Natalizumab is indicated for the treatment of relapsing multiple sclerosis (MS) with insufficient response to first-line disease-modifying therapy (DMT). We studied the efficacy of natalizumab for treatment of MS in a single centre observational design.

A retrospective observational study of 146 patients [66% female; mean age 37.4; 72% relapsing remitting MS (RRMS), 28% secondary progressive MS (SPMS)] referred for natalizumab treatment at St. Michael's Hospital MS Clinic between 2007 and August 2009. Data included demographic, clinical (Expanded Disability Status Scale (EDSS) and annualized relapse rate (ARR)) and patient self-report measures.

The mean duration of treatment was 20 months in those treated with natalizumab and 97% had received prior DMTs. Eighty-three patients (57%) received at least 12 months of natalizumab treatment. In those who received at least 12 months of treatment, baseline ARR and EDSS were 1.6 and 2.7 in RRMS patients versus 1.0 and 5.4 in SPMS with relapses. The ARR decreased with natalizumab treatment to 0.38 (76% reduction, p<0.001) in RRMS versus 0.32 in SPMS patients (68% reduction, p=0.01). There was a treatment associated 11% reduction in EDSS to 2.4 (p=0.04) in RRMS, but no significant change in SPMS. Eighty-five percent of patients reported improved overall quality of life (QOL) and 62% indicated improved energy.

There was a major reduction in relapse rate, stabilization in EDSS and improvement in QOL and energy in some patients on natalizumab, all similar to treatment effects in the pivotal trial.

Free fatty acids (FFAs), an important energy substrate, have an association with cardiovascular diseases, such as atherosclerosis, myocardial dysfunction and abnormal cardiac rhythm. However, limited reports are available on the association between FFAs and ischemic stroke. We hypothesized that plasma FFA concentration could be associated with an ischemic stroke, emphasizing the relationship between FFA and subtypes of ischemic stroke.

A cross-sectional study examined the association between FFA concentration and subtypes of stroke and cerebral atherosclerosis from a hospital-based acute stroke registry.

Data of 715 stroke patients were analyzed. The concentration of FFA was highest in the cardioembolic stroke subtype compared with the other stroke subtypes. Logistic regression analysis revealed that an increase in FFA concentration was significantly associated with the cardioembolic subtype after the adjustment of covariates. FFA concentration was also higher in patients with atrial fibrillation (AF) than those without AF. According to the presence of atherosclerotic stenosis, no significantly difference of FFA concentration was found for intracranial and extracranial cerebral arterial atherosclerosis.

Here we report a significant association between fasting FFA concentration and the cardioembolic stroke subtype. AF is suggested as the mediating factor between FFA and the cardioembolic stroke subtype.

The “chronic cerebrospinal venous insufficiency” or “CCSVI” hypothesis, namely that multiple sclerosis (MS) is caused by abnormalities in the azygous and internal jugular veins with subsequent alterations in venous hemodynamics in the central nervous system, has been a dominant topic in MS care in Canada over the past year. Although there is no methodologically rigorous evidence to support this hypothesis presently, a considerable number of MS patients have undergone endovascular CCSVI procedures. Such procedures include angioplasty or stent placement in jugular and azygous veins. The safety and efficacy of these procedures is unknown, but not without risk.

Chart and patient review of five patients with confirmed MS followed in Calgary were undertaken after patients came to medical attention by referral or admission secondary to complications believed to be associated with CCSVI procedures.

Complications upon investigation and review included internal jugular vein stent thrombosis, cerebral sinovenous thrombosis, stent migration, cranial nerve injury and injury associated with venous catheterization.

As the debate about CCSVI and its relationship to MS continues, the complications and risks associated with venous stenting and angioplasty in jugular and azygous veins are becoming clearer. As increasing numbers of MS patients are seeking such procedures, these five cases represent the beginning of a wave of complications for which standardized care guidelines do not exist. Our experience and that of our colleagues will be used to develop guidelines and strategies to monitor and manage these patients as their numbers increase.

The purpose of this concise update is to describe the emerging treatment of stereotactic body radiotherapy (SBRT) for spinal metastases.

