Background: Computer-assisted navigation (CAN) may guide spinal instrumentation, and requires alignment of patient anatomy to imaging. Iterative-Closest-Point algorithms register anatomical and imaging datasets, which may fail in the presence of significant geometric congruence leading to inaccurate navigation. We computationally quantify geometric congruence in posterior spinal exposures, and identify predictors of potential navigation inaccuracy. Methods: Midline posterior exposures were performed from C1-S1 in four human cadavers. An optically-based CAN generated surface maps of the posterior elements at each level. Maps were reconstructed to include bilateral hemilamina, or unilateral hemilamina with/without the base of the spinous process. Maps were fitted to symmetrical geometries (cylindrical/spherical/planar) using computational modelling, and the degree of model fit quantified. Results: Increased cylindrical/spherical/planar symmetry was seen in the subaxial cervical spine relative to the high-cervical and thoracolumbar spine (p<0.001). Inclusion of the base of the spinous process decreased symmetry independent of spinal level (p<0.001). Registration with bilateral vs. unilateral hemilamina did not significantly reduce geometric symmetry. Conclusions: Geometric congruence is most evident at C1 and the subaxial cervical spine, warranting greater vigilance in navigation accuracy verification. At all levels, inclusion of the base of the spinous process in unilateral registration decreases the likelihood of geometric symmetry and navigation error.

Background: Resting state functional connectivity (RSFC) in the fronto-parietal network (FPN) has been associated with cognitive ability. For this reason, it was hypothesized that RSFC connectivity of the FPN would be related to cognition in patients with diffuse glioma. To assess this relationship, pre-operative cognitive status was correlated to patient specific connectivity within the FPN. Further, we assessed whether RSFC could predict neuropsychological outcome following surgery Methods: Sixteen patients with diffuse glioma underwent neuropsychological assessment and pre-operative task and resting state fMRI. Thirteen had post-operative cognitive assessment at one-month post-surgery. RSFC in a subject-specific FPN was correlated with pre- and post-operative cognitive scores. Results: Higher connectivity within the FPN was associated with lower composite cognitive scores, while higher connectivity of the parietal node of the tumor-affected hemisphere was associated with lower fluid cognition but not crystallized cognition. Higher connectivity values between the parietal node of the healthy hemisphere and the rest of the FPN was associated with better neuropsychological outcome one month after surgery. Conclusions: RSFC between key nodes of the FPN is associated with cognitive performance in patients with diffuse glioma and is a promising biomarker for cognitive outcome following surgery.

Background: Dysphagia is a common and devastating complication after acute stroke. Percutaneous endoscopic gastrostomy (PEG) tubes are often placed for persistent dysphagia. However, little is known regarding outcomes after PEG tube placement. Methods: We used a 10-year Ontario Stroke Registry to shed light on the clinical outcomes of patients with PEG tube insertion after ischemic stroke or intracranial hemorrhage compared to patients with only NG tubes, including rate of pneumonia, disability, and mortality. Results: Using propensity score matching, 1,793 patients were successfully matched and had similar baseline characteristics. Compared with NG, patients with PEG had a higher rate of pneumonia (32.6% vs. 20.6%; RR 1.59), higher disability at discharge (modified Rankin Scale Score 3-5; 74.0% vs. 65.4%; RR 1.13), and higher rate of long-term care placement (27.1% vs. 9.3%; RR 2.9). >From stroke onset, there was a lower rate of death in patients with PEG compared to NG at 30 days (15.3% vs. 34.3%; RR 0.45) but no difference at 2 years (52.8% vs. 53.5%; RR 0.99, p=0.71). *All significant p <0.0001. Conclusions: In conclusion, PEG tube placement after stroke may prolong survival in patients with poor outcomes. Our study provides a framework for discussions between physicians, patients, and families with regards to expected prognosis after PEG tube placement.

