Summary Background Essential tremor is the most common movement disorder and is often refractory to medical treatment. Surgical therapies, using lesioning and deep brain stimulation in the thalamus, ...have been used to treat essential tremor that is disabling and resistant to medication. Although often effective, these treatments have risks associated with an open neurosurgical procedure. MR-guided focused ultrasound has been developed as a non-invasive means of generating precisely placed focal lesions. We examined its application to the management of essential tremor. Methods Our study was done in Toronto, Canada, between May, 2012, and January, 2013. Four patients with chronic and medication-resistant essential tremor were treated with MR-guided focused ultrasound to ablate tremor-mediating areas of the thalamus. Patients underwent tremor evaluation and neuroimaging at baseline and 1 month and 3 months after surgery. Outcome measures included tremor severity in the treated arm, as measured by the clinical rating scale for tremor, and treatment-related adverse events. Findings Patients showed immediate and sustained improvements in tremor in the dominant hand. Mean reduction in tremor score of the treated hand was 89·4% at 1 month and 81·3% at 3 months. This reduction was accompanied by functional benefits and improvements in writing and motor tasks. One patient had postoperative paraesthesias which persisted at 3 months. Another patient developed a deep vein thrombosis, potentially related to the length of the procedure. Interpretation MR-guided focused ultrasound might be a safe and effective approach to generation of focal intracranial lesions for the management of disabling, medication-resistant essential tremor. If larger trials validate the safety and ascertain the efficacy and durability of this new approach, it might change the way that patients with essential tremor and potentially other disorders are treated. Funding Focused Ultrasound Foundation.
On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also ...known as a clinically isolated syndrome) to multiple sclerosis.
During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T
-weighted MRI, cumulative number of new lesions enhanced on T
-weighted MRI "enhancing lesions", and cumulative combined number of unique lesions new enhancing lesions on T
-weighted MRI plus new and newly enlarged lesions on T
-weighted MRI).
A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval CI, 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo.
The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887 .).
To determine the causative genetic lesion in 3 adult siblings with a slowly progressive, juvenile-onset phenotype comprising cerebellar atrophy and ataxia, intellectual decline, hearing loss, ...hypogonadism, hyperreflexia, a demyelinating sensorimotor neuropathy, and (in 2 of 3 probands) supratentorial white matter changes, in whom numerous prior investigations were nondiagnostic.
The patients' initial clinical assessment included history and physical examination, cranial MRI, and nerve conduction studies. We performed whole-exome sequencing of all 3 probands, followed by variant annotation and selection of rare, shared, recessive coding changes to identify the gene responsible. We next performed a panel of peroxisomal investigations in blood and cultured fibroblasts, including assessment of D-bifunctional protein (DBP) stability and activity by immunoblot and enzymologic methods, respectively.
Exome sequencing identified compound heterozygous mutations in HSD17B4, encoding peroxisomal DBP, in all 3 probands. Both identified mutations alter a conserved residue within the active site of DBP's enoyl-CoA hydratase domain. Routine peroxisomal screening tests, including very long-chain fatty acids and phytanic acid, were normal. DBP enzymatic activity was markedly reduced.
Exome sequencing provides a powerful and elegant tool in the specific diagnosis of "mild" or "atypical" neurometabolic disorders. Given the broad differential diagnosis and the absence of detectable biochemical abnormalities in blood, molecular testing of HSD17B4 should be considered as a first-line investigation in patients with compatible features.
Background
: Multiple sclerosis (MS) has a profound impact on patients’ health-related quality of life (HRQoL). It is unclear how HRQoL can be best assessed for different purposes. This study aimed ...to compare two HRQoL questionnaires of differing lengths for feasibility of administration, patient perceptions and psychometric properties.
Methods
: This was an open-label, 24-month study in 334 patients with relapsing MS treated with subcutaneous interferon β-1a. At baseline and months 6, 12, 18 and 24, patients completed the Multiple Sclerosis International Quality of Life (MusiQoL) and Multiple Sclerosis Quality of Life-54 (MSQOL-54) questionnaires and compared them using an evaluation questionnaire. HRQoL scores over time and psychometric properties (correlations with clinical disease measures, relative validity and responsiveness to change) of the questionnaires were assessed.
Results
: A minority of patients had missing items on either HRQoL measure. Completion time was significantly shorter for MusiQoL versus MSQOL-54 (p<0.0001). Patients felt that MusiQoL was easier to use than MSQOL-54 but preferred MSQOL-54 in terms of thoroughness. Mean HRQoL scores increased significantly from baseline to 24 months; correlations of both measures were stronger with an anxiety and depression measure than with disability or recent relapse occurrence. Relative validity and responsiveness to change were similar for both instruments.
Conclusion
: The shorter MusiQoL is suitable for evaluating HRQoL in patients with MS and may be more practical to administer than the more thorough MSQOL-54.
