Background: Acquired brain injury is a critical public health and socioeconomic problem in Canada, leaving many patients in vegetative, minimally conscious, or locked-in states, unresponsive and unable to communicate. Recent advances in neuroimaging research have demonstrated residual consciousness in a few exemplary patients with acquired brain injury, suggesting potential misdiagnosis and changes in prognosis. Such progress, in parallel with research using multimodal brain imaging technologies in recent years, has promising implications for clinical translation, notwithstanding the many challenges that impact health care and policy development. This study explored the perspectives of Canadian professionals with expertise either in neuroimaging research, disorders of consciousness, or both, on the potential clinical applications and implications of imaging technology. Methods: Twenty-two professionals from designated communities of neuroimaging researchers, ethicists, lawyers, and practitioners participated in semistructured interviews. Data were analyzed for emergent themes. Results: The five most dominant themes were: (1) validation and calibration of the methods; (2) informed consent; (3) burdens on the health care system; (4) implications for the Canadian health care system; and (5) possibilities for improved prognosis. Conclusions: Movement of neuroimaging from research into clinical care for acquired brain injury will require careful consideration of legal and ethical issues alongside research reliability, responsible distribution of health care resources, and the interaction of technological capabilities with patient outcome.

Background: Myotonic dystrophy (DM1) is an autosomal dominant, progressive, and multisystem condition that impacts affected individuals physically, socially, and emotionally. Understanding individuals’ perceptions of their disease is critical to ensuring appropriate information, education, and counseling. Methods: We conducted a content analysis of findings from a larger study that used a novel, qualitative research approach called photovoice to explore nine patients’ experiences of living with DM1. Participants took pictures that illustrated barriers or facilitators to living with DM1; their photographs then formed the basis of semistructured interviews. Transcripts were analyzed and, among themes, we identified one titled “DM1 truths and misinformation” that described participants’ disease knowledge. Analysis revealed four categories within this broader theme: “the physical and emotional cost of DM1,” “managing my DM1,” “genetics and me” and “patients as advocates and educators.” Results: Findings showed that DM1 participants had good core knowledge with respect to their disease and its implications. However, each participant held as fact fragments of misinformation that shaped decision-making and pointed to a clear need for strategies to mitigate variable interpretation of health information. Conclusions: We conclude that there is a need for increased education and awareness about symptoms, genetic information and treatment strategies for patients, their family members, and health care providers.

Background: This study examines whether age is a key determinant for inflammatory response, oligodendroglial apoptosis and axonal survival after traumatic spinal cord injury (SCI). Methods: This study includes post-mortem spinal cord tissue from 64 cases of SCI (at cervical or high-thoracic level) and 38 controls cases. Each group was subdivided into younger and elderly individuals (≥65 years). Alternating sections from 2 to 3 segments caudal to SCI and age/sex/level-matched segments from controls were stained for: (i) neuroinflammation (neutrophils, macrophages, lymphocytes); (ii) apoptotic oligodendrocytes; (iii) axons; (iv) extent of degeneration. The number of cells or axons was counted in the motor and sensory areas within the spinal cord using unbiased stereological techniques. Results: Younger and elderly individuals had statistically similar number of inflammatory cells in most of the stages post-SCI. Younger and elderly individuals had similar number of oligodendrocytes in apoptosis in all stages following SCI. The number of preserved axons did not significantly differ between younger and elderly individuals with SCI and without prior CNS injury. Extend of degeneration within the spinal cord white matter did not significantly differ between the two groups. Conclusions: Our results indicate that age at the time of injury does not adversely affect the cellular inflammatory response, oligodendroglial apoptosis and axonal survival after traumatic SCI.

Background: Recent evidence suggests that an extreme shift may occur in sphingosine metabolism in neuroinflammatory contexts. Sphingosine 1-phosphate (S1P)-metabolizing enzymes (SMEs) regulate the level of S1P. We recently found that FTY720, a S1P analogue, and SEW2871, a selective S1P receptor 1 (S1P1) agonist, provide protection against neural damage and memory deficit in amyloid beta (Aβ)-injected animals. This study aimed to evaluate the effects of these two analogues on the expression of SMEs as well as their anti-inflammatory roles. Methods: Rats were treated with intracerebral lipopolysaccharide (LPS) or Aβ. Memory impairment was assessed by Morris water maze and the effects of drugs on SMEs as well as inflammatory markers, TNF- α and COX-II, were determined by immunoblotting. Results: Aβ and LPS differentially altered the expression profile of SMEs. In Aβ-injected animals, FTY720 and SEW2871 treatments exerted anti-inflammatory effects and restored the expression profile of SMEs, in parallel to our previous findings. In LPS animals however, in spite of anti-inflammatory effects of the two analogues, only FTY720 restored the levels of SMEs and prevented memory deficit. Conclusion: The observed ameliorating effects of FTY720 and SEW7821 can be partly attributed to the interruption of the vicious cycle of abnormal S1P metabolism and neuro-inflammation. The close imitation of the FTY720 effects by SW2871 in Aβ-induced neuro-inflammation may highlight the attractive role of S1P1 as a potential target to restore S1P metabolism and inhibit inflammatory processes.

