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Multiple sclerosis is the leading non-traumatic cause of disability in young adults, affecting up to 100,000 Canadians. This chronic inflammatory and neurodegenerative disease of the central nervous system leads to irreversible neurologic disability if inadequately controlled. Though many current medications are available that reduce inflammatory damage, most patients continue to show some evidence of disease activity and accrue disability. In this review, we discuss the role of immune ablation followed by autologous hematopoietic stem cell transplantation (AHSCT), a therapeutic option for select patients with a more aggressive disease course. By “resetting” the immune system with a variety of ablative conditioning regimens, followed by immune reconstitution, this therapy has shown a durable response in halting evidence of inflammatory activity in most patients, without the need for continued disease-modifying therapies (DMT). Since the introduction of this therapy, there have been advances in patient selection and supportive care, such that morbidity has significantly declined and treatment-related mortality is minimized. Recent phase-II trials have shown excellent results in efficacy and safety of AHSCT; however, challenges exist which require ongoing study. The future challenges include comparing the variety of AHSCT conditioning regimens with each other as well as with existing highly effective DMT; identifying patients with an aggressive disease course through novel biomarkers who may benefit the most from AHSCT; and surveillance of long-term outcomes of different treatment protocols. In select patients, replacing the immune system with AHSCT holds promise of fundamentally altering the trajectory of their aggressive disease course.
Our clinical experience at a specialized brain injury clinic suggests that numerous patients with traumatic brain injury (TBI) are using cannabis to alleviate their symptoms. While this patient population often inquires about the evidence of using cannabis post-head injury for the neurosensory, neurocognitive, and neuropsychiatric sequelae, most health professionals have little to no knowledge of this evidence. Given the recent legalization of recreational cannabis in Canada, questions and guidance related to cannabis use following a TBI are likely to become more common. This article reviews the evidence for cannabis use in psychiatric disorders with or without TBI. Overall, we found that the evidence for the use of cannabis among TBI patients is sparse and that patients tend to have little knowledge of the proven benefits and diverse effects of cannabis use. We feel this paper can serve as a stepping stone for future studies that explore the impact of cannabis use in a TBI population and can guide clinicians in advising their patients.
The management of patients harboring central nervous system (CNS) hemangiopericytomas (HPCs) is a partially answered challenge. These are rare locally aggressive lesions, with potential for local recurrence, distal neural metastasis (DNM), and extraneural metastasis (ENM). Resection, when feasible, remains the initial treatment option, providing histological diagnosis and immediate relief of tumor-related mass effect. Patients receiving surgery alone or surgery and external beam radiotherapy (EBRT) show improved overall survival (OS) and progression-free survival as compared to those undergoing a biopsy alone (p = 0.01 and p = 0.02, respectively). Yet, in many instances, patient and tumor-related parameters preclude complete resection. EBRT or stereotactic radiosurgery (SRS) shares a significant role in achieving local tumor control, not shown to impact OS in HPC patients. The benefits of SRS/EBRT are clearly limited to improved local tumor volume control and neurologic function, not affecting DNM or ENM development. SRS provides acceptable rates of local tumor volume control coupled with treatment safety and a patient-friendly apparatus and procedure. Single-session SRS is most effective for lesions measuring <2 cm in their largest diameter (10 cm3 volume), with prescription doses of at >15 Gy. Systemic HPC disease is managed with various chemotherapeutic, immunotherapeutic, and anti-angiographic agents, with limited success. We present a short discussion on CNS HPCs, focusing our discussion on available evidence regarding the role of microsurgical resection, EBRT, SRS, chemotherapy, and immunotherapy for upfront, part of adoptive hybrid surgery approach or for recurrent HPCs.
Parkinson’s disease (PD) and other synucleinopathies, namely dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), are common degenerative neurological disorders that share synuclein pathology. Although certain cardinal features of parkinsonism, including bradykinesia and rigidity, respond well to levodopa, axial features, such as gait and balance impairment, are less reliably responsive to dopaminergic therapy and surgical interventions. Consequently, falls are common in PD and other synucleinopathies and are a major contributor toward injury and loss of independence. This underscores the need for appropriate fall risk assessment and implementation of preventative measures in all patients with parkinsonism. The aim of this review is therefore to explore modifiable and non-modifiable risk factors for falls in synucleinopathies. We next review and evaluate the evidence for pharmacological, nonpharmacological, and surgical approaches for fall prevention, and emphasize individualized and multifaceted approaches.
Although the efficacy of endovascular thrombectomy (EVT) for acute ischemic stroke caused by intracranial anterior circulation large vessel occlusion (LVO) is proven, demonstration of local effectiveness is critical for health system planning and resource allocation because of the complexity and cost of this treatment.
