Showing papers in "Multiple sclerosis and related disorders in 2015"
TL;DR: This work proposes a new treatment paradigm that individualises treatment based on a choice between two interchangeable therapeutic strategies of maintenance-escalation or induction therapy, and proposes treating- to-target of no evident disease activity (NEDA) as defined using clinical and MRI criteria.
Abstract: The management of multiple sclerosis is becoming increasingly complex with the emergence of new and more effective disease-modifying therapies (DMT). We propose a new treatment paradigm that individualises treatment based on a choice between two interchangeable therapeutic strategies of maintenance-escalation or induction therapy. We propose treating- to-target of no evident disease activity (NEDA) as defined using clinical and MRI criteria. This algorithm requires active monitoring with a rebaselining MRI, at a point in time after the specific DMT concerned has had sufficient time to work, and at least annual MRI studies to monitor for subclinical relapses. Disease activity on the maintenance-escalation therapy arm of the algorithm indicates a sub-optimal treatment response and should trigger a discussion about switching, or escalating, therapy or the consideration of switching to the induction therapy arm of the algorithm. In comparison, disease activity on an induction therapy arm would be an indication for retreatment or a switch to the maintenance-escalation therapy arm. We envisage the definition of NEDA evolving with time as new technological innovations are adopted into clinical practice, for example the normalisation of whole, or regional, brain atrophy rates and cerebrospinal fluid neurofilament levels.
263 citations
TL;DR: Preliminary data suggest that high doses of biotin might have an impact on disability and progression in progressive MS.
Abstract: No drug has been found to have any impact on progressive multiple sclerosis (MS). Biotin is a vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Among others, biotin activates acetylCoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis. The aim of this pilot study is to assess the clinical efficacy and safety of high doses of biotin in patients suffering from progressive MS. Uncontrolled, non-blinded proof of concept study 23 consecutive patients with primary and secondary progressive MS originated from three different French MS reference centers were treated with high doses of biotin (100-300mg/day) from 2 to 36 months (mean=9.2 months). Judgement criteria varied according to clinical presentations and included quantitative and qualitative measures. In four patients with prominent visual impairment related to optic nerve injury, visual acuity improved significantly. Visual evoked potentials in two patients exhibited progressive reappearance of P100 waves, with normalization of latencies in one case. Proton magnetic resonance spectroscopy (H-MRS) in one case showed a progressive normalization of the Choline/Creatine ratio. One patient with left homonymous hemianopia kept on improving from 2 to 16 months following treatment׳s onset. Sixteen patients out of 18 (89%) with prominent spinal cord involvement were considered as improved as confirmed by blinded review of videotaped clinical examination in 9 cases. In all cases improvement was delayed from 2 to 8 months following treatment׳s onset. These preliminary data suggest that high doses of biotin might have an impact on disability and progression in progressive MS. Two double-blind placebo-controlled trials are on going.
187 citations
TL;DR: The efficacy of EU-approved disease-modifying therapies on conventional MS outcome measures (relapses, disability progression and paraclinical magnetic resonance imaging endpoints) in addition to brain volume loss, a measure of diffuse damage in the brain are provided.
Abstract: Therapies that target the underlying pathology of multiple sclerosis (MS), including focal and diffuse damage, may improve long-term disease control. Focal damage (inflammatory lesions) manifests clinically mainly as relapses, whereas diffuse damage (neurodegeneration and brain volume loss) has been more closely associated with disability progression and cognitive decline. Given that first-line therapies such as beta-interferon and glatiramer acetate, which are primarily directed against inflammation, might fail to adequately control disease activity in some patients, it has been recommended to switch these patients early to a therapy of higher efficacy, possibly targeting both components of MS pathology more rigorously. This review provides an overview of the efficacy of EU-approved disease-modifying therapies on conventional MS outcome measures (relapses, disability progression and paraclinical magnetic resonance imaging endpoints) in addition to brain volume loss, a measure of diffuse damage in the brain. In addition, the evidence supporting early treatment optimization in patients with high disease activity despite first-line therapy will be reviewed and an algorithm for optimal disease control will be presented.
