Background: With few evidence-based disease-modifying therapies being available for patients with progressive multiple sclerosis (PMS), how can neurologists best care for their patients? Little is known about the perspectives of patients with respect to the role they would like their neurologist to play in their care. We hereby report an update to our abstract presented at the Canadian Neurological Sciences Federation’s annual congress in 2016. Methods: Patients with PMS having an Expanded Disability Status Scale (EDSS) score of 6 or more were invited to participate. Semi-structured interviews were conducted with patients and their caregivers, and written questionnaires were completed by all participants. Collected data was subjected to thematic coding. Results: We have now interviewed a total of 18 patients (compared to 10 in 2016) and have reached thematic saturation. The majority of patients identified the neurologist as a useful figure in their care. Three main reasons were identified: (1) The neurologist provides information about new research and therapies (2) The neurologist educates patients about their disease and available services (3) The neurologist is viewed as an important supportive figure. Conclusions: Despite a lack of disease-modifying treatments for progressive multiple sclerosis, patients with PMS view the neurologist as an essential provider of care.

Background: We present a 67-year-old male with a two-week history of progressive double vision. Past medical history included oropharyngeal SCC, T4N2cM0, post-CCRT, and remote sarcoidosis. Clinically, the patient had multiple cranial nerve palsies affecting bilateral occular motor function. Neuroimaging showed an enhancing mass involving the sella and cavernous sinuses. Whole-body PET showed FDG-avid lesions in the sella and liver. Transsphenoidal biopsy of the sellar mass was obtained for tissue diagnosis. Methods: Details of the case were obtained from the patient’s EMR. Neuroimaging and neuropathology were reviewed with the appropriate subspecialists. A literature search was performed using multiple databases (PubMed, Web-of-Science) and relevant articles were included for review. Results: Sellar mass biopsy confirmed p16+ve SCC, identical to the patient’s known primary malignancy. On review of enhanced skull-base images, there was no evidence of direct tumor extension, favouring hematogenous spread. Conclusions: This case demonstrates the localizing potential of cavernous sinus masses. SCC metastases to the cavernous sinus are rare, and confer a poor prognosis.The presence of a p16 mutation has public health implications, as this mutation demonstrates more frequent and aggressive distant metastatic potential, and as a surrogate marker for high-risk HPV infection, represents a preventable risk-factor for a rapidly increasing cause of head and neck cancer in the Western world.

Background: The role of extent of surgical resection (EOR) on clinical outcomes in patients with low-grade glioma requires further examination. Methods: We systematically searched MEDLINE, Embase, and the Cochrane Library for studies published between January 1, 1990 and January 5, 2018 on predefined patient outcomes regarding different EOR of low-grade glioma. Results: Our literature search yielded 60 studies including 13,289 patients. Pooled estimates of overall survival showed an increase from 3.79 years (95% CI, 2.37–5.22) in the biopsy group to 6.68 years (95% CI, 4.19–9.16) in STR to 10.65 years (95% CI, 6.78–14.52) in GTR. When compared to STR, GTR prolonged progression-free survival by 2.08 years (95% CI, 0.26–3.89; P=0.025). Pooled estimates of seizure control showed an improvement from 47.8% (95% CI, 26.7–69.6) with biopsy to 54.2% (95% CI, 48.7–59.6) with STR to 81.0% (95% CI, 74.6–86.2) with GTR. Compared to STR, GTR delayed malignant transformation (RR, 0.43; 95% CI, 0.20–0.93; P=0.032), without increasing postoperative mortality (RR, 0.38; 95% CI, 0.07–1.97; P=0.250) or morbidity (RR, 1.22; 95% CI, 0.65–2.28; P=0.540). Conclusions: Among patients with low grade gliomas, higher degrees of safe EOR, were associated with longer overall and progression-free survival, better seizure control, and delayed malignant transformation, without increased mortality or morbidity.