Using our prospective registry, we identified all patients who underwent EVT for out-of-hospital LVO stroke from February 1, 2013 through January 31, 2017 (n = 44), and matched them 1:1 in a hierarchical fashion with control patients not treated with EVT based on age (±5 years), prehospital functional status, stroke syndrome, severity, and thrombolysis administration. Demographics, in-hospital mortality, discharge disposition from acute care, length of hospitalization, and functional status at discharge from acute care and at follow-up were compared between cases and controls.
For EVT-treated patients (median age 66, 50% women), the median onset-to-recanalization interval was 247 min, and successful recanalization was achieved in 30/44 (91%). Alteplase was administered in 75% of cases and 57% of controls (p = 0.07). In-hospital mortality was 11% among the cases and 36% in the control group (p = 0.006); this survival benefit persisted during follow-up (p = 0.014). More EVT patients were discharged home from acute care (50% vs. 18%, p = 0.002). Among survivors, there were nonsignificant trends in favor of EVT for median length of hospitalization (14 vs. 41 days, p = 0.11) and functional independence at follow-up (51% vs. 32%, p = 0.079).
EVT improved survival and decreased disability. This demonstration of single-center effectiveness may help facilitate expansion of EVT services in similar health-care jurisdictions.
Endovascular thrombectomy (EVT) is efficacious for ischemic stroke caused by proximal intracranial large-vessel occlusion involving the anterior cerebral circulation. However, evidence of its cost-effectiveness, especially in a real-world setting, is limited. We assessed whether EVT ± tissue plasminogen activator (tPA) was cost-effective when compared with standard care ± tPA at our center.
We identified patients treated with EVT ± tPA after the Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing computed tomography to recanalization times trial from our prospective stroke registry from February 1, 2013 to January 31, 2017. Patients admitted before February 2013 and treated with standard care ± tPA constitute the controls. The sample size was 88. Cost-effectiveness was assessed using the net monetary benefit (NMB). Differences in average costs and quality-adjusted life years (QALYs) were estimated using the augmented inverse probability weighted estimator. We accounted for sampling and methodological uncertainty in sensitivity analyses.
Patients treated with EVT ± tPA had a net gain of 2.89 [95% confidence interval (CI): 0.93–4.99] QALYs at an additional cost of $22,200 (95% CI: −28,902–78,244) per patient compared with the standard care ± tPA group. The NMB was $122,300 (95% CI: −4777–253,133) with a 0.85 probability of being cost-effective. The expected savings to the healthcare system would amount to $321,334 per year.
EVT ± tPA had higher costs and higher QALYs compared with the control, and is likely to be cost-effective at a willingness-to-pay threshold of $50,000 per QALY.
Epilepsy is a common neurological condition that shows a marked genetic predisposition. The advent of next-generation sequencing (NGS) has transformed clinical genetic testing by allowing the rapid screen for causative variants in multiple genes. There are currently no NGS-based multigene panel diagnostic tests available for epilepsy as a licensed clinical diagnostic test in Ontario, Canada. Eligible patient samples are sent out of country for testing by commercial laboratories, which incurs significant cost to the public healthcare system.
An expert Working Group of medical geneticists, pediatric neurologists/epileptologists, biochemical geneticists, and clinical molecular geneticists from Ontario was formed by the Laboratories and Genetics Branch of the Ontario Ministry of Health and Long-Term Care to develop a programmatic approach to implementing epilepsy panel testing as a provincial service.
The Working Group made several recommendations for testing to support the clinical delivery of care in Ontario. First, an extension of community healthcare outcomes-based program should be incorporated to inform and educate ordering providers when requesting and interpreting a genetic panel test. Second, any gene panel testing must be “evidence-based” and takes into account varied clinical indications to reduce the chance of uncertain and secondary results. Finally, an ongoing evaluative process was recommended to ensure continued test improvement for the future.
This epilepsy panel testing implementation plan will be a model for genetic care directed toward a specific set of conditions in the province and serve as a prototype for genetic testing for other genetically heterogeneous diseases.
The diagnosis of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis relies on the detection of NMDAR IgG autoantibodies in the serum or cerebrospinal fluid (CSF) of symptomatic patients. Commercial kits are available that allow NMDAR IgG autoantibodies to be measured in local laboratories. However, the performance of these tests outside of reference laboratories is unknown.
To report an unexpectedly low rate of NMDAR autoantibody detection in serum from patients with anti-NMDAR encephalitis tested using a commercially available diagnostic kit in an exemplar clinical laboratory.