95 citations
TL;DR: The MS in the 21st Century Steering Group devised a set of themes that require action with regard to patient engagement in MS, namely: setting and facilitating engagement by education and confidence-building, increasing the importance placed on QoL and patient concerns through patient-reported outcomes (PROs); and encouraging treatment adherence through engagement.
Abstract: While advances in medicine, technology and healthcare services offer promises of longevity and improved quality of life (QoL), there is also increasing reliance on a patient׳s skills and motivation to optimize all the benefits available. Patient engagement in their own healthcare has been described as the 'blockbuster drug of the century'. In multiple sclerosis (MS), patient engagement is vital if outcomes for the patient, society and healthcare systems are to be optimized. The MS in the 21st Century Steering Group devised a set of themes that require action with regard to patient engagement in MS, namely: 1) setting and facilitating engagement by education and confidence-building; 2) increasing the importance placed on QoL and patient concerns through patient-reported outcomes (PROs); 3) providing credible sources of accurate information; 4) encouraging treatment adherence through engagement; and 5) empowering through a sense of responsibility. Group members independently researched and contributed examples of patient engagement strategies from several countries and examined interventions that have worked well in areas of patient engagement in MS, and other chronic illnesses. The group presents their perspective on these programs, discusses the barriers to achieving patient engagement, and suggests practical strategies for overcoming these barriers. With an understanding of the issues that influence patient engagement in MS, we can start to investigate ways to enhance engagement and subsequent health outcomes. Engaging patients involves a broad, multidisciplinary approach.
91 citations
TL;DR: Rates of mortality and several comorbidities are higher in the MS versus non-MS cohort, and early recognition and management of comorebidities may reduce premature mortality and improve quality of life in patients with MS.
Abstract: Background Data are limited for mortality and comorbidities in patients with multiple sclerosis (MS). Objectives Compare mortality rates and event rates for comorbidities in MS ( n =15,684) and non-MS ( n =78,420) cohorts from the US Department of Defense (DoD) database. Methods Comorbidities and all-cause mortality were assessed using the database. Causes of death (CoDs) were assessed through linkage with the National Death Index. Cohorts were compared using mortality (MRR) and event (ERR) rate ratios. Results All-cause mortality was 2.9-fold higher in the MS versus non-MS cohort (MRR, 95% confidence interval [CI]: 2.9, 2.7–3.2). Frequent CoDs in the MS versus non-MS cohort were infectious diseases (6.2, 4.2–9.4), diseases of the nervous (5.8, 3.7–9.0), respiratory (5.0, 3.9–6.4) and circulatory (2.1, 1.7–2.7) systems and suicide (2.6, 1.3–5.2). Comorbidities including sepsis (ERR, 95% CI: 5.7, 5.1–6.3), ischemic stroke (3.8, 3.5–4.2), attempted suicide (2.4, 1.3–4.5) and ulcerative colitis (2.0, 1.7–2.3), were higher in the MS versus non-MS cohort. The rate of cancers was also higher in the MS versus the non-MS cohort, including lymphoproliferative disorders (2.2, 1.9–2.6) and melanoma (1.7, 1.4–2.0). Conclusions Rates of mortality and several comorbidities are higher in the MS versus non-MS cohort. Early recognition and management of comorbidities may reduce premature mortality and improve quality of life in patients with MS.
84 citations
TL;DR: The origin of EDSS, the Expanded Disability Status Scale for multiple sclerosis, was some 30 years before its only publication in 1983 when it was trying to assess a potential treatment and found no published methods.