Comparaison, dans un échantillon national, de deux mesures de la qualité de vie dans la sclérose en plaques :
Contexte:
La sclérose en plaques (SP) a un impact important sur la qualité de vie reliée à la santé (QVS) chez les patients qui en sont atteints. La meilleure façon d’évaluer la QVS à différentes fins demeure à préciser. Le but de l’étude était de comparer deux questionnaires de QVS de différente longueur pour évaluer la faisabilité d’administration, les perceptions des patients et les propriétés psychométriques.
Méthode:
Il s’agit d’une étude ouverte de 24 mois portant sur 334 patients atteints de SP cyclique traités par l’interféron ß-1a sous-cutané. Les patients ont complété les questionnaires Multiple Sclerosis International Quality of Life (MusiQoL) et Multiple Sclerosis Quality of Life-54 (MSQOL-54) au début de l’étude, à 6, 12, 18 et 24 mois du début et ils les ont comparés au moyen d’un questionnaire d’évaluation. Les scores au QVS et les propriétés psychométriques (corrélations avec les mesures de la maladie clinique, la validité relative et la capacité d’adaptation au changement) des questionnaires ont été évalués.
Résultats:
L’une ou l’autre des mesures de la QVS comportait des items manquants pour une minorité de patients. Le temps requis pour compléter les questionnaires était significativement plus court pour le MusiQoL que pour le MSQOL-54 (p<0,0001). Les patients estimaient que le MusiQoL était plus facile à utiliser que le MSQOL-54, mais préféraient le MSQOL-54 qui est plus approfondi. Les scores moyens aux QVS avaient augmenté significativement à 24 mois par rapport aux scores initiaux. Les corrélations entre les deux mesures étaient plus fortes pour la mesure de l’anxiété et de la dépression que pour l’invalidité ou une récurrence récente de la maladie. La validité relative et l’adaptation au changement étaient semblables pour les deux instruments.
Conclusion:
Le Questionnaire MusiQoL, qui est plus court, est approprié pour évaluer la QVS chez les patients atteints de SP et peut être plus pratique à administrer que le MSQOL-54 qui est plus approfondi.
Intravenous tissue plasminogen activator for ischemic stroke is approved for eligible patients who can be treated within a 3-hour window, but treatment rates remain disappointingly low, often <5%. To ...improve rapid access to stroke thrombolysis in Toronto, Canada, a citywide prehospital acute stroke activation protocol was implemented by the provincial government to transport acute stroke patients directly to one of 3 regional stroke centers, bypassing local hospitals. This comprised a paramedic screening tool, ambulance destination decision rule, and formal memorandum of understanding of system stakeholders. This report describes the initial impact of the activation protocol at our regional stroke center.
We compared consecutive patients with stroke arriving to our stroke center during the first 4 months of this new triage protocol (February 14 to June 14, 2005) versus the same 4-month period in 2004.
The protocol resulted in an immediate doubling in the number of patients with acute stroke arriving to our regional stroke center within 2.5 hours of symptom onset. We observed a 4-fold increase in patients who were eligible for and treated with tissue plasminogen activator. The tissue plasminogen activator treatment rate for ischemic stroke patients increased from 9.5% to 23.4% (P=0.01), and one in 2 patients with ischemic stroke arriving within 2.5 hours received thrombolysis during this period (one in 5 of patients with ischemic stroke overall). The median onset-to-needle time for tissue plasminogen activator-treated patients was significantly reduced. Many implementation challenges were identified and addressed.
This prehospital triage was immediately successful in improving tissue plasminogen activator access for patients with ischemic stroke, enabling our center to achieve one of the highest tissue plasminogen activator treatment rates in North America and underscoring the need for coordinated systems of acute stroke care. Sustainability of such an initiative will be dependent on interdisciplinary teamwork, ongoing paramedic training, adequate hospital staffing, bed availability, and repatriation agreements with community hospitals.
Multiple sclerosis (MS) is characterized by chronic inflammation in conjunction with neurodegeneration within the central nervous system. Most individuals with MS begin with a relapsing remitting ...course that later transitions to secondary progressive MS. Currently available disease-modifying therapies (DMTs) for relapsing MS have been demonstrated to reduce disease activity, however most patients require a change in therapy over the course of their disease. Treatment goals include the prevention of relapses and disability accumulation and to achieve this objective requires careful planning. Sequencing of DMTs for individual patients should be designed in such a way to maximize disease control and minimize risk based on the mechanism of action, pharmacokinetic and pharmacodynamic properties of each therapy. This includes the DMT patients are being switched from to those they are being switched to. The reversibility of immune system effects should be a key consideration for DMT sequence selection. This feature varies across DMTs and should factor more prominently in decision making as newer treatments become available for the prevention of disability accumulation in patients with progressive MS. In this short review, we discuss the landscape of existing therapies with an eye to the future when planning for optimal DMT sequencing. While no cure exists for MS, efforts are being directed toward research in neuroregeneration with the hope for positive outcomes.
