Background: NEDA is a composite measure that may ultimately influence clinical decisions concerning switches of disease modifying therapy (DMT) for relapsing remitting multiple sclerosis (RRMS) patients. Cohort studies from MS clinics suggest NEDA is not sustained over time in most patients despite DMT but may be limited by referral bias. We investigated NEDA in a population-based RRMS cohort. Methods: We identified all incident cases of RRMS in Olmsted County from 01/01/2000-12/31/2011. Retrospective chart review was conducted to determine persistence of NEDA -following RRMS diagnosis. NEDA failure was defined as new MRI activity, relapse, or expanded disability status scale (EDSS) -worsening. Results: There were 93 incident cases of RRMS with 82 individuals having sufficient follow-up to determine persistence of NEDA. Prior to NEDA failure 44 were not on DMT, 37 were on first-tier, injectable DMT, and 1 received mitoxantrone. NEDA was maintained by 63% at 1 year, 38% at 2 years, 19% at 5 years, and 12% at 10 years. Disability measured by EDSS was no different at 10 years in patients maintaining NEDA versus those that failed NEDA at one year (p=0.3). Conclusions: Maintenance of NEDA beyond 2 years is infrequent among a population-based cohort of newly diagnosed RRMS patients and similar to prior clinic-based cohorts.

Objective: This study aimed to systematically review the effects of currently prescribed antiparkinson medication on cognition in patients with mild-to-moderate Parkinson’s disease (PD) who were either cognitively intact or mildly impaired. Methods: English- and French-language studies published between 1969 and 2017 were accessed via MedLine, PsychNET, EMBASE and EBSCO databases. Methodological quality (MQ) was evaluated with the quality assessment instrument of the Cochrane Collaboration Depression, Anxiety and Neurosis Review (scores from 0% to 44% indicate very low quality; scores from 45% to 64% indicate low quality; scores from 65% to 84% indicate medium quality; and scores from 85% to 100% indicate high quality). Hedges’ g and Student’s t-test were performed on all cognitive outcome measures reported. Results: In total, 14 studies assessed the cognitive effects of levodopa (L-D), pramipexole (PRX), selegiline (SEL) and rasagiline (RAS) in mild-to-moderate non-demented PD patients. The MQ was overall low, with an average score of 49.1%. Results for L-D showed deleterious effects on a test of cognitive inhibition, as well as benefits on tests of attention/processing speed/working memory, executive functions and episodic memory. Pramipexole was associated with a worsening of episodic memory and impulse control. Results on SEL indicated a deterioration of global cognition over time and of concept formation. Rasagiline had some benefits on working memory and verbal fluency. Conclusion: Antiparkinson medications can have deleterious (L-D; PRX; SEL) and beneficial (L-D; RAS) effects on cognition. However, randomized double-blind placebo-controlled trials with larger sample sizes are required to better elucidate this issue.

BACKGROUND: Adult medulloblastomas account for less than 1% of adult neoplasms. They are challenging to treat due to their rarity and the heterogeneity of treatment options, all of which have limited evidence. In this retrospective review, we examined cases of adult medulloblastoma diagnosed in Alberta during a 70-year period. METHODS: We reviewed the charts of patients diagnosed with medulloblastoma between 1944 and 2014. We performed Cox and logistic regression analysis to elucidate features that may influence recurrence risk and survival. RESULTS: We found 86 and analyzed 78 cases. The median age at diagnosis was 27 (range 16 to 71). Most were male (68%). Most had surgery (92%). By COG risk stratification, 54% were standard risk while 21% were poor risk. RT was administered to 85% of patients, and craniospinal irradiation (CSI) to 81%. Chemotherapy was administered to 48%. Median survival was 4.4 years from diagnosis (range 0 to 20). At last follow-up, 39% were alive and recurrence-free. Patients who had CSI and posterior fossa boost had longer survival (p=0.047 and<0.01, respectively) and were less likely to recur (p=0.041 and<0.01). Chemotherapy was also associated with decreased recurrence (p=0.025). CONCLUSIONS: Medulloblastomas carry a significant recurrence risk, especially for patients who had subtotal resection. CSI and posterior fossa boost were associated with fewer recurrences and improved survival. COG risk stratification, Chang staging, desmoplastic histology, vermian location, 4th ventricle involvement, tumor enhancement, presence of hydrocephalus and cerebrospinal fluid (CSF) involvement are not significantly prognostic.