Background: Supratentorial ventricular hemangioblastoma (HB) associated with Von Hippel Lindau (VHL) are extremely rare. Due to their vascularity and location, their management can be difficult. Methods: A 35 year old female with VHL, has been followed for 25 years with multiple intracranial and spinal tumours. Surgical removal was carried out on one large cystic and solid posterior fossa lesion. In addition, she underwent adrenalectomy for pheochromocytoma. There were no pancreatic or renal lesions. On serial follow up for years, a left frontal ventricular lesion showed increasing size with clinical signs of increased ICP and marked hydrocephalus, requiring shunting procedures, which were carried out 11 years ago. She has been clinically stable since. Results: Hemangioblastomas of the CNS are rare and account for 2% of primary CNS tumours. Supratentorial location is estimated at 4% for sporadic and 13% for HB associated with VHL. The lateral ventricular location is extremely rare. Review of the literature revealed a total of 9 cases of supratentorial ventricular location. The majority of the lesions are associated with VHL and they are solid and vascular lesions. In our cases there was a cystic component. Conclusions: If removal is contemplated, angiography with possible preoperative embolization may be required.

Background: Peritumoral brain edema(PTBE) in meningiomas had been a subject of interest; its occurrence in an extra-axial tumor was the reason of many studies and published data.Our study was made to evaluate the exact implication of Peritumoral brain edema in meningiomas in intraoperative and short postoperative prognosis. Methods: During 2006 to 2011,45 patients with supratentorial meningiomas were studied.Intraoperatively,certain findings were reported including: easy or difficult resection,Simpson’s grade of removal,brain tumor interface,plane of cleavage, pial vascularization of the tumor and arachnoid disruption.Morbidity and mortality were recorded;also postoperative CT and/or MRI were obtained within the first 3 months. Results: There were 26 meningiomas (57.7%) with peritumoral edema and 19 meningiomas without (42.3%).Pial vascularization of the tumor was defined in 24 patients (53.3%),four patients(21%) had a pial blood supply in edema negative group compared to 20 patients (76.9%) in edema positive group. In this study, there was one case mortality (2.2%) in edema positive group.As regard morbidity, eight (30.6%) patients in edema positive group suffered an early postoperative morbidity this is in comparison to four patients(21%) in the edema negative group. Conclusions: Our study shows that PTBE in meningiomas affects the surgical prognosis and confers a higher risk of morbidity and postoperative complications.Preoperative management of PTBE and immediate post-operative monitoring are important.

Background: The nasoseptal flap, commonly used in endoscopic transsphenoidal surgical, is typically held in position for several days post-operatively by a nasal Foley catheter balloon. The purpose of this study is to describe our experience with an alternative technique to buttress the nasoseptal flap that renders the use of a Foley catheter unnecessary. Methods: A review of our Halifax Neuropituitary Program’s database identified patients who underwent endoscopic transsphenoidal surgery for a pituitary macroadenoma with nasoseptal flap, secured with small rolls of GelfoamTM rather than a nasal Foley catheter. Minimum follow-up clinical and MRI assessments: 3 months. Results: 69 patients (mean follow-up: 22 months) met the inclusion criteria: 53 non-functioning and 16 functioning pituitary adenomas. 36 patients had an intraoperative CSF leak: 29 high flow and 7 low flow leaks. 35 patients were repaired by a fat +/- fascia graft. One patient had a post-operative CSF leak repaired by subsequent surgery without the use of a Foley catheter. Conclusions: In our experience, 1 of the 69 (1.4%) patients required post-operative CSF leak repair, well within the incidence of 1 to 3% reported in the literature. Securing the nasoseptal flap can be achieved without the use of a nasal Foley catheter.

