Background: The benefit of prophylactic antibiotic use in endoscopic endonasal transsphenoidal surgery (EETS) for pituitary lesions is controversial. Many surgeons administer antibiotics perioperatively not based on clear guidelines but “to be safe”. Methods: A systematic review using PRISMA guidelines was performed to assess the efficacy of perioperative antibiotic use to prevent infectious complications in patients undergoing EETS. Inclusion criteria: randomized controlled trials, systematic reviews, observational studies, and case series. Data extracted: study design, year of publication, sample size, surgery type, perioperative antibacterial treatment (antibiotic, dose, and duration), number of patients with 30-days post-operative meningitis and/or sinusitis. End points: rates of meningitis and sinusitis post-EETS. Results: A total of 280 articles were identified. Four observational studies met inclusion criteria. Based on GRADE score these studies were considered low in quality. 633 patients were -included in those studies. The most common antibiotics used were cefazolin and ceftazidime. The rate of infection ranged from 0.5% to 3.1 % for meningitis as the most common infection. Conclusions: The need to use antibiotic(s) perioperatively is not clear in patients with pituitary lesions undergoing EETS. Randomized control trials are needed to evaluate the efficacy of prophylactic antibiotic use in patients with pituitary lesions undergoing EETS.

Background: Continuous video-EEG (cvEEG) monitoring is the standard of care for diagnosis and management of neonatal seizures. However, it is labour-intensive. We aimed to establish consistency in monitoring of newborns utilising NICU nurses. Methods: Neonatal nurses were trained to apply scalp electrodes, troubleshoot technical issues. Guidelines, checklists and visual training modules were developed. A central network system allowed remote access to the cvEEGs by the epileptologist for timely interpretation and feedback. We compared 100 infants with moderate to severe HIE before and after the training program. Results: 192 cvEEGs were performed. Of the 100 infants compared; time to initiate brain monitoring decreased by average of 31.5 hours, in electrographic seizure detection increased(20% compared to 34% a), seizure clinical misdiagnosis decreased (65% compared to 36% ), and Anti-Seizure burden decreased. Conclusions: Training experienced NICU nurses to set-up, start and monitor cvEEG can decrease the time to initiate cvEEG which may lead to better seizure diagnosis and management.

Background: Our goal was to perform a scoping systematic review of the literature on the application of the FOUR score within critically ill patients. Methods: 6 databases were searched. Two reviewers independently screened the results. Inclusion and exclusion criteria were applied to each article to obtain final articles for review. Results: The initial search yielded 1709 citations. Of those used, 49 were based on adult and 6 on pediatric populations. All but 8 retrospective adult studies were performed prospectively. Patient categories included traumatic brain injury, intraventricular hemorrhage, intracerebral hemorrhage, subarachnoid hemorrhage, ischemic stroke, general/combined neurology and neurosurgery, post-cardiac arrest, medicine/general critical illness, and patients in the emergency department. A total of 9092 adult patients were studied. 14 studies demonstrated good inter-observer reliability of the FOUR score. 9 studies demonstrated prognostic value of the FOUR score in predicting mortality and functional outcomes. 31 studies demonstrated equivalency or superiority of the FOUR score compared to GCS in prediction of mortality and functional outcomes. Similar results were seen for the pediatric population. Conclusions: The FOUR score has been shown to be a useful outcome predictor in many patients with depressed level of consciousness. It displays good inter-rater reliability among physicians and nurses.

Background: Therapeutic hypothermia (TH) improves the outcome in HIE but cvEEG is vital to detect any seizures that occur. Unfortunately, the costs associated with cvEEG can make it impractical. We studied outcomes in TH with the objective of optimizing the length of cvEEG required. Methods: Term infants with HIE were treated with 72 h of TH followed by 6 h of rewarming. cvEEG reports were quantified (background, sharp transients, seizures) and compared with pre and post-cooling variables to determine whether risk stratification was possible. Results: 25/78 infants had seizures during the TH, however, most seizures occurred early, with 7 infants seizing prior to cooling and 15 having their first seizure within 24h. Only 3 infants had their first seizure between 24-48h and none were recorded after. Novel seizures after 24h were brief and did not require treatment. EEG variables such as frequent sharp transients and first seizures within 24h were correlated with MRI abnormalities. Conclusions: For the majority of infants undergoing TH, 24h of cvEEG may be sufficient with few infants requiring longer than 48h. A combination of clinical variables (abnormal neurological exam) and EEG traits (frequency of discharges, seizures) can help to decide on the likelihood of seizures and length of EEG recording needed.