Abstract: The origin of EDSS, the Expanded Disability Status Scale for multiple sclerosis, was some 30 years before its only publication in 1983 when we were trying to assess a potential treatment and found no published methods. Findings from the complete neurologic examinations in over 200 patients were consolidated into mutually exclusive but all-inclusive neurophysiologic entities called Functional Systems (FS), and these provided the basis for an 11 step 0-10 rank order scale, the Disability Status Scale (DSS). This was used successfully, as well as in the first two Class I treatment trials performed, with the second one also incorporating the 8 FS. Both measures were part of an assessment of a natural history series derived from men hospitalized for MS in the US Army in World War II and followed for some 20 years. Describing each of the 8 FS as affected (1) or normal (0) defined 256 possible patterns of involvement for all patients. Half the patients at diagnosis had one of the 14 most common patterns. Each FS worsened in frequency and severity of involvement in correlation with the DSS, which overall showed a unimodal distribution, until in another series of patients 16 years post onset bimodality first appeared. Observations that the 11 step DSS might have too few steps for treatment trials led to the EDSS of 20 steps with each grade between 1 and 9 divided into two. The system of EDSS+FS to summarize all the CNS involvement as defined by objective findings on neurologic examination thereafter remained unchanged to the present. I just learned that the unpublished system copyrighted in Switzerland as "neurostatus" has been called and referenced as my EDSS. It is not.
71 citations
TL;DR: Overall, the review found low level evidence for the effectiveness of telerehabilitation on reducing short-term disability and reducing and/or improving symptoms, such as fatigue.
Abstract: Background Telerehabilitation, a service delivery model using telecommunications technology to provide therapy at a distance, is used in persons with multiple sclerosis (pwMS), but evidence for their effectiveness is yet to be determined. Objective To investigate the effectiveness and safety of telerehabilitation intervention pwMS. Method A comprehensive literature search was conducted using medical and health science electronic databases. Three reviewers selected potential studies and independently assessed the methodological quality. A meta-analysis was not possible due to heterogeneity amongst included trials, and a qualitative analysis was performed for best evidence synthesis. Results Ten RCTs and 2 observational studies (n=564 participants) investigated a wide variety of telerehabilitation intervention in pwMS, which included: physical activity; educational, behavioural and symptom management programmes. All studies scored “low to moderate” on the methodological quality assessment implying high risk of bias. Overall, the review found low level evidence for the effectiveness of telerehabilitation on reducing short-term disability and reducing and/or improving symptoms, such as fatigue. There was low level evidence suggesting some benefit of telerehabilitation in improving functional activities; improving symptoms in the longer-term; and psychological outcomes and quality of life. There is limited data on safety, process evaluation and no data on cost-effectiveness of telerehabilitation. Conclusions A wide range of telerehabilitation is used in pwMS, however, the quality of evidence on these interventions was low. More robust trials are needed to build evidence about these interventions.
69 citations
TL;DR: The Hungarian version of the BICAMS test is a valid and reliable method for the evaluation of MS patients' cognitive function and it seems that because of the short retest period, the members of the HC group remembered the CVLT-II words thus performed better than the patients did.
Abstract: Background Multiple Sclerosis (MS) causes not only somatic, but also cognitive impairment regardless of the patients׳ age or the course of the disease. The Brief International Cognitive Assessment for MS (BICAMS) test, published in 2011, is a short cognitive questionnaire: a fast, reliable, sensitive and specific tool for the evaluation of the patients׳ cognitive state. Objectives Our primary objective was to assess the validity of the Hungarian version of the BICAMS test. Our secondary objective was to evaluate the impact of the cognitive impairment on the patient׳s quality of life and fatigue׳s impact on the patients׳ cognitive state. Methods 65 RR-MS patients and 65 age, sex and education matched healthy control (HC) subjects completed the test and were retested after 3 weeks. The patients also completed the MS Quality of Life 54 (MSQoL54) and the Fatigue Impact Scale (FIS) assessments. Group differences were calculated by paired sample T-tests. The test-retest reliability was measured by intraclass correlation coefficients. To analyze the difference between the test-retest performances of the two groups we used two-way repeated measures ANOVA where the BICAMS battery was the single composite outcome and one-way repeated measures ANOVA. To assess the impact of the cognitive decline on the patients׳ quality of life and fatigue׳s impact on the cognitive state, we examined the correlations between results in the BICAMS and the MSQoL54 and FIS. Results We found significant difference ( p ≤0.001, p =0.017 in the first CVLT-II assessment) between MS patients and members of the HC group in all four evaluated parameters of BICAMS test in both sessions. The correlation coefficients were very strong between the tests and retests ( r >0.8; p r =0.678, p p =0.020) better in the retest sessions as compared to their original performance than the patients did and this difference is solely due to the difference between the CVLT-II performances. We have found significant negative correlation between the patients׳ cognitive function and the fatigue score ( r p r >0.3; p Conclusions The Hungarian version of the BICAMS test is a valid and reliable method for the evaluation of MS patients׳ cognitive function. It seems that because of the short retest period, the members of the HC group remembered the CVLT-II words thus performed better than the patients did. Also apparently fatigue can have a negative impact on the patients׳ cognitive state, and cognitive impairment could worsen the patients׳ quality of life.