Background: Leptomeningeal dissemination of hemangioblastomas (HB), whether sporadic or associated with Von Hippel Lindau (VHL), are extremely rare. Very scanty literature is available. Methods: A 36 year old female with VHL and stable pancreatic, adrenal and renal lesions was operated upon 4 years ago for a large symptomatic cervicomedullary cystic and solid tumor. 2 years after surgery the tumour recurred and further removal was unsuccessful due to medullary adhesions. Radiation was given to the posterior fossa area and to several small nodules over the cauda equina resulting in severe pain. Serial follow up imaging revealed diffuse leptomeningeal dissemination increasing in size of the suprasellar region, ambient cistern and Sylvian fissures. Clinically, she has been stable with small dose of steroids and VP shunt insertion for papilledema. Results: Review of the literature consists of 2 series of 7 and 21 patients each with leptomeningeal dissemination involving sporadic HB and VHL associated HB. Leptomeningeal dissemination is estimated at about 4.3%. It is postulated that the tumour starts in the Pia and spreads in an extra medullary fashion throughout the subarachnoid spaces. Conclusions: Long term recurrence has been noted raising the question of aggressive treatment with some drug therapy related to angiogenesis is postulated.

Background: Malignant gliomas are the most common and deadly brain tumors. Mean survival rate for a patient diagnosed with a glioblastoma multiforme (GBM) remains slightly over one year. Standard of care consists of treatment with temozolomide (TMZ) and radiotherapy. Recent work has highlighted functions of long non-coding RNAs (lncRNAs) in GBM progression and TMZ response even though the information regarding these newly discovered molecules is sparse. The overarching objective of this project was thus to assess the expression of select lncRNAs in GBM tumor samples and in models of TMZ resistance. Methods: A qRT-PCR-based approach was undertaken to measure six lncRNAs in 19 primary GBM samples, four GBM cell lines and in-house developed TMZ-resistant GBM cells. Results: Elevated levels of Hotair and H19 were observed in primary GBM tumors while decreased expression of MEG3 was recorded in the same samples. Interestingly, levels of PANDA increased 3.4-fold in GBM cells resistant to TMZ when compared with their sensitive counterparts. Conclusions: Overall, this work provides evidence of lncRNA deregulation in GBM tumors and reveals a previously unexplored lncRNA potentially involved in TMZ resistance. Modulation of lncRNA targets via RNAi-mediated approaches is envisioned to clarify their function and to strengthen their position as therapeutic options in GBMs.

Background: In-hospital Endocrinology consultation (IHEC) following transsphenoidal surgery is often routine but may be -unnecessary, lead to excessive blood testing, and prolong in-hospital stay. Purpose of this study: to determine whether the necessity of IHEC can be predicted by a standardized operative assessment tool. Methods: Retrospective review of all transsphenoidal surgeries from January 1, 2016, when we instituted an operative assessment tool to identify patients for which IHEC is required. Minimum follow-up: 3 months. Results: 78 patients (42 male; mean age: 57 yrs); the assessment tool identified 17 patients (22%) for IHEC and accurately identified those who would not require IHEC. IHEC patients had longer hospital stay (8.3 vs. 2.9 days), higher rate of new post-operative hormonal deficit (17.6% vs. 0%) and higher 30-day readmission rates (35% vs. 16%). Less than 10% had transient symptoms attributable to steroids; there were no long-term complications from routine post-operative steroid administration. Conclusions: Use of our operative assessment tool shows that at least three quarters of pituitary surgery patients can be managed safely without IHEC. Our data indicate that identifying these patients may reduce in-hospital stay and costs with no evidence of compromise of hormone-related care.

Background: Secondary hormonal deficiency (SHD) in patients with sellar masses (SM) is associated with significant morbidity. Purpose: to compare long-term risk of new-onset SHD in SM found incidentally (ISM) versus those clinically manifesting (CMSM). Methods: From the Halifax Neuropituitary Program’s database, we identified all patients having non-functioning and non-pituitary SM from January 1, 2006, with ≥ 12 months follow-up. Results: There were 214 CMSM (108 with baseline SHD) and 148 ISM (37 with baseline SHD) patients (mean follow-up: 5.7 and 5.0 years, respectively). In patients who underwent early surgery (<90 days from diagnosis), 3-month post-op hormonal function was considered baseline. Despite unchanged tumour size in over 95%, 129 (35.6%) developed new-onset SHD at up to 120 months. The risk of developing new-onset SHD was similar in CMSM and ISM groups (HR = 1.10; CI= 0.69-1.75; p= 0.7), and in surgical and nonsurgical patients (HR=1.24; CI= 0.59-2.61; p = 0.58). Conclusions: More than one third of patients with non-functioning or non-pituitary SM, presenting either with clinical manifestations or as incidental lesions, will develop new-onset SHD. Furthermore, SHD may develop several years later and despite stability of tumors, highlighting the need for ongoing, long-term hormonal assessment.

