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.

Background: Chronic Inflammatory demyelinating polyradiculoneuropathy is a rare disorder of the peripheral nerves. A disease affecting up to 8.9 out of 100,000 people, and a yearly incidence of 1.6/100,000 people, CIDP is a condition that is treatable but still relatively unknown outside of the neuromuscular community. The purpose of this research, initiated by the GBS/CIDP Foundation, is to better understand a patient’s journey living with the disease and identify unmet needs. Methods: The research consists of a mix of structured interviews, digital ethnography and patient records. A total of 10 Canadian patients living with CIDP and their caregivers, 7 Canadian neurologists and 3 Canadian neuroscience nurses will be the subjects for our research. Results: In order to identify key interactions between patients and the healthcare system, the report will map a patient’s experience on 4 distinct planes. Clinical journey (ex: first symptoms, diagnosis, disease progression), Patient emotional journey (the emotional states the patient undergoes throughout his/her journey), Caregiver emotional journey, and Outcomes (ex: delays in care, damaged relationships, commitment to therapy). The report will identify key areas along the patient journey where more intervention is possible and where more research may be needed. Conclusions: The research is expected to be completed by April 2019.

Background: The response of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) to Intravenous Immunoglobulins (IVIG) treatment is well established . However, determination if patients not responding to 2 IVIG treatments or those whose condition stabilizes (ICE Trial) may benefit from additional doses remains unclear. We aim to identify time period required to reach maximal strength gains from IVIG treatment. Methods: Retrospective chart review of 14 patients with CIDP was performed. Change in Grip strength (GS), Knee extension (KE), Elbow Flexion (EF) and Dorsflexion(DF) was analyzed with a dynamometer during IVIG therapy. Averages for : percent change from baseline(Max%Δ),cumulative grams(g) of IVIG and time in weeks(w) required for maximal strength recovery was determined per function (+/−SEM).Anciliary therapy for all patients was recorded. Results: Strongest improvement was observed for DF(124+/−30%,p<0.001), followed by KE(113+/−19%,p<0.01),GS(100+/−21%,p<0.001) and EF(98+/−14%p<0.05).GS improved the fastest(19.1+/−3w) followed by DF(29.5+/−7w),KE(29.6+/−4w) and EF(31+/−6w). Cumulative IVIG dose to reach Max%Δ was highest for EF(869+/−201g) and lowest for GS(573+/−78g). Conclusions: Our study has demonstrated effectiveness of multiple treatments with IVIG to reach significant improvement in strength. Different muscle groups manifested different time-dependency ,reflecting variable amounts of IVIG required. Improvement was identified to be present on a ongoing basis ,with therapy lasting between 19.1-31 weeks,requiring between 869-573g of IVIG.

Background: “Neurophobia” describes a fear of Neurology on the part of medical students. This contrasts with the “neurophilia” that exists in society with increasing awareness of disorders such as stroke and multiple sclerosis. Ideally, we should take advantage of “neurophilia” to promote our specialty’s strengths. One step would be to better understand what students learn from a Neurology elective. Methods: This was a qualitative study. Students completing an elective between September 2011 and March 2015 at the Jewish General Hospital (JGH) in Montreal completed written pre- and post-elective questionnaires. Results: 36 students participated; 15 from McGill, 11 from other Canadian medical schools, and 10 from International medical schools. Many students changed their opinion about Neurology, with fewer citing lack of treatments or poor patient prognoses as negatives after completing their elective. They valued knowledge acquired about the neurological exam and problem-solving, while the range of cases and subspecialties surprised them. Many would diversify the setting of their elective to better experience this variety. Conclusions: More diversified elective experiences could showcase the strengths of our specialty and the scope of neurological practice. Presenting Neurology as a challenging, intellectually stimulating specialty that emphasizes problem solving could increase student interest.