67 citations
TL;DR: Although frequently criticized and challenged by other scales, the (E)DSS and its FS have persisted and hold a central role as an assessment tool in MS observational and therapeutic studies and have also – with some caveats – entered daily practice for the description and communication about the status of individual patients.
Abstract: In his commentary (Kurtzke, 2015) Dr. Kurztke recapitulates the rationale and the underlying evidence for the development of the Functional Systems (FS), the Disability Status Scale (DSS) and the Expanded Disability Status Scale (EDSS). This commentary and several of the author's previous publications on this topic (Kurtzke, 1955, 1965, 1970, 1983, 1989, 2007, 2008) underline his unique and widely appreciated contribution: Dr. Kurtzke created a scale that was a major step in comprehensively assessing neurologic impairment and disability in people with MS in the course of their disease. Although frequently criticized and challenged by other scales, the (E)DSS and its FS have persisted and hold a central role as an assessment tool in MS observational and therapeutic studies and have also – with some caveats – entered daily practice for the description and communication about the status of individual patients. Reemphasizing a statement from a previous review (Kurtzke, 2008), Dr. Kurtzke acknowledges that following his publications, the (E)DSS and FS entered the public domain and started being used in variable contexts all over the world. With increasing experience it was inevitable that investigators would also realize the scale's limitations. Many peer reviewed original publications, reviews and consensus statements (Willoughby
58 citations
TL;DR: This study suggests that this drug may have immunosuppressive properties evidenced by significant sustained reduction in CD8 lymphocyte counts and, to a lesser extent, CD4 lymphocytes counts.
Abstract: Dimethyl fumarate (Tecfidera™) is an effective therapy for relapsing forms of multiple sclerosis (MS). Our study suggests that this drug may have immunosuppressive properties evidenced by significant sustained reduction in CD8 lymphocyte counts and, to a lesser extent, CD4 lymphocyte counts. This observation is relevant in light of the recent case of progressive multifocal leukoencephalopathy in a patient receiving this drug.
54 citations
TL;DR: The GLACIER study demonstrates a favorable IRAE and convenience profile of GA40 for RRMS patients and perception of treatment convenience improved for GA40-treated patients soon after converting and was sustained.
Abstract: Background The efficacy and safety of glatiramer acetate (GA) 20mg/mL once-daily subcutaneous injections (GA20) in relapsing-remitting multiple sclerosis (RRMS) is well-established. However, injection - related adverse events (IRAEs) may impede treatment adherence and tolerability. GA 40mg/mL three-times weekly (GA40) also has a favorable efficacy and safety profile. Objective To evaluate the safety, tolerability, and patient experience when converting from GA20 to GA40. Methods/trial design GLACIER was an open-label, randomized, parallel-group trial conducted at 31 sites in the US between June 2013 and December 2013. Stable RRMS patients on GA20 were randomized in a 1:1 ratio to continue with GA20 or convert to GA40. The adjusted mean annualized rate of IRAEs was the primary endpoint for this study. Additionally, the severity of IRAEs, rate of injection-site reactions (ISRs) , and patient-reported MS impact and treatment satisfaction were compared for the two treatment groups over the 4-month core study. Results A total of 209 patients were randomized to convert to GA40 ( n =108) or continue with GA20 ( n =101). The adjusted mean annualized rate of IRAEs was reduced by 50% with GA40 (35.3 events per year; n =108) versus GA20 (70.4 events per year; n =101) (risk ratio (RR)=0.50; 95% confidence interval [CI]=0.34–0.74; p =0.0006). There was a 60% reduction in the rate of moderate/severe events (GA40 ( n =108): 0.9 events per year versus GA20 ( n =101): 2.2 events per year; RR=0.40; p =0.0021). Perception of treatment convenience improved for GA40-treated patients soon after converting and was sustained. Conclusions The GLACIER study demonstrates a favorable IRAE and convenience profile of GA40 for RRMS patients. Trial registration NCT01874145 available at clinicaltrial.gov.