Background: Glioblastoma (GBM) is the most common primary malignant brain tumour. Despite aggressive therapy, median survival is only 14 months. Death typically results from treatment failure and local recurrence. The GBM microenvironment is highly hypoxic, which correlates with treatment resistance. Cytoplasmic RNA stress granules (SGs) form in response to hypoxic stress and act as sights of mRNA triage, allowing preferential translation of pro-survival mRNA during stress. We hypothesize that SGs may play a role in hypoxia-induced resistance to therapy, and may be targetable by chemotherapeutics to improve outcomes. Methods: We screened 1280 approved compounds to identify drugs that inhibited formation or dissolution of SGs in U251 glioma cells. Raloxifene inhibited SG dissolution in a dose dependent manner. We treated cells with raloxifene and incubated them in hypoxia, and then measured rates of cell death using cell counting and Presto blue. Results: Cell death rates were synergistically higher in cells treated with the combination of raloxifene and hypoxia compared to either treatment alone. Conclusions: Raloxifene inhibits the dissolution of SGs in glioma cells, and combination treatment results in synergistic tumour cell death. Taken together, this provides evidence that inhibition of SG dissolution may be a viable target for future GBM chemotherapeutics.

Background: Diffuse low-grade gliomas (LGGs) are infiltrative, slow-growing primary brain tumors that remain relatively asymptomatic for long periods of time before progressing to aggressive high-grade gliomas. Methods: We retrospectively identified LGG patients that were stably managed by observation with numerous (≥ 8) serial magnetic resonance imaging (MRI) studies. Tumour volumes were measured by manual segmentation on imaging to study the growth of the lesion. Patient demographic information, tumour characteristics, and histological data were collected from electronic medical records. Results: Of 74 LGG patients, 10 (13.5%) patients were included in the study. The number of MRIs acquired ranged from 8 to 18 (median, 11) over a median of 79.7 months (range, 39.8-113.8 months). Tumor diameter increased at a median rate of 2.17 mm/year in a linear trajectory. Cox regression analysis revealed that initial tumour volume predicted time to clinical intervention, and Mann-Whitney U test found that patients diagnosed prior to age 50 had significantly slower-growing tumors. Clinical intervention was more likely for tumours larger than 73.8 mL. Conclusions: We retrospectively analyzed the natural history of LGGs in patients with numerous serial MRIs managed at a single institution. Comparisons to the literature suggest that this is a subset of particularly slow-growing and low-risk tumours.

Background: Children diagnosed with medulloblastoma (MB) that are refractory to upfront therapy or experience recurrence have very poor prognoses. Reports of phase I and II studies for these children exist, but bear significant treatment related morbidity and mortality. Methods: A retrospective review of children diagnosed with a pediatric MB from 2002-2015 from the McMaster Pediatric Brain Tumour Study Group (PBTSG) captured a number of pediatric recurrent MB. Results: Over the 13-year period, 31 children with a histological diagnosis of MB were treated. At two years, 21 (67.7%) of 31 patients were free of recurrence and 25 (80.6%) survived. Thirteen children had recurrent or treatment refractory MB. mean time to recurrence was 14.6 months. The mean follow-up for survivors of recurrent MB was 4.0 years. In 3 recurrent MB, the disease had significantly progressed and the patients palliated. For the remaining children, therapy offered included surgery, radiation, and chemotherapy agents either in isolation or in varying combinations. Conclusions: Recurrent MB in our cohort carried a poor prognosis despite administration of salvage therapy. Though there is standardization of the upfront treatment exists, we observed great heterogeneity in the treatment of our 13 patients experiencing recurrence. A greater understanding of the biology of recurrent MB has the potential to guide salvage therapy.