Background: This is an updated on-line survey of the awareness and knowledge of stroke and heart disease amongst Chinese-Canadians carried out in 2017. Methods: 1001 randomnly selected Chinese-Canadians from Toronto and Vancouver area. Results: 46% were > 45 years old and male to female ratio was: 49.3 : 50.8, with native language being Cantonese in 40%, Mandarin 24% and 31% English. 82% were Canadian citizens and 31% had been in Canada < 10 years. 44% were from Mainland China, 37% Hong Kong , 6% Taiwan and 12% were borned in Canada. 85% were able to name at least one symptom of heart attack (p=0.005) while 80% were able to name at least one symptom of stroke (p=0.0008). 85% would call 911 in response to symptoms of heart attack or stroke compared to only 20% in a previous 2004 telephone survey (p=0.00001) . Conclusions: There is a dramatic improvement in the awareness and knowledge of stroke and heart disease amongst Chinese-Canadians compared to a previous telephone survey in 2004. This significant change could be due to difference in survey technique, but these improvements could also be due to the ongoing health promotion efforts by the Chinese-Canadian Council in support of the Heart & Stroke Foundation.

Background: Flow diversion is an established endovascular method for the treatment of intracranial aneurysms. The Pipeline Embolization Device (PED) remains the only FDA-approved stent available in USA and Canada since 2011. Stent position plays an important role in determining long-term success. The Leonardo Workstation(Siemens) is used for planning the ideal stent size and post-deployment destination. This first-ever study evaluates the accuracy of modeling software in predicting PED location post-deployment. Methods: 48 PED-assisted cases were performed 2012-2018 at the University of Alberta Hospital. 20 fit our preliminary inclusion criteria (single stents, simple anatomy). The proximal and distal landing zones were used to model the ideal stent using Leonardo. Accuracy was measured by comparing the Leonardo-predicted stent length vs known length. Results modeling against the dimensions predicted by AngioSuite, an app-based interface designed for use in the planning stages. Results: Leonardo workstation is accurate within 5mm at predicting final length for stents oversized by ≥0.25 cm. The predicted difference by Leonardo workstation & AngioSuite did not demonstrate statistical significance (P=0.36, P=0.24 respectively). Conclusions: Current angiographic planning tools are accurate at predicting PED deployment within 5mm. Complex vascular anatomy and deployment of multiple stents make prediction challenging. Analysis of these complex cases is currently underway.

Background: Telestroke can improve ischemic stroke patient outcomes by improving access to physicians specialized in stroke care and increasing the rate of thrombolysis. The aim of this study to assess the effect of the newly implemented Telestroke service on ischemic stroke patient outcomes in New Brunswick, Canada, a province with a high rural population. Methods: By means of a retrospective chart review, data for 366 adult acute ischemic stroke patients (Telestroke = 15.3%; non-Telestroke = 84.7%) were collected from emergency departmentsspanning five sites in the province. Outcomes included home discharge rates, complications (i.e., hemorrhage,angioedema), mortality, rate of thrombolysis and time to treatment. Results: No significant differences emerged for home discharge rates, complications, mortality or door-to-needle time. Telestroke patients had a significantly greater rate of thrombolysis treatment (51.8% vs 6.1%) and significantly less door-to-CT time (M= 27.63 min vs M= 100.78 min) compared to the non-Telestroke group. Conclusions: Overall, both groups had similar outcomes with some trends toward improvements for patients utilizing Telestroke.

Background: There are only few studies approaching the prevalence and cause of stroke in children and adults with Down Syndrome (DS). Methods: We did a retrospective study of our cohort of 4962 patients of Jerome Lejeune Institute since 2007. We collected age of stroke, clinical presentation, cause (TOAST classification), treatment and clinical course. Results: We identified 20 patients from 6 to 56 years old .In all cases, it was a stroke of ischemic origin.: 8 children with a prevalence of 0.33%. 4 had a cardio-embolic origin, 3 secondary to Moya-Moya syndrome and one of undetermined origin. 12 adults (21 to 52 years old) with a prevalence of 0.46%.The majority of the causes of these ischemic strokes are indeterminate (9 of 12), Conclusions: We found a low prevalence and an ischemic cause in all cases of stroke, which differs from the general population. For pediatric stroke, the causes are expected thromboembolic in a context of heart disease most often or secondary to a Moya-Moya syndrome. For adult strokes, the average age is younger than that in the general population and the cause is indeterminate in most cases. We must better explore our patients to identify the risk factors in DS population.