Background: To evaluate efficacy, safety, and tolerability of ubrogepant for acute treatment of migraine attacks. Methods: Multicenter, double-blind, phase 3 study (NCT02867709). Randomized patients (1:1:1, placebo or ubrogepant 25mg or 50mg) had 60 days to treat one migraine attack (moderate/severe pain intensity). Co-primary efficacy endpoints (2 hours post initial dose): headache pain freedom and absence of most bothersome migraine-associated symptom (MBS). Secondary endpoints: pain relief, sustained pain relief, sustained pain freedom, and absence of migraine-associated symptoms. Results: 1686 patients were randomized (safety population: n=1465; mITT population: n=1355). Mean age: 41 years; white: 81%; female: 89%. Significantly greater proportions of ubrogepant- than placebo-treated patients achieved 2-hour pain freedom (placebo: 14.3%; 25mg: 20.7%, adjusted P=0.0285; 50mg: 21.8%, adjusted P=0.0129) and absence of MBS for 50mg (placebo: 27.4%; 50mg: 38.9%, adjusted P=0.0129). Secondary endpoints (except absence of nausea at 2h) met statistical significance versus placebo for ubrogepant 50mg. Absence of MBS and secondary outcomes were not significant for 25mg after multiplicity adjustment. Ubrogepant’s and placebo’s AE profiles were similar. Conclusions: Co-primary endpoints were met for ubrogepant 50mg. Ubrogepant 25mg was significantly superior to placebo for 2h pain freedom. Ubrogepant was well tolerated. Results support the efficacy, tolerability, and safety of ubrogepant for acute treatment of migraine attacks.

Background: We assessed long-term health-related quality of life (HRQoL) and functioning in adults receiving onabotulinumtoxinA for CM. Methods: Interim analysis of multicentre, prospective, observational study in adults naïve to botulinum toxin (NCT02502123). Mean change from baseline in Migraine-Specific Quality of Life (MSQ) score (primary); healthcare resource utilization (HRU) and work productivity (secondary) assessed in patients receiving 4 of 7 onabotulinumtoxinA treatments (Tx4; ~10 months). Results: Across treatments (baseline, n=196, post-Tx2, n=173, post-Tx4, n=137), the mean (SD) between-session interval and onabotulinumtoxinA dose was 13.1 weeks and 170.4 (17.2) U, respectively. MSQ scores increased significantly (P<0.0001) (baseline to post-Tx4; all role function domains). Patient percentages declined from baseline to post-Tx2 and post-Tx4 for emergency room visits (17.3%; 9.3%; 6.6%), hospital admissions (3.6%; 2.9%; 1.5%), and headache-related diagnostic testing (35.9%; 15.9%; 8.1%). The percentages of patients employed at baseline (73.5%) and post-Tx4 (72.3%) were similar. Hours worked increased slightly from baseline to post-Tx4 (28.0 [SD=15.4]; 29.4 [SD=16.0]). Headache-related missed work hours decreased (5.9 [SD=9.5]; 2.5 [SD=5.9]). Patients reported less headache-related impact on work productivity from baseline to post-Tx4 (5.4 [SD=2.1] vs 3.9 [SD=2.6]) and ability to perform daily activities (6.1 [SD=2.1] vs 4.2 [SD=2.8]). Conclusions: OnabotulinumtoxinA for CM improved HRQoL and work productivity and reduced HRU.

Background: Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disease due to mutation of the VPS13A gene encoding the protein chorein. ChAc is a slowly progressive disorder that typically presents in early adulthood, and whose clinical features include chorea and dystonia with involuntary lip, cheek and tongue biting. Some patients also have seizures. Treatment for ChAc is symptomatic. A small number of ChAc patients have been treated with bilateral deep brain stimulation (DBS) of the globus pallidus interna (GPi), and we now present an additional case. Methods: Patient chart, functional measures, and laboratory findings were reviewed from the time of ChAc diagnosis until 6 months after deep brain stimulation (DBS) surgery. Results: Here we present a case of ChAc in a 31 year old male positive for VPS13A gene muations who presented with chorea, tongue biting, dysarthria, weight loss, and mild cognitive dysfunction. GPi-DBS using monopolar stimulation was associated with significant improvement in chorea and dysarthria. Conclusions: This case adds to the current state of knowledge regarding the efficacy and safety of bilateral GPi-DBS for symptomatic control of drug-resistant hyperkinetic movements seen in ChAc. Controlled trials are needed to better assess the impact of DBS in ChAc.