Background: Predicting epilepsy following a first seizure is difficult. Network abnormalities are observed in patients with epilepsy using resting-state functional MRI (rs-fMRI), which worsen with duration of epilepsy. We use rs-fMRI to identify network abnormalities in patients after a first seizure that can be used as a biomarker to predict development of epilepsy. Methods: Patients after a single, unprovoked seizure and age/sex matched healthy controls underwent 7 Tesla structural and resting-state functional MRI. Data were analyzed using graph theory measures. Patients were followed for development of epilepsy. Results: Nine patients and nine control subjects were analyzed. There were no differences in baseline characteristics. No patients developed epilepsy (average follow-up 3 months). No differences between groups occurred on a whole-brain network level. At a 20% threshold, significant differences occurred in the default mode network (DMN). Patients demonstrated an increased local efficiency (p=0.02) and clustering coefficient (p=0.04), and decreased path length (p=0.02) and betweenness centrality (p=0.02). Conclusions: No whole-brain network changes occur after a single unprovoked seizure. No patient has developed epilepsy suggesting this group does not have network alterations after a single seizure. In the DMN, the alterations noted indicate increased segregation of network function.

Background: Perinatal stroke is the most common cause of hemiparetic cerebral palsy. Post-stroke plasticity is well studied in adults, but mechanisms in children are poorly understood. To better understand the relationship between functional connectivity and disability, we used rsfMRI to compare connectivity with sensorimotor dysfunction. Methods: Subjects with periventricular venous infarction were compared to controls. Resting-state BOLD signal was acquired on 3T MRI and analyzed using SPM12. Functional connectivity was computed between S1 and M1 of the left/non-lesioned and right/ lesioned hemisphere. Primary outcome was connectivity expressed as a Pearson correlation coefficient. Motor function was measured using the Assisting Hand Assessment (AHA), and Melbourne Assessment (MA). Proprioceptive function was measured using a robotic position matching task (VarXY). Results: Subjects included 17 PVI and 21 controls. AHA and MA in patients were negatively correlated with connectivity (increased connectivity=poorer performance). Correlations between AHA and connectivity between non-lesioned M1 to bilateral S1s were significant. VarXY in PVI was inversely correlated with connectivity (increased connectivity=improved performance), significantly between non-lesioned S1 and bilateral M1s. Control VarXY was positively correlated with connectivity between non-dominant S1 to bilateral M1s. Conclusions: We demonstrated significant correlations between connectivity and motor/sensory function in PVI patients. Greater insight into understanding reorganization of brain networks following perinatal stroke may facilitate personalized rehabilitation.

Background: Fatigue was recently reported to be the largest contributor to poor health-related quality of life (HRQOL) in paediatric Duchenne muscular dystrophy (DMD). Additional studies are necessary to confirm the generalizability of this finding. Our objective was to explore the longitudinal relationship between fatigue and HRQOL in an additional cohort of DMD patients. Methods: We performed a secondary analysis of data from a clinical trial (NCT00592553), which enrolled patients with nonsense mutation DMD, aged 5–20 years, from 37 sites in 11 countries (N=174). Fatigue and HRQOL were assessed using the PedsQLTM Multidimensional Fatigue Scale and Generic Core Scales, respectively, by patient- and parent-report at baseline and over 48 weeks. Results: Patients reported greater fatigue than healthy controls from published data. There was no significant difference between patient- and parent-reported fatigue. Fatigue was significantly correlated with worse HRQOL at baseline, by patient-report (r=0.70, P<0.001) and parent-report (r=0.70, P<0.001); and at 48 weeks, by patient-report (r=0.79, P<0.001) and parent-report (r=0.74, P<0.001). Change in fatigue was significantly correlated with change in HRQOL over 48 weeks, by patient-report (r=0.64, P<0.001) and parent-report (r=0.67, P<0.001). Conclusions: Fatigue is a major contributor to HRQOL in DMD. The strong association between fatigue and HRQOL corroborates previous studies, and suggests that reducing fatigue may improve HRQOL.