Background: Flow cytometry in the cerebrospinal fluid (CSF) is used as an adjunct to cytology to increase the sensitivity of detecting central nervous system (CNS) lymphoma. We aim to evaluate CSF flow cytometry as a diagnostic tool for lymphoma in patients presenting with undifferentiated neurologic symptoms. Methods: We retrospectively reviewed all CSF flow cytometry samples sent in the Calgary region from 2012-2015. Clinical data, laboratory investigations, radiologic imaging studies, and pathological data were analyzed. Clinical review extended to 2 years post CSF flow cytometric testing. Results: The number of samples of CSF flow cytometry that were positive for a hematological malignancy was 43/763 (5.6%). The overall sensitivity of the test was 72.9%. A positive result was more likely to occur in patients with a prior history of a hematological malignancy or abnormal enhancement on MRI (p<0.0001). In fact, CSF flow cytometry was negative in all patients who did not have a previous hematological malignancy or abnormal enhancement on MRI (n = 247). Conclusions: CSF flow cytometry has very limited role in the screening for primary CNS lymphoma, unless a strictly endorsed testing algorithm is applied. It is, however, an invaluable tool in assessing CNS involvement in patients with previous diagnosis of hematolymphoid malignancy.

Background: CNS innate immune cells, microglia and macrophages (MMs), are the largest component of the inflammatory infiltrate in glioblastoma (GBM). They initially participate in tumor surveillance, but are co-opted by GBM to further angiogenesis and invasion. There are no effective immunotherapies against GBM in part because GBM-associated MMs are not well understood. We hypothesized that the extent and inflammatory phenotype of MM infiltration into GBM is variable between patients. This variability could have important implications on immunotherapy selection and treatment outcomes. Methods: Using automated quantitation of fluorescently labeled human GBMs, flow cytometry/live cell sorting, collection of conditioned GBM-associated MM media, and corroboration with TCGA and previously published scRNA-seq data, we have uncovered there is surprisingly marked variation in the amount of MM infiltration between tumors. Results: MM infiltration can range from almost non-existent, to comprising ~70% of GBM cells. By detecting cell surface markers and secreted cytokines, we determined that a mixture of pro- and anti-inflammatory MMs are found in each tumor. The overall inflammatory phenotype did not depend on the amount of infiltration. Interestingly, IDH-mutant GBM-associated MMs are more pro-inflammatory and less heterogeneous than IDH-wildtype GBMs. Conclusions: Taken together, the highly variable immunologic status of GBMs suggests the success of immunotherapies hinges on selecting appropriately vulnerable tumors.

Background: Lactate, a by-product of glycolysis, has been well established as a marker of poor tissue perfusion. Elevated lactate production is observed in tumor glycolysis known as the Warburg effect. We have previously shown that serum lactate correlated with brain tumor grade. In this prospective study we aimed to determine if the preoperative serum lactate correlated with preoperative MR spectroscopy and in lactate levels in the fresh frozen tissue samples. Methods: Twenty-one glioma patients (13 male, 8 female) ages 34 – 86 underwent craniotomy at a single institution by lead author. Tumor pathology revealed a Glioblastoma (n=16), grade II (oligodendroglioma n=1) and Grade III Glioma (anaplastic astrocytoma n=4). Preoperative spectroscopy was performed on 18 patients. A fellowship trained neuro-radiologist (JPC) was blinded to the serum and tissue lactate levels and graded the spectroscopy lactate levels as low or elevated. Results: There was direct correlation of spectroscopy tissue lactate levels with serum lactate levels. Pre-operative serum lactate (range 6.6- 29.9 mg/dl) was directly correlated with the fresh frozen tissue lactate levels (range 0.1 – 0.39 ug/mg; Pearson r=0.6 p = 0.0021). Conclusions: This study supports that serum lactate correlates with spectroscopy and tissue lactate levels.