Background: People with Parkinson disease (PD) face progressive mobility loss, but medical treatment is dependent on clinical assessment and examination. Regional patient and physician density patterns pose further problems to accessing care. Telehealth may improve access particularly among rural populations, but an approach to this problem should consider patient perspectives. Methods: We surveyed and conducted a focus group for people with PD and their caregivers. Questions assessed perceptions of barriers to neurological care and use of telehealth for PD management. Thematic analysis was performed to classify qualitative data. Results: 18 individuals completed the survey and 7 parties joined the focus group. 52% of participants travel >50km for neurologist appointments (range = 59 to 842km). Perceived barriers include cost and difficulty of travel, wait times, lack of interdisciplinary healthcare and deep brain stimulation outside large cities. 80% of participants (95% C.I. 64-96%) would likely or very likely use telehealth for follow-up neurologist appointments if proven as good as in-office visits. Participants associated telehealth with improved quality of care, improved access to care, and cost savings. Conclusions: This sample of people with PD and their caregivers report willingness to access care via telehealth to reduce perceived cost and travel for specialty care.

Background: The clinical benefit of onabotulinumtoxinA in cervical dystonia (CD) is proven, but its impact on health-related quality of life (HRQoL) is largely unknown. Methods: Multicentre, prospective, observational study (NCT01655862) of CD patients treated with onabotulinumtoxinA at physician discretion (maximum 9 treatments). Patient-reported HRQoL outcomes and work productivity were collected at baseline, 4- or 8-weeks post-treatment, and final visit (prior to 9th treatment). OnabotulinumtoxinA utilization was assessed. Results: 61 patients received ≥1 treatment; 74.1% completed all treatments. Average total dose/treatment was 186.9U. The splenius capitis was most frequently treated (100% patients). Average pain numeric rating scale score was significantly improved at final visit (2.1) versus baseline (4.6; p<0.001) as were CD impact profile questionnaire-58 scores across all subscales (head/neck symptoms, pain/discomfort, sleep, upper limb activities, walking, annoyance, mood, psychosocial functioning; all p<0.001). Fewer patients (16.0%) reported loss of work productivity at final visit versus baseline (48.4%). 121 AEs were reported by 67.2% patients. 62 AEs in 44.3% patients were treatment-related, the most common being neck pain (18%). One serious AE (not treatment-related) was reported by 1 patient. No new safety signals were identified. Conclusions: Long-term use of onabotulinumtoxinA is a safe, effective treatment for CD, improving HRQoL and work productivity.

Background: Parkinson’s disease (PD) varies in clinical manifestations and course of progression from person to person. Identification of distinct PD subtypes is of great priority to develop personalized care approaches. We aimed to compare long-term progression and prognosis between different PD subtypes. Methods: Data on 421 individuals with de novo early-onset PD was retrieved from Parkinson’s Progression Markers Initiative (PPMI). Using a newly developed multi-domain subtyping method (based on motor phenotype, RBD, autonomic disturbance, early cognitive deficit), we divided PD population into three subtypes at baseline: “mild motor-predominant”, “Diffuse malignant” and “Intermediate”. Rate of global progression (mixed motor and non-motor features) and developing dementia were compared between the subtypes. Results: Patients with “diffuse malignant” PD experienced 0.5 z-score further worsening of global composite outcome (p=0.017) and 2.2 further decline in MOCA score (p=0.001) after 6-years of follow-up. Hazard for MCI/dementia was significantly higher in “diffuse malignant” (HR=3.2, p<0.001) and “intermediate” (HR=1.8, p<0.001) subtypes. Individuals with “diffuse malignant” PD had the lowest level of CSF amyloid-beta (p=0.006) and SPECT striatal binding ratio (p=0.001). Conclusions: This multi-domain subtyping is a valid method to predict subgroups of PD with distinct patterns of long-term progression at drug-naïve early-stage with potential application in real-life clinical practice.