Spinal metastases are common and can present complex clinical challenges that conventional treatment cannot always meet satisfactorily. Examples include a history of prior irradiation at the same site or radio-resistant tumor histology. Stereotactic body radiotherapy makes it possible to deliver high doses of radiation with the aim of improving tumor control and palliation. It is increasingly being offered to selected patients including those requiring re-irradiation and post-operative treatment.

It is important that specialists managing patients with spinal metastases are aware of the potential advantages of SBRT and how this can complement and extend existing treatment approaches, including spinal decompression and stabilization.

Neurosurgical patients may be unaware of components of their intra-operative care. The relationship between patient gender and comfort level in the neurosurgical operating room (OR) has not been previously studied. Our objective was to gain insight into patients' perspective of the OR environment, including staffing and observers, the role of medical students, catheterization, exposure, and verbiage, using a qualitative needs assessment.

Face-to-face semi-structured interviews were conducted with 20 patients (14 female, six male) who had a neurosurgical operation under general anesthetic within the previous two years. The majority underwent craniotomy for benign tumours. Interviews were transcribed and subjected to modified thematic analysis.

Nine themes emerged: 1) perception of the intra-operative environment varies between men and women; 2) lacking awareness about observers is anxiety-provoking for women; 3) being unaware of the hands-on involvement of students is a concern for all patients; 4) disclosure of implantation of foreign and permanent materials into patients is important; 5) catheterization is anxiety provoking for women; 6) pre-operative menstruation screening may minimize embarrassment for women; 7) patients perceive extraneous conversation as a distraction for surgeons; 8) patients trust their surgeon; 9) a relationship exists between interviewer gender and patient comfort in the interview.

Although most male and female patients are unaware of OR activities, they are generally not fearful since they trust their surgeon. Women appear to have greater information needs. Patients' information needs must be met without provoking anxiety and yet preserving their personal sense of modesty in the intra-operative environment.

To evaluate the educational effectiveness of a novel, web-based neuroanatomical localization application.

A prototype version of a neuroanatomical localization application was developed, limited to lesions involving Cranial Nerve (CN) VII. Second year medical students at the University of Ottawa were recruited to participate in the study. Participants were exposed to a didactic teaching session on CN VII anatomy. They were subsequently randomized to two groups - one group was granted access to the localization application (the “intervention group”), while the other group was given a booklet of standard textbook resources (the “control group”). Participants then completed a case-based multiple choice test on localization of neurologic lesions associated with CN VII, followed by a questionnaire regarding the experience.

Thirty-nine students volunteered to participate. Twenty were randomized to the intervention group and 19 to the control group. There was a mean test score difference of 1.3 (CI.95 = 0.2, 2.3) that was significantly higher in the intervention group when compared to the control group. Significance was determined by aWilcoxon rank test (p = 0.028). Questionnaire results were similar for both groups, showing an overall favourable evaluation of the localization application.

The results support our hypotheses that students using the application would perform better on the multiple choice question (MCQ) test and there would be an overall preference for its use. The demonstrated educational benefit of the application, in addition to the demand for such a resource expressed by the participants, warrant further investigation into the development of a neurological localization application.

Amyloid-β (Aβ) related angiitis (ABRA) is a recently described clinicopathological entity characterized by cerebrovascular Aβ deposition and arteritis. Cerebral Aβ deposition is commonly present in cerebal amyloid angiopathy (CAA) and Alzheimer's disease (AD) but is rarely associated with inflammatory infiltration of vessel walls. Our objective is to help clarify the clinical spectrum, radiographic findings, response to treatment, and outcomes of ABRA. The neuropathological relationship between ABRA, cerebral amyloid angiopathy, and Alzheimer's disease is discussed.

We present three cases of ABRA managed at a tertiary care centre.

All three patients presented with seizures and cognitive dysfunction; one had multifocal neurologic findings. Brain biopsies revealed inflammatory arteritis with Aβ deposits in the vessel walls. All were treated with steroids and cyclophosphamide. Two had favorable outcomes and one stabilized but with severe residual neurologic disability.