Background: Electroencephalography (EEG) is a routine clinical tool that is used to evaluate thalamocortical function in comatose patients. The presence or absence of reactivity in background EEG patterns to afferent stimuli is believed to be an important indicator of clinical outcome. At present, there are no guidelines or standardized testing protocols for the assessment of EEG reactivity in critically ill patients. Moreover, the inter-rater reliability of subjectively identifying presence or absence of reactivity is known to be poor. Methods: Here we report the implementation of a clinical protocol formalizing the use of afferent stimuli – name-calling, clapping, nasal tickle, central painful stimuli and tracheal suction – administered during the routine EEG evaluation of behaviourally unresponsive patients in the critical care units at London Health Sciences Centre. EEGs were evaluated by qualified electroencephalographers. Results: This retrospective observational study of consecutive patients describes the inter-rater reliability of detecting presence or absence of EEG reactivity since implementation of the clinical protocol. Moreover it evaluates the relationship between EEG reactivity and clinical outcome to determine its reliability as a prognostic tool. Conclusions: The implementation of clinical protocols to standardize testing parameters may improve the ability to provide a reliable neurologic prognosis for critically ill patients in a comatose and behaviourally unresponsive state.

Background: We investigated whether the presence of dural sinus narrowing is a more reliable marker of intracranial hypertension / shunt failure in children than the imaging finding of hydrocephalus. -Methods: Cranial MRIs of n=12 children were included when being well and when there was definitive intracranial hypertension as per follow-up and intraoperative results (gold standard). Images werde assessed for hydrocephalus on T2w images and narrowing of dural sinuses on MR vengraphy (diameter of <50%). Results: Dural sinuses narrowing was detected with a sensitivity of 0.67, a specificity of 1.0, PPV of 1.0 and NPV of 0.75 (Table 1). Hydrocephalus was detected with a sensitivity of 0.5, a specificity of 0.83, PPV of 0.75 and NPV of 0.63. Results differed between the test methods (p = 0.01, Cochrane Q test). Conclusions: Dural sinus narrowing more reliably predicted intracranial hypertension, a sign which might significantly improve care in critically ill children.

Background: The hippocampus can be divided longitudinally into the head, body, and tail; and unfolded medial-to-laterally into the subiculum, cornu ammonis (CA) sectors, and the dentate gyrus. Ultra-high field (≥ 7 Tesla; 7T) magnetic resonance imaging (MRI) enables submillimetric visualization of these hippocampal substructures which could be valuable for surgical targeting. Here, we assess the feasibility of using 7T MRI in conjunction with a novel computational unfolding method for image-based stereotactic targeting of hippocampal substructures. Methods: 53 patients with drug-resistant epilepsy were identified undergoing first-time implantation of the hippocampus. An image processing pipeline was created for computationally transforming post-operative electrode contact locations into our hippocampal coordinate system. Results: Of 178 implanted hippocampal electrodes (88 left; 49.4%), 25 (14.0%) were predominantly in the subiculum, 85 (47.8%) were in CA1, 23 (12.9%) were in CA2, 18 (10.1%) were in CA3/CA4, and 27 (15.2%) were in dentate gyrus. Along the longitudinal axis, hippocampal electrodes were most commonly implanted in the body (92; 51.7%) followed by the head (86; 48.3%). Conclusions: 7T MRI enables high-resolution anatomical imaging on the submillimeter scale in in vivo subjects. Here, we demonstrate the utility of 7T imaging for identifying the relative location of SEEG electrode implantations within hippocampal substructures for the invasive investigation of epilepsy.