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.

People with epilepsy (PWE) are less physically active compared with the general population. Explanations include prejudice, overprotection, unawareness, stigma, fear of seizure induction and lack of knowledge of health professionals. At present, there is no consensus on the role of exercise in epilepsy. This paper reviews the current evidence surrounding the risks and benefits associated with physical activity (PA) in this group of patients. In the last decade, several publications indicate significant benefits in physiological and psychological health parameters, including mood and cognition, physical conditioning, social interaction, quality of life, as well as potential prevention of seizure presentation. Moreover, experimental studies suggest that PA provides mechanisms of neuronal protection, related to biochemical and structural changes including release of β-endorphins and steroids, which may exert an inhibitory effect on the occurrence of abnormal electrical activity. Epileptic discharges can decrease or disappear during exercise, which may translate into reduced seizure recurrence. In some patients, exercise may precipitate seizures. Available evidence suggests that PA should be encouraged in PWE in order to promote wellbeing and quality of life. There is a need for prospective randomized controlled studies that provide stronger clinical evidence before definitive recommendations can be made.

Neuromuscular ultrasound is a rapidly evolving technique for diagnosing, monitoring and facilitating treatment of patients with muscle and nerve disorders. It is a portable point-of-care technology that is non-invasive, painless and without ionizing radiation. Ultrasound can visualize muscle texture alterations indicating dystrophy or denervation, changes in size and anatomic continuity of nerve fascicles, and its dynamic imaging capabilities allow capturing of contractions and fasciculations. Ultrasound can also provide real-time guidance for needle placement, and can sometimes make a diagnosis when electromyography is not tolerated or not informative anymore. This review will focus on the technical and practical aspects of ultrasound as an imaging technique for muscles and nerves. It will discuss basic imaging principles, hardware and software setup, and provide examples of ultrasound use for visualizing muscle and nerve abnormalities with accuracy and confidence. The review is intended as a practical “how-to” guide to get started with neuromuscular ultrasound in daily practice.

Background: Neurolymphomatosis is a process of neoplastic endoneurial invasion, most strongly associated with non-Hodgkin’s lymphoma. It must be distinguished from paraneoplastic, metabolic, nutritional and treatment-related causes of neuropathy that are common in this patient population. Methods: This brief case series illustrates the protean manifestations of neurolymphomatosis of the brachial plexus, ranging from focal distal mononeuropathy to multifocal brachial plexopathy, either as the index manifestation of lymphoma or as a complication of relapsing disease. Results: Prominent asymmetry, pain and nodular involvement on neuroimaging may help distinguish neurolymphomatosis from paraneoplastic immune demyelinating radiculoneuropathy. MR neurography criteria for the diagnosis of neurolymphomatosis include hyperintensity on T2 and STIR sequences, focal and diffuse nerve enlargement with fascicular disorganization and gadolinium enhancement. No specific anatomical distribution within the brachial plexus has, however, been found to be characteristic. Fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging is the imaging modality with the highest sensitivity for detection of nodal or extranodal spread in lymphoma. Conclusions: Brachial plexus neuropathy in neurolymphomatosis is highly protean in its distribution, semiology and relation to lymphoma staging. Dedicated MRI and PET-CT imaging are leading diagnostic modalities.

Objective: Perceived upright depends on three main factors: vision, graviception, and the internal representation of the long axis of the body. We assessed the relative contributions of these factors in individuals with sub-acute and chronic stroke and controls using a novel tool; the Oriented Character Recognition Test (OCHART). We also considered whether individuals who displayed active pushing or had a history of pushing behaviours had different weightings than those with no signs of pushing. Method: Three participants experienced a stroke <3 months before the experiment: one with active pushing. In total, 14 participants experienced a stroke >6 months prior: eight with a history of pushing. In total, 12 participants served as healthy aged-matched controls. Visual and graviceptive cues were dissociated by orienting the visual background left, right, or upright relative to the body, or by orienting the body left, right, or upright relative to gravity. A three-vector model was used to quantify the weightings of vision, graviception, and the body to the perceptual upright. Results: The control group showed weightings of 13% vision, 25% graviception, and 62% body. Some individuals with stroke showed a similar pattern; others, particularly those with recent stroke, showed different patterns, for example, being unaffected by one of the three factors. The participant with active pushing behaviour displayed an ipsilesional perceptual bias (>30°) and was not affected by visual cues to upright. Conclusion: The results of OCHART may be used to quantify the weightings of multisensory inputs in individuals post-stroke and may help characterize perceptual sources of pushing behaviours.