Paired CSF and serum samples from seven patients with definite anti-NMDAR encephalitis were tested for NMDAR IgG autoantibodies using commercially available cell-based assays run according to manufacturer’s recommendations. Rates of autoantibody detection in serum tested at our center were compared with those derived from systematic review and meta-analyses incorporating studies published during or before March 2019.
NMDAR IgG autoantibodies were detected in the CSF of all patients tested at our clinical laboratory but not in paired serum samples. Rates of the detection were lower than those previously reported. A similar association was recognized through meta-analyses, with lower odds of NMDAR IgG autoantibody detection associated with serum testing performed in nonreference laboratories.
Commercial kits may yield lower-than-expected rates of NMDAR IgG autoantibody detection in serum when run in exemplar clinical (nonreference) laboratories. Additional studies are needed to decipher the factors that contribute to lower-than-expected rates of serum positivity. CSF testing is recommended in patients with suspected anti-NMDAR encephalitis.
Isolated, subtle neurological abnormalities (ISNA) are commonly seen in aging and have been related to cerebral small vessel disease (SVD) and subcortical atrophy in neurologically and cognitively healthy aging subjects.
To investigate the frequency of ISNA in different mild cognitive impairment (MCI) types and to evaluate for each MCI type, the cross-sectional relation between ISNA and white matter hyperintensities (WMH), lacunes, caudate atrophy, and ventricular enlargement.
One thousand two hundred fifty subjects with different MCI types were included in the analysis and underwent brain magnetic resonance imaging. WMHs were assessed through two visual rating scales. Lacunes were also rated. Atrophy of the caudate nuclei and ventricular enlargement were assessed through the bicaudate ratio (BCr) and the lateral ventricles to brain ratio (LVBr), respectively. Apolipoprotein E (APOE) genotypes were also assessed. The routine neurological examination was used to evaluate ISNAs that were clustered as central-based signs, cerebellar-based signs, and primitive reflexes. The items of Part-III of the Unified Parkinson’s Disease Rating Scale were used to evaluate ISNAs that were clustered as mild parkinsonian signs. Associations of ISNAs with imaging findings were determined through logistic regression analysis.
The ISNAs increase with the age and are present in all MCI types, particularly in those multiple domains, and carrying the APOE ϵ4 allele, and are associated with WMH, lacunes, BCr, and LVBr.
This study demonstrates that cortical and subcortical vascular and atrophic processes contribute to ISNAs. Long prospective population-based studies are needed to disentangle the role of ISNAs in the conversion from MCI to dementia.
Hyperbaric oxygen therapy (HBOT) shows promising results in treating radionecrosis (RN) but there is limited evidence for its use in brain RN. The purpose of this study is to report the outcomes of using HBOT for symptomatic brain RN at a single institution.
This was a retrospective review of patients with symptomatic brain RN between 2008 and 2018 and was treated with HBOT. Demographic data, steroid use, clinical response, radiologic response and toxicities were collected. The index time for analysis was the first day of HBOT. The primary endpoint was clinical improvement of a presenting symptom, including steroid dose reduction.
Thirteen patients who received HBOT for symptomatic RN were included. The median time from last brain radiation therapy to presenting symptoms of brain RN was 6 months. Twelve patients (92%) had clinical improvement with median time to symptom improvement of 33 days (range 1–109 days). One patient had transient improvement after HBOT but had recurrent symptomatic RN at 12 months. Of the eight patients with evaluable follow-up MRI, four patients had radiological improvement while four had stable necrosis appearance. Two patients had subsequent deterioration in MRI appearances, one each in the background of initial radiologic improvement and stability. Median survival was 15 months with median follow-up of 10 months. Seven patients reported side effects attributable to HBOT (54%), four of which were otologic in origin.
HBOT is a safe and effective treatment for brain RN. HBOT showed clinical and radiologic improvement or stability in most patients. Prospective studies to further evaluate the effectiveness and side effects of HBOT are needed.
Rapid eye movement (REM) sleep behavior disorder (RBD) and REM sleep without atonia (RWA) have assumed much clinical importance with long-term data showing progression into neurodegenerative conditions among older adults. However, much less is known about RBD and RWA in younger populations. This study aims at comparing clinical and polysomnographic (PSG) characteristics of young patients presenting with RBD, young patients with other neurological conditions, and normal age-matched subjects.
A retrospective chart review was carried out for consecutive young patients (<25 years) presenting with clinical features of RBD; and data were compared to data from patients with epilepsy, attention deficit hyperactivity disorder (ADHD), and autism, as well as normal subjects who underwent PSG during a 2-year-period.