Background: Language mapping is a key goal in neurosurgical planning. With the discontinuation of the Wada test in Canada, neurosurgeons often rely on fMRI and intraoperative techniques for determining language lateralization. Recent studies have also evaluated the utility of diffusion tensor imaging (DTI) for preoperative language lateralization, but further research is needed to confirm its efficacy. We report a patient with a left frontal AVM. fMRI and DTI was used to localize language and motor functioning. Methods: The tasks included word reading, picture naming, pseudohomophones (e.g., dawg) and semantic questions. All fMRI analyses were performed using BrainVoyager. Tensors were tracked from 30-direction diffusion MR images using DSI-Studio. Results: The fMRI results revealed consistent Broca’s and Wernicke’s areas, confirming left hemisphere dominance. There was also a region of activation in the precentral gyrus near the surgical resection. The results were loaded onto the neuronavigation system to help determine safe surgical margins. The DTI results revealed that the left arcuate and uncinate -fasciculus had three times more tracts than the right hemisphere, further supporting left hemisphere dominance. Conclusions: This case highlights the value of a combined, multimodal approach for preoperative language localization, which will further enhance surgical safety by helping preserve regions for essential brain functions.

Background: Neurogenic orthostatic hypotension (NOH), defined as a drop in systolic blood pressure (SBP) ≥30mmHg on standing or head-up tilt, is associated with autonomic dysfunction. The cortical autonomic network (CAN) is a network of brain regions associated with autonomic function. Our aim was to investigate CAN activation patterns in NOH patients during autonomic testing. Methods: Fifteen controls (61±14 years) and 13 NOH patients (68±6 years;p=0.1) completed: 1)Deep Breathing (DB), 2)Valsalva maneuver (VM) and 3)Lower-body negative pressure (LBNP) during a functional MRI. Blood-oxygen level dependent (BOLD) contrasts were obtained and contrasted. Results: Compared to controls (C), patients (NOH) had significantly smaller heart rate (HR) responses to DB (C:15.3±9.6 vs.NOH:6.0±2.2) and VR’s (C:2.1±0.47 vs.NOH:1.2±0.1;p<0.001). Patients had larger SBP drops during LBNP (C: -22.3±6 vs.NOH: -61±22) with -significantly smaller compensatory tachycardias (19±8.5 vs.7.6±4.3)(p<0.001). BOLD response: During VM, controls had greater activation in the right (R) hippocampus (T-value:7.34), left (L) posterior cingulate (T-value:7.22) bilateral mid-cingulate (TR-value:5.76; TL-value:6.84) and bilateral thalamus (TR-value:7.23, TL-value:8.16)(pFWE<0.001). Following subtraction analysis, brain activation patterns showed no significant differences in the regions of interest in response to DB and LBNP. Conclusions: During tests of autonomic function, NOH patient had different cortical activation patterns during VM only. Cortical activation pattern during DB and LBNP showed similar patterns to that of controls.

Background: Serine deficiency disorders can result from deficiency in one of three enzymes. Deficiency of the second enzyme in the serine biosynthesis pathway, 3-phosphoserine aminotransferase (PSAT), has been reported in two siblings when the eldest was investigated for acquired microcephaly, progressive spasticity and intractable epilepsy. Methods: Our patient had neurological symptoms apparent at birth. Fetal magnetic resonance imaging (MRI) at 35 weeks gestation demonstrated microencephaly and simplification of the the gyration (anterior>posterior) which was confirmed upon subsequent post-natal MRI. Congenital microcephaly was apparent at birth. Results: PSAT deficiency was confirmed when exome sequencing identified biallelic mutations in PSAT1; c.44C>T, p.Ala15Val and; c.432delA, p.Pro144fs and biochemical testing noted low plasma serine 22 mcmol/L (normal 83-212 mcmol/L) and low CSF serine 10 mcmol/L (normal 22-61 mcmol/L). Despite oral serine and glycine supplementation at 4 months old the patient showed little neurodevelopmental progress and developed epileptic spasms at 10 months old. Serological testing for TORCH infections was negative. Conclusions: PSAT deficiency should be considered for patients with congenital microcephaly. Although further characterization of MRI findings in other patients is required, microencephaly with simplified gyral pattern could provide imaging clues for this rare metabolic disorder.

