Background: The widely accepted treatment for idiopathic normal-pressure hydrocephalus (iNPH) is a cerebrospinal fluid (CSF) diversion shunt procedure, to which approximately 80% of patients will respond. The purpose of this systematic review was to identify which CSF biomarkers have been investigated in predicting shunt responsiveness in iNPH patients, and to analyze the level of evidence for each. Methods: To find all relevant articles, a comprehensive search of Medline, Embase, and PsycINFO was conducted. Results: The literature search identified 344 unique citations, of which 13 studies satisfied the inclusion criteria and were analyzed in our review. These 13 studies reported on 37 unique biomarkers. Conclusions: The available studies suggest that there is evidence for the utility of CSF biomarkers in predicting shunt responsiveness in iNPH patients, though none have been shown to predict shunt response with both high sensitivity and specificity. We found that there is no available evidence for the use of Aβ38, Aβ40, Aβ43, APL1β25, APL1β27, APL1β28, sAPP, aAPPα, sAPPβ, TNF-α, MCP-1, sCD40L, sulfatide, MBP, L-PGDS, cystatin C, transthyretin, TGF-β2, or YKL-40 in predicting shunt response. There is minimal evidence for the use of TGF-β1, TBR-II, homocysteine, and interleukins (particularly IL-1β, IL-6, and IL-10). However, the available evidence suggests that these biomarkers warrant further investigation. Aβ42, tau, p-tau, NFL, and LRG have the greatest amount of evidence for their predictive value in determining shunt responsiveness in iNPH patients. Future research should be guided by, but not limited to, these biomarkers.

Background: There is a significant need for a targeted therapy for essential tremor (ET), as medications have not been developed specifically for ET, and the ones prescribed are often not well-tolerated, so that many patients remain untreated. Recent work has shown that, unlike previous experience, kinematically guided individualized botulinum toxin type A (BoNT-A) injections provide benefit along with minimal weakness. Ours is the first long-term (96-week) safety and efficacy study of BoNT-A as monotherapy for ET using kinematically driven injection parameters. Methods: Ten ET patients were administered six serial BoNT-A treatments every 16 weeks and were assessed at 6 weeks following treatment. During each study visit, the Fahn–Tolosa–Marin (FTM) scale, the Unified Parkinson’s Disease Rating Scale, and the Quality of Life for Essential Tremor Questionnaire (QUEST) were administered along with kinematic assessment of the treated limb. Participants performed scripted tasks with motion sensors placed over each arm joint. Dosing patterns were determined using the movement disorder neurologist’s interpretation of muscles contributing to the kinematically analyzed upper limb tremor biomechanics. Results: There was a 33.8% (p<0.05) functional improvement (FTM part C) and a 39.8% (p<0.0005) improvement in QUEST score at week 96 compared to pretreatment scores at week 0. Although there was a 44.6% (p<0.0005) non-dose-dependent reduction in maximal grip strength, only 2 participants complained of mild weakness. Following the fourth serial treatment, mean action tremor score was reduced by 62.9% (p=0.001) in the treated and by 44.4% (p=0.03) in the untreated arm at week 96 compared to week 48. Conclusions: Individualized BoNT-A dosing patterns to each individual’s tremor biomechanics provided an effective monotherapy for ET as function improved without functionally limiting muscle weakness.

