Background: Interhospital transfer is an important but resource-intensive pattern of care. The use for stroke patients is highly dependent upon health system structure. We examined the impact of hospital transfers for stroke care in Canada. Methods: We analyzed hospital administrative data within the Canadian Institute for Health Information (CIHI) Database for the 3 fiscal years 2011/12, 2012/13 and 2013/14. Patients with clinical stroke syndrome (ischemic or hemorrhagic) were identified using International Classification of Diseases. Stroke centers were defined by Heart & Stroke Foundation of Canada stroke report. Results: During the 3-year period,397 patients in Canada (excluding Quebec) were admitted to hospital for clinical stroke syndrome. Median age was 75 (interquartile range [IQR] 64–84) years; 50.6 % were male. Less than 5% (n=4030) of patients were transferred. Patients transferred to stroke centers were younger (p<0.001) and had shorter median length of stay (p<0.001). The highest probability of discharge home was associated with sole care at stroke center (43.8%). Transfer to stroke center from community hospital had the highest probability for discharge to rehabilitation facility (25%) and lowest to either long-term (2.1%) or complex community care (2.0%). Transferred patients had lower mortality at discharge. Conclusion: Younger patients were transferred more frequently to stroke centers; older patients were more likely treated in community hospitals. Sole stroke center care was associated with high discharge rate to home; transfer to a stroke center was associated with high discharge rate to rehabilitation and lower mortality rates.

The radiological detection of BMs is essential for optimizing a patient’s treatment. This statement is even more valid when stereotactic radiosurgery (SRS), a non-invasive image guided treatment that can target BM as small as 1-2 mm, is delivered as part of that care. The timing of image acquisition after contrast administration can influence the diagnostic sensitivity of contrast enhanced MRI for BM. Objective: Investigate the effect of time delayed acquisition after administration of intravenous Atavist® (Gadobutrol 1mmol/ml) on the detection of BM. Methods: This is a prospective IRB approved study of 50 patients with BM who underwent post-contrast MRI sequences immediately after injection of 0.1 mmol/kg Gadavist® as part of clinical care (t0), followed by axial T1 sequences after a 10 minutes (t1) and 20 minute delay (t2). MRI studies were blindly compared by 3 neuro-radiologists. Results: Single measure intraclass correlation coefficients were very high (0.914, 0.904 and 0.905 for t0, t1 and t2 respectively), corresponding to a reliable inter-observer correlation. The t2 delayed sequences showed a significant and consistently higher diagnostic sensitivity for BM by every participating neuroradiologist as well as for the entire cohort (p=0.016, p=0.035 and 0.034 respectively). A disproportionately high representation of BM detected on the delayed studies was located within posterior circulation territories (compared to predictions based on tissue volume and blood-flow volumes). Conclusion: Considering the safe and potentially high yield nature of delayed MRI sequences, it should supplement the basic MRI sequences in all patients in need of precise delineation of their intracranial disease.

In this review, we have gathered all the available evidence to guide medication management after deep brain stimulation (DBS) in Parkinson’s disease (PD). Surprisingly, we found that almost no study addressed drug-based management in the postoperative period. Dopaminergic medications are usually reduced, but whether the levodopa or dopamine agonist is to be reduced is left to the personal preference of the treating physician. We have summarized the pros and cons of both approaches. No study on the management of cognitive problems after DBS has been done, and only a few studies have explored the pharmacological management of such DBS-resistant symptoms as voice (amantadine), balance (donepezil) or gait disorders (amantadine, methylphenidate). As for the psychiatric problems so frequently reported in PD patients, researchers have directed their attention to the complex interplay between stimulation and reduction of dopaminergic drugs only recently. In conclusion, studies addressing medical management following DBS are still needed and will certainly contribute to the ultimate success of DBS procedures.