Background: Limbic encephalitis (LE) is a rare autoimmune syndrome affecting limbic system structures and causing variety of manifestations including memory changes, temporal epilepsies, and psychiatric symptoms. It is a rare disease in children but with a well-recognizable combination of clinical, neuroimaging and/or histological signature. Beyond the association with anti-neuronal auto-antibodies, no clear immune system phenotype has been associated with limbic encephalitis. Our aim is to characterize the clinical and paraclinical features of non-paraneoplasic limbic encephalitis and to correlate them with potential underlying immune deficiencies. Methods: Retrospective case series of seven patients with limbic encephalitis recruited at the Montreal Children’s Hospital (MCH) with a focus on the immune- and neuro-phenotypes, including anti-neuronal antibodies, lymphocyte sub-typing, key markers of immunoglobulin and complement systems. Literature review showed 77 cases of non-paraneoplastic non-NMDA limbic encephalitis. Results: Symptoms included temporal epilepsy (n=5), psychiatric symptoms such as ADHD or autistic symptoms (n=2), and memory changes (n=3). One patient was positive for both voltage gated potassium channel antibodies (VGKC) and anti-thyroid peroxidase antibodies (TPO) and two were positive only for anti TPO antibodies. One patient showed low CD19, and immunoglobulins. Three patients showed chronic low CD56 cell count. Conclusions: The study is still ongoing, but at least 3 patients already display some traits of immune dysregulation.

Anaplastic ependymomas are relatively uncommon, WHO grade III tumours that can occur in any location of the central nervous system. Low, as well as high grade tumours may show an additional component, most frequently cartilage or bone. Ganglionic differentiation has been demonstrated in only very few cases, usually young individuals. The purpose of this communication is to describe six examples of anaplastic ependymomas with a definite ganglionic component. All tumours were supratentorial and occurred in adults, 36-81 years of age. With the exception of one with a cystic component, all showed a diffuse MRI pattern and variable enhancement. All tumours displayed necrosis, vascular proliferation and marked pleomorphism, due to a mixture of epithelioid, giant, rhabdoid and gemistocytic, as well as clear and undifferentiated cells. Immunohistochemistry revealed reactivity for EMA (often atypical), GFAP and markers of neuronal differentiation, usually synaptophysin and chromogranin. All displayed high MIB-1 and occasional P53-positive nuclei. Two cases showed sarcomatous differentiation with desmin, smooth muscle actin and very rich reticulin staining. Electron microscopy revealed “zippering” intercellular junctions, basal bodies and cilia. Neuronal differentiation was expressed by neurosecretory granules and/or rich endoplasmic reticulin, large nuclei with nucleoli, and rare neuritic processes with microtubules. Differentiation of these rare tumours from glioblastomas might be important for the future development of tumour-specific molecular therapies. Electron microscopy is highly recommended for correct diagnosis of atypical variants of Anaplastic Ependymoma.

