Use of natalizumab in persons with multiple sclerosis: 2022 update.

BACKGROUND: Natalizumab is a humanized monoclonal antibody used for treatment of highly active relapsing-remitting multiple sclerosis (MS). With more than 15 years of post-marketing experience with natalizumab in Canada, several real-world studies have shown the long-term efficacy and safety of natalizumab. In addition, risk stratification/mitigation strategies for progressive leukoencephalopathy (PML), an adverse effect associated with natalizumab based on the John Cunningham virus (JCV) index; treatment duration beyond 24 months; and prior exposure to immunosuppressant drugs have been developed. METHODS: A group of neurologists from various MS clinics across Canada met in September 2021 to update the 2015 Canadian practice recommendations for the use of natalizumab in persons with MS (PwMS). RESULTS: The recommendations focused on the long-term efficacy and safety data from real-world studies, patient selection according to JCV index criteria, risk management strategies for PML (including extended interval dosing), and options for switching to currently available disease-modifying therapies for MS. CONCLUSIONS: The recommendations of clinical neurologists seek to optimize the management of PwMS who may benefit from treatment with natalizumab.

Sleep Quality in Neuromyelitis Optica Spectrum Disorder: A Systematic Review.

Background: This review summarizes the literature on sleep quality in neuromyelitis optica spectrum disorder (NMOSD) and discusses these findings in the context of current knowledge of sleep physiology. Methods: A literature search was performed using Ovid MEDLINE, Embase, and Scopus from inception to September 3, 2020. All included studies reported at least 1 measure of sleep quality in individuals with NMOSD. Pittsburgh Sleep Quality Index (PSQI) scores of individuals from 4 studies were compared with those from a data set of controls. Results: Thirteen studies (1041 individuals with NMOSD) were included in the review. Disturbed sleep was demonstrated across subjective metrics based on patient surveys and objective metrics such as polysomnography. An estimated 70% of individuals with NMOSD can be classified as poor sleepers. Standardized mean difference between PSQI scores of 183 individuals with NMOSD and those of 9284 controls was 0.72 (95% CI, 0.57-0.86; P < .001). Decreased sleep quality was significantly associated with decreased quality of life and increased anxiety, depression, and disability status. Sleep disturbances in NMOSD were similar in severity to those in multiple sclerosis. Conclusions: Sleep disturbances are a major contributor to NMOSD disease burden and may arise from the disruption of sleep circuitry, in addition to physical and psychological complications. Multiple processes involved in sleep regulation may be affected, such as, but not limited to, neural circadian circuit disruption, direct effects of inflammation, aminergic projecting system abnormalities, glymphatic system impairment, and development of sleep disorders such as restless legs syndrome/sleep apnea. A better understanding of these mechanisms is necessary for developing effective therapies for NMOSD-associated sleep disturbances.

Modelling System of Two Insulin-Glucose Delays to Achieve the Dynamics of Glucose Changes.

Background: Due to the increased prevalence of diabetes and the irreparable complications of this disease, it is important to measure and monitor the blood glucose levels of diabetic patients. The only way to treat type 1 diabetes is monitoring insulin, and in this type of diabetes, insulin should be injected into the body in order to reduce the patient's blood glucose as prescribed by the physician at certain times. In addition, the only way to treat type 2 diabetes is through diet and exercise daily. Objective: We aim to use an ordinary differential equation model with two-delays to control the rate of changes in blood glucose levels throughout the day, based on the amount of food that the person consumes. Material and Methods: In this analytical study, we extended an ODE model which is parameterized by data collected in this study to capture dynamics of glucose and insulin. We used global sensitivity analysis method to assess model robustness with respect to parameter perturbations. Results: Our results have shown that utilizing the dynamics of changes in blood glucose levels throughout the day can be used to prevent hypoglycemia and hyperglycemic in the diabetic patients. Conclusion: Dynamic modeling can help us to prevent hypoglycemia and hyperglycemia in the diabetic patients.

Clinical characteristics and outcomes of multiple sclerosis patients with COVID-19 in Toronto, Canada.