Background: Pediatric onset multiple sclerosis (MS) negatively affects cognitive function, mood and health related quality of life (HRQOL). We aimed to explore the cognitive, psychological and HRQOL impacts of pediatric MS on young adults and to explore the relationships between disability, disease duration, cognition, mood and HRQOL in this hypotheses generating study. Methods: Thirty-four young adults with pediatric onset MS at St. Michael’s Hospital in Toronto were included in this cross-sectional study (mean age 21.3 years, 56% female). Participants completed assessments of physical disability (Expanded Disability Status Scale (EDSS)), cognitive function (Symbol Digit Modalities Test (SDMT)), mood (Beck Depression Inventory II (BDI-II)), and HRQOL (Short Form Health Survey (SF-36v2)). Findings were compared to age- and gender- matched normative data. Results: Individuals with pediatric MS performed worse on the SDMT compared to normative data, with 53% demonstrating cognitive impairment. There was no difference in BDI-II scores from normative data, but 21% showed at least mild depression. There was a non-significant impairment in physical HRQOL compared to normative data. Decreased physical HRQOL was related to disability (EDSS), while mental HRQOL was related to depression (BDI-II). Conclusions: Young adults with pediatric MS have reduced cognitive function. Non-significant reductions in HRQOL may be partly attributed to physical disability and depression. These factors should be addressed in the care of adults with pediatric MS. Further studies including control groups and longitudinal design are needed to confirm these findings.

Objective: To evaluate epidemiological patterns and lifetime costs of traumatic brain injury (TBI) identified in the emergency department (ED) within a publicly insured population in Ontario, Canada, in 2009. Methods: A nationally representative, population-based database was used to identify TBI cases presenting to Ontario EDs between April 2009 and March 2010. We calculated unit costs for medical treatment and productivity loss, and multiplied these by corresponding incidence estimates to determine the lifetime costs of identified TBI cases across age group, sex, and mechanism of injury. Results: In 2009, there were more than 133,000 ED visits for TBI in Ontario, resulting in a conservative estimate of $945 million in lifetime costs. Lifetime cost estimates ranged from $279 million to $1.22 billion depending on the diagnostic criteria used to define TBI. Peak rates of TBI occurred among young children (ages 0-4 year) and the elderly (ages 85+ years). Males experienced a 53% greater rate of TBI and incurred two-fold higher costs compared with females. Falls, sports/bicyclist-related injuries, and motor vehicle crashes represented 47%, 12%, and 10% of TBI presenting to ED, respectively, and accounted for a significant proportion of costs. Conclusions: This study revealed an enormous health and economic burden associated with TBI identified in the ED setting. Our findings underscore the importance of ongoing surveillance and prevention efforts targeted to vulnerable populations. More research is needed to fully appreciate the burden of TBI across a variety of health care settings.

A child with Dravet syndrome shakes family life to the core. Dravet syndrome usually has three phases: (1) up to 1-1½ years: with episodes of febrile status epilepticus but normal development; (2) age 1½ to ~6-10 years: with frequent seizures of varying types, developmental stagnation, behavioural and sleep problems; (3) after ~10 years: improvement in seizures, deteriorating gait, intellectual disability but some developmental gains. Complete seizure control is rare—simply prescribing medication is inadequate to help families. Based on structured interviews with 24 families and confirmed by more informal discussions with other families, we suggest strategies for coping with this catastrophe. A child with Dravet syndrome usually means that one parent cannot work—financial pressures should be anticipated. In Stage 1, the approach to status should include a written protocol. An indwelling catheter for rapid venous access may be helpful. In Stage 2, assistance finding qualified babysitters is required, and the extended family needs encouragement to help. Appropriate equipment, rescue medication and protocols should travel with the child. Siblings may benefit from a system of one parent “on call.” An internet support group provides an invaluable lifeline. In Stage 3, family isolation may be extreme—respite care and personal time for parents are important. Death from status, accidents and SUDEP (sudden unexplained death in epilepsy) occurs in 15%. Fear of SUDEP needs to be addressed. Moving from paediatric to adult care is frightening; an epilepsy transition clinic is useful. Attention to these realities may improve the quality of life for both child and family.

In this review, the available evidence to guide clinicians regarding eligibility for deep brain stimulation (DBS) in the main conditions in which these forms of therapy are generally indicated—Parkinson’s disease (PD), tremor, and dystonia—is presented. In general, the literature shows that DBS is effective for PD, essential tremor, and idiopathic dystonia. In these cases, key points in patient selection must include the level of disability and inability to manage symptoms using the best available medical therapy. Results are, however, still not optimal when dealing with other aetiologies, such as secondary tremors and symptomatic dystonia. Also, in PD, issues such as age and neuropsychiatric profile are still debatable parameters. Overall, currently available literature is able to guide physicians on basic aspects of patient selection and indications for DBS; however, a few points are still debatable and controversial. These issues should be refined and clarified in future studies.