ABRA is an unusual but likely under-recognized and potentially treatable disorder. As in other reported cases, our findings suggest that many patients respond favorably to immunosuppressive therapy. We believe that all biopsy specimens consistent with primary angiitis of the central nervous system (CNS) should be further examined for vascular Aβ deposition.

The maintenance of post-operative lordosis has been shown to be a key factor in decreasing adjacent level disc stress. Previous studies of the PEEK (polyetherether ketone) cage have used intervertebral bony fusion as the primary measure of surgical success; however, little is known about its effects on spinal curvature. Our objective was to compare the PEEK cage to the cervical plate with respect to the maintenance of cervical lordosis at one year. Secondary outcomes included fusion and complication rates.

We performed a retrospective study of patients who underwent ACDF (anterior cervical discectomy and fusion) by two different methods; 13 patients were treated with the PEEK cage, and 22 with allograft and plating.

Patient and treatment characteristics were similar in both groups. Average global lordotic curvature (C2-C7) was increased by 1.7 degrees for the PEEK cage and decreased by 1.6 degrees for the plate after an average follow-up of 12.46 and 14.95 months, respectively. Regional lordosis for the PEEK cage and plate was decreased by 2.5 and 2.1 degrees, respectively for the same time period. These differences did not achieve statistical significance. Bony fusion was observed in all patients. One patient in each group developed persistent mild dysphagia.

The PEEK cage is comparable to the anterior cervical plate in the maintenance of post-operative cervical lordosis.

Cytosol Ca2+ overload plays a vital role in ischemic neuronal damage, which is largely contributed by the Ca2+ influx through L-type voltage-gated calcium channels (L-VGCCs) and N-methyl-D-aspartate (NMDA) type glutamate receptors. In this article, L-VGCCs were activated by depolarization to investigate the cross-talk between NMDA receptors and L-VGCCs.

Depolarization was induced by 20 minutes incubation of 75 mM KCl in cultured rat cortical neuron. Apoptosis-like neuronal death was detected by DAPI staining. Tyrosine phosphorylation of NMDA receptor subunit 2A (NR2A), interactions of Src and NR2A were detected by immunoblot and immunoprecipitation.

Depolarization induced cortical neuron apoptosis-like cell death after 24 hours of restoration. The apoptosis was partially inhibited by 5 mM EGTA, 100 μM Cd2+, 10 μM nimodipine, 100 μM genistein, 20 μM MK-801, 2 μM PP2 and combined treatment of nimodipine and MK-801. NR2A tyrosine phosphorylation increased after depolarization, and the increase was inhibited by the drugs listed above. Moreover, non-receptor tyrosine kinase Src bound with NR2A after depolarization and restoration. The binding was also inhibited by the drugs listed above.

The results indicated that depolarization-induced neuronal death might be due to extracellular Ca2+ influx through L-VGCCs and subsequently Src activationmediated NR2A tyrosine phosphorylation.

Differences in patient adherence to various disease-modifying drugs (DMDs) in the treatment of multiple sclerosis (MS) are not well understood. The goal of this study was to evaluate adherence of adult MS patients in Ontario with public drug plan coverage to various DMDs: intramuscular interferon beta-1a (i.m. IFNβ-1a, Avonex), subcutaneous interferon beta-1a (s.c. IFNβ-1a, Rebif), subcutaneous interferon beta-1b (IFNβ-1b, Betaseron) or glatiramer acetate (Copaxone).

In this retrospective cohort study, Ontario Public Drug Plan beneficiaries aged 15 or older who were newly treated with i.m. IFNβ-1a, s.c. IFNβ-1a, IFNβ-1b or glatiramer acetate between April 2006 and March 2008 were followed forward until treatment discontinuation, switch to another DMD or a maximum two year follow-up period. Cumulative persistence rates were analyzed by the Kaplan-Meier method. The proportion of patients reaching the study endpoints after the two year follow-up period was also calculated.

Cumulative persistence rates for all four DMDs were similar over time (p=0.80), ranging from 73.6-79.1% at six months, 59.1-63.1% at one year and 41.5-47.4% at two years. After two years, the proportion of patients who had discontinued treatment, switched to another DMD or died was similar among DMDs (p=0.79, Fisher's exact test). Switching between DMD types was low and occurred in 3.4-6.5% of new DMD users.

