Background: Seizures in childhood absence epilepsy (CAE) are typically easily controlled with anti-seizure medications (ASMs). Factors predictive of treatment resistance remain unclear. Our objectives were to assess prevalence of neuropsychiatric problems and factors influencing treatment resistance in a cohort of CAE at a single centre. Methods: We retrospectively reviewed patients with CAE diagnosed between January 1999 and December 2016 with at least 1-year follow-up. Treatment resistance was defined as failure to respond to two appropriate ASMs. Exclusion criteria included eyelid myoclonia with absence, myoclonic absence, and generalized tonic-clonic (GTC) seizures prior to absence seizures. Results: The study population comprised 164 patients (65 males) with mean age at seizures onset of 6.1years. 21% had treatment-resistant seizures. The first ASM was Ethosuximide (63.4%), Valproic acid (23.2%), and Lamotrigine (6.7%). 32.9% of children had learning disabilities, 28.7% ADHD, and 12.8 % anxiety.

A stepwise binary logistic regression analysis identified GTC seizures, learning disability (LD) and ongoing general spike and wave on EEG as predictors of treatment resistance. At last follow-up (average of 5.4 years), 43.3% of children were seizure-free off ASMs. Conclusions: 21% of children with CAE had treatment-resistant seizures. LD, GTC and failure of normalization of the EEG were associated with treatment resistance.

Background: Greater variability of neuronal signalling, measured as the standard deviation of the blood oxygen dependent signal (BOLDSD), relates to information processing capacity. Resting-state functional magnetic resonance imaging was used to determine differences in BOLDSD between children with and without epilepsy. Methods: We studied 24 controls (mean age 8.52 ± 1.35 years) and 18 patients (mean age 11.5 ± 3.4 years) with medically refractory epilepsy that underwent imaging for preoperative planning.Standard preprocessing steps (FSL v6.0, FMRIB) were followed and AAL atlas was used. Whole-brain two sample t-tests were used for group comparisons and significance was set at p <0.05 FDR-corrected. Results: Children with epilepsy showed significantly lower BOLDSD in left inferior and middle temporal gyri (p < 0.001), right caudate nucleus (p < 0.01), cuneus (p < 0.001), and fusiform gyrus (p < 0.001), and significantly increased BOLDSD bilaterally in inferior occipital gyri (p < 0.0001). There were no significant differences when comparing whole-brain BOLDSD values. Conclusions: Neuroplastic changes in epilepsy may depend on an optimal amount of internal neural variability driven by the identified key regions. Certain temporal and occipital regions may underlie neural processing differences in children with epilepsy. Further studies may correlate these findings with behavioral testing.

Background: Effort mobilization is important in older adults to stay healthy, notably for decision-making. The process of decreasing subjective value of a reward as required effort increases is called effort discounting. By identifying underlying neural correlates related to effort discounting, we can better understand factors affecting normal cognitive aging. Methods: We acquired resting-state functional magnetic resonance images from 19 cognitively normal older adults (10 males; 66±6 years). Participants completed a computerized cognitive task—called Effort Expenditure for Rewards Task—capturing the willingness to expend effort for rewards through binary choices between high-reward-high-effort or low-reward-low-effort option to obtain varying monetary rewards. We modelled subjective value to assess the k parameter, effort discounting. A functional connectivity analysis examined the involvement of regions associated to the salience network. Results: The seed-to-voxel analysis revealed increased connectivity within the precuneus cortex and to clusters in the right temporal and posterior cingulate gyri, with increased k-value or decreased willingness to expend effort. There was also decreased connectivity between the anterior cingulate and right lateral occipital cortex, and between the left anterior insula to the cerebellum and precuneus cortex. Conclusions: The process of effort discounting is correlated to functional connectivity changes involving the precuneus, anterior cingulate, and left anterior insula in healthy older adults.