Background: Persistent post-concussive symptoms (PCS) have been linked to increased cortical network activation and decreased cerebrovascular reactivity. Decreased cerebral perfusion could help explain PCS and may be a biomarker to track recovery. Methods: Children (ages 8 to 18 years) symptomatic with PCS at one month post-injury were studied. Children who recovered following a mTBI (asymptomatic group) and healthy children acted as controls. Pseudocontinuous arterial spin labeling MRI was used to quantify cerebral blood flow (CBF). All subjects were imaged at approximately 40 days post-injury. Symptomatic group underwent repeat neuroimaging 4-5 weeks later. Results: Seventy-two participants (14.1 years; 95% CIs: 13.5, 14.8) underwent neuroimaging at 40 days post-injury. Global CBF was significantly higher in the symptomatic group compared to healthy controls, and lower in the asymptomatic group (F(2,57) 9.734 p<0.001). Symptomatic children had increased CBF in the frontal and occipital regions, and asymptomatic children had decreased CBF in the temporal regions compared to healthy controls. CBF decreased in symptomatic children over time. CBF was a predictor of cognition (R2=0.235;p=0.001). Conclusions: Cerebral perfusion is altered in children with mTBI and is associated with recovery trajectory. Asymptomatic children had decreased CBF suggesting cerebral recovery is ongoing. Further longitudinal studies are required to determine if these perfusion patterns continue to change over time.

Background: Perinatal stroke is a common disorder in neonates with unknown etiology. Previous studies have linked anatomic variations in the Circle of Willis to adult stroke. This study aimed to understand the potential relationship between circle anatomy and common forms of perinatal stroke: NAIS, APPIS, and PVI. Methods: 94 subjects (62 NAIS/APPIS, and 32 PVI) were identified from the Alberta Perinatal Stroke Project. Inclusion criteria were: MRI-confirmed perinatal stroke, 3D-TOF MRA, and absence of other disorders. Images were classified as complete, incomplete posterior circulation, incomplete anterior circulation, and incomplete anterior and posterior circulation. Fisher Exact Test compared completeness against stroke type and segment absence ipsilateral to stroke. Mann-Whitney U compared completeness and lesion volume. Results: Completeness was more common in PVI than NAIS/APPIS (p=0.500) and in healthy controls than total stroke population (p=0.251). Ipsilesional absent segments were more frequent in NAIS/APPIS (p= 0.270). NAIS/APPIS patients with complete CoW had larger median lesion volume was compared to those with incomplete circles (p=0.484), with contralateral absence (p=0.943), and with ipsilateral absence (p=1.00). The opposite was found in PVI patients for all lesion volume comparisons (p=0.321, 0.362, 0.739 respectively). Conclusions: Circle anatomy is highly variable in perinatal stroke. Absence of segments is not associated with stroke type, lesion side, and lesion volume.

Purpose: Computed tomography perfusion (CTP) has been performed to predict which patients with aneurysmal subarachnoid hemorrhage are at risk of developing delayed cerebral ischemia (DCI). Patients with severe arterial narrowing may have significant reduction in perfusion. However, many patients have less severe arterial narrowing. There is a paucity of literature evaluating perfusion changes which occur with mild to moderate narrowing. The purpose of our study was to investigate serial whole-brain CTP/computed tomography angiography in aneurysm-related subarachnoid hemorrhage (aSAH) patients with mild to moderate angiographic narrowing. Methods: We retrospectively studied 18 aSAH patients who had baseline and follow-up whole-brain CTP/computed tomography angiography. Thirty-one regions of interest/hemisphere at six levels were grouped by vascular territory. Arterial diameters were measured at the circle of Willis. The correlation between arterial diameter and change in CTP values, change in CTP in with and without DCI, and response to intra-arterial vasodilator therapy in DCI patients was evaluated. Results: There was correlation among the overall average cerebral blood flow (CBF; R=0.49, p<0.04), mean transit time (R=–0.48, p=0.04), and angiographic narrowing. In individual arterial territories, there was correlation between changes in CBF and arterial diameter in the middle cerebral artery (R=0.53, p=0.03), posterior cerebral artery (R=0.5, p=0.03), and anterior cerebral artery (R=0.54, p=0.02) territories. Prolonged mean transit time was correlated with arterial diameter narrowing in the middle cerebral artery territory (R=0.52, p=0.03). Patients with DCI tended to have serial worsening of CBF compared with those without DCI (p=0.055). Conclusions: Our preliminary study demonstrates there is a correlation between mild to moderate angiographic narrowing and serial changes in perfusion in patients with aSAH. Patients developing DCI tended to have progressively worsening CBF compared with those not developing DCI.