Background: Optic pathway gliomas (OPG) represent 5% of pediatric brain tumours. Visual acuity measures are used to evaluate treatment response. Current clinical tests to assess visual field integrity are subjective and require verbal cooperation. Thus, the objective of this study was to evaluate the clinical effectiveness of Steady State Visual Evoked Potentials (ssVEPs) to measure visual field integrity in a non-invasive and objective manner. Methods: SsVEPs were obtained in ten children with OPGs and 42 controls ages 3 to 21. The stimuli consisted of two circular dartboard patterns stimulating fovea and peripheral zones at two flickering frequencies, so that central and peripheral visual fields could be assessed simultaneously. The test consisted of eight stimuli presentations of 10 seconds. Results: Results indicate significantly lower ssVEP amplitudes in children with OPGs (M=2.52, 95% CI [1.13, 3.92]) compared to controls (M=13.26, 95% CI [8.85, 17.67]) in the central visual field (p=.021). However, no between group differences were detected in the peripheral field (p >.05). There were no significant differences between age groups (p>0.05). Conclusions: This objective, affordable, and non-invasive method appears to be effective in detecting central visual field deficits in children with OPGs rapidly and consistently.

Background: The surgical risk factors and neuro-imaging characteristics associated with cerebellar mutism (CM) remain unclear and require further investigation. We aimed to examine surgical and MRI findings associated with CM in children following posterior fossa tumor resection. Methods: Using our data registry, we retrospectively collected data from pediatric patients who acquired CM and were matched based on age and pathology type with patients not acquiring CM after posterior fossa surgery. The strength of association between surgical and MRI variables and CM were examined using odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Results: A total of 22 patients were included. Medulloblastoma was the most common pathology among CM patients (91%). Tumor attachment to the floor of the fourth ventricle (OR, 6; 95% CI, 0.7-276), calcification/hemosiderin deposition (OR 7; 95% CI 0.9-315.5), and post-operative peri-ventricular ischemia on MRI (OR, 5; 95% CI, 0.5-236.5) were found to have the highest association with CM. Conclusions: Our results may suggest that tumor attachment to the floor of the fourth ventricle, pathological calcification, and post-operative ischemia are relatively more prevalent in patients with CM. Collectively, our work calls for a larger multi-institutional study of CM patients to further investigate the determinants and management of CM to potentially minimize its development and predict onset.

Background: Oligodendroglioma (ODG), a molecularly defined subtype of glioma, is a treatment responsive, slow growing tumour strongly associated with IDH mutation and 1p19q co-deletion. Mutations in Capicua (CIC), located on chromosome 19q, have been found in up to 70% of IDH mutated, 1p19q co-deleted ODGs; suggesting that loss or altered function of CIC may be crucially associated with ODG’s unique biology. CIC and ATXN1L have previously been implicated in neurodegeneration, however, this interaction has not been studied in cancer. Methods: Transcriptome profiling of CIC knockout HEK293 cell lines generated using CRISPR was performed using microarray. CIC and ATXN1L interaction was confirmed using immunoprecipitation and immunofluorescence. Transcript and protein changes of CIC targets were tested using RT-qPCR and Western blot following ATXN1L siRNA knockdown. Results: Transcriptomic profiling of CIC knockout cell lines resulted in a list of candidate CIC target genes validated against clinical samples. Immunoprecipitation and immunofluorescence confirmed CIC and ATXN1L interaction. Derepression of candidate CIC targets at transcript and protein levels was seen upon siRNA knockdown of ATXN1L. Conclusions: The interaction between CIC and ATXN1L is necessary for the repression of CIC target genes, including known oncogenes. Further research into the relationship between CIC and ATXN1L may lead potentially novel avenues of therapeutic approaches for less favorable gliomas.