OBJECTIVE: To report clinical characteristics and outcomes of people with multiple sclerosis (PwMS) who developed COVID-19 infection in Toronto, Canada. METHODS: Descriptive, retrospective, single-center study that included all known PwMS at the St. Michael's Hospital MS Clinic who had PCR-confirmed COVID-19 infection between March 2020 and May 2021. RESULTS: Of 7000 PwMS in our clinic, 80 (1.1%) tested positive for SARS-CoV-2. Fifty-four (67.5%) were on disease-modifying therapy (DMT) without over-representation of any single treatment. Seventy-one patients (88.8%) had mild symptoms, but nine (11.3%) were hospitalized and one 70-year-old male patient not on treatment died. Of those hospitalized, one-third were treated with ocrelizumab. CONCLUSION: In Toronto, PwMS did not appear to have higher prevalence of COVID-19 infection compared to the general population, but disease severity may be affected by DMT use. Our findings add to the accumulating global data regarding COVID-19 infection in PwMS.

Cortical morphology predicts placebo response in multiple sclerosis.

Despite significant insights into the neural mechanisms of acute placebo responses, less is known about longer-term placebo responses, such as those seen in clinical trials, or their interactions with brain disease. We examined brain correlates of placebo responses in a randomized trial of a then controversial and now disproved endovascular treatment for multiple sclerosis. Patients received either balloon or sham extracranial venoplasty and were followed for 48 weeks. Venoplasty had no therapeutic effect, but a subset of both venoplasty- and sham-treated patients reported a transient improvement in health-related quality of life, suggesting a placebo response. Placebo responders did not differ from non-responders in total MRI T2 lesion load, count or location, nor were there differences in normalized brain volume, regional grey or white matter volume or cortical thickness (CT). However, responders had higher lesion activity. Graph theoretical analysis of CT covariance showed that non-responders had a more small-world-like CT architecture. In non-responders, lesion load was inversely associated with CT in somatosensory, motor and association areas, precuneus, and insula, primarily in the right hemisphere. In responders, lesion load was unrelated to CT. The neuropathological process in MS may produce in some a cortical configuration less capable of generating sustained placebo responses.

Comparable Efficacy and Safety of Teriflunomide versus Dimethyl Fumarate for the Treatment of Relapsing-Remitting Multiple Sclerosis.

BACKGROUND: The aim of this observational study is to investigate the efficacy and safety of two approved oral disease-modifying therapies (DMTs) in patients with remitting-relapsing multiple sclerosis (RRMS): dimethyl fumarate (DMF) vs. teriflunomide (TRF). METHODS: A total of 159 RRMS patients (82 on TRF and 77 on DMF) were included. The expanded disability status scale (EDSS), confirmed disability improvement (CDI), confirmed disability progression (CDP), and annualized relapse rate (ARR) were evaluated for the two-year period prior to enrollment in our study. The drug-associated adverse effects (AEs) were recorded. We conducted propensity matching score to compare the efficacy between TRF and DMF. RESULTS: After matching for the confounders, TRF- and DMF-treated groups were not different in terms of EDSS (P value = 0.54), CDI (P value = 0.80), CDP (P value = 0.39), and ARR (P value >0.05). TRF discontinuation occurred in 2 patients (2.43%) due to mediastinitis and liver dysfunction, while a patient (1.29%) discontinued DMF due to depression. Incidence rate of AEs in the TRF-treated group was 81.4%: hair thinning (hair loss) (62.9%), nail loss (20.9%), and elevated aminotransferase (14.8%) were the most common AEs; in DMF-treated patients, AEs were 88.2% with predominance of flushing (73.2%), pruritus (16.9%), and abdominal pain (16.9%). CONCLUSION: Based on our findings, DMF is as efficacious and safe as TRF for the treatment of RRMS in our Iranian study population. Multicentric studies need to corroborate these findings in other populations.

Clinical and MRI characteristics of multiple sclerosis in patients of Middle Eastern and North African ancestry residing in Ontario, Canada.