Background: Eye movements reveal neurodegenerative disease processes due to overlap between oculomotor circuitry and disease-affected areas. Characterizing oculomotor behaviour in context of cognitive function may enhance disease diagnosis and monitoring. We therefore aimed to quantify cognitive impairment in neurodegenerative disease using saccade behaviour and neuropsychology. Methods: The Ontario Neurodegenerative Disease Research Initiative recruited individuals with neurodegenerative disease: one of Alzheimer’s disease, mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, or cerebrovascular disease. Patients (n=450, age 40-87) and healthy controls (n=149, age 42-87) completed a randomly interleaved pro- and anti-saccade task (IPAST) while their eyes were tracked. We explored the relationships of saccade parameters (e.g. task errors, reaction times) to one another and to cognitive domain-specific neuropsychological test scores (e.g. executive function, memory). Results: Task performance worsened with cognitive impairment across multiple diseases. Subsets of saccade parameters were interrelated and also differentially related to neuropsychology-based cognitive domain scores (e.g. antisaccade errors and reaction time associated with executive function). Conclusions: IPAST detects global cognitive impairment across neurodegenerative diseases. Subsets of parameters associate with one another, suggesting disparate underlying circuitry, and with different cognitive domains. This may have implications for use of IPAST as a cognitive screening tool in neurodegenerative disease.

Background: The advent of real-time quaking-induced conversion (RT-QuIC) assays has transformed the diagnostic approach to sporadic Creutzfeldt-Jakob disease (CJD) facilitating earlier recognition of affected patients. Recognizing this, we evaluated the performance of clinical features and diagnostic tests for CJD in the modern era. Methods: Clinical data were extracted from the electronic medical records of 115 patients with probable or definite CJD assessed at Mayo Clinic from 2014-2021. Clinical features and diagnostic tests were evaluated at presentation, and associations with diagnosis and prognosis determined. Results: Mean age-at-symptom onset was 64.8±9.4 years; 68 patients were female (59%). The sensitivity of clinical markers (myoclonus) and tests historically considered in patients with suspected CJD was poor (stereotyped EEG abnormalities, 16%; CSF 14-3-3, 60%). Conversely, RT-QuIC (93%), t-tau >1149 pg/mL (88%), and characteristic signal abnormalities on MRI (77%) identified most patients. Multivariable linear regression confirmed shorter days-to-death in patients with myoclonus (125.9, CI95% 23.3-15.5, p=0.026), visual/cerebellar signs (180.19, CI95% 282.2-78.2, p<0.001), positive 14-3-3 (193, CI95% 304.9-82.9; p<0.001), and elevated t-tau (9.0, CI95% 1.0-18.0, for every 1000 pg/ml elevation; p=0.041). Conclusions: CSF RT-QuIC and elevated t-tau, and stereotyped MRI abnormalities were consistently detected in CJD patients. Myoclonus, EEG findings, and CSF protein 14-3-3 were less useful in the modern era.

Background: A clear understanding of the neuropathological causes of RPD is needed to inform the diagnosis and treatment of patients with rapidly progressive dementia (RPD). Methods: Patients with <4.0 years from symptom onset to death were identified within the Mayo Clinic Neurodegenerative Brain Bank (1998-2020). Relevant clinical details were extracted from available records. Neuropathological diagnoses were assigned following standard protocols. Results: 310/8586 (3.6%) cases met RPD criteria. Relative to typically progressive cases, prion disease most commonly presented as RPD (74%, 32/43), followed by progressive supranuclear palsy/corticobasal degeneration (PSP/CBD: 7.5%, 142/1894), other frontotemporal lobar degeneration (FTLD: 5.7%, 32/561), Lewy body disease (LBD: 4.1%, 49/1202), and Alzheimer disease (AD: 1.8%, 48/2687). Average age-at-symptom onset was 69.5±10.4 years. Average disease duration was 2.9±1.0 years. Prion diseases had the most rapid disease course (1.6±1.3 years). Comorbid cerebrovascular disease (25.5%), and clinically symptomatic depression (41.3%), psychoses (37.1%), and sleep disturbances (39.4%) were common across groups. Only psychosis was associated with shorter disease duration (β=-0.31 years, CI95% -0.53, -0.082, controlling for age-at-symptomatic onset). Conclusions: Although prion disease commonly presented as RPD, atypical presentations of more prevalent neurodegenerative diseases accounted for most cases of RPD. Rapidly progressive variants of typical neurodegenerative diseases warrant consideration in clinical practice.

