Introduction: Patients presenting with high grade (HG) subarachnoid hemorrhage (SAH) from aneurysmal rupture may have persisting neurologic deficits which may lead to questioning the decision of treating aggressively. The objective of this study aims at analyzing outcome and long-term quality of life (QOL) of patients with HG SAH treated surgically. Methods: Retrospective study of patients with Hunt Hess (HH) grade IV or V SAH treated surgically at our institution. Long-term outcome was evaluated based on the modified Rankin Scale (mRS) at 3 years. Survivors were evaluated for QOL using various scales. Results: 63 patients (mean age of 52 year-old) were included. Intraparenchymal hemorrhage (IPH) was found in 85% of cases. 19 patients died. Predictive factors of poor prognosis and mortality were initial cerebral ischemia (p=0.003) and IPH (p=0.007). Favourable outcome (mRS 0-3) was found in 41% of patients. QOL questionnaires revealed that 80 % of responders showed more than 50% recovery. Mild or absent depression was observed in 78% of patients. Conclusion: In this surgical series, performed in an endovascular era, nearly all patients presented with SAH-associated IPH at admission. Despite the presence of such negative prognostic factor and the poor condition at admission, a high rate of favourable outcome and QOL was observed, therefore justifying aggressive surgical treatment.

Background: Fundoscopy is an important component of the neurological examination, but can be challenging in uncooperative children. This study explores whether playing a video during eye examination, improves the success, duration and ease of pediatric fundoscopy. Methods: We completed a prospective, multi-clinic, block-randomized trial. Patients 1-4 years were recruited in the emergency department, neurology, spinal cord and general pediatric clinic. Patients were randomized (by eye examined) to video/non-video assisted fundoscopy. Successful exams were defined as visualizing the fundus within 60 seconds. Time to visualize optic disc was recorded and difficulty of exam was examined using a 10-point Likert scale. Results: 101 subjects were recruited, with a mean age of 2.8 years. Overall, there was a 20% absolute improvement in the success rate of visualizing the optic disc in the video versus non-video group (p<0.01). Time to visualize optic disc was also improved (Δ5.3s, p<0.01). Improvement in ease of examination with video were noted by caregivers and practitioners (p<0.01). Conclusion: Playing a video improved the ease, duration and most importantly the success of fundoscopy in younger children. This simple, inexpensive adjunct has great potential to improve the ease and efficacy of this aspect of the neurological examination.

Background & Objectives: Of patients with pyridoxine-dependent epilepsy (PDE) due to ATQ deficiency, 75% suffer intellectual disability despite adequate seizure control with high dose pyridoxine. We aimed to assess the safety and efficacy of two novel therapeutic strategies to reduce accumulation of toxic intermediates in this cerebral lysine degradation defect. Methods: In two open-label observational studies, seven children with confirmed ATQ deficiency were started on dietary lysine restriction with regular nutritional monitoring, and outcome evaluation pipecolic acid, AASA levels in body fluids; development/cognition via age-appropriate tests and parental observations; epilepsy). Subsequently additional arginine supplementation was initiated to reduce cerebral lysine flux (cation transporter competitive inhibition).. Results: Lysine-restriction was well tolerated and diet is safe, resulted in reduction of lysine intermediates in all body fluids in all patients (up to 80% reduction AASA in cerebrospinal fluid), with beneficial effects on seizure control and psychomotor development. Additional arginine fortification resulted in normalization of biomarkers and dramatic improvement of psychomotor development. Discussion: Triple therapy is effective, especially if implemented early; studies for PDE newborn screening have been initiated. For dissemination and evidence generation, our PDE Consortium published Recommendations, developed a Digital Diet App and established a RedCap study database (www.pdeonline.org).