Background and Purpose: Carotid artery stenting (CAS) has been, historically, an alternative to open endarterectomy (CEA) for stroke prevention in high risk patients with carotid atherosclerosis. We sought to determine the rates of periprocedural and long-term stroke or death and the risk factors for complications after CAS in our high risk patient population. Methods: Clinical and treatment variables of consecutive CAS procedures performed between 2002 and 2011 were analyzed. Using univariate and multivariate logistic regression analyses we examined how patient characteristics influenced outcomes and changes in modified Rankin Score (mRS). Results: In 152 patients, the composite total of periprocedural death, stroke, transient ischemic attack (TIA) and myocardial infarction (MI) rate was 3.95% (6/152). Chronic kidney disease (CKD) was strongly associated with periprocedural complications (p<0.001). Coronary artery disease/peripheral vascular disease (CAD/PVD) (p=0.03), dyslipidemia (p=0.02), CKD (p=0.01), and contralateral internal carotid artery stenosis (p=0.02) were non-modifiable risk factors for mRS increase. There were 25 deaths, 8 strokes, 11 TIAs, and 1 MI (mean follow-up 38.4 months, range 0-116 months). The presence of CAD/PVD (p=0.009) and dyslipidemia (p=0.002) were significantly associated with long-term complications. Conclusion: CAS was performed with low periprocedural complications in high-risk patients. Our rates compare very favorably to large-scale trials that have ideal patients. This data encourages the consideration of CAS in patients considered high risk for CEA and provides possible patient characteristics (CKD) to help with periprocedural risk stratification.

Background: Intensive care unit (ICU) patients with neurological impairments often require neuroimaging. However, the relative sensitivity of various imaging modalities of the brain has not yet been explored in this population. Methods: In this study, we compare the findings of CT and MRI scans in ICU patients to (1) identify the number and rate of clinically relevant lesion detected by MRI while missed by CT and vice versa and (2) determine specific lesion types for which CT versus MRI discrepancies exist. A review of medical records included CT and MRI reports of patients who underwent these procedures while they were patients in our ICUs between July 2004 and July 2009. MRI and CT were compared regarding their ability to detect clinically relevant abnormalities. Odds ratios with 95% confidence limits were calculated to compare diagnostic categories regarding the rate of discrepant MRI versus CT findings, followed by power analyses to estimate sample sizes necessary to allow for further testing in a larger trial. Results: MRI revealed clinically relevant additional abnormalities over CT in 129 of 136 patients (95%) that included the detection of additional finding for 15/27 hemorrhagic lesions (55.6%), 33/36 (92%) ischemic strokes, 19/27 (70%) traumatic lesions, 8/14 (57%) infections, 15/24 (62.5%) metabolic abnormalities, and all seven neoplasms. Odds ratio analysis revealed the added sensitivity of MRI to be greater for ischemic and neoplastic lesions than for trauma, metabolic-related abnormalities, infection, or hemorrhage. Conclusions: MRI is more sensitive than CT in identifying clinically meaningful lesions in at least a subset of ICU patients, regardless of pathology.

Background: Cranioplasty encompasses various cranial reconstruction techniques that are used following craniectomy due to stroke or trauma. Despite classical infectious signs, symptoms, and radiologic findings, however, the diagnosis of infection following cranioplasty can be elusive, with the potential to result in definitive treatment delay. We sought to determine if fever or leukocytosis at presentation were indicative of infection, as well as to identify any factors that may limit its applicability. Methods: Following institutional review board approval, a retrospective cohort of 239 patients who underwent cranioplasty following craniectomy for stroke or trauma was established from 2001-2011 at a single center (Massachusetts General Hospital). Analysis was then focused on those who developed a surgical site infection, as defined by either frank intra-operative purulence or positive intra-operative cultures, and subsequently underwent operative management. Results: In 27 total cases of surgical site infection, only two had a fever and four had leukocytosis at presentation. This yielded a false-negative rate for fever of 92.6% and for leukocytosis of 85.2%. In regard to infectious etiology, 22 (81.5%) cases generated positive intra-operative cultures, with Propionibacterium acnes being the most common organism isolated. Median interval to infection was 99 days from initial cranioplasty to time of infectious presentation, and average follow-up was 3.4 years. Conclusions: The utilization of fever and elevated white blood cell count in the diagnosis of post-cranioplasty infection is associated with a high false-negative rate, making the absence of these features insufficient to exclude the diagnosis of infection.