Pompe disease is a lysosomal storage disorder caused by a deficiency of the enzyme acid alpha-glucosidase. Patients have skeletal muscle and respiratory weakness with or without cardiomyopathy. The objective of our review was to systematically evaluate the quality of evidence from the literature to formulate evidence-based guidelines for the diagnosis and management of patients with Pompe disease. The literature review was conducted using published literature, clinical trials, cohort studies and systematic reviews. Cardinal treatment decisions produced seven management guidelines and were assigned a GRADE classification based on the quality of evidence in the published literature. In addition, six recommendations were made based on best clinical practices but with insufficient data to form a guideline. Studying outcomes in rare diseases is challenging due to the small number of patients, but this is in particular the reason why we believe that informed treatment decisions need to consider the quality of the evidence.

Background: Perinatal regionalization is linked to improved neonatal outcomes; however, the effects on long-term outcomes in cerebral palsy (CP) are not known. We estimate the effect of highest levels of neonatal care available at delivery on the risk of developing a nonambulatory CP status. Methods: Children with CP born in Quebec from the Canadian CP Registry excluding postneonatal causes were included (N=360). We estimate the effect of level of care available at delivery on risk of nonambulatory status among children with CP using propensity score matching and instrumental variables methods to adjust for differences in case mix among the three groups of hospitals. The outcome variable is an indicator for CP nonambulation assigned according to Gross Motor Function Classification System (levels IV and V). This study used data that predated therapeutic hypothermia in Quebec. Results: Propensity score estimates of change in the adjusted risk of having a nonambulatory CP status because of birth at level II versus level I is −0.081, 95% confidence interval (CI; −0.2182 to 0.0562); level III versus level I is −0.072 95% CI (−0.225 to 0.08), and level III versus level II is 0.157 95% CI (0.027 to 0.286). Conclusions: Differences in levels of neonatal care available at hospital where the delivery was carried out are not associated with the risk of a nonambulatory CP phenotype. This suggests that level of care and associated medical technology within the Quebec regionalized neonatal-perinatal system is used efficiently because it does not offer any further marginal benefit in the reduction of severe CP outcomes. The system works well as it is, which is supportive of the perinatal regionalization. The success of the neonatal resuscitation program and referral of high-risk births to regional hospitals with sufficient obstetric and perinatal competence and resources may contribute to this lack of variability.

The National Population Health Study of Neurological Conditions, a partnership between Neurological Health Charities Canada and the Government of Canada, was the largest study of neurological diseases, disorders, and injuries ever conducted in Canada. Undertaken between 2009 and 2013, the expansive program of research addressed the epidemiology, impacts, health services, and risk factors of 18 neurological conditions and estimated the health outcomes and costs of these conditions in Canada through 2031. This review summarizes highlights from the component projects of the study as presented in the synthesis report, Mapping Connections: An Understanding of Neurological Conditions in Canada. The key findings included new prevalence and incidence estimates, documentation of the diverse and often debilitating effects of neurological conditions, and identification of the utilization, economic costs, and current limitations of related health services. The study findings will support health charities, governments, and other stakeholders to reduce the impact of neurological conditions in Canada.

Brain Metastases (BM) represent a leading cause of cancer mortality. While metastatic lesions contain subclones derived from their primary lesion, their functional characterization has been limited by a paucity of preclinical models accurately recapitulating the stages of metastasis. This work describes the isolation of a unique subset of metastatic stem-like cells from primary human patient samples of BM, termed brain metastasis initiating cells (BMICs). Utilizing these BMICs we have established a novel patient-derived xenograft (PDX) model of BM that recapitulates the entire metastatic cascade, from primary tumor initiation to micro-metastasis and macro-metastasis formation in the brain. We then comprehensively interrogated human BM to identify genetic regulators of BMICs using in vitro and in vivo RNA interference screens, and validated hits using both our novel PDX model as well as primary clinical BM specimens. We identified SPOCK1 and TWIST2 as novel BMIC regulators, where in our model SPOCK1 regulated BMIC self-renewal and tumor initiation, and TWIST2 specifically regulated cell migration from lung to brain. A prospective cohort of primary lung cancer specimens was used to establish that SPOCK1 and TWIST2 were only expressed in patients who ultimately developed BM, thus establishing both clinical and functional utility for these gene products. This work offers the first comprehensive preclinical model of human brain metastasis for further characterization of therapeutic targets, identification of predictive biomarkers, and subsequent prophylactic treatment of patients most likely to develop BM. By blocking this process, metastatic lung cancer would effectively become a localized, more manageable disease.