Adherence to DMDs in adult MS patients in Ontario is poor, which is consistent with previously reported adherence rates to MS DMDs in other regions. No significant differences in adherence exist between the DMDs evaluated in this study.

We have recruited a group of four living and reviewed the records of six deceased distantly related French-Canadians of Acadian descent affected by a childhood-onset form of recessive limb-girdle muscular dystrophy (LGMD). All cases originate from the small archipelago of the Magdalen Islands (population: 13,000) isolated in the Gulf of St-Lawrence.

Based on the likely sharing of the same founder mutation we completed a 319K SNPs genome-wide scan to identify the disease locus and then screen candidate genes in this region.

All patients had normal initial motor milestones. They presented with limb girdle weakness at the average age of seven years (5-11). Progressive weakness led to loss of ambulation at a wide range of ages (10-39). Patients also developed macroglossia, large calves and mild to moderate contractures, hyperlordosis and decreased pulmonary function. Creatine kinase levels were elevated (1,800-10,000 U/L) in the first decades, but decreased with progression of disease. Homozygosity mapping uncovered a shared chromosomal region of 6.33Mb. The alpha sarcoglycan (SGCA) gene, mutated in LGMD2D, lay in this candidate interval. Sequencing of all SGCA exons uncovered a shared homozygous missense mutation (c.229C>T, p.R77C), the most common SGCA mutation internationally reported. Using demographic data, we estimated a high carrier rate of 1/22.

The p.R77C mutation has also been observed in many populations, including in France and Spain (Basques). This corresponds to the first reported recessive founder disease for the Magdalen Islands, an archipelago settled in the XlXth century, largely by Acadian immigrants.

Optic Neuritis (ON) is one of the most common clinically isolated syndromes which develops into clinically diagnosed Multiple Sclerosis (CDMS) over time.

To assess the conversion rate of Iranian patients presenting with idiopathic ON to CDMS as well as monitoring potential demographic and clinical risk factors.

Atotal of 219 patients' medical records of idiopathic ON from March 2001 to May 2009 were reviewed. Demographic findings, ophthalmologic characteristics on admission and discharge, diagnostic approaches, type and dosage of therapy were retrospectively reviewed. A structured telephone interview was then conducted to identify patients who had subsequently been diagnosed with MS. Survival analysis was used to evaluate the cumulative probability of MS conversion and contributory risk factors.

From the 219 ON patients, 109 [age 11-51, female: 81%] were followed up. Among the male gender the mean age of patients developing MS was significantly lower (P=0.01). In cox regression model, female sex (p=0.07), bilateral ON (p=0.003), MRI abnormalities (p <0.001) and high dose (5g) corticosteroid therapy (p<0.001) were identified as risk factors for the development of MS. The two and five year cumulative probability of developing MS were 27% and 45%, respectively.

Idiopathic ON in Iranian patients carries higher risk of progression to MS compared to other Asian countries. MRI lesions are the strongest independent risk factor of developing CDMS. Bilateral ON, female gender and high dose corticosteroid therapy are also important factors in predicting CDMS development.

There is no consensus on the best management of adults with presumed low grade glioma (LGG). Studies have suggested uncertainty and anxiety associated with a wait and see approach contribute to reduced quality of life. This study aims to explore the impact of a diagnosis of LGG, to address concerns regarding the uncertainty of the diagnosis and the role of wait and see from the patient's perspective.

Qualitative research methodology was used. A semi-structured interview was conducted with 24 patients with imaging evidence of LGG but no prior intervention. All patients had been followed for at least one year prior to interview. Verbatim transcripts were subjected to thematic analysis.

The median age of participants was 47 (range 21 - 82) and the median duration of follow-up 37 months (range 12 - 156 months). Fifty percent presented with seizures. Five overarching themes emerged from the data; 1) patients experience initial devastation followed by acceptance and low anxiety; 2) absence of symptoms mitigates anxiety concerning the possibility of progression; 3) patients would prefer to defer surgery until there is progression or a change in their quality of life; 4) anxiety is reduced by trust in the physician; 5) quality of life is not affected by the diagnosis, as fear of morbidity from intervention is greater than the fear of uncertainty.

