Background: EMBRACE (NCT02462759) Part 1 is a randomized, double-blind, sham-procedure controlled study assessing safety/tolerability of intrathecal nusinersen (12-mg equivalent dose) in symptomatic infants/children with SMA who were not eligible to participate in ENDEAR or CHERISH. Methods: Eligible participants had onset of SMA symptoms at ≤6 months with 3 SMN2 copies; onset at ≤6 months, age >7 months and 2 copies; or onset at >6 months, age ≤18 months, and 2/3 copies. Safety/tolerability was the primary endpoint. Exploratory endpoints included Hammersmith Infant Neurological Examination Section 2 (HINE-2) motor milestone attainment, change in ventilator use, and growth. Results: EMBRACE Part 1 was terminated early based on positive results from ENDEAR. Safety/tolerability was similar to previous trials. More nusinersen-treated (11/14;79%) vs. sham–treated individuals (2/7;29%) were HINE-2 motor milestone responders. Between Day 183 and 302, mean (SD) hours of ventilator use changed by +1.236 (3.712) hours in nusinersen-treated (n=12) and +2.123 (3.023) hours in sham–treated individuals (n=7). Similar increases in weight and body length were observed in nusinersen-treated and sham–treated individuals by Day 183. Conclusions: In EMBRACE Part 1, nusinersen demonstrated a favorable benefit-risk profile. These results add to the aggregated efficacy, safety/tolerability data of nusinersen in SMA.

Study Supported by: Ionis and Biogen

Introduction: Radiation-induced brain necrosis (RN) is a relatively uncommon (5-20%) but potentially severe adverse effect of stereotactic radiosurgery (SRS) for brain metastasis(BM). We attempted to establish the effect of hypo-fractionation on RN rates by reviewing patients having simultaneous multi-fraction and single fraction treatment of BM at our centre. Methods: Patients receiving simultaneous 1 (20-24Gy) or 3 fraction (21-24Gy) SRS treatments were identified in our institution’s database. Serial post-SRS MRIs were reviewed to determine the lesion quotient (LQ), or maximum cross sectional area on T1 plus gadolinium divided by T2 FLAIR sequences. LQ less than 0.3 was considered RN. Result: Twenty-two patients were followed for a median 320 days. Sixteen patients developed radionecrosis in 21 of 62 lesions (33%), four of which were symptomatic (20%). Eleven of these lesions received 3 fractions and ten received one fraction. RN risk increased with increasing tumor volume (log odds ratio=1.12, p=0.04). There was no difference in incidence of RN in patients who received whole brain radiotherapy (WBRT) (p=0.11), hypo-fractionation (p=0.98) or had a higher maximum dose (p=0.71). Radiographic RN, however, did not clear in any patients who developed it. Eight patients developed a local recurrence (12%), six of which occurred in the single fraction group. Conclusion: Radionecrosis was significantly related to tumor volume but not fractionation, WBRT, or maximum dose. Overall, our results indicate patients receiving SRS for multiple brain metastasis have a higher rate of radionecrosis than the literature and poorer survival despite having equivalent local control.

This case series aimed to describe clinicoradiological, electromyographic, and etiological spectra in palatal tremor (essential=1; symptomatic=26). Patients with symptomatic palatal tremor had 2 to 10 Hz arrhythmic electromyographic bursts, a spectrum of changes in inferior olivary nucleus, with/without lesions in Guillain Mollaret triangle, and varied etiologies (genetic=9, vascular=6, trauma=3, infections=3). Exome sequencing showed variations in POLG, WDR81, NDUFS8, TENM4, and EEF2. Clinical phenotypes of patients with POLG, WDR81, and NDUFS8 variations were consistent with that described in literature. We highlight salient magnetic resonance imaging features, electrophysiological observations, and diverse etiologies in a large cohort of palatal tremor.

Background: Spinal Muscular Atrophy (SMA) is an autosomal recessive neurodegenerative disease. In June 2017, Health Canada approved Nusinersen, currently the only available drug for SMA. Since 2016, patients in Ontario have been treated clinically with Nusinersen through different access programs. Methods: Retrospective case series of patients with SMA treated clinically with Nusinersen in Ontario, describing clinical characteristics and logistics of intrathecal Nusinersen administration. Results: Twenty patients have been treated across four centres. To date, we have reviewed 8 cases at one centre (seven SMA Type I, one SMA Type II). Age at first dose ranged from 3-156 months and disease duration 9-166 months. Patients had received 4-7 doses at last evaluation. Three patients with scoliosis (2 with spinal rods) required fluoroscopy-guided radiologist administration, and 4 required general anesthesia. No complications/adverse events were reported. At last follow up, 5/8 families reported improved daily activities. Of 5 patients with baseline and follow up motor function testing, 3 demonstrated improved scores. One patient died due to respiratory decline at age 9 months, despite improved motor outcome scores. Conclusions: We describe the first Canadian post-marketing experience with Nusinersen. Timely dissemination of this information is needed to guide clinicians, hospital administrators, and policy-makers.