Background: Natalizumab is an efficacious disease modifying therapy (DMT) for relapsing remitting multiple sclerosis (RRMS), however, duration of therapy is often limited by risk of progressive multifocal leukoencephalopathy (PML). We describe the clinical course of RRMS patients switched from natalizumab to another DMT in a Canadian MS clinic. Methods: We conducted a retrospective study of prospectively collected data from the Dalhousie Multiple Sclerosis Research Unit (DMSRU). We identified all RRMS patients treated with natalizumab for >3 months who discontinued therapy with serum JC virus antibody positive status and switched to another DMT. Results: There were 84 individuals who switched to another DMT following natalizumab with 57 (68%) switching to fingolimod. Survival without a relapse on fingolimod was 92% (95% confidence interval 80-97%) at 6 months, 90% (77-96%) at 12 months, 85% (71-93%) at 24 months, 74% (56-86%) at 36 months. Survival without disease progression on fingolimod was 90% (95% CI 78-96%) at 6 months, 86% (72-93%) at 12 months, 78% (63-88%) at 24 months, 78% (63-88%) at 36 months. Conclusions: Although alternative DMTs may be used post-natalizumab, fingolimod remains an effective therapy with a high proportion of patients remaining free of relapses or progression at 3 years.

Background: Diagnosis of autoimmune encephalitis (AE) is complicated by issues with sensitivity/specificity of antibody testing, non-specific MRI/EEG/CSF findings, and competing differential diagnoses. We explored practice differences in AE diagnosis and management. Methods: We utilized a worldwide electronic survey with practice-related demographic questions, and clinical questions about 2 cases: (1) a 20-year-old woman with a neuropsychiatric presentation strongly suspicious of AE, (2) a 40-year-old man with new temporal lobe seizures and cognitive impairment. Responses among different groups were compared using multi-variable logistic regression. Results: We received 1,333 responses from 94 countries; 12.0% identified as neuro-immunologists. Case 1: Those treating >5 AE cases/year were more likely to send antibodies in both serum and CSF (aOR vs 0/year: 3.29,95%CI 1.31-8.28,p=0.011), pursue empiric immunotherapy (aOR:2.42,1.33-4.40,p=0.004), and continue immunotherapy despite no response and negative antibodies at 2-weeks (aOR:1.65,1.02-2.69,p=0.043). Case 2: Neuro-immunologists were more likely to send antibodies in both serum and CSF (aOR:1.80,1.12-2.90,p=0.015). Those seeing >5 AE cases/year (aOR:1.86,1.22-2.86,p=0.004) were more likely to start immunotherapy without waiting for antibody results. Conclusions: Our findings highlight the heterogenous management of AE. Neuroimmunologists and those treating more AE cases generally take a more proactive approach to testing and immunotherapy than peers. Results emphasize the need for higher-quality treatment/outcome data and evidence-based guidelines.

Background: Motor evoked potentials (MEP’S) measure myelin/axonal integrity of the central nervous system. MEP’s reliability and correlation to conventional clinical measures in multiple sclerosis (MS) patients have yet to be demonstrated. Alemtuzumab is a high efficacy therapy used in patients with MS. Its longitudinal impact on electrophysiological measures has yet to be examined. Methods: This is a single center, observational study. 10 patients with MS who received their first cycle of alemtuzumab within less than 3 months were evaluated with both clinical and MEP’s measures at baseline and every 6 months thereafter for 36 months. MEP’s were repeated two weeks after every time point. We report our preliminary analyses. Results: Patient follow-up ranges from 6 to 36 months. The intraclass correlation coefficient (ICC) between two consecutive time points were good with values of 0.774 for the biceps and 0.867 for the tibialis anterior with p values less than 0.0005 for both. The correlation for the biceps MEP’s to the 9 hole peg test (9HPT) was 0.51 with p less than 0.0005 and for the tibialis anterior MEP’s to the 6 minute walk test (6MWT) was -0.411 with p=0.01. Conclusions: Our preliminary analyses demonstrate that MEP results are reproducible and correlate with clinical measures.