Background: Riboflavin transporter deficiency (RTD), formerly known as Brown-Vialetto-van Laere syndrome, is an early-onset neurodegenerative disorder with distinctive phenotypes. RTD is caused by mutations in either the SLC52A2 or SLC52A3 genes that encode riboflavin transporters RFVT-2 and RFVT-3, respectively. Methods: This was a 3-year retrospective case review from the Cure RTD International Registry. Results: 73 individuals (~60% female, 14 deceased) from 56 families had genetically confirmed RTD Type 2, including 30 novel SLC52A2 mutations (24 missense, 2 nonsense, 4 deletion). The mean ages at symptom onset and at diagnosis were 2.4 years (SD 1.5, range 0.25–8, n=63) and 12.0 years (SD 10.2, range 0.75–52, n=56) respectively. Most common presenting symptoms were sensory ataxia (n=43), sensorineural hearing loss (n=22), nystagmus/visual loss secondary to optic atrophy (n=14), upper limb weakness (n=11), and respiratory insufficiency (n=9). Treatment included high dose riboflavin, other supplements, and supportive care; 7 individuals required transfusions for anemia pre-riboflavin treatment and 17 (25%) received a cochlear implant. The minimum prevalence of RTD was estimated to be 1 per million, with >100 new cases each year. Conclusions: This is the largest case series of RTD to date. Early recognition and prompt riboflavin treatment is essential for survival and optimal outcome.

Background: Selective amygdalohippocampectomy (SAH) is a surgical option in well-selected cases of pediatric medically refractory temporal lobe epilepsy (TLE). The objective of this study was to compare the surgical outcome and the rate of reoperation for ongoing or recurrent seizures between SAH and anterior temporal lobectomy (ATL) in pediatric TLE. Methods: Retrospective review of 78 pediatric intractable TLE patients referred to the Comprehensive Epilepsy Program at our institution between 1988 and 2015 treated initially with either a trans-middle temporal gyrus SAH (19) or ATL (59). Patients underwent baseline long-term video electroencephalography and 1.5-Tesla MRI. Neuropsychological testing was performed preoperatively and 12-months postoperatively (including reoperations). Results: The mean follow-up was 64 months (range, 12-186 months). The average age at initial surgery was 10.6±5 years with an average delay of 5.7±4 years between seizure onset and surgery. Ultimately 78% were seizure-free (61/78) at most recent follow-up. Seizure freedom after initial surgical treatment was achieved in 81% of patients who underwent ATL (48 patients) versus 42% in SAH (8 patients; p<0.001). Of patients with ongoing disabling seizures following SAH, reoperation (ATL) was offered in 8 resulting in seizure freedom in 63%, without interval neuropsychological decline. Conclusions: SAH amongst well-selected pediatric TLE results in significantly worse seizure control compared with ATL.

Background: Cerebral palsy (CP) is a debilitating disorder (1). Based on neuromotor impairments it is divided to spastic, dyskinetic and ataxic types (2). Inborn Errors of Metabolism (IEMs), monogenic and chromosomal disorders mimic CP (3). We aimed to identify causal genetic variants in patients with atypical dyskinetic CP in whom known IEMs were ruled out. Timely diagnosis is essential for proper management, especially in conditions that mimic CP and are treatable. Methods: We enrolled 23 patients with unexplained atypical dyskinetic CP, for whole exome sequencing. Variants were filtered against public and in-house databases to identify variants predicted as damaging (in silico tools and ACMG criteria). We applied a virtual gene panel of known and suspected CP and movement disorder genes and investigated each sample. Results: The participants presented with symptoms including: spasticity, dystonia, choera-athetosis, ataxia and cognitive delays. We identified 23 diagnoses: 13 dominant,6 recessive and 4 X-linked. 12 patients had movement disorders. In 4, the diagnoses enabled targeted treatment (neurotransmitter supplements in Unverricht Lundborg diseases (CSTB) and PAK3 deficiency, deep brain stimulation in GNAO1 deficiency, medical diet in Glutaric Aciduria (GCDH). Conclusions: Whole Exome Sequencing contributes to establishing diagnosis in patients with atypical dyskinetic CP resulting in precision medicine and improved health outcomes.