Lambert–Eaton syndrome (LES) is a rare immune-mediated disorder characterized by proximal leg weakness, autonomic symptoms and hypoactive tendon reflexes. The paraneoplastic form is associated with small-cell lung cancer in 50-60% of cases, whereas the remaining cases are found in younger adults with a higher likelihood of coexisting autoimmune disease. The early recognition of LES is crucial for improving clinical outcomes but remains a major challenge. In this review, we analyze the clinical characteristics and diagnostic considerations in treating LES through a series of three case studies, one of which showed definitive response to pyridostigmine and corticosteroid combination therapy, followed by spontaneous remission. Patients were assessed by image-based screening, serological testing and electrophysiological evaluations, which included respiratory and autonomic testing. A better understanding of the common pitfalls in the clinical, serological and neurophysiologic diagnosis of LES through assessment of typical LES dysfunction throughout the nervous system should enable improved recognition and treatment of this syndrome.

Dravet syndrome is among the most challenging electroclinical syndromes. There is a high likelihood of recurrent status epilepticus; seizures are medically refractory; and patients have multiple co-morbidities, including intellectual disability, behaviour and sleep problems, and crouch gait. Additionally, they are at significant risk of sudden unexplained death. This review will focus predominantly on the prophylactic medical management of seizures, addressing both first-line therapies (valproate and clobazam) as well as second-line (stiripentol, topiramate, ketogenic diet) or later options (levetiracetam, bromides, vagus nerve stimulation). Sodium channel agents—including carbamazepine, oxcarbazepine, phenytoin and lamotrigine—should be avoided, as they typically exacerbate seizures. Several agents in development may show promise, specifically fenfluramine and cannabidiol, but they need further evaluation in randomized, controlled trials. In addition to prophylactic treatment, all patients need home-rescue medication and a status epilepticus protocol that can be carried out in their local hospital. Families must be counselled on non-pharmacologic strategies to reduce seizure risk, including avoidance of triggers that commonly induce seizures (including hyperthermia, flashing lights and patterns). In addition to addressing seizures, holistic care for a patient with Dravet syndrome must involve a multidisciplinary team that includes specialists in physical, occupational and speech therapy, neuropsychology, social work and physical medicine.

Objective: Administrative data validation is essential for identifying biases and misclassification in research. The objective of this study was to determine the accuracy of diagnostic codes for acute stroke and transient ischemic attack (TIA) using the Ontario Stroke Registry (OSR) as the reference standard. Methods: We identified stroke and TIA events in inpatient and emergency department (ED) administrative data from eight regional stroke centres in Ontario, Canada, from April of 2006 through March of 2008 using ICD–10–CA codes for subarachnoid haemorrhage (I60, excluding I60.8), intracerebral haemorrhage (I61), ischemic (H34.1 and I63, excluding I63.6), unable to determine stroke (I64), and TIA (H34.0 and G45, excluding G45.4). We linked administrative data to the Ontario Stroke Registry and calculated sensitivity and positive predictive value (PPV). Results:: We identified 5,270 inpatient and 4,411 ED events from the administrative data. Inpatient administrative data had an overall sensitivity of 82.2% (95% confidence interval [CI95%]=81.0, 83.3) and a PPV of 68.8% (CI95%=67.5, 70.0) for the diagnosis of stroke, with notable differences observed by stroke type. Sensitivity for ischemic stroke increased from 66.5 to 79.6% with inclusion of I64. The sensitivity and PPV of ED administrative data for diagnosis of stroke were 56.8% (CI95%=54.8, 58.7) and 59.1% (CI95%=57.1, 61.1), respectively. For all stroke types, accuracy was greater in the inpatient data than in the ED data. Conclusion: The accuracy of stroke identification based on administrative data from stroke centres may be improved by including I64 in ischemic stroke type, and by considering only inpatient data.