Background: Accurate etiologic diagnoses are needed in patients with rapidly progressive dementia (RPD) to ensure access to symptomatic and disease-modifying therapies when available. Methods: Patients with RPD were prospectively enrolled and evaluated at Washington University (Saint Louis, MO; 2016-2019) and Mayo Clinic (Jacksonville, FL; 2020-2021). Etiologic diagnoses were independently assigned by two dementia specialists integrating clinical features and the results of diagnostic tests; disagreements were resolved via blinded review by a third specialist. Results: 160 RPD patients were enrolled and followed. Average age-at-symptom onset was 60.0±15.9 years; 50% were female. Inter-rater reliability (91% agreement; Cohen’s κ=0.88, p<0.001) and clinicopathologic correlation were excellent (100% agreement in 24 patients with neuropathologic data). Autoimmune encephalitis was the leading cause of RPD (39%), followed by Alzheimer disease and related dementias (29%), Creutzfeldt-Jakob disease (15%), and other causes (15%). Patients with potentially treatable causes of RPD were younger (54.5±18.2 than those with neurodegenerative causes (67.3±9.5; p<0.001), and more likely to present with altered levels of consciousness, seizures, or CSF pleocytosis (p<0.05). Conclusions: Etiologic diagnoses can be reliably established in RPD patients using available clinical data. The prevalence of autoimmune encephalitis in this series justifies routine screening for potentially treatment-responsive causes of RPD, particularly in younger patients.

Background: Temporal lobe epilepsy (TLE) has been redefined as a disorder associated with network-level dysfunction not limited to the epileptic zone. As such, as resting state (rs) fMRI has been used to evaluate the implicated resting state networks (RSN) and their ensuing functional impairments. However, few studies have analyzed patients with (TLE-HS) and without (TLE-nonHS) hippocampal sclerosis independently. Whereas TLE-HS often warrants surgical intervention, drug-resistant TLE-nonHS might pose challenges for diagnosis and treatment decisions. Methods: This study aimed to investigate functional connectivity changes (FC) of RSNs beyond the hippocampus using rs-fMRI. Rs-fMRI data was acquired from 16 TLE-HS and nine TLE-nonHS, along with 25 healthy controls (HC). RSNs were established using a data-driven independent component analysis approach, in order to determine significant connections between HC and patient groups ipsilateral and contralateral to the seizure focus. Results: When comparing TLE-HS to HC, FC changes were found for the dorsal-attentional (DAN), visual, fronto-parietal (FPN), sensorimotor and default-mode networks (DMN). Alterations in the DAN, DMN and FPN were found when comparing TLE-nonHS to HC. Conclusions: This study demonstrated widespread network reorganization across TLE subtypes. These FC patterns hold promise as a prognostic biomarker, and may be used to define subsequent function and dysfunction in this patient population.

Background: In Canada, approximately 300,000 women with epilepsy (WWE) are of childbearing potential. Given the unique aspects of providing care for WWE, our objective was to gather demographic and practice characteristics of health care professionals providing care for WWE to identify potential gaps. Methods: We developed a questionnaire to understand the demographic and practice characteristics of professionals providing care for WWE. We invited all French and English practitioners (physicians, physician assistants and nurse practitioners), recruited through the Canadian League Against Epilepsy (CLAE), Canadian Neurological Sciences Federation (CNSF) and Canadian Epilepsy nursing Group (CENG), to complete our online questionnaire. Results: Preliminary data show 43% were between 32-40 years of age and 76% were medical doctors. Sixty-three percent had been in practice for less than 20 years; 81% considered themselves epilepsy specialists and 66% devoted their practice entirely to epilepsy patients and 78% practiced exclusively in academic centers. Conclusions: Our data shows providers involved in the care of women with epilepsy in Canada are predominantly academic experts in epilepsy. Potential gaps in care include mid-late career physicians, non-specialized health care practitioners, and community-based practices, as less likely to provide care for WWE. This snapshot may provide future insights to the unmet needs of WWE Canada.