BACKGROUND: Multiple sclerosis (MS) incidence is rising in traditionally low-burden regions, including the Middle East and North Africa (MENA). OBJECTIVES: Our objective was to evaluate disease characteristics in MS patients of MENA descent (MENA-MS). METHODS: MENA-MS patients and age- and sex-matched MS patients of European descent (EUR-MS) were identified through the MS Clinic Registry of St. Michael's Hospital in Toronto, Canada. Disease activity and severity were evaluated by the annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, change in the Expanded Disability Status Scale (EDSS), progression index (PI), and MS Severity Score (MSSS). RESULTS: All MS patients within the registry identified to be of MENA origin (n = 192), and age- and sex-matched EUR-MS patients were included. Mean age was 42.9 years, 67% female. A total of 25% and 24% of EUR-MS and MENA-MS had progressive disease, with similar mean disease durations (11.5 and 11.4 years, respectively). Clinical and radiological disease activity (ARR, proportion with new/enlarging MRI lesions) was similar. MENA-MS showed greater disability progression over time (EDSS change = 0.24 vs. 0.06, p = 0.01), a higher MSSS (3.12 vs. 2.67, p = 0.04), and higher PI (0.34 vs. 0.27, p = 0.07). CONCLUSION: MENA-MS patients demonstrate higher disease severity compared to EUR-MS patients, despite having similar inflammatory measures of disease activity, with disability progression in the absence of relapses. These observations illustrate the importance of the intersections of environmental, socioeconomic, and genetic determinants in optimizing individualized MS care.

Selective Colour Vision Deficits in Multiple Sclerosis at Different Temporal Stages.

Multiple sclerosis (MS) without optic neuritis causes color-vision deficit but the evidence for selective color deficits in parvocellular-Red/Green (PC-RG) and koniocellular-Blue/Yellow (KC-BY) pathways is inconclusive. We investigated selective color-vision deficits at different MS stages. Thirty-one MS and twenty normal participants were tested for achromatic, red-green and blue-yellow sinewave-gratings (0.5 and 2 cycles-per-degree (cpd)) contrast orientation discrimination threshold. Red-green mean threshold at 0.5cpd in established-MS and blue-yellow mean threshold in all MS participants were abnormal. These findings show blue-yellow versus red-green color test is useful in differentiating MS chronicity, which helps to better understand the mechanism of colour-vision involvement in MS.

Safety and efficacy of venoplasty in MS: A randomized, double-blind, sham-controlled phase II trial.

OBJECTIVE: To determine the safety and efficacy of balloon vs sham venoplasty of narrowing of the extracranial jugular and azygos veins in multiple sclerosis (MS). METHODS: Patients with relapsing or progressive MS were screened using clinical and ultrasound criteria. After confirmation of >50% narrowing by venography, participants were randomized 1:1 to receive balloon or sham venoplasty of all stenoses and were followed for 48 weeks. Participants and research staff were blinded to intervention allocation. The primary safety outcome was the number of adverse events (AEs) during 48 weeks. The primary efficacy outcome was the change from baseline to week 48 in the patient-reported outcome MS Quality of Life-54 (MSQOL-54) questionnaire. Standardized clinical and MRI outcomes were also evaluated. RESULTS: One hundred four participants were randomized (55 sham; 49 venoplasty) and 103 completed 48 weeks of follow-up. Twenty-three sham and 21 venoplasty participants reported at least 1 AE; one sham (2%) and 5 (10%) venoplasty participants had a serious AE. The mean improvement in MSQOL-54 physical score was +1.3 (sham) and +1.4 (venoplasty) (p = 0.95); MSQOL-54 mental score was +1.2 (sham) and -0.8 (venoplasty) (p = 0.55). CONCLUSIONS: Our data do not support the continued use of venoplasty of extracranial jugular and/or azygous venous narrowing to improve patient-reported outcomes, chronic MS symptoms, or the disease course of MS. CLINICALTRIALSGOV IDENTIFIER: NCT01864941. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with MS, balloon venoplasty of extracranial jugular and azygous veins is not beneficial in improving patient-reported, standardized clinical, or MRI outcomes.

Fluid-Attenuated Inversion Recovery Signal Intensity as a Predictor of Gadolinium Enhancement in Relapsing-Remitting Multiple Sclerosis.