Background: Surgical treatment of trigeminal neuralgia (TN) can be highly effective, but durability of pain relief varies and factors influencing surgical failure are poorly understood. We hypothesized that structural brain differences—assessed using magnetic resonance imaging (MRI)—might distinguish surgical responders from early non-responders. Methods: We retrospectively identified 35 TN patients treated surgically from 2005-2017 with high-resolution, -pre-operative MRI scans adequate for quantitative structural analysis. Patients were classified as non-responders if, within 12-months after surgery, they: 1) underwent or were offered another surgical procedure; or 2) reported persistent, inadequately-controlled pain. Volumes of pain-relevant subcortical structures (amygdala, thalamus, and hippocampus) were measured on T1-weighted MRI scans using an automated approach (FSL-FIRST). Results: Surgical responders had significantly larger hippocampi bilaterally compared to early non-responders. Thalamus and amygdala volumes did not differ between groups. Conclusions: Pre-operative differences in brain structure, notably in the hippocampus, may predict durability of response to surgery in patients with TN.

Background: Myasthenia Gravis ( MG) is an autoimmune disease that affects the neuromuscular junction. It typically presents with fluctuating muscle weakness which can affect respiratory muscles. Data about the prevalence of sleep disordered breathing in children with MG and the benefits of non-invasive ventilation outside the setting of MG crisis has not been studied so far. Methods: Eleven children between 3 and 18 years old with confirmed MG were recruited from the The Hospital for Sick Children Neuromuscular clinic in a prospective observational study. Informed consent was obtained and patients underwent PFTs, MIP/MEP, SNIP, FVC and standard polysomnography testing’s. Results: In our study, we found that 2/11 children had abnormal Apnea Hypopnea index (AHI) and were diagnosed with obstructive sleep apnea (OSA). One of them has juvenile ocular MG with mild to moderate OSA and the second child has congenital MG with mild OSA. CPAP therapy was initiated for both patients. Conclusions: In our cohort, obstructive sleep apnea rate was significantly higher in children with MG than the known prevalence in general pediatric population ( 18% vs 2-3% ). Early diagnosis and management of OSA can have great impact on children’s health and quality of life. A larger study is needed to validate our findings.

Background: Methionyl-tRNA synthetase (MARS) links methionine to its cognate tRNA required for translation. MARS mutations have been linked to adult-onset CMT2U. Methods: The proband had weakness in her first year of life, sitting at 11 months and walking at 20 months old. At 4 years old she was areflexic with distal > proximal weakness. Nerve conduction studies showed normal median and sural sensory responses with absent common peroneal, low median and tibial motor amplitudes. EMG noted denervation and quadriceps biopsy revealed neurogenic atrophy. Genetic testing for spinal muscular atrophy and sequencing of MNF2, RAB7A, LMNA, MPZ, HSPB1, NEFL, GADP1, TRPV4, HSPB8, GJB1 and PLEK8G5 were negative. She stopped walking at 9 years old and could not raise her arms above her head at 11 years old. Results: Exome sequencing identified MARS: c.1189G>A; p.Ala397Thr. To determine the functional consequences of p.A397T-MARS, yeast complementation assays were performed. Wild type or mutant MARS were cloned into yeast lacking the endogenous MARS ortholog. Wild-type MARS supported robust cellular growth, while the p.A397T-MARS insert did not support cellular growth confirming deleterious effect of this variant. Conclusions: Our patient’s phenotype was similar to children with motor-predominant GARS mutations. Functional data notes this MARS variant to be damaging and predictive of a severe, early-onset phenotype.