Background: The electroencephalography (EEG) pattern extreme delta brush (EDB) is felt to be highly specific for anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. This study aimed to characterize EEG findings in anti-NMDAR encephalitis patients looking for the proportion of abnormal EEGs, presence of EDB, and to relate EDB to clinical outcomes (Glasgow Outcomes Scale (GOS) at 6 months, need for ICU admission, and death). Methods: This retrospective single centre study included anti-NMDAR encephalitis patients who had ≥1 EEGs obtained from 2014-2021. EEGs were retrospectively analyzed by 2 reviewers. Clinical outcomes of interest were extracted through hospital and clinic chart review. Results: Twenty-one patients with anti-NMDAR encephalitis were included. Sixty-four EEGs were analyzed. Four EEGs (6.3%) were within normal limits. Focal or generalized slowing (without EDB) was seen on 44 EEGs (68.8%). EDB was seen on 16 EEGs (25.0%) in 9 of 21 patients. The presence of EDB was significantly associated with need for ICU admission (p=0.02), poorer outcome at 6 months as per the GOS (p=0.002), and with death (p=0.02) Conclusions: The presence of EDB on EEG in anti-NMDAR encephalitis patients is associated with increased need for ICU admission, risk of death, and worse functional outcomes at 6 months.

Background: Cortical electrical stimulation (CES) may produce different motor responses according to the brain area stimulated. In this study, we describe a new motor response characterized by finger movements such as a person playing piano, which we named the Piano Player Hand (PPH) sign. Methods: We retrospectively reviewed the CES results of 252 patients with drug-resistant epilepsy who underwent SEEG between January 2005 and December 2019 at the Grenoble-Alpes University Hospital. The patients’ characteristics, SEEG findings and CES parameters were extracted to find common clinical and anatomical features. Results: The PPH sign was identified 20 times from 12 patients, with stimulation of either the supplementary motor area (SMA), anterior cingulate gyrus (ACG), pre-SMA, middle frontal gyrus and anterior insula. It was obtained with high frequency stimulation, with intensity ranging from 0,7 to 3mA and mostly contralateral to the stimulation side (19/20). It was part of the ictal semiology of five patients. An afterdischarge was observed in five of the relevant CES. Conclusions: The PPH sign is a novel clinical sign, obtained mainly, but not exclusively, with CES of a small vicinity encompassing the SMA, pre-SMA and ACG. The PPH sign, when occurring ictally, may point to the premotor mesial frontal surface of the brain.

Background: New-onset refractory status epilepticus (NORSE) is a rare clinical presentation affecting previously healthy individuals. Febrile infection-related epilepsy syndrome (FIRES) is a subcategory of NORSE and applies when a preceding fever occurs. The NORSE/FIRES Family Registry has been developed to gain insight into risk factors and to assess the spectrum of clinical outcomes amongst survivors. Methods: Survivors, surrogates, and physicians can enter patient data into the REDCap-based registry: https://www.norseinstitute.org/norse-registry-2. Information collected includes medical history, clinical presentation, and quality of life, among others. Participants are invited to complete follow-up surveys for up to two years following presentation of seizures. Enrollment is ongoing in multiple languages. Results: 56 participants are enrolled from 12 countries (2-78 years, median: 12.5, IQR: 20.5, 31 survivors). At ≥6 months after onset, survivors experience a mean of ≥12 seizures per month and remain on a median of 4 (IQR: 3) anti-seizure medications. The median quality of life amongst all survivors was rated 4/10 (IQR: 3.5). Conclusions: Preliminary data suggests that survivors of NORSE/FIRES have a high seizure burden and poor quality of life. This international multi-lingual family registry will help develop hypotheses for future studies and provides an opportunity for families to contribute to the scientific understanding of this disease.