Background: Wearable activity trackers are an innovative tool for measuring sleep and physical activity. The Resident Activity Tracker Evaluation (RATE) is a prospective observational study evaluating the impact of work-hours, sleep, and physical activity on resident well-being, burnout, and job satisfaction. Methods: Residents were recruited from: 1. general surgery and orthopedics (SURG), 2. internal medicine and neurology (MED) and 3. anesthesia and radiology (RCD). Groups 1 and 2 do not enforce on-call duration restrictions and group 3 had 12-hour restricted-call durations (RCD). Participants wore FitBit activity trackers for 14 days and completed four validated surveys assessing self-reported health, sleepiness, burnout, and job satisfaction. Results: Fifty-nine residents completed the study. 778 days of activity and 244 on-call periods were tracked. Surgical residents worked 24 more hours per week than non-surgical residents (84.3 vs 60.7). Surgical residents had 7 less hours of sleep per week and reported significantly higher Epworth Sleepiness scores. Nearly two-thirds of participants (61%) scored high burnout on the Maslach depersonalization subscore. Total steps per day and self-reported well-being, burnout, and job satisfaction were comparable between the groups. Conclusions: Despite a positive correlation between work-hours and sleepiness, burnout and well-being were similar among residents. Physical activity did not prevent burnout. These findings are relevant to work-hours policies.

Background: Fluoroquinolones (FQs) are one of the most prescribed classes of antibiotics in North America. There have been a number of cases reports linkingn FQs with secondary pseudotumor cerebri syndrome (PTCS) but data from large epidemiological studies are lacking. Methods: We conducted a case-control study of people 15-60 years of age from the LifeLink Database (IMS, USA). Cases had the first international classification for disease 9th edition clinical modification (ICD-9 CM) code for benign intracranial hypertension (BIH) as well as having received a procedure code for an MRI or CT scan and a lumbar puncture within 15 days or 30 days of receiving the BIH code. For each case, ten controls were selected and matched to the cases by age, gender and calendar time. Results: From a cohort of 6,110,723 people, there were 339 cases of PTCS and 3,390 corresponding controls. In the primary analysis, the adjusted rate ratio (RR) for current users for fluoroquinolones for both the 15 day and 30 day definitions were 5.67 (95% CI:2.72-11.83) and 4.15 (95% CI:2.29-7.50) respectively. Conclusions: Our study suggests an increase in the risk of PTCS with current users of fluoroquinolones. Patients who experience symptoms of raised intracranial pressure including headaches and double vision when on FQs should seek medical attention.

Background: Insular cortex involvement as a part of epileptogenic zone is often suspected in the context of operculo-insular semiology and can be confirmed by routine interrogation of the insula with stereo-electroencephalography (SEEG). However the safety and efficacy of insular resections remains unclear. Methods: We reviewed all the patients who underwent insular resection for drug-resistant epilepsy, from 2002 – 2016, in the Calgary Epilepsy Program. Details of the comprehensive pre-surgical evaluation, surgery performed, complications and seizure outcome at the latest follow-up were collected. Results: Fifteen patients (8 males, 7 females) with age range 3 – 41 years were identified. MRI was normal in 9 patients. The decision to resect the Insula was made based on clinical semiology and structural and functional imaging in 6 patients and on SEEG findings in 9 patients. Insular resection was total in 11 and partial in 4 patients. Four (26%) patients had transient hemiparesis and 1 patient had permanent mild upper extremity weakness following total resection. After a mean follow-up period of 45.6 months (range 2 – 150 months), 40% of the patients are seizure free. Conclusions: Insular cortex resections for drug resistant epilepsy can be performed safely and may contribute to additional effectiveness in seizure outcomes in patients with challenging extra-temporal epilepsy.

Background: We published the world’s first case of hemi-laryngpharyngeal spasm (HELPS) syndrome cured by microvascular decompression (MVD) of the Xth cranial nerve in 2016. We now present a small cohort of patients (n=3) successfully treated with surgery in order to better delineate the common characteristics of this syndrome, diagnostic tests of choice, nuances of their surgical care and outcomes of their treatment. Methods: The history and physical examination of three patients with HELPS syndrome are presented. Pre-operative laryngoscopy, neuroimaging, response to botox and intra-operative videos are detailed. Post-operative outcome and complications are presented. Results: Each patient reported similar motor (choking) and sensory (coughing) features in their history. Episodic choking relentlessly progressed over the years until it occurred while sleeping and with frightening severity prompting tracheostomy in one patient and intubation in another. A “tickling” sensation deep in the throat triggered episodic coughing that worsened over the years until it occurred while sleeping and with frightening severity (syncope and incontinence). Conclusions: A review of the literature suggests that patients with similar symptoms, often called episodic laryngospasm in the past, have been treated with psychotherapy or antacids. With the recognition that a clearly defined subset of these patients have HELPS syndrome, we can offer them the potential of a neurosurgical cure.