Background: Glioblastoma Multiforme (GBM) has well documented systemic and local immunosuppressive mechanisms to escape immune surveillance and grow. GBM tumor cells as well as the microglia within it have a high incidence of PD-L1 surface expression which makes it more susceptible to anti-PD-L1 antagonism and ADCC through avelumab therapy. Methods: This is a single center, phase 2, open label, add-on, single dose study of 156 weeks duration in patients receiving standard therapy for newly diagnosed GBM. In total 30 patients will be entered into the study within 3 weeks of finishing their last day of combined radiotherapy/temozolomide. The following are the results of the first interim analysis completed when the first eight patients completed 52 weeks or an end of study visit. Results: 24 patients have so far started therapy. There as been no unexpected treatment emergent adverse event (TEAE). Two patients transiently withheld therapy because of immune related TEAE’s and none permanently. The objective response rate at week 52 for the first eight patients was 50% with 2 (25%) having a complete response and 1 (12.5%) a partial response. Conclusions: These preliminary results suggest that the addition of avelumab to standard therapy in patients with GBM is safe. Efficacy trends look promising.

Background: Targeted temperature management (TTM) is a recognized treatment to decrease mortality and improve neurological functionin hypoxic ischemic encephalopathy (HIE). An esophageal cooling device (ECD) has been studied in animal models but human data is limited. ECD appear to offer similar benefits to intravascular cooling catheters with potentially less risk to the patient. We studied whether the ECD could act as a substitute for intravascular cooling catheters. Methods: Eight ICU patients admitted following cardiac arrest who required TTM were enrolled prospectively. The primary outcome measures were timeliness of insertion, ease of insertion, user Likert ratings, time to achieve a target temperature of 36˚C and time target temperature was maintained within 0.5˚C of the 36˚C goal for 24 hours using an ECD. Results: Time to reach target temperature 0 min to 540 min. ECD appeared to be effective at maintaining a target temperature of 36˚C for most patients. In general, the catheter was easy to insert and use. Conclusions: For patients requiring TTM, use of an ECDadequately allowed for TTM goalsto be achieved and maintained. Overall user evaluationwas positive.

Background: Inhibitors of BRAF and MEK, enzymes in the mitogen-activated protein kinase (MAPK) pathway, are now widely used in the treatment of metastatic melanoma. We report a case of acetylcholine receptor (AChR) antibody-positive myasthenia gravis developing after exposure to dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor. Methods: A 68-year-old man presented with dysarthria, dysphagia, cough, dyspnea, and fever. Examination revealed fatigable ptosis and proximal muscle weakness. He had started dabrafenib and trametinib for metastatic melanoma two weeks prior. He was diagnosed with myasthenia gravis and superimposed aspiration pneumonia. AChR antibodies were positive. Dabrafenib and trametinib were stopped. He improved rapidly with pyridostigmine alone, and remained free of myasthenic symptoms for the next two months. Another course of dabrafenib and trametinib was given, and seven weeks later, his myasthenic symptoms recurred. Pyridostigmine produced only partial improvement, and treatment with intravenous immunoglobulin and prednisone was initiated. Results: We are unaware of prior reports of an association between BRAF/MEK inhibitors and seropositive myasthenia gravis. The development of myasthenic symptoms twice after BRAF/MEK inhibitor exposure suggests that the association is more than coincidental. Conclusions: Myasthenia gravis may be a complication of treatment of melanoma with dabrafenib and trametinib. The mechanism by which this occurs is unknown.

Background: The physician-reported Quantitative Myasthenia Gravis (QMG) test was a key efficacy measure in REGAIN, a 26-week, phase 3, placebo-controlled study of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalized MG. Ocular and generalized weakness have shown variable responses to therapies including prednisone and intravenous immunoglobulin/plasma exchange. Using the patient-reported MG Activities of Daily Living (MG-ADL) scale during REGAIN, eculizumab showed a consistent trend toward rapid and sustained improvement across bulbar, respiratory, limb and ocular domains. We analyzed the effect of eculizumab on bulbar, respiratory, gross motor and ocular domains during REGAIN, using the QMG test. Methods: QMG domain score changes to REGAIN week 26 were determined for patients with abnormal baseline scores. Repeated-measures analyses were performed for bulbar (swallowing/speech), respiratory (forced vital capacity), gross motor (limb/axial motor items) and ocular (ocular/facial muscles) domains. Results: Eculizumab-treated patients showed improvements in all four QMG domain scores to week 26. Rapid, sustained improvements were demonstrated across all domains, with a trend toward significant differences between eculizumab and placebo (bulbar, p=0.0628; respiratory, p=0.0682; gross motor, p=0.0114; ocular, p=0.0017). The eculizumab safety profile was consistent with previous reports. Conclusions: Eculizumab demonstrated a consistent response across all QMG muscle domains. This aligns with previously reported MG-ADL findings with eculizumab. (NCT01997229).

Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a multi-systemic, heterogenous, life-threatening disease. Patisiran resulted in significant improvement in neuropathy and QoL at 18-months compared to placebo, and was generally well-tolerated in the Phase 3 APOLLO study. Methods: Multi-center, OLE study to evaluate the efficacy and safety of long-term patisiran dosing for ≤ 5 years in hATTR amyloidosis patients with polyneuropathy who have completed the APOLLO study (NCT02510261). Endpoints include safety, tolerability and long-term efficacy of patisiran. Measures of clinical benefit are the same endpoints used in APOLLO including changes in mNIS+7 composite neuropathy impairment score and QoL (Norfolk QoL-DN) Results: As of December 2017, 184 of 186 (99%) patients who completed APOLLO and 25 patients from the Ph 2 OLE study enrolled in the Global OLE study. Baseline data for 211(APOLLO/placebo, n=49; APOLLO/patisiran, n=137 and patisiran Ph 2 OLE, n=25) patients included: median age 61 years (26-84); 74% males; 46% V30M. Interim safety data and 12-month efficacy results will be presented. Conclusions: The global OLE study includes a diverse population of hATTR amyloidosis patients. Interim data will include the long-term safety and maintenance of effect in patients continuing on patisiran, as well as the impact of treatment with patisiran on patients previously treated with placebo.

Background: Hereditary transthyretin-mediated (hATTR) amyloidosis a hereditary, multi-systemic and life-threatening disease resulting in neuropathy and cardiomyopathy. In the APOLLO study, patisiran, an investigational RNAi therapeutic targeting hepatic TTR production resulted in significant improvement in neuropathy and QoL compared to placebo and was generally well tolerated. Methods: APOLLO, a Phase 3 study of patisiran vs. placebo (NCT01960348) prespecified a cardiac subpopulation (n=126 of 225 total) that included patients with baseline left ventricular (LV) wall thickness ≥ 13mm and no medical history of aortic valve disease or hypertension. Cardiac measures included structure and function by electrocardiography, changes in NT-proBNP and 10-MWT gait speed. Results: At 18 months, patisiran treatment resulted in a mean reduction in LV wall thickness of 1 mm (p=0.017) compared to baseline, which was associated with significant improvements relative to placebo in LV end diastolic volume (+8.31 mL, p=0.036), global longitudinal strain (-1.37%, p=0.015) and NT-proBNP (55% reduction, p=7.7 x 10-8) (Figure 1). Gait speed was also improved relative to placebo (+0.35 m/sec, p=7.4 x 10-9). Rate of death or hospitalization was lower with patisiran. mNIS+7 results in the cardiac subpopulation will also be presented. Conclusions: These data suggest patisiran has the potential to halt or reverse cardiac manifestations of hATTR amyloidosis.

Background: Chronic intravenous immunoglobulin (IVIg) is used to treat refractory myasthenia gravis (MG). This subgroup analysis evaluated response to eculizumab in patients receiving chronic IVIg before entry to REGAIN, a phase 3, randomized, double-blind, placebo-controlled study of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalized MG. Methods: IVIg was only permitted during REGAIN as rescue therapy; previously treated patients underwent a 4-week washout before randomization. Patients included in this analysis had received chronic IVIg ≥4 times in 1 year, with ≥1 dose within 6 months before REGAIN entry. Exacerbations and MG status changes were assessed. Results: Eighteen patients were evaluated; four experienced exacerbations (eculizumab-treated, 1/9; placebo-treated, 3/9). Clinically relevant improvements were larger with eculizumab than placebo, respectively (mean change, standard deviation [SD]: MG Activities of Daily Living score [MG-ADL], -5.3 [4.0] vs -2.1 [2.8]; Quantitative MG score [QMG], -4.1 [6.1] vs -1.3 [3.5]). More patients receiving eculizumab (7/9) had clinically meaningful responses (MG-ADL ≥3 and/or QMG ≥5 points) than those receiving placebo (3/9). Eculizumab safety was consistent with previous reports. Interim data from the open-label extension of REGAIN will be presented. Conclusions: In patients previously receiving chronic IVIg, eculizumab showed a trend toward meaningful clinical improvements and fewer exacerbations compared with placebo. (NCT01997229, NCT02301624).