Background: Little knowledge exists on the availability of paediatric neurology positions. Our study aimed to: 1) obtain information regarding the availability of positions for paediatric neurologists in academic centres; 2) survey paediatric neurology trainees regarding their perceptions of employment issues and career plans; 3) survey practicing community paediatric neurologists 4) convene a group of paediatric neurologists to develop a consensus regarding how to address these workforce issues. Methods: Surveys addressing workforce issues regarding paediatric neurology in Canada were sent to: 1) all paediatric neurology program directors in Canada who then solicited information from division heads and from paediatric neurologists in surrounding areas; 2) paediatric neurology trainees in Canada and; 3) community paediatric neurologists. A meeting was held with relevant stakeholders to develop a consensus on how to approach employment issues. Results: We found that the number of projected positions in academic paediatric neurology is fewer than the number of paediatric neurologists that are being trained. Paediatric neurology residents are concerned about job availability and desire more career counselling. Conclusions: There is a current and projected clinical demand for paediatric neurologists despite a lack of academic positions. Training programs should focus on community neurology as a viable career option.

Background: Term neonates with congenital heart disease (CHD) demonstrate a high incidence of white matter injury (WMI), together with increased average diffusivity and decreased fractional anisotropy (FA) on MR diffusion tensor imaging. EEG background activity is a robust measure of functional brain maturation that becomes less discontinuous, contains more fast activity and shows higher complexity of EEG patterns with increasing age. We sought to determine the association between structural brain abnormalities and functional brain maturation in term neonates with CHD. Methods: Thirteen term newborns with CHD underwent pre-operative MR imaging and continuous EEG recordings (cEEG). The proportion of cEEG with discontinuous vs. continuous background activity was quantified by visual analysis. During continuous epochs, we differentiated between two states: wakefulness/active sleep vs. quiet/transitional sleep, and applied algorithms to measure spectral power and EEG complexity. Results: Three patients had multifocal WMI which was associated with greater EEG background discontinuity (P<0.05). Moreover, lower white matter diffusivity was associated with higher power of fast activity (P<0.05 for wakefulness/active sleep EEG pattern), while higher white matter FA showed a trend toward being associated with increased EEG complexity (P<0.1 for quiet/transitional sleep pattern). Conclusions: In this series of term neonates with CHD, structural and microstructural white matter abnormalities are associated with impaired maturation of brain function.

Background: It has been hypothesized that [18F]-sodium fluoride (NaF) uptake imaged with positron emission tomography (PET) binds to hydroxyapatite molecules expressed in regions with active calcification. Therefore, we aimed to validate NaF as a marker of hydroxyapatite expression in high-risk carotid plaque. Methods: Eleven patients (69 ± 5 years, 3 female) scheduled for carotid endarterectomy were prospectively recruited for NaF PET/CT. One patient received a second contralateral endarterectomy; two patients were excluded (intolerance to contrast media and PET/CT misalignment). The bifurcation of the common carotid was used as the reference point; NaF uptake (tissue to blood ratio - TBR) was measured at every PET slice extending 2 cm above and below the bifurcation. Excised plaque was immunostained with Goldner’s Trichrome and whole-slide digitized images were used to quantify hydroxyapatite expression. Pathology was co-registered with PET. Results: NaF uptake was related to the extent of hydroxyapatite expression (r=0.45, p<0.001). Upon classifying bilateral plaque for symptomatology, symptomatic plaque was associated with cerebrovascular events (3.75±1.1 TBR, n=9) and had greater NaF uptake than clinically silent asymptomatic plaque (2.79±0.6 TBR, n=11) (p=0.04). Conclusion: NaF uptake is related to hydroxyapatite expression and is increased in plaque associated with cerebrovascular events. NaF may serve as a novel biomarker of active calcification and plaque vulnerability.

Background: Recent consensus recommendations for Tuberous Sclerosis Complex (TSC) stress the importance of multidisciplinary follow-up for these patients. The objective of our study was to review the manifestations of TSC seen in our hospital to determine the care needs of this population. Methods: This was a systematic, retrospective chart review of children with TSC treated at our institution. Patients were identified through epilepsy and clinical neurophysiology databases. Results: The study population comprised 81 patients, born between 1987-2014, who were a median 10 (Range 0.2-23.2) years of age at last follow-up. 88% of patients had epilepsy, including 30% with a history of infantile spasms. Developmental delay was reported in 65%, while 40% had intellectual disability. Psychiatric co-morbidities occurred in 49%. The most common psychiatric diagnoses were autism (25%), ADHD (19%), and anxiety (16%). Cardiac rhabdomyomas occurred in 35% of patients and renal angiomyolipomas in 42%, while only 4% had polycystic kidneys. Subependymal giant cell astrocytomas were observed in 14% of patients. 86% had skin manifestations. Conclusions: This study reaffirms the multi-system manifestations of TSC and the need to provide comprehensive, multidisciplinary care. As many children are still very young, the prevalence of autism and intellectual disability is likely underestimated.