TL;DR: Investigating the relationship between RFD and maximal muscle strength of knee extensors and flexors and measures of functional capacity in PwMS found that maximal isokinetic strength of the weaker leg is the better predictor of walking performance in persons with mild to moderate multiple sclerosis.
Abstract: Background: Maximal muscle strength has been shown to be an important predictor of functional capacity for persons with multiple sclerosis (PwMS). Another muscle strength parameter known to be important for functional capacity in other patient groups is rate of force development (RFD) in knee extensors and flexors. This has not been investigated for PwMS. Thus, the purpose of this study was to investigate the relationship between RFD and maximal muscle strength of knee extensors and flexors and measures of functional capacity in PwMS. Methods: 35 PwMS (Expanded Disability Status Scale 2–4) underwent isokinetic dynamometry to determine RFD and maximal isometric and isokinetic muscle strength for both legs. Furthermore all participants performed timed 25 foot walk tests (T25FWT), two minute walk tests (2MWT), stairclimb tests and 5-time sit-to-stand (5STS) tests to determine functional capacity. Multiple linear regressions were performed to determine which muscle strength parameter would serve as a stronger predictor of walking performance. Results: Both RFD and maximal muscle strength correlated with functional capacity. Correlations were strongest for knee extensors and flexors of the weaker leg, while no clear ranking of the influence of the knee extensors vs. flexors on walking was evident. Multiple linear regressions showed that maximal isokinetic strength of the weaker leg is a better predictor for T25FWT and 2MWT performance than RFD. Conclusions: Maximal muscle strength of the weaker leg is the better predictor of walking performance in persons with mild to moderate multiple sclerosis. RFD, although also important for
TL;DR: This study demonstrates that BICAMS is an easy test to administer and should be used as a basic tool to identify patients with cognitive impairment who may benefit from further neuropsychological assessment.
Abstract: Background Cognitive impairment is common in multiple sclerosis (MS) irrespective of disease stage or subtype. It is typically underreported and neuropsychological testing can be required to detect more subtle evidence of cognitive impairment. The Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS) was an initiative undertaken by a panel of experts with the primary objective of identifying a brief cognitive assessment tool that could be administered by healthcare professionals without formal neuropsychological training to identify early or subtle cognitive impairment among MS patients. Objectives To validate BICAMS in Irish patients with MS and healthy controls. Methods Consecutive patients attending the MS outpatient department from January to April 2014 were recruited. Age, gender, education, handedness, MS subtype, expanded disability status scale (EDSS) and disease duration were recorded. They were administered BICAMS composed of Symbol Digit Modalities Test (SDMT), California Verbal Learning Test (CVLT-II) and Brief Visuospatial Memory Test (BVMT-R). Depression and anxiety were assessed using the Hospital Anxiety and Depression Scale (HADS). Control participants were composed of unaffected relatives, spouses or carers attending the clinic with a patient and were matched by age, gender and years of education. Impairment on individual tests was defined as −1.5 SD below reference group means. Results 67 patients [73% women; mean age: 43.9yrs (12.1); mean years of education: 13.6yrs (2.7)] and 66 controls [68% women; mean age 42.7yrs (12.7); mean years of education: 14.1yrs (3.2)] were recruited. Of the MS patient group: 70% were classified as having relapsing remitting MS, 28% secondary progressive MS and 2% primary progressive MS (PPMS). Mean EDSS scores were 1.8 (SD: 0.9), 5.7 (SD: 1.4) and 7.0 in each group respectively with mean disease duration of 10.2 (SD: 8.4) years, 20.6 (10.2) and 17 years. Mean scores and standard deviations for patients and control participants respectively were 46 (12.9) and 55.9 (10.9), p d =0.83 for SDMT; 45.3 (10.2) and 52.8 (8.8), p d =0.79 for CVLT-II an d 17.9 (7.1) and 20.7 (6.6), p =0.02; d =0.41 for BVMT-R. Using regression based norms derived from the control sample only 43% of patients compared to 83% of control