Background: Drug resistant epilepsy is present in nearly 30% of patients. Resection of the epileptogenic zone has been found to be the most effective in achieving seizure freedom. The study of temporal lobe epilepsy for surgical treatment is extensive and complex. It involves a multidisciplinary team in decision-making with initial non-invasive studies (Phase I), providing 70% of required information to elaborate a hypothesis and treatment plans. Select cases present more complexity involving bilateral clinical or electrographic manifestations, have contradicting information or may involve deeper structures as a part of the epileptogenic zone. Methods: A review of the literature was done with key terms such as: “temporal lobe epilepsy”and “SEEG”and “intracranial EEG”, “epilepsy surgery”, un Pubmed, EMBASE, Medlink and Scielo. Most cutting edge, controversial subjects surrounding this field were considered. Results: In this comprehensive review, we explore the indications, usefulness, discoveries in interictal and ictal findings, pitfalls, and advances in the science of presurgical stereo-encephalography for temporal lobe epilepsy. Conclusions: Intracranial recording follows original concepts since its development by Bancaud and Talairach, but great advances have been made in the field. Stereo-electroencephalography is a growing field of study, treatment and establishment of seizure pattern complexities.

Background: In refractory epilepsy patients with possible autoimmune-associated epilepsy (AAE) but negative antibody testing(-AB), immunotherapy trials (IMT) may still be pursued.The value of (IMT) in such patients remains unclear. For this reason, we reviewed their immunotherapy responses. Methods: Retrospective review of epilepsy patients admitted to the Epilepsy Unit between (2018-2021) who received (IMT). All had (-AB) and received immunotherapy (methylprednisolone (IVMP)-immune globulin (IVIg)-plasma exchange (PLEX)- rituximab).We considered responders when their seizure reduction was ≥ 50%. Results: 14 patients identified. Of them, 50%(n=7) females. Median age (43.5 year. IQR= 28.75-63.25). All refractory to ≥ 2 anti-seizure medications (ASM). Median epilepsy onset was (39.5 years. IQR=23.75-60.25).Median time from diagnosis until received immunotherapy was (15.5 months. IQR=12.75 -21.75). Patients received either IVIG+IVMP (35.7%, n=5) or IVIG alone (28.5%, n=4) or IVIG+IVMP+PLEX (21.4%, n=3) or IVMP alone (7.1%, n=1) or IVIG+IVMP+rituximab (7.1%, n=1). Median follow-up was 25 months.Although early immunotherapy responses were common, sustained response to immunotherapy at last follow-up was only in 21.4% (n=3). Factors confounding determination of immunotherapy efficacy were present in all responders (e.g:concurrent changes in ASM). Conclusions: Our findings suggest that (IMT) in patients with suspected (AAE) but with (-AB) are largely unsuccessful. This suggests an insufficient therapeutic effect after (IMT) or alternatively,non-immune-mediated mechanisms causing this type of epilepsy. Critical evaluations of (IMT)in such cases are needed.