Objective: To define the prevalence of psychiatric symptoms of anxiety and depression in patients at the time of their first seizure presentation to a neurologist. Methods: Our pilot study uses a cohort approach with multimodal data (clinical, social, structural [3T magnetic resonance imaging], and functional [electroencephalogram]). We screened 105 patients referred to the Halifax First Seizure Clinic between 2014 and 2016 and 51 controls. All participants completed two screening questionnaires: Neurological Disorders Depression Inventory for Epilepsy and Generalized Anxiety Disorder 7-Item. After applying the exclusion criteria, the study population consisted of 57 patients with unprovoked first seizure and 31 controls. The prevalence of anxiety and depression was based on cutoff scores of >15 and >14 respectively. Results: Unprovoked first seizure patients showed higher prevalence of depression (33%) compared with control (6%) with an odds ratio (OR) of 2.75 (95% confidence interval [CI], 0.72-10.5). There was no significant difference in the prevalence of anxiety between control subjects (9.7%) and unprovoked first seizure patients (23%). Subcategory analysis conducted after diagnosis confirmation revealed significantly increased OR of depression in patients diagnosed with new-onset epilepsy (OR, 11.6; 95% CI, 2.1-64.0) and newly diagnosed epilepsy (OR, 20.0; 95% CI,2.2-181), but not first seizure only patients (OR, 2.2; 95% CI,0.28-17.6) compared with control. Conclusions: Our study supports a bidirectional relationship between the first seizure and depression. Prevalence rate of depression increased with duration of undiagnosed epilepsy at the time of first clinical assessment.

Glioblastoma multiforme (GBM) is the deadliest brain tumor with an approximate 14 month survival rate after diagnosis and treatment. Temozolomide (TMZ), the chemotherapeutic drug of choice for GBM, is an alkylating agent that causes DNA damage. TMZ treatment results in the induction of apoptosis in GBM cells, however, it induces autophagy and consequently chemoresistance. Statins are mevalonate (MEV) cascade inhibitors with beneficial effects on the enhancement of the survival rate of patients with different types of cancer. Here, we determined the effect of simvastatin (Simva), a blood brain barrier permeable statin, on the sensitization of GBM cells to TMZ induced apoptosis through inhibition of autophagy flux. We pretreated two GMB cell lines, U251 and U87 cells, with low doses of Simva (1 and 2.5 M, respectively) with or without different intermediates of the mevalonate cascade and then treated cells with TMZ (100 M) for 48-96 hrs. A signficiantly reduced viability and increased in the population of apoptotic dead cells were observed in GBM cells treated with the Simva-TMZ compared to cells treated with TMZ alone. Addition of MEV, Farnesyl pyrophosphate, Geranylgeranyl pyrophosphate and cholesterol did not attenuate these effects significantly. Sima-TMZ treatment did not alter the total cholesterol pool in U87 and U251 cells compared to controls. Western blot analysis, immunocytochemistry and transmission electron microscopy revealed that Simva-TMZ inhibited autophagic flux. Overall, the results suggest that sensitization of GBM cells to TMZ-induced apoptosis by Simva is independent on the cholesterol biosynthetic pathway but may involve inhibition of autophagy.

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.

A majority of patients with Guillain-Barré syndrome (GBS) have tendency of a good recovery. Our aim was to evaluate the outcome of the disease 1 and 3 years after GBS symptom onset. Methods: During 2014, GBS was diagnosed in 82 patients in seven tertiary healthcare centers. Neurological follow-up was conducted in 57 (70%) patients after 1 year, and in 54 (66%) after 3 years. Functional disability was estimated according to the GBS disability scale (GDS), with a score of 0-3 indicating mild disability and a score of 4-6 indicating severe disability during acute phase, whereas a score >1 indicated poor recovery on follow-ups. Visual analog scale was used to assess sensory symptoms and musculoskelatal pain, and Krupp’s Fatigue Severity Scale was used to asses fatigue. Results: Poor functional outcome was found in 39% of GBS patients at year 1 and 30% at year 3. Paresthesias/dysesthesias were detected in 60% of patients after 1 year and 43% after 3 years. Musculoskeletal pain was present in 40% of patients at year 1 and 33% at year 3. Significant fatigue after 1 year was found in 21% of subjects and after 3 years in 7%. Parameters associated with poor functional outcome after 1 year were age >55 years (p=0.05), severe disability at admission (p<0.05), and on discharge (p<0.01). Poor functional outcome after 3 years was associated with male gender (p<0.05) and severe disability on discharge (p=0.06). Conclusion: One and even three years after GBS onset, a substantial number of patients had neurological sequelae, including functional disability, sensory symptoms, pain, and fatigue.