Background: Recurrent glioblastoma portends a poor prognosis and the role of repeat surgery in improving survival remains uncertain. Our systematic review and meta-analysis aims to address whether re-resection provides a meaningful survival benefit and to what degree. Methods: Articles were collected from Pubmed, -CINAHL, EMBASE, Medline and Cochrane from January 1990 to 2018. Studies in the temozolomide era with both single surgery and re-resection cohorts were included. Primary outcomes were odds ratio for survival at 6, 12, and 24 months following re-resection and initial surgery. Results: Fourteen articles were included for analysis (3048 patients). Meta-analysis showed improved overall survival following re-resection 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). Overall survival from diagnosis or first surgery was also improved in patients who underwent re-resection at -recurrence, similarly 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. Subgroup analyses were done for patients stratified by age, performance status, and number of re-resections. 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.

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome classically associated with mental disability, seizure disorder and adenoma sebaceum, among other anomalies. One of the major causes of mortality and morbidity in adults is the exclusive occurrence of subependymal giant cell astrocytoma (SEGA) which responds in at least 35% of cases to everolimus, mTOR inhibitor. However, drug treatment is associated with 33% rate of adverse events and requires long-term treatment Methods: In this report, we present a case of 49-year old female with TSC and a left enlarging SEGA that was approached endoscopically in order to minimize morbidity associated with open surgical approaches. Results: The use of NICO Myriad system is described in this case to achieve successful tumor debulking without post-operative neurologic morbidity. Conclusions: This report reveals the value of minimally invasive neuroendoscopic techniques in the management of challenging intraventricular tumors while avoiding injury to crucial deep venous structures.

Background: Gliomas demonstrate epigenetic dysregulation highlighted by the Glioma CpG-Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. IDH1 mutation perturbs the balance between 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) by inhibiting TET-mediated active demethylation. The role 5hmC plays in IDH1 mutant tumors remains poorly understood. Methods: We profiled 5hmC in high grade IDH1 mutant (n = 12) and wild-type (n = 9) tumors on the Illumina MethylationEPIC Beadchip. We examined regions with high 5hmC abundance (top 1% probes), and differentially hydroxymethylated regions (DHMR). 5hmC profiles were correlated with gene expression. Results: Mean 5hmC b-values were 4.6%% and 3.8% for IDH1 mutant and wild-type tumors, respectively. Top 1% and DHMR probes demonstrated increased 5hmC among IDH1 mutants. 5hmC enriched for enhancer and super-enhancers. Among G-CIMP target genes, 22/50 were hydroxymethylated in our IDH1 mutant cohort, suggesting that 5hmC contributes to their overall methylation. Gene expression was associated with gene body 5hmC. 48 genes differentially expressed between IDH1 cohorts showed a positive Spearman correlation between 5hmC and gene expression, in particular for genes upregulated in IDH1 mutants. Conclusions: Locus-specific gain of 5hmC, targeting regulatory regions and associated with over-expressed genes, suggests a significant role for 5hmC in IDH1 mutant HGG.

Background: A 28 year old male with a previous diagnosis of Ewing’s Sarcoma in 2008, and a revised diagnosis to Hodgkin’s lymphoma in 2016, presented to the Neurology service 6 months after starting the novel monoclonal antibody, Brentuximab. Concurrent therapy included adriamycin, vincristine and daunorubicin. He was referred for progressive weakness and sensory symptoms starting in the legs and spreading to the arms over 6 months. Methods: Examination demonstrated distal symmetric weakness with power of 3 proximally and distally in the lower extremities. Reflexes were absent at the ankles and severely reduced at the patella. Gait was consistent with a sensory ataxia, and there was pseudoathetosis of the left hand. Results: MRI demonstrated no relevant abnormalities. Electrophysiology was consistent with a motor predominant, distal symmetric sensorimotor axonal neuropathy. Conclusions: A review of the literature demonstrated that the monoclonal antibody brentuximab has a high incidence (48%; n = 89) of a reversible distal symmetric polyneuropathy. The mechanism likely relates to microtubule dysfunction by the conjugated compound monomethyl auristatin E. This case adds to the existing body of literature around a severe but potentially reversible neuropathy, resulting from the new monoclonal antibody brentuximab, which may also serve as a model of disease in neuropathy with a well elucidated mechanism of toxicity.