Frataxin deficiency causes the complex neurological and cardiac phenotype of Friedreich ataxia (FRDA). The most common cause of death is cardiomyopathy. The results presented here are based on a systematic study of fixed and frozen archival heart specimens and include measurement of cardiomyocyte hypertrophy, frataxin assay, X-ray fluorescence (XRF) of iron (Fe) and zinc (Zn), inductively-coupled plasma optical emission spectrometry of these metals in digests of left ventricular wall (LVW), right ventricular wall (RVW), and ventricular septum (VS), Fe histochemistry, and immunohistochemistry and double-label immunofluorescence microscopy of cytosolic and mitochondrial ferritins, and of the inflammatory markers CD68 and hepcidin. Frataxin levels in LVW were extremely low at less than 15 ng/g wet weight (normal: 214.1±81.2). On cross-sections, cardiomyocytes were significantly larger than normal with case means ranging from 635-1856 μm2 for LVW and 483-1150 μm2 for VS (normal LVW, 140-460; normal VS, 237-613). Fe accumulations varied from minute granules to coarse aggregates in fibers undergoing phagocytosis. Measured by XRF, regional Fe concentration in LVW and VS were significantly increased while Zn remained normal. Total heart Fe and Zn did not differ from normal levels. Cytosolic and mitochondrial ferritins exhibited extensive co-localization, representing translational and transcriptional responses to Fe, respectively. All cases met the criteria of myocarditis. Inflammatory cells contained CD68 and ferritin, and most expressed the Fe-regulatory hormone hepcidin. In conclusion, inflammation plays a major role in the pathogenesis of FA cardiomyopathy, and hepcidin-induced retention of Fe in macrophages contributes to cardiac damage in FRDA.

Background: Our goal was to perform a systematic review of the literature on the use of modern inhalational anesthetic agents for refractory status epilepticus and their 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 March 2014), reference lists of relevant articles, and gray literature were searched. The strength of evidence was adjudicated using both the Oxford and Grading of Recommendation Assessment Development and Education methodology by two independent reviewers. Results: Overall, 19 studies were identified, with 16 manuscripts and 3 meeting abstracts. A total of 46 patients were treated. Adult (n=28) and pediatric patients (n=18) displayed 92.9% and 94.4% seizure control with treatment, respectively. Isoflurane was used in the majority of cases. Hypotension was the only complication described. Conclusions: Oxford level 4, Grading of Recommendation Assessment Development and Education D evidence exists to support the use of isoflurane in refractory status epilepticus to obtain burst suppression. Insufficient data exist to comment on the efficacy of desflurane and xenon at this time.

Background: When patients with cranial glioblastoma develop weakness, a rare differential diagnosis is spinal metastases. Methods: Chart and literature reviews were performed. Results: The reported patient had delayed onset spinal drop metastasis that was only detected by magnetic resonance imaging (MRI). A 48-year-old patient had supratentorial glioblastoma, treated with radiotherapy (RT) and concurrent temozolomide followed by six cycles of adjuvant temozolomide. Four years after completion of all treatments (62 months from initial presentation), he developed low backache and weakness in both legs. Positron emission tomography/computed tomography scans demonstrated intracranial recurrence only. Spinal drop metastases were detected only by MRI scan. Local spinal RT 40 Gy in 20 fractions with concurrent and maintenance temozolomide were given. Because of disease progression after nine cycles of temozolomide, systemic therapy was changed to bevacizumab, which greatly improved his symptoms for 4 months before deterioration of mental status. He is still alive with disease at 22 months after diagnosis of spinal metastases (84 months from initial glioblastoma diagnosis). Conclusions: MRI is the diagnostic imaging of choice for spinal metastases. This illustrative case of delayed-onset spinal metastases shows unusual slow progression. Local RT, temozolomide, and targeted therapy may improve survival. This illustrative case is the first report of bevacizumab as a second-line therapy in drop metastasis of glioblastoma.

Background: To examine stereotactic radiosurgery (SRS) following whole brain radiotherapy for metastases in eloquent, central brain locations: brainstem, thalamus, and basal ganglia. Methods: We conducted a retrospective review of patients with metastases in eloquent, central brain locations who were treated with SRS between January 2000 and April 2012. All patients had whole brain radiotherapy. Patients eligible for SRS had one to three brain metastases, metastasis size ≤4 cm, and Karnofsky performance status ≥70. Local progression-free survival and overall survival were calculated using the Kaplan-Meier method. Results: For 24 patients, the median age was 50 years (range, 36-73). Metastases by location were: 11 brainstem, 9 thalamus, and 5 basal ganglia. The median metastasis size was 15 mm (range, 2-33) and the median SRS dose prescription was 15 Gy (range, 12-24). The median local progression-free survival was 13.7 months and median overall survival was 16.4 months. Compared with a cohort of 188 patients with noneloquent brain metastases receiving a median dose of 24 Gy, overall survival of 10.8 months was not significantly different (p=0.16). The only symptomatic complication was grade 2 headache in 8.3%. Asymptomatic adverse radiologic events were radionecrosis in two (8.3%), peritumoural edema in four (16.7%), and hemorrhage in one patient (4.2%). Conclusions: Lower SRS marginal doses do not appear to compromise survival in patients with eloquently located brain metastases compared with higher doses for other brain metastases, with minimal symptomatic complications.