Background: Epilepsy occurs in up to 90% of patients with Tuberous Sclerosis Complex (TSC) and is often refractory to medications. Our objective was to assess the safety and outcome of epilepsy surgery in children with TSC at our institution. Methods: We performed a systematic, retrospective chart review of children with TSC who underwent epilepsy surgery at our institution. Patients were identified through epilepsy and clinical neurophysiology databases. Results: 19 patients (out of 81 with TSC) underwent surgery between 1995-2014. Median age at surgery was 4.2 (Range 1.1-15.6) years, with patients having failed a median 4 (Range 0-10) anti-seizure medications. Surgery comprised corpus callosotomy in 2 and resection of one or more tubers in 17. 2 patients had a subsequent second resection. Minor neurologic deficits occurred after 14% of surgeries. Median follow-up was 2.4 years (Range 0.3 -13.8 years) following surgery . At last follow-up, 47% were seizure free, including 2 patients off anti-seizure medication. Conclusions: Epilepsy surgery is safe and effective in carefully selected TSC patients, with the majority having a good seizure outcome. Children with epilepsy secondary to TSC should be referred for epilepsy surgery assessment.

Background: Neonatal arterial ischemic stroke (NAIS) is a leading cause of brain injury and cerebral palsy. Diffusion-weighted imaging (DWI) has revolutionized NAIS diagnosis and outcome prognostication. Diaschisis refers to changes in brain areas functionally connected but structurally remote from primary injury. We hypothesized that acute DWI can demonstrate cerebral diaschisis and evaluated associations with outcome. Methods: Subjects were identified from a prospective, population-based research cohort (Calgary Pediatric Stroke Program). Inclusion criteria were unilateral middle cerebral artery NAIS, DWI MRI within 10 days of birth, and >12-month follow-up (Pediatric Stroke Outcome Measure, PSOM). Diaschisis was quantified using a validated software method. Diaschisis-scores were corrected for infarct size and compared to outcomes (Mann-Whitney). Results: From 20 eligible NAIS, 2 were excluded for image quality. Of 18 remaining, 16 (89%) demonstrated diaschisis. Thalamus (88%) was most often involved. Age at imaging was not associated with diaschisis. Long-term outcomes available on 13 (81%) demonstrated no association between diaschisis score and PSOM categories. Conclusion: Cerebral diaschisis occurs in NAIS and can be quantified with DWI. Occurrence is common and should not be mistaken for additional infarction. Determining additional clinical significance will depend on larger samples with long-term outcomes.

Introduction: HNPP presentation in childhood is rare and diverse and most of the published literature is based on case reports. Materials and Methods: we analyzed the data of 11 children with deletion in PMP22 gene, reviewed the published reports of HNPP in children and compared our data with the reports from the literature review. Results: Peroneal palsy was the most common presentation (50%) followed by the brachial plexus palsy in 30% of cases. The trigger of the demyelinating event was identified only in 27%. 72% of our cohort developed only one acute episode of nerve palsy. Nerve conduction studies were always suggestive of the diagnosis demonstrating 60% of cases a polyneuropathy, 50% of cases conduction block but 100% of bilateral or unilateral electrophysiologic entrapment of the median nerve at the carpal tunnel. Conclusion: The clinical presentation of HNPP in childhood is heterogeneous and EMG findings are abnormal. Any unexplained mononeuropathy or multifocal neuropathy should lead to PMP22 gene testing to look for the deletion. Early diagnosis is important for the genetic counselling but also for the appropriate care of these patients.

