized patients, 435 had baseline medication overuse. Reductions from baseline in the monthly averagenumber of migraine days were significantly greater with quarterly fremanezumab (least-squares mean [standard error (SE)] change, -3.3 [0.61]) and monthly fremanezumab (-4.6 [0.55]) versus placebo (-0.5 [0.62]; both P <= 0.0001) during 12 weeks of treatment. Reductions from baseline in the monthly average number of headache days of at least moderate severity were also significantly greater with quarterly fremanezumab (least-squares mean [SE] change, -4.0 [0.61]) and monthly fremanezumab (-5.1 [0.54]) versus placebo (-0.8, [0.61]; both P < 0.0001) during 12 weeks of treatment. At 4 weeks of double-blind treatment, changes from baseline in the monthly average number of migraine days and monthly average number of headache days of at least moderate severity were also significantly greater with both dosing regimens of fremanezumab versus placebo (all P < 0.0001). Conclusions Quarterly and monthly fremanezumab provided early and sustained reductions in monthly migraine and monthly headache days of at least moderate severity versus placebo in migraine patients with medication overuse and documented inadequate response to 2 to 4 classes of migraine preventive medications

Objective: The FOCUS study of fremanezumab, a fullyhumanised monoclonal antibody (IgG2DELTAa) that selectively targets calcitonin gene-related peptide (CGRP), was the first and largest study of a migraine preventive treatment in adults with both chronic and episodic migraine (CM and EM) and documented inadequate response to 2-4 classes of migraine preventive medications. Efficacy in a subgroup of patients with medication overuse (use of any acute medication on >=15 days/month or triptans/ergots/combination medications on >=10 days/month) at baseline (BL) was evaluated.
Method(s): Patients were randomised (1:1:1) to quarterly (qtly) fremanezumab (Month [Mo] 1: 675 mg; Mo 2 and 3: placebo), monthly (mthly) fremanezumab (Mo 1: CM, 675 mg; EM, 225 mg; Mo 2 and 3: 225 mg), or matched mthly placebo for 12 weeks. Changes from BL in mthly migraine days and headache days of at least moderate severity at 4 weeks and during 12 weeks of treatment were compared using a mixed-effect model for repeated measures.
Result(s): Of 838 randomised patients, 427 had medication overuse. Reductions from BL in mthly average migraine days and headache days of at least moderate severity at 4 weeks and during 12 weeks of treatment were significantly greater with both fremanezumab regimens vs placebo (all P<=0.0001; Table).
Conclusion(s): Qtly and mthly fremanezumab provided early and sustained reductions in migraine and headache days vs placebo in patients with medication overuse and documented inadequate response to 2-4 classes of migraine preventive medications. (Table Presented)

To gain insight into the specificity of cerebellar vermian abnormalities reported in autism, we conducted a magnetic resonance imaging (MRI) study of boys with either of two conditions associated with autism, Down syndrome and fragile X syndrome, compared with boys with idiopathic autism and controls. The subjects, ranging in age from 3 to 9 years, included 16 boys with Down syndrome + autism and 11 boys with Down syndrome only; 13 boys with fragile X syndrome + autism and 9 boys with fragile X syndrome only; 10 boys with idiopathic autism; and 22 controls. Diagnosis of autism was based on DSM-IV criteria, confirmed primarily by the Autism Diagnostic Interview. T1-weighted midsagittal MRIs were used to measure midline structures. Intracranial area, reflecting brain size, was significantly smaller in subjects with Down syndrome. Therefore, all vermian measures were expressed as ratios to intracranial area. Analysis of covariance (covarying for age and IQ) demonstrated that posterior vermi (lobules VI-VII and VIII-X) were markedly smaller in both Down syndrome groups and those with fragile X syndrome only, whereas only lobules VI-VII were reduced in idiopathic autism. Factorial analyses of variance tested interactions between autism factor and the diagnosis of Down syndrome or fragile X syndrome. The size of lobules VI-VII/intracranial area was dependent on autism status only in fragile X syndrome, with ratios significantly larger in fragile X syndrome with autism with respect to fragile X syndrome only. We conclude that selective posterior vermis hypoplasia is seen not only in idiopathic autism but also in Down syndrome and some individuals with fragile X syndrome. However, reductions in vermian lobules VI and VII appear to be specific to idiopathic autism, whereas increased size of lobules VI and VII is associated with autism in fragile X syndrome. The latter results are consistent with MRI studies showing lobules VI-VII hyperplasia in a subset of subjects with idiopathic autism and cerebral and hippocampal enlargements in fragile X syndrome.