Background and Objective Pain is a frequent symptom in Parkinson’s disease (PD), and the therapeutic alternatives are scarce. The goal of this trial was to measure the effects of botulinum toxin type A (BTXA) in the treatment of limb pain in advanced PD. Methods A randomized double-blind crossover versus placebo study of BTXA for limb pain in advanced Parkinson’s disease was conducted. Subjects received individualized BTXA/placebo dosing per pain distribution in limbs. The primary outcome was a measure of change in global pain on a numeric rating scale (NRS) at 4 and 12 weeks postinjection and on a visual analogue scale 12 weeks after treatment. Secondary outcomes included the percentage of responders, physician-rated clinical global impressions, MDS–UPDRS and PDQ–39 scores, and adverse events. Results A total of 12 subjects completed the trial. Treatment with BTXA (average dose=241.66 U) produced a significant reduction in NRS score 4 weeks after the injections (–1.75 points, range from –3 to 7, p=0.033). However, there was no significant difference compared to placebo (p=0.70). Participants with dystonic pain showed a greater reduction in NRS score after 4 weeks when treated with BTXA (2.66 points vs. 0.75 for placebo). There were no significant differences for any of the secondary outcomes or significant adverse events. Conclusions Targeted BTXA injections were safe in patients with limb pain and advanced PD; however, the present study failed to show a significant effect when compared to placebo. Further studies may be focused on evaluating the effect of BTXA particularly in dystonic pain.

Rationale: Presurgical localization of the epileptogenic focus is critical to successful surgery. Traditionally, localization of the epileptogenic focus depends on seizure semiology, scalp video-electroencephalography (vEEG), magnetic resonance imaging (MRI), neuropsychological assessment, and, when needed, intracranial EEG (iEEG). We aimed to explore the role of positron emission tomography (PET) in the presurgical evaluation of patients with refractory epilepsy. Methods: A retrospective review was conducted on patients from London Health Sciences Centre (London, Ontario) with refractory epilepsy who underwent PET from September of 2011 to April of 2016. The accuracy of epileptogenic focus localization was compared between different investigative modalities (MRI, vEEG, iEEG, PET), and the outcomes were documented, including seizure freedom after surgical resection, improvement of seizure frequency, guidance for further investigations, and exclusion of patients from further evaluation. Patients who underwent surgery were followed up at 3 months and onward. Results: We identified 62 patients with refractory epilepsy who underwent PET. The mean age was 34 years (range=20-68). A total of 36 had concordant PET and vEEG findings: 6 had surgical resection and either became seizure-free (29.4%) or had improvement in seizure frequency (5.9%) at 3 months; 11 had surgical resection and either became seizure-free (29.4%) or had improvement in seizure frequency (35.3%) at 3 months, but required iEEG for final verification. Conclusions: PET has an important role in presurgical evaluation of patients with refractory epilepsy. It may allow resection of the epileptogenic focus without the need for iEEG, guiding intracranial electrode placement for further localization of the epileptogenic focus, or exclusion of patients from further evaluation.

Background: Stereoelectroencephalography has been in regular use at the Montreal Neurological Institute since 1972. The technique has been in constant evolution to incorporate advances in materials, imaging, and robotics technology. MRI-compatible electrodes were introduced in 2007 and robotics in 2011. Here we report on the technique, safety, and advantages of our current method of stereoelectroencephalography implantation. Methods: We retrospectively reviewed all patients who underwent stereoelectroencephalography by the senior author. Technical, clinical, and radiological complications, and postimplantation outcomes were analyzed. Only patients implanted with MRI-compatible electrodes were included to review MRI abnormalities with electrodes in situ. Results: A total of 53 patients were implanted with 550 electrodes (average=10.4 per patient), for an average duration of 14.6 days. There was no mortality, infection, or new neurologic deficit. Two patients had a superficial screw plunge without clinical consequence. Four patients demonstrated asymptomatic MRI abnormalities (7.54% per patient, or 0.72% per electrode). MRI with electrodes in situ was used for neuronavigation in all 29 who underwent resection and yielded a histopathological diagnosis of focal cortical dysplasia in 15 MRI-negative patients. Conclusions: The technique of stereoelectroencephalography described here was associated with no clinical morbidity although not without technical complications or radiologic (MRI) abnormalities. We should therefore remain vigilant in refining the technique and minimizing the number of electrodes required to answer a well-developed hypothesis regarding the epileptogenic zone. The use of MRI-compatible electrodes allowed neuronavigation using the images with the electrodes in situ, which was useful to tailor the eventual definitive resection and in localizing MRI-negative lesions.