Pediatric acquired demyelinating syndromes have overlapping clinical and imaging features, but management and prognosis vary. We describe four children between the ages of 3 and 10 presenting with inflammatory brain disease - one with polyfocal neurological symptoms, one with severe bilateral optic neuritis and two with transverse myelitis, all without encephalopathy. All brain MRIs had extensive involvement of both deep grey and subcortical white matter. Three patients had longitudinally extensive spinal cord lesions. Clinical and radiological findings did not meet criteria for multiple sclerosis, acute disseminated encephalomyelitis, or neuromyelitis optica (NMO). NMO IgG testing was negative. All patients had resolution of clinical and imaging findings after treatment with steroids and IVIg. We found, elevated levels of anti-myelin oligodendrocyte glycoprotein antibodies in all four patients. Three of the children receive monthly IVIg infusions. Two of the patients relapsed once within 18 months of their initial attack and have since remained relapse free for 32 months and 43 months, respectively. The third patient (transverse myelitis) has not had any relapses since her initial attack 15 months ago. It appears that children with this syndrome may have more favourable outcomes when compared to other CNS relapsing inflammatory conditions.

Background: We hypothesized that abnormal blood platelet count (BPC) is associated with poorer outcomes after acute ischemic stroke. Methods: We included data from the Registry of the Canadian Stroke Network on consecutive patients with acute ischemic stroke admitted between July/2003 and March/2008. Patients were divided into groups as follows: low BPC (<150,000/mm3), normal BPC (150,000 to 450,000/mm3) and high BPC (>450,000/mm3). Primary outcome measures were the frequency of moderate/severe strokes on admission (Canadian Neurological Scale: <8), greater degree of disability at discharge (modified Rankin score: 3-6), and 30-day and 90-day mortality. Results: We included 9,230 patients. Both low and high BPC were associated with higher 30-day mortality (p=0.0103) and 90-day mortality (p=0.0189) following acute ischemic stroke. The Kaplan-Meier curves indicate that abnormal BPC is associated with greater mortality after acute ischemic stroke (p=0.0002). Nonetheless, abnormal BPC was not associated with degree of impairment (p=0.3734), degree of disability (p=0.684), or length of stay (LOS) in the acute stroke care center (p=0.9541) after adjustment for major potential confounders. Conclusions: In patients with acute ischemic stroke, thrombocytopenia and thrombocytosis on the initial admission is associated with higher mortality after stroke. Abnormal BPC does not adversely affect the degree of impairment and disability, or LOS in the acute care center after acute ischemic stroke.

Background: Arteriopathy causes most childhood arterial ischemic stroke (AIS). Mechanisms are poorly understood but may include abnormalities of arterial structure. Extracranial dissection is common while intracranial dissection may explain idiopathic focal cerebral arteriopathy (FCA). We aimed to quantify cerebral arterial tortuosity and hypothesized increased tortuosity in extracranial dissection. Methods: Children with AIS were recruited within the Vascular-Effects-of-Infection-in-Pediatric-Stroke (VIPS) study (controls from the Calgary Pediatric Stroke Program). A validated software method calculated mean tortuosity of major cerebral arteries using 3D time-of-flight MR angiography (MRA). Blinded, multi-investigator reviews defined diagnostic categories. Tortuosity was compared between dissection (spontaneous and traumatic), FCA, moyamoya, meningitis, and cardioembolic, and controls (ANOVA, post-hoc Tukey). Results: A total of 116 children were studied. Age and gender were comparable across groups. Tortuosity scores and variances were consistent with validation studies. Tortuosity in controls (1.333±0.039, n=15) was comparable to moyamoya (1.324±0.038, p=0.99, n=15), meningitis (1.348±0.052, p=0.98, n=12) and cardioembolic (1.379±0.056, p=0.19, n=27) cases. Tortuosity was higher in dissection (1.398±0.072, p=0.02, n=22) and FCA (1.421±0.076, p=0.001, n=25). Traumatic (1.391±0.036, n=9) and non-traumatic (1.403±0.090, p=0.671, n=13) scores were not different. Conclusion: Children with dissection have more tortuous arteries. Quantified tortuosity may represent a clinically relevant biomarker of vascular biology in pediatric stroke.