The wait and see approach does not contribute to anxiety or reduction in quality of life in patients with LGG.

The risk of stroke after transient ischemic attack (TIA) is elevated in the days to weeks after TIA. A variety of prediction rules to predict stroke risk have been suggested. In Alberta a triage algorithm to facilitate urgent access based on risk level was agreed upon for the province. Patients with ABCD2 score ≥ 4, or motor or speech symptoms lasting greater than five minutes, or with atrial fibrillation were considered high risk (the ASPIRE approach). We assessed the ability of the ASPIRE approach to identify patients at risk for stroke.

We retrospectively reviewed charts from 573 consecutive patients diagnosed with TIA in Foothills Hospital emergency room from 2002 through 2005. We recorded clinical and event details and identified the risk of stroke at three months.

Among 573 patients the 90-day risk of stroke was 4.7% (95% CI 3.0%, 6.4%). 78% of the patients were identified as high risk using this approach. In patients defined as high risk on the ASPIRE approach there was a 6.3% (95% CI 4.2%, 8.9%) risk of stroke. In patients defined as low risk using the ASPIRE approach there were no recurrent strokes (100% negative predictive value). In contrast, two patients with low ABCD2 scores (ABCD2 score < 4) suffered recurrent strokes.

The ASPIRE approach has a perfect negative predictive value in the population in predicting stroke. However, this high sensitivity comes at a cost of identifying most patients as high risk.

Hypoxia inducible factor 1 (HIF-1) is a key transcriptional factor activated during cerebral ischemia, which regulates a great number of downstream genes, including those associated with cell death. In the present study, we aimed to test the hypothesis that post-ischemic HIF-1α up-regulation might promote autophagy activation; thereby, HIF-1α inhibitor 2ME2 might prevent neurons from ischemic injury through inhibiting autophagy.

Global ischemia was induced using the four-vessel occlusion model (4-VO) in Sprague-Dawley rats (male, 250-280g). 2-Methoxyestradiol (2ME2, 5mg/kg, i.p.) was administrated to down-regulate HIF-1α expression. Post-ischemic beclin-1 and LC3 protein expression was determined at different time points through Western blot assay. Neuronal injury was determined by cresyl violet staining and TUNEL staining in coronal histological sections.

The expression of beclin-1 and the ratio of LC3-II/LC3-I increased significantly at 12 and 24 h after ischemia. 2ME2 could remarkably inhibit the up-regulation of beclin-1 and the increase of LC3-II/LC3-I ratio during reperfusion. Moreover, 2ME2 and 3-MA exhibited powerful protective effects against ischemic/reperfusion induced neuronal injury.

This study confirmed that autophagy participated in post-ischemic neuronal injury. 2ME2, a HIF-1α inhibitor, might significantly decrease autophagy activation after cerebral ischemia and relieve post-ischemic neuronal injury. Our findings demonstrate that autophagy could be a potential target for neuronal protection after cerebral ischemia.

Decompressive hemicraniectomy (DH) has been shown to reduce mortality in patients with malignant middle cerebral artery (MCA) territory infarction. However, many patients survive with moderate-to-severe disability and controversy exists as to whether this should be considered good outcome. To answer this question, we assessed the quality of life (QoL) of patients after DH for malignant MCA territory infarction in our milieu.

The outcome of all patients undergoing DH for malignant MCAterritory infarction between 2001 and 2009 was assessed using retrospective chart analysis and telephone follow-up in survivors. Functional outcome was determined using Glasgow outcome scale, modifed Rankin scale (mRS), and Barthel index (BI). The stroke impact scale was used to assess QoL.

There were 14 patients, 6 men and 8 women, with a mean age of 44 years (range 27-57). All patients had reduced level of consciousness preoperatively. Five had dominant-hemisphere stroke. Median time to surgery was 45 hours (range 1- 96). Two patients died and one was lost to follow-up. Of 11 survivors, 7 (63.6%) had a favorable functional outcome (mRS<4). No patient was in persistent vegetative state. Despite impaired QoL, particularly in physical domains, the majority of interviewed patients and caregivers (7 of 8), including those with dominant-hemisphere stroke, were satisfied after a median follow-up of 18 months (range 6-43).