Background: Hereditary spastic paraplegia (HSP) is a group of genetic diseases that cause progressive degeneration of the corticospinal tract. Historically, this disease was divided into two types:the classic subtype, with leg weakness and hypertonic bladder, and the complicated subtype, with features such as cerebellar ataxia or optic atrophy.Mutations in SPG7 (encoding paraplegin) leads to complicated HSP causing cerebellar ataxia, progressive external ophthalmoplegia in addition to the classical symptoms. AFG3L2 is a binding partner of paraplegin and mutations in AFG3L2 cause a similar syndrome Methods: From a neurogenetic clinic , we identified 11 patients with late-onset HSP. Sequencing of SPG7 and AFG3L2 was performed using a customised assay, and/or clinical diagnostic sequencing panels.SPG7 transcript level quantification was performed from whole blood RNA on a digital droplet qPCR system. Results: We identified 4 patients with pathogenic variants or variants of unknown significance in SPG7. No AFG3L2 mutations were identified. We provide evidence for pathogenicity for three mutations that were not previously associated with SPG7-related disease, based on their occurrence in context of the correct phenotype, and the reduction of transcript levels measured with RT-qPCR.A curious association of the heterozygous p.Gly349Ser mutation in association with an ALS-like syndrome is reported. Conclusions:SPG7 mutations sequencing has high diagnostic yield in late onset paraparesis

Background: When measuring young Duchenne Muscular Dystrophy (DMD) patients’ health-related quality of life (HRQoL), parent-proxy reports are heavily relied on. Therefore, it is imperative that the relationship between parent-proxy and child self-report HRQoL is understood. This study examined the level of agreement between children and their parent-proxy rating of the child’s HRQoL. Methods: We used FOR-DMD clinical trial baseline data. HRQoL, measured using the PedsQL inventory, was reported by 178 parent and child (ages 4 to 7 years) dyads. Intracorrelation coefficients (ICC) measured absolute agreement while paired t-tests determined differences in the average HRQoL ratings between groups. Results: The level of agreement between child and parent-proxy ratings of HRQoL was poor for the generic PedsQL scale (ICC: 0.29) and its subscales; and, similarly low for the neuromuscular disease module (ICC:0.16). On average, parents rated their child’s HRQoL as poorer than the children rated themselves in all scales except for psychosocial and school functioning. Conclusions: Child and parent-proxy HRQoL ratings are discordant in this study sample, as occurs in other chronic pediatric diseases. This should be taken into account when interpreting clinical and research HRQoL findings in this population. Future studies should examine reasons for parents’ perception of poorer HRQoL than that reported by their children.

Background: Cardiac dysfunction has significant impact on morbidity and mortality in patients with mitochondrial disorders. Cardiac screening tests are generally recommended because cardiac dysfunction can occur at any point in the disease course, and is amenable to treatment. However there is no clear evidence indicating the best screening strategy in patients with mitochondrial myopathy. Methods: Systematic review of the literature for cardiac investigations in adult patients with mitochondrial myopathy. We considered 1303 relevant abstracts, from which 58 full-length articles were reviewed. Seventeen articles including 701 total participants met inclusion criteria. Data extracted included age, diagnosis, and results from ECG, echocardiogram, cardiac MRI, nuclear medicine studies, and Holter monitor. Results: We identified echocardiogram and ECG as the principal screening modalities, that identify cardiac structural (26%) and conduction abnormalities (37%) in patients from various mitochondrial myopathy syndromes. Holter monitor was not a high yield investigation and limited studies were identified using cardiac MRI or nuclear medicine. Conclusions: We recommend screening with ECG and echocardiogram every 1-2 years in MERRF/MELAS, and every 3-5 years in milder syndromes when cardiac symptoms are not present. Only five of the included studies provided any follow-up data. We recommend studies of natural history, therapeutic response, and of cardiac MRI as areas for future study.