Background: Whether the dorsal striatum (DS) mediates cognitive control or cognitive effort per se in decision-making is unclear because as cognitive control requirements of a task intensify, cognitive effort requirements increase proportionately. We implemented a task that disentangled cognitive control and cognitive effort to specify the function DS mediates in decision-making. Methods: Sixteen healthy young adults completed a number Stroop task with simultaneous blood-oxygenation-level-dependent response (BOLD) measurement. Participants selected the physically larger number of a pair. Discriminating smaller physical size differences increases cognitive effort, but does not demand greater cognitive control. We also investigated the effect of interdimensional conflict between physical size and numerical magnitude. Selections in this incongruent case are more cognitively effortful and require greater cognitive control to suppress responding to the irrelevant dimension. Enhancing cognitive effort or cognitive control requirements increases response times and error rates. Results: Behavioural interference occurred for both conditions; however, DS BOLD signal only correlated with interference due to increased cognitive control requirements. DS was not preferentially activated for discriminations of smaller relative to larger physical size differences between number pairs, even when using liberal statistical criteria. Conclusions: Our findings support the increasingly accepted notion that DS mediates cognitive control specifically and does not index cognitive effort per se.

Background: There are no disease modifying agents for the treatment of Alzheimer’s disease (AD). Pathologically, AD is associated with the misfolding of two peptides: beta-amyloid (plaques) and tau (tangles). Methods: Using large-scale computer simulations, we modelled the misfolding of both beta-amyloid and tau, identifying a common conformational motif (CCM; i.e. an abnormal peptide shape), present in both beta-amyloid and tau, that promotes their misfolding. We screened a library of 11.8 million compounds against this in silico model of protein misfolding, identifying three novel molecular classes of putative therapeutics as anti-protein misfolding agents. We synthesized approximately 400 new chemical entity drug-like molecules in each of these three classes (i.e. 1200 potential drug candidates). These were comprehensively screened in a battery of five in vitro protein oligomerization assays. Selected compounds were next evaluated in the APP/PS1 doubly transgenic mouse model of AD. Results: Two new classes of molecules were identified with the ability to block the oligomerization of both beta-amyloid and tau. These compounds are drug-like with good pharmacokinetic properties and are brain-penetrant. They exhibit excellent efficacy in transgenic mouse models. Conclusion: Computer aided drug design has enabled the discovery of novel drug-like molecules able to inhibit both tau and beta-amyloid misfolding.

Vagus Nerve Stimulation (VNS) therapy has been widely recognized as an alternative for the treatment of drug resistant epilepsy (DRE), although modification of AEDs during VNS treatment could explain improvement in patients. We retrospectively assessed the efficacy of VNS in 30 adult epileptic patients treated with > 6 months follow-up. The criteria for implantation were the following: a) not candidate for resective epilepsy surgery, b) DRE, c) impairment of quality of life, d) no other option of treatment. We assessed socio-demographics, seizure etiology, seizure classification and AEDs used during treatment with VNS. We assessed adverse effects and efficacy. Responder rate was defined as >50 seizure improvement from baseline, Thirty patients (females-18, males-12; age 35.1+13.3) were included. After 6 months, 12 months, 24 months and 36 months, the response rate was as follows: 13/30(43%), 13/27 (48%), 9/22(41%) and 16/8 (50%), none of them were seizure free. Changes of AEDs were done in 57% of patients at 6 months, 43% at 12, 43% at 24, 43% at 24 months. Other outcomes will be discussed. Our study shows that VNS is an effective therapy although significant changes in medications were done along the therapy, therefore the real effect of VNS could be controversial