participants' results were within the normal range on all three tests. As expected higher rates of unemployment was seen amongst the patient population compared to control participants. Using the HADS 11 patients were classified as depressed and 13 as suffering from anxiety. Neither, these measures or the level of fatigue as measured by the MFIS was significantly associated with any of the three outcome measures (Pearson r Conclusions This study demonstrates that BICAMS is an easy test to administer and should be used as a basic tool to identify patients with cognitive impairment who may benefit from further neuropsychological assessment. Cognitive impairment can put patients at risk of poor self-management of disease including poor mediation adherence, and negatively impact on employment. Once identified appropriate support and monitoring can be put in place. BICAMS may also be used to help guide treatment decisions and rehabilitation. Further studies will be needed to assess its reliability over time and ability to detect meaningful changes.
TL;DR: The clinical interview and standard neurological examination are not sufficiently sensitive to detect cognitive impairment in MS, and the need for a brief, accurate cognitive screen to complement routine clinical evaluation is suggested.
Abstract: Cognitive impairment affects approximately 40-70% of MS patients. As management of MS typically begins with, and is co-ordinated by neurologists, they are often the first to raise concerns about a patient's cognitive functioning. However, it is not known how accurate the neurological examina- tion is in identifying cognitive impairment. To this end, we conducted a retrospective chart review of 97 MS patients referred by neurologists for neuropsychological assessment based on suspected cognitive impairment. Patients were classified as globally-impaired or intact according to failure on 2 or more of 11 cognitive indices comprising the MACFIMS, a recommended neuropsychological battery for MS. Neurologists' accuracy was not significantly different from chance, X 2 =1.25, p=0.26, with 44.3% of patients with suspected cognitive impairment showing global impairment on objective testing. Cognitively intact patients when compared to those who were impaired had higher levels of education and were less likely to have mood disturbances. These findings indicate the clinical interview and standard neurological examination are not sufficiently sensitive to detect cognitive impairment in MS, and suggest the need for a brief, accurate cognitive screen to complement routine clinical evaluation. & 2015 Elsevier B.V. All rights reserved.
TL;DR: Relapses continue to be an impactful experience that requires continued clinical attention and improved follow-up from relapses and relapse treatment might be beneficial.
Abstract: Acute relapses continue to be a significant aspect of multiple sclerosis (MS) on both the epidemiologic level and the individual patient level. Past work demonstrates residual disability from relapses as well as high patient-reported rates of ineffective relapse treatment. To better characterize the impact of MS relapses on the patient, a relapse-specific survey was administered through the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry to 1000 registry participants who had reported at least one relapse in the past 12 months. Thirty percent of respondents confirmed lack of relapse treatment efficacy at one month and at three months. Relapses also impacted socioeconomic measures; for individuals still going to school or working, more than half missed days and their average loss of school or work was 12.7 days. An impact on household tasks was reported by 68% of respondents. A healthcare facility such as a hospital, emergency room or urgent care center was utilized by 20.4% of respondents. The most common relapse symptoms were fatigue, weakness of the lower extremity, sensory symptoms, problems walking, and weakness of the upper extremity. Of the respondents who reported receiving corticosteroid treatment (53.3%), over half reported an adverse event. However, this was not a significant factor in dictating whether or not respondents would seek a different treatment on their next relapse, although 31% would choose a different treatment for their next relapse. Relapses continue to be an impactful experience that requires continued clinical attention. Improved follow-up from relapses and relapse treatment might be beneficial.