Objective. To compare patterns of associations of changes in mental and physical health dimensions of health-related quality of life (HRQoL) over time with relapse occurrence and changes in Expanded ...Disability Status Scale (EDSS) scores in patients with relapsing multiple sclerosis (RMS). Methods. This 24-month, phase IV, observational study enrolled 334 patients with RMS who received interferon β-1a 44 μg or 22 μg subcutaneously three times weekly. At each 6-month visit, patients completed the Multiple Sclerosis Quality of Life-54 (MSQOL-54) and site investigators assessed EDSS and recorded relapse occurrence. A generalized linear model procedure was used for multivariable analyses (per protocol) that explored unique associations of EDSS score change and relapse occurrence with MSQOL-54 physical health composite score (PCS) and mental health composite score (MCS). Results. HRQoL improved over 2 years among those who completed the study. Occurrence of ≥1 relapse was significantly associated with lower MSQOL-54 PCS and MCS. Changes in EDSS score were significantly associated with MSQOL-54 PCS, but not MCS. Conclusions. HRQoL assessments, particularly those that examine mental health, may provide information on the general health status of patients with RMS that would not be recognized using traditional clinician-assessed measures of disease severity and activity. This trial is registered with ClinicalTrials.gov; identifier: NCT01141751.
Background: Prodromal phases are well recognized in many inflammatory and neurodegenerative diseases, including multiple sclerosis. We evaluated the possibility of a prodrome in aquaporin-4 antibody ...positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) using health administrative data. Methods: We investigated individuals with AQP4 + NMOSD and MOGAD, confirmed by medical chart review, in Ontario, Canada. Each NMOSD and MOGAD participant was matched 1:5 to general population controls by sex, birth year, immigrant status, and region. Total outpatient visits and hospitalizations were compared in the 5 years preceding the incident attack in multivariable negative binomial models. Results: We identified 96 people with AQP4 + NMOSD, matched to 479 controls, and 61 people with MOGAD, matched to 303 controls. In the 5 years preceding the incident attack, health care use was elevated for outpatient visits and hospitalizations for the NMOSD cohort (adjusted rate ratio (aRR): 1.47; 95% confidence interval (CI): 1.25–1.73; aRR: 1.67; 95% CI: 1.19–2.36, respectively) but not for MOGAD. Rate ratios steadily increased in NMOSD for outpatient visits in the 2 years preceding the incident attack. Conclusion: Our findings support a prodromal phase preceding clinical onset of AQP4 + NMOSD. Earlier recognition and management of NMOSD patients may be possible.
Background:
Risk factors for aquaporin-4 (AQP4+) antibody neuromyelitis optica spectrum disorder (NMOSD) are not well-established.
Objective:
To investigate demographic and environmental factors ...associated with NMOSD using a validated questionnaire and case–control design.
Methods:
We enrolled patients with AQP4 + NMOSD through six Canadian Multiple Sclerosis Clinics. Participants completed the validated Environmental Risk Factors in Multiple Sclerosis Study (EnvIMS) questionnaire. Their responses were compared to those of 956 unaffected controls from the Canadian arm of EnvIMS. We calculated odds ratios (ORs) for the association between each variable and NMOSD using logistic regression and Firth’s procedure for rare events.
Results:
In 122 participants (87.7% female) with NMOSD, odds of NMOSD in East Asian and Black participants were ⩾8 times that observed in White participants. Birthplace outside Canada was associated with an increased risk of NMOSD (OR = 5.5, 95% confidence interval (CI) = 3.6–8.3) as were concomitant autoimmune diseases (OR = 2.7, 95% CI = 1.4–5.0). No association was observed with reproductive history or age at menarche.
Conclusion:
In this case–control study, risk of NMOSD in East Asian and Black versus White individuals was greater than that observed in many previous studies. Despite the preponderance of affected women, we did not observe any association with hormonal factors such as reproductive history or age at menarche.
Abstract Background Canada has the highest incidence of MS worldwide. Anecdotal evidence reveals that people with MS smoke, ingest or vaporize cannabis for a multiplicity of reasons. With the legal ...situation in relation to use currently in flux, we undertook a study investigating patterns of use amongst people with MS and their attitudes towards the drug. Methods A consecutive sample of people with MS (n=246) attending a neurology (n=118) and a neuropsychiatry (n=107) clinic was enrolled and asked to complete a questionnaire containing demographic, disease and cannabis related variables. Results Of the 246 people approached, 225 (91.8%) agreed to participant. Attitude towards cannabis revealed that 122 (54.3%) participants approved of the drug while 75 (33.2%) were neutral. Legalization was endorsed by 98 (43.7%) participants, while 98 (43.7%) were in favour of legalization for medical use only. Current use was endorsed by 44 (19.5%) people with 125 (56.1%) reporting lifetime use. If cannabis were legal, 113 (50.2%) participants would use it. The most common symptoms for which cannabis was being used were: sleep (86%), pain (75%), anxiety (73%) and spasticity (68%). Participants attending the neuropsychiatry clinic were more likely to use cannabis for managing depression (χ2 =4.99; p=0.03) and pain (χ2 =3.85; p=0.05). Conclusion There is a wide acceptance of cannabis within the MS patient community. One in five people currently use the drug for reasons that differ between neuropsychiatry and neurology clinics. Use could potentially more than double if the drug were legalized.
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