Background: Cerebral venous thrombosis is a rare cause of stroke, with a number of well-defined risk factors. However, there exist few studies that describe trends in the prognosis of this disease over time. Methods: A retrospective study was performed on patients diagnosed with cerebral venous thrombosis at the University of Alberta Hospital during two time periods: 1988-1998 (21 patients) and 1999-2009 (40 patients). Signs and symptoms, risk factors, imaging findings, etiologies, treatment modalities, and status at discharge were examined. Results: Headache, nausea and vomiting, focal motor deficit, and seizure were the most common signs and symptoms, and active hormonal contraception was the most commonly identified risk factor between the two cohorts. Hematoma and hyperdense sinuses were the most commonly identified CT findings between groups. Thrombophilia and the use of hormonal contraception were the most frequently identified etiologies between the two cohorts. Treatment was similar, with the majority of patients in both cohorts receiving unfractionated heparin as first-line therapy. Patients in the 1999-2009 cohort were significantly less likely to have a severe deficit or be dead at discharge (odds ratio [OR]=0.178; 95% confidence interval [CI95%]=0.051, 0.625) and were more likely to have a favorable modified Rankin Scale score of 0 or 1 at discharge (OR=7.98; CI95%=1.79, 35.71). Conclusions: Our data indicate a reduction in severe residual symptoms at discharge and improved functional status at discharge for patients presenting with cerebral venous thrombosis from 1999 to 2009, as compared with 1988-1998.

Background: Pharmacists have become an integral member of the multidisciplinary team providing clinical patient care in various healthcare settings. Although evidence supporting their role in the care of patients with other disease states is well-established, minimal literature has been published evaluating pharmacist interventions in stroke patients. The purpose of this systematic review is to summarize the evidence evaluating the impact of pharmacist interventions on stroke patient outcomes. Methods: Study abstracts and full-text articles evaluating the impact of a pharmacist intervention on outcomes in patients with an acute stroke/transient ischemic attack (TIA) or a history of an acute stroke/TIA were identified and a qualitative analysis performed. Results: A total of 20 abstracts and full-text studies were included. The included studies provided evidence supporting pharmacist interventions in multiple settings, including emergency departments, inpatient, outpatient, and community pharmacy settings. In a significant proportion of the studies, pharmacist care was collaborative with other healthcare professionals. Some of the pharmacist interventions included participation in a stroke response team, assessment for thrombolytic use, medication reconciliation, participation in patient rounds, identification and resolution of drug therapy problems, risk-factor reduction, and patient education. Pharmacist involvement was associated with increased use of evidence-based therapies, medication adherence, risk-factor target achievement, and maintenance of health-related quality of life. Conclusions: Available evidence suggests that a variety of pharmacist interventions can have a positive impact on stroke patient outcomes. Pharmacists should be considered an integral member of the stroke patient care team.

Background: Bevacizumab has been used in recurrent glioblastoma (rGBM) since 2010 in Canada. Given its cost, potential toxicities, and unclear efficacy, further studies are required to better define suitable candidates for therapy. Methods: A single-center retrospective review of patients started on bevacizumab for rGBM from 2012 to 2015 was performed. Patient demographics, tumor characteristics, treatment regimen, and dates of clinical progression and death were collected. Overall survival (OS) and progression-free survival (PFS) were used as clinical outcomes and estimates. Radiological response was assessed using modified Response Assessment in Neuro-Oncology criteria. Results: A total of 80 patients were included. There were 67 reported deaths, and the median OS was 9.2 months (95% confidence interval [CI95%]=7.0-10.1 months), with a 12-month OS of 31% (CI95%=21.9-43.5%). Some 79 patients were included for analysis of clinical progression, among whom 61 had documented clinical progression. The median clinical PFS was 4.6 months (CI95%=3.8-6.4 months), and the 6-month clinical PFS was 39% (CI95%=29.0-52.9%). Addition of chemotherapy did not improve clinical outcomes. A total of 68 patients were included for radiological progression analysis, with 58 radiological progressions. The median radiological PFS was 5.8 months (CI95%=4.2-6.7 months), and the 6-month radiological PFS was 46% (CI95%=35.6-60.0%). Conclusions: This is the first reported Canadian experience with bevacizumab for rGBM. Our clinical outcomes are consistent with published data from multicenter phase II and III trials on bevacizumab in rGBM. More research is required to determine which subtype(s) of patients with rGBM could benefit from bevacizumab upon recurrence.