The olfactory bulb exhibits architecture unique amongst laminar cortices, lacking molecular and subplate zones and having superficial synaptic glomeruli. Its ontogenesis also is unique because neuroblasts do not migrate radially but stream in from the rostral telencephalon; an ependymal-lined olfactory ventricle is transitory. The olfactory is the only sensory system to not project to the thalamus but incorporates a thalamic equivalent. It is a repository of progenitor cells in the mature brain. The aim was to define olfactory bulb development in the human foetus: synaptogenesis and cellular maturation.

Immunoreactivity in paraffin sections of synaptophysin, NeuN, calretinin, vimentin and nestin was examined at autopsy in olfactory bulb in 20 foetuses, 9-40wks gestation. Synaptophysin reactivity was seen around the somata of mitral and tufted neurons at 9wks, synaptic glomeruli at 13wks. The granule cell layer in the core exhibited NeuN-reactive nuclei in cells of the outer half at 20wks; 60% of granular neurons reacted by term. Synaptophysin reactivity in the granular layer initiates at 15wk. GABAergic calretinin-reactive neurons and neurites and synaptic glomeruli appeared at 13wks. Nestin- and vimentin-reactive bipolar progenitor cells were shown at all gestational ages, mainly in the granular layer, the ratio to other cells remaining constant. Synapses form in the small accessory olfactory bulb of the nervus terminalis earlier than in the main bulb. Development of synaptic vesicles in the human fetal olfactory bulb is precise both spatially and temporally, but not yet fully mature at term.

In brain malformations and congenital metabolic and genetic diseases, the olfactory bulb may be affected and provide additional neuropathological data. Therapeutic autologous transplantation of olfactory progenitor cells focus renewed interest in the olfactory bulb.

Background: Treatment options for essential (ET) and Parkinson disease (PD) tremor are suboptimal, with significant side effects. Botulinum toxin type A (BoNT A) is successfully used in management of various focal movement disorders but is not widely used for tremor. Method: This study examines complexity of wrist tremor in terms of involvement of its three anatomical degrees of freedom (DOF) in two common situations of rest and posture. The study examines tremor in 11 ET and 17 PD participants by kinematic decomposition of motion in 3-DOF. Results: Tremor decomposition showed the motion involved more than one DOF (<70% contribution in one DOF) in most ET (rest: 100%, posture: 64%) and PD (rest: 77%, posture: 77%) patients. Task variation resulted in change in both amplitude and composition in ET, but not in PD. Amplitude significantly increased from rest to posture in ET. Directional bias was observed at the wrist for ET (pronation), and PD (extension, ulnar deviation, pronation). Average agreement between clinical visual and kinematic selection of muscles was 55% across all subjects. Conclusion: This study shows the complexity of tremor and the difficulty in visual judgment of tremor, which may be key to the success of targeted focal treatments such as BoNT A.

Background: This study examines whether abnormal blood hemoglobin concentration (bHB) is associated with worse clinical outcomes and poorer prognosis after acute ischemic stroke. Methods: We included data from the Registry of the Canadian Stroke Network on consecutive patients with ischemic stroke who were admitted between July/2003 and March/2008. Patients were divided into groups as follows: low bHB, normal bHB, and high bHB. 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: Higher bHB than the superior normal limit is associated with greater degree of impairment (OR=1.45, 95%CI: 1.06-1.95, p=0.0195) and disability (OR=1.49, 95%CI: 1.03-2.15, p=0.0331), and higher 30-day mortality (HR=1.98, 95%CI: 1.44-2.74, p<0.0001) after adjustment for major potential confounders. The Kaplan-Meier curves indicate that abnormal bHB is associated with higher mortality after acute ischemic stroke (p<0.0001). Lower bHB than the inferior normal limit is associated with longer stay in the acute stroke care center (OR=1.11, 95%CI: 1.02-1.22, p=0.017). Conclusions: Polycythemia on the initial admission is associated with poorer prognosis regarding the degree of impairment and disability, and 30-day mortality after an acute ischemic stroke. Anemia on admission is associated with longer stay in the acute stroke center.