Background: There is a paucity of research regarding ALS epidemiology in Canada. Previously published data from Newfoundland and Labrador (NL) demonstrate an average incidence of 2.4/100,000 from 2000-2004 (peak 3.3 in 2001, the highest reported in Canada). Local neurologists believe that the incidence has continued to increase. Methods: Clinicians affiliated with the electromyography (EMG) lab at the Health Sciences Centre in St. John’s compiled a list of patients diagnosed with ALS from 2012-2016, based on recall. Their medical records were reviewed and demographic information collected. This was cross-referenced with new referrals to the ALS Society NL per year. Results: Based on new referrals to ALS Society NL the average incidence between 2012-2016 was 2.81/100,000 (peak 3.6 in 2015). Average age-adjusted incidence from the EMG lab was 1.33 (peak 1.73 in 2016). The EMG lab documented a crude incidence of 3.97 in 2018. Conclusions: The incidence of ALS in NL is increased compared to the usual incidence of 1-2/100,000 per year. After the preliminary study, the EMG lab maintained more thorough records and an incidence of 3.97/100,000 was found in 2018. This makes a compelling argument for future research which could explore potential genetic or environmental causes for the increased incidence in this population.

Background: Mutations of the slow skeletal muscle troponin-T1 (TNNT1) gene are a rare cause of nemaline myopathy. The phenotype is characterized by severe amyotrophy and contractures. Death from respiratory insufficiency occurs in infancy. We report on four French Canadians with a novel congenital TNNT1-related myopathy. Methods: Patients underwent MRI of leg muscles, quadriceps biopsy and genetic testing. Wild type or mutated human TNNT1 mRNAs were co-injected with morpholinos in a zebrafish knockdown model to assess their relative abilities to rescue the morphant phenotype. Results: Three adults and one child shared a novel missense homozygous pathogenic variant in the TNNT1 gene. They developed from childhood slowly progressive limb-girdle weakness with spinal rigidity and contractures. They suffered from restrictive lung disease and recurrent episodes of infection-triggered rhabdomyolysis, which were relieved by dantrolene in one patient. Older patients remained ambulatory into their sixties. MRI of leg muscles showed symmetrical atrophy and fatty infiltration in a proximal-to-distal gradient. Biopsies showed multi-minicores, while nemaline rods were seen in half the patients. Wild type TNNT1 mRNA rescued the zebrafish morphants but mutant transcripts failed to rescue the morphants. Conclusions: This study expands the spectrum of TNNT1-related myopathy to include a milder clinical phenotype caused by a functionally-confirmed novel missense mutation.

Background: FOSMN is a recently describe neurological syndrome, characterizes by slow onset of facial sensory abnormalities and motor deficits. The initial description showed a very uniform clinical presentation. Since the initial description there are clinical cases describe in literature with subtle phenotype variations. Methods: We describe a clinical case associated with NHL. We will report clinical data, laboratory and neurophysiological findings. Results:Patient initiated with left perioral and mental sensory symptoms on her left side. It spread up to include left V2 area and spread to the right side. After 2 years she developed sensory symptoms on her right hand. Progressed to weakness and atrophy on the right upper limb. Also developed dysarthria, dysphonia, dysphagia, as well as photophobia, anisocoria and double vision. Had thorough work-up and everything unrevealing. Except for Spep that showed increased free kappa. Bone marrow biopsy showed evidence of a clonal cell expansion consistent with indolent lymphomaConclusions: This case provides evidence of FOSMN associated with NHL. To our knowledge this is a first case describe with NHL. There had been reports with motor neuro diseases phenotype with lymphoma that may represent a paraneoplastic disorder. Our patient expands the clinical presentation. This finding should not lessen the diagnosis of FOSMN.