BACKGROUND: Magnetic resonance imaging (MRI) is used to diagnose and monitor disease activity in relapsing-remitting multiple sclerosis (RRMS). The objective of this study was to explore the association of "ultrabright" axial fluid-attenuated inversion recovery (FLAIR) lesions with gadolinium enhancement in patients with RRMS using qualitative and quantitative approaches. METHODS: MRIs from patients with RRMS from 2010 to 2015 were reviewed. Two radiologists independently identified ultrabright lesions on axial FLAIR sequences. The contrast-to-noise ratio (CNR) was measured for ultrabright and control lesions. RESULTS: Of 301 lesions included in the study, 77 (26%) were identified by both radiologists as ultrabright. Interrater agreement was moderate (κ = 0.77, P < .001). Lesions identified by both radiologists as ultrabright demonstrated an association with gadolinium enhancement (χ21 = 30.8, P < .001) but were not associated with MRI magnet strength (χ21 = 0.24, P = .65). Higher CNR values were associated with gadolinium enhancement for 1.5-T studies (OR, 1.05; 95% CI, 1.02-1.07; P = .001) and 3-T studies (OR, 1.02; 95% CI, 1.02-1.03; P < .001). Diagnostic accuracy of the quantitative model was good for 1.5-T studies (area under the curve, 0.79; 95% CI, 0.68-0.9; P < .001) and 3-T studies (area under the curve, 0.78; 95% CI, 0.73-0.84; P < .001). Positive predictive value of 100% was obtained for CNR values of 92 for 1.5-T and 184 for 3-T studies. CONCLUSIONS: Qualitatively and quantitatively identified ultrabright axial FLAIR lesions are significantly associated with gadolinium enhancement.

Multifocal leukoencephalopathy in cocaine users: a report of two cases and review of the literature.

BACKGROUND: Cocaine abuse is associated with several mechanisms of brain injury including ischemic, hemorrhagic and metabolic. Recently two case reports of leukoencephalopathy in cocaine users implicated a commonly used cocaine adulterant, levamisole. One well-documented adverse effect of levamisole, when used alone as antihelminthic or immunomodulatory drug, is multifocal inflammatory leukoencephalopathy. Therefore, immune mechanisms may also contribute to cocaine-induced brain injury. CASE PRESENTATIONS: Two cocaine users with multifocal leukoencephalopathy, treated with steroids and plasmapheresis, are described. The first is a 25-year-old man who presented with unilateral motor and sensory impairment progressing to bilateral deficits, dysphagia, dysarthria and confusion over several days. Serial MRI showed increasing abnormal FLAIR signal lesions with patchy restricted diffusion and heterogenous enhancement deep in the right and left hemispheres, including periventricular white matter as well as in the pons and cerebellar peduncle. The second patient is a 41-year-old woman who presented with confusion and impaired balance. MRI showed bilateral periventricular FLAIR lesions with scattered restricted diffusion and subtle gadolinium enhancement of some of the lesions. She initially stabilized with supportive care only, but after further cocaine use was re-admitted six weeks later with marked neurological deterioration and MRI showed prominent worsening of the lesions. Both patients received steroid and plasma exchange and showed substantial improvement clinically and on imaging, which was sustained during out-patient follow-up. CONCLUSION: Multifocal leukoencephalopathy associated with cocaine use may have an inflammatory/immune basis, possibly related to levamisole contamination, at least in some patients. Three cases, including the present two, have been described wherein good neurological improvement was seen in association with steroid treatment. However, in the absence of appropriate clinical trials, it remains unknown whether immunotherapy is truly beneficial for these patients.

Epidemiology of neuromyelitis optica in the world: a systematic review and meta-analysis.