Background: In phase 3 ADVANCE, atogepant 60mg reduced mean monthly migraine days (MMDs) from 7.8 days (baseline) to 3.0 (weeks 9-12; Δ=−4.7) in the overall episodic migraine population [treatment responders and nonresponders (i.e., marked benefit and minimal benefit)], which obscures information regarding magnitude of treatment effect in these populations. Here, magnitude of treatment effect in atogepant responders and nonresponders is characterized. Methods: Mean MMDs, acute medication use-days (MUDs), and Migraine-Specific Quality of Life-Role Function-Restrictive (MSQ-RFR) scores were calculated in treatment responders (based on MMD percentage reduction) and nonresponders from ADVANCE participants. Results: From baseline to weeks 9-12, ≥50% improvement was achieved by 71% (139/195) of participants. In these responders, MMDs reduced from 7.6 to 1.3 (Δ=−6.3). 50% (97/195) of participants achieved ≥75% response. In this group, MMDs reduced from 7.7 to 0.6 (Δ=−7.1). Atogepant 60mg nonresponders (<25% reduction in MMDs; 15% [30/195 participants]) showed MMD change from 7.7 to 9.1 (Δ=+1.4). Acute MUDs in ≥50% MMD responders decreased 7.1 to 1.6 (Δ=−5.5). In treatment-nonresponders, acute MUDs were 7.3 (baseline) and 7.2 (weeks 9-12; Δ=−0.1). Similar mean MSQ-RFR score changes were observed in both populations. Conclusions: Of participants who experienced ≥50% reduction in MMDs, 71% had substantial treatment effect (ΔMMD=−6.3), representing 83% reduction in MMDs.

Background: To examine changes in the occurrence, severity, and symptoms of headache episodes in patients with chronic migraine (CM) following eptinezumab treatment. Methods: PROMISE-2 (NCT02974153) was a double-blind, placebo-controlled, parallel-group trial that randomized adults with CM to eptinezumab 100 mg, 300 mg, or placebo IV every 12 weeks for up to 24 weeks (2 infusions). Headache episodes (migraine and non-migraine) and their characteristics were reported in daily electronic diaries during the 28-day baseline period and throughout the 24-week treatment period. Results: A total of 1072 patients were included. Patients reported a mean of 20.4–20.6 monthly headache days during baseline across treatment groups. Mean monthly headache days decreased by 8.9 (100 mg) and 9.7 (300 mg) with eptinezumab versus 7.3 with placebo over weeks 1-24. Mean monthly headache episodes also decreased by 8.4 (100 mg) and 9.0 (300 mg) compared to 7.1 with placebo over weeks 1-24. Among headaches occurring post-treatment, decreases in severe pain, nausea, phonophobia, photophobia, and physical activity limitations were numerically greater than placebo. Conclusions: In patients with CM, eptinezumab numerically decreased the frequency and severity of monthly headache days and episodes more than placebo. Patients treated with eptinezumab reported a decrease in burdensome symptoms of headache episodes.

Background: Patients administered eptinezumab during an active migraine had larger numerical improvement in the 6-item Migraine Treatment Optimization Questionnaire (mTOQ-6) total score compared to placebo. The mTOQ-6 was used to determine success of acute treatment. Methods: RELIEF (NCT04152083) was a double-blind trial that randomized adults eligible for preventive migraine treatment to eptinezumab 100mg or placebo, administered intravenously within 1–6 hours of migraine onset. mTOQ-6 was captured at baseline and Week 4 and rescored into mTOQ-4. Patients were grouped by baseline mTOQ-4 total scores. Results: 226 eptinezumab-treated and 232 placebo patients were included. The percentage of patients in the combined very poor and poor optimization subgroups at baseline with eptinezumab (n=155; 68.6%) versus placebo (n=138; 59.5%) decreased by 26.6 percentage points (n=95; 42.0%) and 9.9 percentage points (n=115; 49.6%), respectively, at Week 4. Of the 155 eptinezumab-treated and 138 placebo patients who were very poorly/poorly optimized at baseline, 73 (47.1%) versus 35 (25.4%) were moderately/maximally optimized at Week 4, respectively. Greater improvements in mTOQ-6 scores were noted in patients more poorly optimized at baseline than those more optimized. Conclusions: Eptinezumab showed greater acute migraine medication optimization and decreased headache-related impact compared to placebo, suggesting that eptinezumab may work synergistically with acute medications.