Background: The interaction between mutations in two or more genes is increasingly recognised as an important contributor to the phenotypic variability in genetic disorders. Co-occurrence of variants in SQSTM1 and TIA1 is reported as a cause of myopathy in 3 prior cases, but limited clinical data were presented. We present detailed clinical features of a family with two siblings having a distal myopathy with rimmed vacuoles (DMRV), and genetic variants in SQSTM1 and TIA1. Methods: Clinicopathologic study of a family with DMRV to describe clinical features, laboratory and neurophysiology studies, neuroimaging, and genetic sequencing. Results: Two siblings with variants in SQSTM1 and TIA1 developed myopathy in their early 60’s, with early involvement of ankle dorsiflexors and finger extensors. A decade after onset, patients remain ambulatory and have not developed cardiac or respiratory complications. MRI of the legs showed selective involvement of adductor magnus, vastus lateralis, and in lower legs the anterior compartment and medial gastrocnemius. Muscle pathology demonstrated rimmed vacuoles, disrupted myofibrillar architecture, and mislocalised TDP43. Two unaffected family members had one genetic variant but not both. Conclusions: We describe a fourth family with co-occurrence of TIA1 and SQSTM1 genetic variants and describe their detailed phenotype. Future study should address the mechanism of the interaction between these two variants.

Background: The association of myasthenia gravis (MG) and inflammatory myositis (IM) is rare and often only one of the diseases is diagnosed. Methods: In this study, we reviewed medical records of patients seen at NMDU from 2004 to 2017 who had diagnosis of concurrent MG and IM. The data is presented descriptively. -Results: We identified 7 patients with MG-IM overlap. Clinical features, laboratory and pathology data of the patients are summarized in Table 1. Conclusions: This is one of the largest case series with MG-IM overlap. It is very important to recognize such association and the different pattern of muscle involvement because therapies may be adjusted to treat both conditions. In patients with thymic pathology, conventional disease modifying agents, IVIG and glucocorticoid in addition to thymoma resection appear to be effective. In patients with refractory MG and myositis who were AChR negative, rituximab may be effective.

Background: Duchenne muscular dystrophy (DMD) is an X-linked disorder affecting 1:3500-5000 live male births, causing a life-limiting form of muscular dystrophy. Whole exon deletions disrupting the reading frame result in near-absence of sarcolemmal dystrophin, essential for muscle function. Eteplirsen is a phosphorodiamidate morpholino oligomer (PMO) designed to induce production of internally-truncated dystrophin in certain patients. Methods: As of June 2016, 150 patients (4-19 years of age) with DMD received eteplirsen in 7 clinical trials. 143 patients received ≥1 intravenous infusion of eteplirsen (range: 0.5 - 50 mg/kg). 81 (54%) received treatment for ≥1 year (Range: 1-4+ years). Results: Common (>15%) adverse events (AEs) were cough, headache, vomiting, back pain, extremity pain, contusion, nasopharyngitis, upper respiratory tract infection, nasal congestion, arthralgia and rash. Non-serious facial flushing, erythema and mild transient temperature elevation occurred with eteplirsen. 10 (6.7%) patients experienced severe AEs; 12 (8%) patients experienced serious AEs. All serious and all but 1 severe AEs were considered unrelated to eteplirsen by the treating physicians. Serial echocardiograms in 12 treated patients demonstrated no functional decline over 4+ years. Conclusions: Eteplirsen’s tolerability will continue to be assessed in ongoing clinical trials.

An updated data summary will be presented.

Background: Congenital Myasthenic Syndromes (CMS) are heterogeneous disorders caused by genetically determined structural or functional differences in proteins involved with the neuromuscular junctions. Clinical and molecular genetics studies of CMS patients have revealed significant locus heterogeneity; there are 21 known genes related to CMS, but other genes may mimic the phenotype, justifying the use of a multi-gene panel for genetic testing Methods: Our group developed custom sequence capture probes designed to flank 27 different genes associated with CMS, including enrichment for all coding exons as well the flanking intronic regions. We enrolled 20 patients from the paediatric and adult neuromuscular clinic with a clinical phenotype of CMS. Using custom analytical, we -assessed the sequence variants and exon-level CNVs for each patient. Results: Thirteen male and seven female patients with median age of 12.25 years (range 1.5-39y) were assessed. We identified missense and CNVs in 17 patients, including established pathogenic mutations confirming the diagnosis in 5 patients Conclusions: The use of Next Generation Sequence with CNV for CMS can help determine the underlying causes of most CMS disorders and allow appropriate medical treatment, refined genetic counseling, and improved understanding of prognosis, justifying the implementation in the standard clinical screening of CMS.