Background. Neuromyelitis optica (Devic's disease) is a severe autoimmune inflammatory disorder of the central nervous system. Epidemiological aspects of NMO have not been systemically reviewed. In this study we systematically reviewed and assessed the quality of studies reporting the incidence and/or prevalence of NMO across the world. Methods. A comprehensive literature search using MEDLINE, EMBASE, and Web of Science for the terms "Neuromyelitis optica," "devic disease," "incidence," "prevalence," and "epidemiology" was conducted on January 31, 2015. Study quality was assessed using an assessment tool based on recognized guidelines and designed specifically for this study. Results. A total of 216 studies were initially identified, with only 9 meeting the inclusion criteria. High level of heterogeneity amongst studies precluded a firm conclusion. Incidence data were found in four studies and ranged from 0.053 per 100,000 per year in Cuba to 0.4 in Southern Denmark. Prevalence was reported in all studies and ranged from 0.51 per 100,000 in Cuba to 4.4 in Southern Denmark. Conclusion. This review reveals the gaps that still exist in the epidemiological knowledge of NMO in the world. Published studies have different qualities and methodology precluding a robust conclusion. Future researches focusing on epidemiological features of NMO in different nations and different ethnic groups are needed.

Thrombotic microangiopathy in Interferon Beta treated multiple sclerosis patients: Review of literature and report of two new cases.

Beta interferons (IFN-ß) were the first approved disease modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) and are still the most-widely prescribed medications for this disease. Despite good overall long-term safety data with prolonged use of this group of drugs, they can rarely cause serious and sometimes life threatening adverse effects. In this article we report two cases of thrombotic microangiopathy occurring during prolonged use of IFN-ß and review the available literature on this topic.

Embolization of the deep cervical collaterals--a unique endovascular approach to prevent repeated posterior fossa strokes refractory to medical therapy.

We present a 69-year-old man with advanced vertebral artery atherosclerotic disease and repeated posterior fossa strokes, refractory to aggressive medical treatment. CT angiogram showed heavily calcified long segment occlusion of the dominant right vertebral artery. Beyond the occlusion, the vertebral artery was reconstituted by hypertrophic deep cervical collaterals which had multiple long and short segments of severe stenosis and antegrade flow. The ostium of the right vertebral artery was heavily calcified, and multiple attempts to catheterize the vertebral artery were unsuccessful. Flow reversal was eventually achieved in the right vertebral artery by embolizing the hypertrophied deep cervical artery which reconstituted the right vertebral artery. The patient has remained asymptomatic since the procedure for a follow-up period of 12 months.

Cognitive impact of anticholinergic medication in MS: Adding insult to injury?

BACKGROUND: Cognitive impairment in Multiple Sclerosis (MS) is well recognized, being documented even in the earliest stages of the disease. Anticholinergic drugs (ACD) are frequently used to address bladdder symptoms in this population. ACD are known for their deleterious cognitive effects in older individuals; however their potential impact on cognition has received less attention in the context of MS. OBJECTIVE: To explore possible detrimental effects of bladder-directed ACD on cognitive functioning in MS. METHODS: 42 MS patients who had been on classical, bladder-directed ACD for ≥6 months were compared to 46 patients not receiving ACD, in terms of their scores on Symbol Digit Modality Test (SDMT) and Selective Reminding Test (SRT). Patients also completed questionnaires for fatigue (Modified Fatigue Impact Scale - MFIS) and depression (Beck Depression Inventory-Fast Screen - BDIFS). RESULTS: Patients using ACD showed significantly lower SDMT and SRT scores compared to those not using ACD (p<0.001; t-test). The association of lower cognitive test performance with ACD usage was robust, even when other variables (like age, gender, EDSS, etc.) were considered. CONCLUSION: Our results suggest that chronic use of classical ACD for bladder symptoms may have a negative impact on cognitive functioning in MS patients. These potential cognitive side effects need to be considered both in clinical practice and research settings.

Therapy of MS.

The era of disease-modifying drugs (DMDs) in multiple sclerosis (MS) treatment began in the 1990s, first with interferon-beta (IFNbeta), and the number of agents has increased steadily since then. Currently, there are six different parenteral formulations approved for MS treatment and many other oral and parenteral ones are in different stages of investigation or awaiting approval by federal agencies. All of these medications have demonstrated partial efficacy along with different side effect profiles. Increasing our understanding about the natural behaviour of MS and its different types and stages, diversity of different therapies, their strength and weaknesses, and their serious and sometimes life-threatening side effects have created challenges for treating physicians; making the choice of individualized optimal treatment increasingly more complicated. In this review, we will summarize present and future treatment options and also address clinical challenges we are regularly facing in arriving at treatment choices for our patients.