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: Epidemiologic studies have suggested that concussion, or mild traumatic brain injury (mTBI), is associated with a twofold or greater increase in relative risk for the development of post-traumatic epilepsy. To assess the clinical validity of these findings, we analyzed the incidence of epilepsy in a large cohort of post-concussion patients in whom concussion was strictly defined according to international guidelines. Methods: A retrospective cohort study of 330 consecutive post-concussion patients followed by a single concussion specialist. Exclusion criteria: abnormal brain CT/MRI, Glasgow Coma Scale<13 more than 1-hour post-injury, hospitalization >48 hours. Independent variable: concussion. Outcome measure: epilepsy incidence (dependent variable). Results: The mean number of concussions/patient was 3.3 (±2.5), mean age at first clinic visit 28 years (±14.7), and mean follow-up after first concussion 7.6 years (±10.8). Eight patients were identified whose medical records included mention of seizures or convulsions or epilepsy. Upon review by an epileptologist none met criteria for a definite diagnosis of epilepsy: four had episodic symptoms incompatible with epileptic seizures (e.g., multifocal paraesthesiae, multimodality hallucinations, classic migraine) and normal EEG/MRI investigations; four had syncopal (n=2) or concussive (n=2) convulsions. Compared with annual incidence (0.5/1000 individuals) in the general population, there was no difference in this post-concussion cohort (p=0.49). Conclusion: In this large cohort of post-concussion patients we found no increased incidence of epilepsy. For at least the first 5-10 years post-injury, concussion/mTBI should not be considered a significant risk factor for epilepsy. In patients with epilepsy and a past history of concussion, the epilepsy should not be presumed to be post-traumatic.

Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector (RRV). RRVs selectively infect cancer cells due to innate and adaptive immune response defects in cancers that allow virus replication, and the requirement for cell division for virus integration into the genome. Toca 511 spreads through tumors, stably delivering an optimized yeast cytosine deaminase gene that converts the prodrug Toca FC (investigational, extended-release 5-FC) into 5-FU within the tumor microenvironment. 5-FU kills infected dividing cancer cells and surrounding tumor, myeloid derived suppressor cells, and tumor associated macrophages, resulting in long-term tumor immunity in preclinical models. Data from a Phase 1 resection trial showed six durable CRs and extended mOS compared to historical controls. The FDA granted Breakthrough Therapy Designation for Toca 511 & Toca FC in the treatment of patients with rHGG. Toca 5 is an international, randomized, open-label Phase 3 trial (NCT02414165) of Toca 511 & Toca FC versus SOC in patients undergoing resection for first or second recurrence of rHGG. Patients will be stratified by IDH1 status, KPS, and geographic region. Primary endpoint is OS, and secondary endpoints are durable response rate, durable clinical benefit rate, duration of durable response, and 12-month survival rate. Key inclusion criteria are histologically proven GBM or AA, tumor size ≥1cm and ≤5cm, and KPS ≥70. Immune monitoring and molecular profiling will be performed. Approximately 380 patients will be randomized. An IDMC is commissioned to review the safety and efficacy data which includes 2 interim analyses. Enrollment is ongoing.

Pleomorphic xanthoastrocytoma (PXA) is a rare tumour comprising <1% of all primary central nervous system tumours and the majority (~98%) occur supratentorially. We report on a 40-year-old female with a past medical history of a rare posterior fossa/cerebellar PXA who presented with a right-sided neck mass, decreased shoulder power and longstanding right tongue deviation with right-sided hemi-atrophy. The patient had prior tumour debulking. Recent MRI demonstrated an enhancing posterior fossa mass extending to the skull base at the jugular foramen and another mass in the upper neck along the jugular bulb with displacement and encasement of the right common carotid artery down to C5. Resection of the neck mass reveals an anaplastic PXA. The tumour has close approximation with adjacent peripheral nerves and is positive in 2 lymph nodes. Comparison with the original tumour molecular and immunohistochemical profiles reveals a conserved BRAF V600E mutation but the transformed malignant glioma now expresses dot-like EMA positivity and ATRX is completely lost (mutated). Transformation of a PXA (WHO Grade II) into an anaplastic PXA (WHO Grade III) has been well documented, but extracranial extension is extraordinarily rare. We report herein the first documented case of a posterior fossa PXA that underwent malignant transformation and extracranial invasion to the parapharyngeal space.