Background: The benefits of increasing extent of resection (EOR) for both overall survival and progression-free survival (PFS) in glioblastoma has been well documented. However, models predicting surgical outcomes have failed to incorporate a patient’s IDH status, a known prognostic factor. We isolate the impact of IDH on surgical outcomes. We determine the effect modification of increasing EOR and decreasing residual tumor volume (RTV) on IDH status. Methods: We performed a retrospective cohort study of 98 patients with glioblastoma who had undergone either biopsy or surgical resection. Tumor volumes were determined by volumetric analysis. Univariable and multivariable Cox PH Regression models were built using overall survival and PFS as endpoints. Results: Increasing EOR and decreasing RTV were both associated with prolonged overall survival and PFS. When IDH status was added to multivariable models, the model utilizing RTV provided a slightly better fit compared to EOR. An interaction term between RTV and IDH status was characterized, such that at low RTVs the prognosis of an IDH mutant is significantly better than that of an IDH wild-type, an effect that is less important as RTV increases. The significance of this term was confirmed by improved fit upon insertion into multivariable models. Conclusion: Minimizing RTV and increasing EOR are important prognostic factors for both IDH wild-type and IDH mutant glioblastoma. The protective benefit of the IDH mutation at lower RTVs suggests these patients are the best candidates for aggressive surgical resection.

Background: Microvascular decompression (MVD) is commonly used in the treatment of trigeminal neuralgia with positive clinical outcomes. Fully endoscopic microvascular decompression (E-MVD) has been proposed as a minimally invasive, effective alternative, but a comparative review of the two approaches in the literature has not been conducted. Methods: We performed a meta-analysis comparing patient outcome rates and complications for both techniques. From a pool of 1,039 studies, 22 articles were selected for review: 12 open MVD and 10 E-MVD. The total number of patients was 6,734. Results: Good pain relief was achieved in 81% of MVD and 88% of E-MVD patients, with a mean recurrence rate of 14% and 9% respectively. Average rates of complications in MVD versus E-MVD included facial paresis or weakness, 9%, 3%; -hearing loss, 4%, 1%; cerebrospinal leak, both 3%; cerebellar damage and infection, 2%, <1%; and mortality <1%, 0% respectively. Conclusions: The reviewed literature revealed similar clinical outcomes with respect to pain relief for both approaches. Recurrence rate and incidence of complications, notably facial paresis and hearing loss were higher for MVD. We concluded that E-MVD appears to offer at least as good a surgical outcome as MVD, with possibly a shorter operative time, smaller craniectomy and lower recurrence rates.

Background: Recurrent glioblastoma portends a poor prognosis and the role of repeat surgery in improving survival remains uncertain. Therefore, we undertook a systematic review and meta-analysis in order to determine if repeat surgical resection provides a meaningful survival benefit for patients with recurrent glioblastoma. Methods: Two independent reviewers searched for articles that reported on overall-survival of patients with recurrent glioblastoma using MEDLINE, Embase, Google Scholar, and Cochrane from January 2000 to 2018. Studies that compared overall survival of patients treated with single surgery compared to repeat surgery in the temozolomide era were included for analysis.Primary outcomes were odds ratio for survival at 6, 12, and 24 months from date of initial diagnosis. Secondary outcomes were ratio odds ratio for survival at 6, 12, and 24 months from date of repeat surgery. The proportions of patients who had the outcomes of interest were pooled using random-effects model. Quality assessment was performed using the Newcastle Ottawa Scale. Heterogeneity across trials was quantified by the I2 statistic. Publication bias was evaluated visually using funnel plots and quantified by the Egger regression. Results: Fourteen articles reporting on 3048 patients were included for analysis. The majority of articles were deemed to be of high quality with Newcastle Ottawa scale greater than 7 points. Pooled analysis showed improved overall survival following repeat surgery at 6- (OR 1.73, 95% CI 1.23-2.45, p<0.05), 12- (OR 1.71, 95% CI 1.20-2.45, p<0.05), and 24-months (OR 2.24,95% CI 1.01-4.95, p<0.05) and from date of initial diagnosis at 6- (OR 8.22, 95% CI 5.23-12.93, p<0.01), 12- (OR 4.16, 95% CI 3.25-5.36, p<0.01), and 24- (2.35, 95% CI 1.77-3.11, p<0.05) months. Conclusions: Repeat surgery for recurrent glioblastoma is associated with a significant survival advantage independent of other salvage therapies that include chemotherapy, radiation, and other antineoplastic regimens.