Background: Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction in which a clinical diagnosis may be confirmed with serological testing. The most common autoantibodies used to support a diagnosis of MG are anti-acetylcholine receptor antibodies and anti-muscle-specific tyrosine kinase antibodies. In cases in which both of these autoantibodies are negative (termed double-seronegative [dSNMG]), other autoantibodies such as low-density lipoprotein receptor-related protein 4 (LRP4) may be used to aid in diagnosis. Methods: We have undertaken a systematic literature review to identify studies that have assessed the frequency of anti-LRP4 antibodies in dSNMG patients and the characteristics of anti-LRP4+ dSNMG patients (epidemiology, clinical features, electromyographic findings, or management). PubMed, EMBASE, Medline, and Scopus were searched on January 14, 2017, using the medical subject headings “myasthenia gravis” and “low-density lipoprotein receptor-related protein 4” or “LRP4.” Results: The initial search identified 367 articles. Fourteen publications met the inclusion criteria. There were ten cross-sectional research studies, three were case series, and one was a case report. The majority of studies were limited by small sample sizes of LRP4+ dSNMG. There has been a wide range of frequencies of anti-LRP4 antibodies detected in different MG patient populations, some involving different laboratory techniques. Conclusions: LRP4+ dSNMG is more likely than LRP4– dSNMG to have a younger onset of disease and occur in females. LRP4+ dSNMG most often is mild in severity and often involves isolated ocular weakness. It typically responds well to pyridostigmine or prednisone.

Objective: The concomitant presence of pituitary adenoma (PA) with Rathke’s cleft cyst (RCC) is rare, and most of the literature published is case reports. RCC’s clinicopathological features have not been well described. Methods: We retrospectively reviewed the data of 15 patients with PA associated with RCC. We also provide a systematic review of the literature. Results: The patients included males and seven females. The transsphenoidal approach was adopted for all patients except one, who underwent right frontal craniotomy. Complete resection was achieved in nine cases, with grossly complete resection in five and partial removal in one. Of the PA subtypes available, five patients had nonfunctional pituitary adenomas, three had multiple-hormone secreting PAs, three had prolactin-producing adenomas, and one had a growth hormone-secreting adenoma. All of the patients’ symptoms and abnormal endocrine test results resolved or were relieved after surgery. The mean follow-up time was 27.6±16.6 months. All of the patients recovered well and had no signs of recurrence during their follow-up, except for one patient. Conclusions: A cyst-like signal indicated on images or cystic materials encountered during operation in a patient with PA suggest the possibility of PA associated with RCC. Transsphenoidal surgery is the preferred approach and can resolve or relieve patients’ symptoms to a great extent. Histologically, nonfunctional PA and prolactinoma are the most common types of PA coexisting with RCC; the mechanisms of PA associated with RCC need to be investigated further.

Introduction: Engaging residents across a multiyear training spectrum is challenging given the heterogeneity of experience and limited time available for educational activities. A “flipped classroom” model, in which residents prepare ahead of time for mentored topic discussions, has potential advantages. Methods: We implemented a curriculum consisting of topics distributed across the specialty. Weekly, each resident was randomly assigned to research a specific aspect of an assigned topic appropriate to his or her level of experience: junior residents about what characterizes each clinical entity, midlevel residents about when to intervene, and chief residents about how to administer treatment. Residents completed an anonymous survey 6 months after implementation. Board examination performance was assessed before and after implementation. Results: A total of 12 residents participated in the program. Weekly, 1.75±0.40 hours were spent in preparation, with senior residents reporting less time than junior residents. All residents indicated that the accumulation of experience across 7 years of residency was a major advantage of this program, and all preferred it to lectures. Performance on the board examination significantly increased after implementation (from 316±36 to 468±45, p<0.05). Conclusions: The flipped classroom is a viable approach to resident education and is associated with increased engagement and improved performance using validated knowledge-assessment tools.