Background: As the second leading cause of years lived with disability in the world, and the first in people under 50, migraine represents a major burden to healthcare systems. This study examined treatment patterns and healthcare resource utilization (HRU) in patients with migraine using real-world data from Alberta. Methods: This was a retrospective cohort study of patients with ≥1 ICD-9-CM/ICD-10-CA code for migraine or ≥1 prescription for a triptan from April 1st, 2012 to March 31st, 2018. Descriptive statistics were used to characterize the study outcomes. Results: The incidence of migraine exceeded 1,000 cases per 100,000 person-years over the study period. The mean age of the cohort (n=199,931) was 40.0, and 72.3% were women. Migraine-related HRU accounted for 3%-10% of all HRU across endpoints (e.g., ED visits, hospitalization, physician visits). One-third of the cohort were prescribed acute medications (non-steroidal anti-inflammatories, triptans or other (including opioids)), whereas fewer than one-fifth were prescribed at least one migraine preventive such as tricyclic anti-depressants (proportion: 15%), anti-convulsants (13%), beta-blockers (7%), or neurotoxins (4%). Conclusions: The low medication prescription rates and high HRU indicates the potential unmet need and high disability in patients with migraine. The impact of migraine treatment patterns on HRU is an avenue for future research.

Background: Typical migraine clinical trial endpoints assess only ictal burden. Methods: Adults (N=462) with episodic or chronic migraine with previous failure of 2-4 preventive medication categories were randomized 1:1 to 3-month double-blind treatment with placebo or galcanezumab 120mg. Primary endpoint was mean change from baseline in monthly migraine headache days. Migraine Interictal Burden Scale-4 (MIBS-4) measured migraine-related burden on non-headache days for past 4 weeks (0=no burden, 1-2=mild, 3-4=moderate, 5-12=severe). Migraine Disability Assessment (MIDAS), Migraine-Specific Quality of Life Questionnaire (MSQ), Patient Global Impression-Severity (PGI-S), depression (Patient Health Questionaire-9 [PHQ-9]), and anxiety (Generalized Anxiety Disorder Scale [GAD-7]) were assessed. Relationships among measures were assessed at baseline using Spearman’s rank correlation coefficient. Results: MIBS-4 was moderately correlated with PHQ-9 (r=.55) and MSQ total (r=−.53). Other correlations with MIBS-4 were low (GAD-7, r=0.42; MIDAS, r=0.41; PGI-S, r=0.32) or negligible (migraine headache days, r=0.22). After 3 months, from a mean baseline of 13.2 monthly migraine headache days, galcanezumab patients improved by 4.4 vs 1.3 days for placebo (p<.0001). From mean MIBS-4 baseline of 5.5, galcanezumab patients improved by 1.8 vs 0.8 points for placebo (p<.0001). Conclusions: Galcanezumab significantly reduced ictal and interictal burden of migraine. Results suggest interictal burden is a distinct effect of the disease.

Background: A phase 3 trial, ADVANCE (NCT03777059), demonstrated that atogepant, an oral, CGRP receptor antagonist dosed once daily, results in clinically meaningful reductions in mean monthly migraine days. This open-label extension for ADVANCE trial completers evaluated long-term safety and tolerability of atogepant over 40-weeks. Methods: Participants in this trial (NCT03939312), rolled over from the ADVANCE trial, were treated with atogepant 60mg once daily for 40-weeks, with a 4-week safety follow-up. Only safety data were collected. Results: 685 participants took at least one dose of study drug, 74.6% completed the 40-week treatment period; mean age of 41.8 years, 88.2% female, 84.4% white, and mean BMI of 30.58 kg/m2. Mean (SD) treatment duration was 233.6 (89.32) days. 62.5% of participants experienced a treatment-emergent adverse event (TEAE), with 8.8% considered treatment-related by the investigator; serious adverse events (SAEs) occurred in 3.4% of participants, none were treatment-related. The most frequent AEs leading to discontinuation was nausea (0.4%, n=3); the most frequent TEAEs observed included upper respiratory tract infection (5.5%, n=38) and urinary tract infection (5.3%, n=36). No deaths or hepatic safety issues were observed. Conclusions: Safety results are consistent with known safety profile of atogepant and support long-term safety and tolerability of once daily dosing of atogepant 60mg.