Twelve patients fulfilling RBD diagnostic criteria, 22 autism patients, 10 with ADHD, 30 with epilepsy, and 14 normal subjects were included. Eight patients with autism (30%), three with ADHD (30%), one with epilepsy (3.3%), and six patients who had presented with RBD like symptoms (50%) had abnormal movements and behaviors during REM sleep. Excessive transient muscle activity and/or sustained muscle activity during REM epochs was found in all patients who had presented with RBD, in 16/22 (72%) autistic patients, 6/10 (60%) ADHD patients compared to only 6/30 (20%) patients with epilepsy and in none of the normal subjects.
We observed that a large percentage of young patients with autism and ADHD and some with epilepsy demonstrate loss of REM-associated atonia and some RBD-like behaviors on polysomnography similar to young patients presenting with RBD.
Multiple sclerosis (MS) is the most common cause of neurological disability, other than trauma, among young adults of reproductive age. In contrast to the past, today there is very little lag time from clinical onset to diagnosis. Disease-modifying therapies are also now available outside of clinical trials. However, there is very little evidence-based population data to help an individual with MS make informed decisions with respect to reproductive options.
The objective of this study is to develop a Canada-wide, prospective population-based registry of women with MS who are either trying to become pregnant and/or have become pregnant.
The study represents a “real-world” scenario. Women with MS are invited to participate, regardless of clinical course, therapy, disease duration, and/or disability. The methodology to develop such a registry is very complex making it imperative to understand the design and rationale when interpreting results for clinical purposes.
This paper is a comprehensive discussion of the study rationale and methodology.
The study is ongoing, with over 100 potential participants. Numerous future publications are envisioned as the study progresses. The present paper is thus designed to be the key referral paper for subsequent publications in which it will not be possible to provide the necessary detailed information on rationale and methodology.
A 32-year-old male presented to the emergency department for confusion, dyspnea, and a “white out” of his central vision over the preceding 24 hours. The patient had recently consumed a bottle of alcohol purchased overseas. Bloodwork revealed a severe metabolic acidosis (pH 6.90) and a critically high methanol level of 28.9 mmol/l. Shortly after presentation, the patient went into respiratory failure and became comatose. He was intubated and admitted to the ICU.
Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is a rare progressive maternally inherited mitochondrial disease that clinically harbours various neurological and systemic manifestations.
A 65-year-old healthy woman presented with a 15-year history of binocular horizontal diplopia worse when looking left. She had previously been thoroughly investigated multiple times for a left sixth nerve palsy (6NP) 15 years ago and had three normal magnetic resonance imaging (MRI) scans of the brain/orbits with contrast, normal acetylcholine receptor antibodies, normal thyroid function tests, normal cerebrospinal fluid, and normal nerve conduction studies and single-fibre electromyography. She was treated with prism glasses, which resulted in resolution of her symptoms in primary position.
This is a case of a 30-year-old right-handed male patient who presented to the hospital in 2014 after hitting his head on the mat during a wrestling match followed by headache and temporary peripheral vision limitation. The patient’s past medical history was unremarkable. On physical examination, Glasgow Coma Scale was 15 with no focal neurological deficits. Unenhanced head computed tomography (CT) and enhanced brain magnetic resonance imaging (MRI) were performed (Figure 1). The patient was managed conservatively, and follow-up CT and MRI in 2015 (Figure 2) demonstrated significant decrease in size of the previously seen right frontoparietal lesion with also changes in its radiological features. The patient remained asymptomatic for about 3 years when in 2018 he presented to the Emergency Department with increasing headaches and peripheral vision loss. MRI demonstrated an increase in the right frontal lesion size (Figure 3). He underwent surgical resection of the lesion.
A 61-year-old male presented to our hospital complaining of claudication: bilateral leg weakness impeding mobility. Symptoms started after 100 m of walk and recede after several minutes of rest. The patient was obese, with a body mass index (BMI) of 41 kg/m2 and reported a weight gain of about 55 pounds in the last year. Patient’s comorbidities were dyslipidemia, hypertension, and antithrombin III deficiency. The patient also suffered from chronic low-back pain recently worsened and cervical pain. Pulses in the lower limbs were present. Neurological examination was also unremarkable.
Vestibular impairment (VI) and cognitive impairment (CI) are risk factors for senior falls. We tested the feasibility of a self-directed 12-week vestibular rehabilitation (VR) program in Memory Clinic patients (65 years+) with a fall, CI and VI. We assessed recruitment, exercise adherence and ability to complete questionnaires/assessments. Twelve patients with CI and falls were screened and 8/12 (75% – prevalence) had VI. All patients completed the screening tests/questionnaires (100% – completeness); 7/8 patients were recruited (87.5% – recruitment); 1/7 (85.7% – attrition) patient attended follow-up. VI is prevalent in patients with CI experiencing falls but traditional VR is not feasible, so a novel delivery of VR must be explored.