Exactly 200 years ago, the London surgeon-apothecary James Parkinson (1755-1824) published a 66-page-long booklet entitled An Essay on the Shaking Palsy, which contains the first clear clinical description of the shaking palsy or paralysis agitans, which we now refer to as Parkinson’s disease. However, the value of this essay was not fully recognized during Parkinson’s lifetime, which spanned the American Revolution, the French Revolution, and the Napoleonic Wars. James Parkinson was one of the most singular figures of his time and place. He was successively or concomitantly a virulent political activist, a popular medical writer, a scholarly medical contributor, a highly appreciated parish doctor, a prominent amateur chemist, a devoted madhouse doctor, and a renowned paleontologist. It is that branch of geology that brought Parkinson fame during his lifetime. He was an insatiable collector of fossils, minerals, and shells that came to form the core of the museum that he set out at his home in Shoreditch, England. These specimens are beautifully illustrated in his Organic Remains of a Former World (1804-1811), a three-volume treatise that rapidly became a standard paleontology textbook. Parkinson was a founding member of the Geological Society of London, and in recognition of his contribution to the nascent field of paleontology his name was given to many fossils, particularly ammonites (e.g. Nautilus parkinsoni). Hence, we owe much to Mr. Parkinson, the Paleontologist, as he used to be referred to after his death, for such a vast and multifaceted contribution to natural science and medicine.

Between July of 2012 and December of 2014, 39 patients were enrolled prospectively to investigate the prevalence of glucose transporter 1 (GLUT1) deficiency in a ketogenic diet clinic. None of them had GLUT1 deficiency. All patients seen in the same clinic within the same period were reviewed retrospectively. A total of 18 of these 85 patients had a genetic diagnosis, including GLUT1 deficiency, pathogenic copy number variants, congenital disorder of glycosylation, neuronal ceroid lipofuscinosis type II, mitochondrial disorders, tuberous sclerosis, lissencephaly, and SCN1A-, SCN8A-, and STXBP1-associated epileptic encephalopathies. The prevalence of genetic diagnoses was 21% and prevalence of GLUT1 deficiency was 2.4% in our retrospective cohort study.

Some nonmotor symptoms (NMS) of Parkinson’s disease (PD) have been shown to increase the risk of developing dementia. A total of 52 PD patients without dementia at baseline were examined for NMS over 36 months. Mini-Mental State Examination, Dementia Rating Scale–2, and caregiver-derived (Clinical Dementia Rating) scores were employed to rate patients as having either clear progression or not. Some 20 of 48 participants (41.7%) had clear cognitive decline. Univariate binary regression analysis was statistically significant for age (odds ratio [OR] (CI95%)=1.24, 1.07–1.45, p=0.006) and orthostatic hypotension (OH) (OR (CI95%)=4.91, 1.24–19.5, p=0.024). Multivariate analysis showed that only age (OR (CI95%)=1.19, 1.0–1.41, p=0.05) and OH (OR (CI95%)=5.57, 1.0–30.97, p=0.05) were correlated with an increased risk of cognitive decline. The presence of OH at baseline may be a significant predictor of progression to dementia in PD.

We report the clinical and electrophysiological findings in seven patients with orthostatic myoclonus (OM) associated with gait initiation failure and falls. OM is one of the causes of unsteadiness of stance and gait, and it may develop as a symptom of neurodegenerative disorders. Both positive myoclonic bursts and negative myoclonus may be seen in electrophysiological recordings, and electrophysiological analysis suggests a subcortical origin for OM.