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.

Background: Acquired brain injury is a critical health problem in Canada, placing greater demands on health resources as improvements in intensive care lead to more patients in long-term care. Clinical diagnosis of patients with disorders of consciousness remains difficult, but advances in neuroimaging research have the potential to reshape clinical management of such patients or provide unprecedented ways to communicate with them. Building on our earlier work, this study identifies ethically salient priorities for research and policy before translation of this promising technology. Methods: We interviewed 27 Canadian researchers, ethicists, lawyers, practitioners, allied health care professionals, and patient advocacy leaders, with expertise in neuroimaging or disorders of consciousness. Interviews were semi-structured and data were analyzed for emergent themes. Results: Participants were optimistic that neuroimaging could lead to improved clinical care. They discussed mitigating the risks of misinterpreting results and communication, creating guidelines for clinical use, and defining legal competence in this neuroimaging context as key ethical priorities for translation. Conclusions: The transition of neuroimaging techniques for disorders of consciousness from research to clinical care may yield substantial benefits to these patients, but first requires resolution of research, policy, and translational issues.

Background: To identify differences in the recurrence pattern of surgically-resected skull base meningiomas compared with superficial intra-cranial meningiomas Methods: A retrospective hospital-based study of all patients referred to our institution from 1990 to 2014 for surgical resection of meningiomas was conducted (both primary and recurrent cases). Survival analysis was performed using IBM SPSS v22.0. Results: Overal, 398 intra-cranial meningiomas –129 (32%) skull base - were reviewed. Skull base tumors had a lower MIB-1 index (p = 0.001) and were more likely to be WHO I (p = 0.003). Meningiomas in all locations demonstrated a recurrence rate of 30% at 100 months of follow-up. Afterwards, the recurrence of skull base meningiomas plateaued (longest follow-up: 250 months) whereas superficial lesions had a recurrence rate of 80% at 230 months (p = 0.02). In multivariable analysis, patients with a first-time diagnosis (p = 0.02), those with WHO I or II tumors (p= 0.02 and 0.05), and those with a total resection (p < 0.01) were less likely to experience a recurrence. Conclusions: Skull base meningiomas are less aggressive than superficial lesions and may not need to be followed beyond 100 months. The WHO grade, complete resection, and prior recurrence are predictive factors of recurrence.

Background: The American Board of Neurological Surgeons (ABNS) made persons beginning neurosurgical training in Canada after 1997 ineligible for ABNS board exams and certification in the United States (US). We set out to track employment outcomes for graduates who are “ABNS ineligible.” Methods: Graduates from Canadian neurosurgical programs who began training from 1998 to 2008 (ABNS ineligible) were followed regarding their employment status (n=143). Data was obtained from public-domain websites and direct connections though Canadian Neurosurgical Society (CNSS) members. Association between pursuit of research during residency (MSc, PhD, or ≥ 2 years of non-degree research) and full employment was determined by Fisher’s exact test. Results: 60% and 26% of graduates currently have full-time staff positions in Canada and the US, respectively. “Underemployment,” defined as failure to secure a full-time position in neurosurgery despite a desire to do so (including locums, additional fellowship positions, unemployment and career changes) is currently seen in 12% of graduates, with 20% having been underemployed at some point within 5 years of graduation. Pursuit of research during residency was significantly associated with obtaining full employment (94% vs. 73%, p=0.011). Conclusions: Underemployment is a significant issue in recent neurosurgical graduates from Canadian training programs. Research training during residency appears strongly associated with obtaining full employment.

Background: Bilateral jumped facets (BJF) are serious cervical spine injuries that require reduction and surgical stabilization. Closed reduction often performed, however, the argument of having disc herniation suggested deferred treatment until MRI is done. The later has been criticised for delaying the treatment. Methodology: We conducted a systematic review focusing on BJF in order to assess the validity of performing an MRI prior to closed reduction. The immediate neurological state after reduction and long term outcome were the primary goals. Results: A total of 49 articles were found (1973-2014). Only 20 of them fit our criteria. A total of 203 BJF were evaluated with C6/7 and C5/6 being the most common level of injury. Closed reduction was performed in 194 patients with no MRI in 118 patients. Clinical changes had occurred in 7 patients (3 improved, 2 worsened, 2 transient worsening). The long term outcome showed no significant difference between the two groups who had closed reduction before or after the MRI (p>0.05) Conclusion: The risk of neurological worsening with closed reduction prior to MRI is low and insignificant. The MRI will be helpful post reduction to assess the status of the cord and adequacy of closed reduction, especially in comatose patients.

Objective: Failed back surgery syndrome (FBSS) describes neuropathic pain that occurs when extremity symptoms in lumbar disease persist despite structurally corrective spinal surgery. It is unclear whether specific preoperative pain characteristics predict patients prone to such postoperative disabling symptoms. Methods: This prospective study analyzed surgical patients with painful radiculopathy secondary to lumbar degenerative disease. Clinical parameters included general demographic information, preoperative and postoperative clinical examination, self-reported pain and disability scores, and neuropathic pain scoring. The neuropathic pain screening tests used in this study were the Douleur Neuropathique 4 (DN4) and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), with correlation tested for ordinal score and screen positivity. Multiple logistic regression analysis defined predictors of postoperative symptomatology. Results: Among 250 surgical radiculopathy patients, 12% were classified with FBSS. The condition was highly associated with abnormal preoperative screens for neuropathic pain, but not gender, smoking status, or preoperative pain severity (multiple logistic regression, α=0.05). Good correlation was seen between the two screening tests used in this study for absolute ordinal score (Spearman’s ρ=0.84, p<0.001) and thresholding for neuropathic pain features (Spearman’s ρ=0.48, p<0.001). Conclusion: Higher neuropathic pain screening scores correlated with likelihood of postoperative leg pain. Further work will develop more accurate prognostication tools for radiculopathy patients undergoing structural spinal surgery.

Background: The Registry has collected data on spinal injuries in hockey for 30 years. This paper identifies the nature and incidence of spinal injuries in Canadian ice hockey and the impact of prevention programs. Methods: Data about spinal injuries with and without spinal cord injury in ice hockey have been collected by Parachute Canada/ThinkFirst’s Canadian Ice Hockey Spinal Injury Registry since 1981 through retrospective questionnaires from practitioners, ice hockey organizations and media reports. Injury risk factors assessed include age, gender, location, and injury mechanism. Results: From 1943-2011, 355 cases have been documented. Injuries were primarily sustained by males (97.7%), and were cervical (78.9%)in location, resulting mainly from impact with the boards (64.2%). Checking/pushing from behind (36.0%) was the most common cause of injury, although slightly lower during 2006-2011. Major differences between provinces continue; Ontario and Quebec, continue to show markedly different injury rates, with Ontario’s more than twice that of Quebec. Conclusions: Spinal injuries in hockey continue to occur, although at lower rates than in the peak years from 1981-2000. Injury prevention education and rules reinforcement (e.g. no checking/pushing from behind). Data indicate that multifaceted prevention programs have reduced the risk of injury.