Most patients report satisfactory QoL despite significant disability even in the face of moderate-to-severe disability and dominant-hemsiphere stroke. Dominant-hemisphere malignant MCA territory infarction should not be considered a contraindication to DH.

To guide development of public awareness and caregiver support resources for frontotemporal dementia (FTD) syndromes.

We used an online survey to explore their needs. The survey was self-administered by self-identified, English-speaking caregivers for patients with FTD in several countries.

Of 79 caregiver respondents, approximately half were caring for patients with behavioural variant FTD or semantic dementia. The most common initial symptoms were Changes in Thinking and Judgment. Half of the respondents identified “failure to recognize the early stage of illness as a dementia” as the most troublesome aspect. Accordingly, over 40% of respondents had difficulty obtaining an accurate diagnosis for the patient. Caregivers prioritized family counseling and the public educational message that dementia can affect young people.

The largest international survey of FTD caregivers to-date showed that support is needed for all family members adapting to the shock of early-onset dementia, and this may be most readily provided online.

The American Academy of Neurology recommended using phenytoin or carbamazepine to prevent early post-traumatic seizures (PTS) in severe traumatic brain injuries (TBI). In this study, we examined the effects of using phenytoin prophylaxis on mild, moderate, and severe TBIs. There have been no studies looking at compliance rate and side effects of systematic use of phenytoin at a large population scale. The goal of this study is to determine 1) the proportion of TBI patients receiving phenytoin prophylaxis; 2) which parameters decided when to decide administer phenytoin; 3) prophylaxis efficacy and complication rate.

We retrospectively studied all patients admitted with a TBI over a two year-period and collected the following information: age, GCS score, CT-scan Marshall grade, incidence of early PTS, incidence of phenytoin use and time delay, side effects, and incidence of over-dosage or under-dosage.

1008 patients were included. 5.4 % had early PTS, 2.3 % while on prophylaxis and 3.1% while not on prophylaxis, 1.9% before reaching the hospital and 1.2% prior to phenytoin administration while in hospital. Delay of administration was 5 hours. 64.8% received prophylaxis and physicians used positive CT scan as the primary decision-making parameter (p<.001). Compliance with guidelines was 99.7%. Adverse reactions occurred in 0.5%. Levels were drawn in 42.2% (52% therapeutic, 41% low, 7% high).

Phenytoin is used according to guidelines, with CT scan being the main decision factor for its use. The frequency of early PTS rate is low and side effects are rare. However, earlier administration of phenytoin and adequate levels could further prevent early PTS.

Caseating granuloma is a classic histopathological feature of mycobacterial infections. Occasionally, no infectious organism is demonstrated despite extensive examination of intracranial caseating granulomas. The pathogenesis and optimal management strategy for patients with such intracranial caseating granulomas with no detectable infectious organism (ICGNs) remain unclear.

The study was a retrospective case-series design in a referral hospital setting. Patients with intracranial caseating granulomas in whom no infectious etiology was identified after appropriate investigations were reviewed.

Eight patients with ICGN (four females and four males) were identified in an eight-year-period. Average age on presentation was 46 years (range 21-69 years). Cerebrospinal fluid showed lymphocytic pleocytosis, elevated protein and decreased glucose. Neuroimaging showed multiple or single intraparenchymal and meningeal enhancements. Intracranial ICGN were demonstrated on biopsy. Immunomodulation was tried and resulted in improvement in five out of eight patients. In four patients, anti-mycobacterial treatment resulted in no improvement or worsening of clinical or radiological features.

The response to therapy of intracranial caseating granulomas where no organism is identified after thorough investigations hints to non-infectious causes, and suggests current dogma regarding the significance of necrosis in granulomatous diseases should be re-evaluated. Our retrospective series suggests that patients may benefit from an early trial of immunomodulation therapy, a hypothesis to be tested in a randomized trial.