Introduction: Decompressive craniectomy (DC) in severe traumatic brain injury (TBI) is controversial. The impact DC on cause of death is unclear in the literature to date. Methods: We performed an institutional retrospective review, from June 2003 to June 2013, of patients with severe blunt TBI undergoing DC whom subsequently died. We compared this group to a retrospectively matched cohort based: age, pre-hospital mRS, Marshall diffuse and TBI grades, Injury Severity Scores, and admission laboratory values. The goal was to determine the cause of death between those receiving DC and those managed medically. Results: Nineteen patients received DC and were compared to 16 retrospectively matched patients. The mean age of the DC and matched cohort were 47.1 and 43.6 years, respectively. The mean admission GCS/Marshall diffuse CT grades were 5.8/3.4 for the DC group, and 4.1/3.1 for the matched medical cohort. Overall, in the DC group 94.7% of the deaths occurred secondary to cardiac arrest after withdrawal of life sustaining treatment (WLST), with only 5.3% progressing to brain death. Alternatively, in the matched cohort 62.5% died of cardiac arrest post WLST, with 37.5% progressing to brain death. Conclusions: Progression to brain death appears to be more common in those severe blunt TBI patients treated medically compared to those undergoing DC.

Introduction: Our goal was to perform a systematic review of the literature on the use of intravenous lidocaine in adults for status epilepticus (SE) and refractory status epilepticus (RSE) to determine its impact on seizure control. Methods: All articles from MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform (inception to November 2014), and gray literature were searched. The strength of evidence was adjudicated using both the Oxford and GRADE methodology by two independent reviewers. Results: Overall, 13 studies were identified, with 11 manuscripts and 2 meeting abstracts. Seventy-six adult patients were treated for 82 episodes of SE/RSE. Patients had varying numbers of anti-epileptic drugs (AEDs), 1 to 12, on board prior to lidocaine therapy. During 69 of the 82 (84.1%) episodes of SE/RSE, phenytoin was on board. The dose regimen of lidocaine varied significantly. Overall, 70.7% of seizures responded to lidocaine, with complete cessation and greater than 50% reduction seen in 64.1% and 6.1% respectively. Patient outcomes were sparingly reported. Conclusions: There currently exists level 4, GRADE C evidence to support the consideration of lidocaine for SE and RSE in the adult population. Further prospective studies of lidocaine administration in this setting are warranted.

Background: Cognitive impairments are now recognized in Parkinson’s disease. Some of these deficits owe to disease pathology itself whereas others are due to paradoxical effects of dopaminergic medications, such as levodopa. The dopamine overdose hypothesis proposes that dissimilar effects of medication on cognition depend on baseline endogenous dopamine levels in underlying brain regions. We sought to directly test this prevalent theory. Methods: We tested healthy adults, who presumably have optimal endogenous dopamine levels, in two sessions. Participants received 100/25 mg of levodopa/carbidopa in one session and an equal volume of placebo in the other. During each session, participants completed a probabilistic reversal learning task. The number of trials to task completion was used as a behavioural proxy of learning performance. Results: A paired t-test covaried with drug-placebo order revealed that healthy adults learned more poorly on levodopa compared to placebo. Conclusions: Our findings suggest that baseline endogenous dopamine levels are a critical factor determining the effects of dopaminergic medications on cognition, independent of Parkinson’s disease pathology. Partitioning which cognitive functions are helped versus hindered by medication and improving our understanding of the underlying psychopharmacology of these effects is important for improving treatment strategies in Parkinson’s disease.

Introduction: A cost-minimization analysis (CMA) was performed comparing IVIg and PLEX in the management of patients with exacerbation of myasthenia gravis (MG). Methods: This study combines Ontario-based health costing data with clinical data from a randomized clinical trial where patients with moderate/severe MG received either IVIg or PLEX. The CMA was undertaken under the perspective of a public health care insurer and under the perspective of a tertiary hospital payer. Results: The IVIg group (n=32) was comparable with the PLEX group (n=38) regarding demographics, disease characteristics and severity. PLEX was less costly than IVIg among patients with body mass index (BMI) ≤15.7 Kg/m2, under the perspective of a public health care insurer (CAN$6,271.18 versus CAN$8,309.72, p<0.0001). However, PLEX was more costly than IVIg under the perspective of the hospital payer when the costs of blood products were excluded (CAN$4,815.36 versus CAN$1,486.12, p<0.0001). Conclusions: PLEX may be a short-term cost-minimizing therapy when compared with IVIg for treatment of MG exacerbation among patients with BMI ≤15.7 Kg/m2, under the perspective of a public health care insurer. However, when the costs of blood products are absorbed by a third party, the hospital administration may see IVIg as a more attractive therapeutic alternative.