Background: In an effort to better understand why cognitively normal patients are referred to a memory clinic, we sought to identify features of “worried well” patients to better identify those more likely to be cognitively normal. Methods: Three hundred and seventy-five consecutive patients referred by primary care practitioners to a Rural and Remote Memory Clinic, were categorized into two groups based on their neurologic diagnosis, “worried well” (cognitively normal, N=81) or “other” (patients with any neurologic diagnosis, N=294). The two groups were compared using a t-test and a Chi-squared test. The same comparison was done between the same set of “worried well” patients (N=81) and the subgroup of patients with a diagnosis of Alzheimer’s disease (N=146) from the “other” group. Ethics approval was obtained from the University of Saskatchewan Biomedical Research Ethics Board. Results: Significant differences included younger age, more formal education, more frequent previous psychiatric diagnosis and more self-reported alcohol consumption in the “worried well” group. The “worried well” and “Alzheimer’s Disease” comparison had the same significant differences as the “worried well” and “other” comparison. Conclusions: We observed a pattern of differences between the “worried well” patients and those with cognitive disease. Taking multiple factors into account when evaluating a patient may help with clinical decision making.

Background: Jacklin et al. (2013) described a rising incidence and a younger onset of dementia in Albertan First Nations compared to non-First Nations patients. Canadian research is limited in Indigenous patients with dementia, leaving it difficult to understand factors contributing to the differences in incidence and prevalence. Methods: 375 patients (41 Indigenous) was seen at the clinic. The questionnaire given during initial assessments were reviewed and differences between groups (non-Indigenous patients versus Indigenous) were assessed. Results: Compared to the non-Indigenous patient, Indigenous patients were younger (p=0.007), were more likely to be female (p=0.033) and had less education (p=0.055). They were less likely to live solely with a partner (p<0.001) and more likely to have a daughter as caregiver (p=0.004). The Indigenous patients were more likely to smoke (p<0.001). Although no differences in diagnosis of mental health disorders were seen (p=0.735), the Indigenous patients scored significantly higher on the CES-D (p<0.0001). Conclusions: This comparison highlights differences potentially affecting the health of Indigenous patients. Acknowledging these differences is critical to individualized patient care. Further research is required to explore how these factors affect dementia disease course and treatment, and how these factors play a role in the differences in incidence and prevalence demonstrated in previous studies.

Background: Vestibular Schwannomas (VS) have a well- documented response to Gamma Knife® Stereotactic radiosurgery (SRS). However, there is limited data available regarding the volumetric response of cystic tumors. This report correlates the radiographic appearance of VS before radiosurgery with the delayed volumetric response. Methods: This study reviewed 219 VS patients between 2003 and 2013. Patients were treatment naïve and had a significant extracanalicular tumor volume. MRI at SRS identified; 42 contrast enhancing macrocystic tumors, 45 contrast enhancing microcystic tumors, and 132 homogeneously enhancing tumors with no intra-tumoral cyst formation. The median follow-up was 49.1 months. The median tumor volume was 2.6cm3 (0.70-16.1cm3) and the median dose was 12.5Gy (11-13Gy). Results: The actuarial tumor control rate was 99.4% at 2-years and 96.4% at 5-years. A volumetric reduction of >20% occurred in 85.4% of macrocystic tumors, 76.1% of microcystic tumors and 62.8% of homogeneously enhancing VS. The median volume decrease per year for macrocystic, microcystic and homogenous tumors was 17.2%, 7.5% and 7.9% per year respectively (p<0.001). Serviceable hearing was maintained in 61.5% of patients that had Gardner-Robertson grade I-II hearing. Conclusions: SRS provided VS tumor control in >95% of patients, regardless of radiographic characteristics. Tumor volume regression was most evident in patients with cystic tumors.