TL;DR: Lymphocyte subsets may help to provide better understanding of immunologic and safety impact of DMF in patients treated with dimethyl fumarate in comparison to the baseline pre-DMF levels.
Abstract: Objective To evaluate changes in absolute lymphocyte counts, lymphocyte subsets, and infections in patients treated with dimethyl fumarate (DMF) in comparison to the baseline pre-DMF levels. Methods A retrospective chart review was conducted of 23 MS patients treated with DMF. Absolute lymphocyte counts and lymphocyte subsets were obtained at baseline and after at least 3 months of DMF treatment. Data on infections requiring medical attention were also collected. Results A total of 23 patients were included in this analysis, 11 male (48%), 12 female (52%), with a mean age of 44.5±14.1 years, disease duration of 13.7±8.9 years, and EDSS of 3.5±1.7. The time between baseline and treatment lymphocyte counts was 3.9±1.2 months. Significant reductions in absolute lymphocyte counts by 35% ( p + by 34% ( p + by 34% ( p + by 40% ( p + counts by 48% ( p =0.0098) were found. Grade 2 lymphopenia occurred in 24% of patients and grade 3 lymphopenia occurred in 1 patient. Infections occurred in 26% of patients, mainly as urinary tract infections (22%) and one fatal case of West Nile encephalitis in a patient with grade 3 lymphopenia, who had been on DMF for 5 months. A detailed summary of this fatal case is provided. Conclusion Lymphocyte subsets may help to provide better understanding of immunologic and safety impact of DMF.
TL;DR: AQP4 detection in serum with immunoassay is a great tool for the diagnosis of patients with NMO, due to the high specificity, allowing the clinician to differentiate this disease from other neurological conditions that resemble NMO.
Abstract: Objective Antibodies against water channel protein aquaporin 4 (AQP4) in astrocytes play a role in the etiology and physiopathology of neuromyelitis optica (NMO); detection of this immunoglobulin in serum is highly suggestive of this diagnosis. There are several immunoassays to detect the antibody with different sensitivities and specificities. We conducted a meta-analysis to determine the overall diagnostic accuracy from these tests. Methods We conducted a systematic review in five different electronic databases: Pubmed, Embase, The Cochrane Library, Scopus, Database of Abstracts of Reviews of Effect (DARE) and Lilacs. We included both case control and consecutive enrollment studies that evaluated the performance of the immunoassays in patients with suspected NMO in comparison with the 2006 Wingerchuk diagnostic criteria. Articles were assessed by two different reviewers, who also extracted data. Results 30 studies for three different immunoassays were included in the meta-analysis. To obtain a summary estimate for the sensitivity and specificity with 95% confidence interval a bivariate random effect model was used. The approximated sensitivity for the cell based assay (CBA), the tissue-based assay (TBA) and the ELISA test were 0.76(95% CI 0.67–0.82), 0.59(95% CI 0.50–0.67), and 0.65(95% CI 0.53–0.75) respectively. The mean specificity of the CBA was 0.99 (95% CI 0.97–0.99), TBA 0.98 (95% CI 0.97–0.99) and ELISA 0.97(95% CI 0.96–0.99). Conclusions AQP4 detection in serum with immunoassay is a great tool for the diagnosis of patients with NMO, due to the high specificity, allowing the clinician to differentiate this disease from other neurological conditions that resemble NMO.
TL;DR: Autonomic symptom burden is correlated with decreased quality of life and increased fatigue in patients with multiple sclerosis and may reflect aspects of disease burden that are not well-captured by current disability measures.
Abstract: Background Nonspecific symptoms such as fatigue and dizziness are common in multiple sclerosis (MS), even in patients with normal exams. Little is known about the relationship of autonomic dysfunction with these symptoms and quality of life. Objective Assess the association of autonomic symptom burden with fatigue, clinical status and quality of life. Methods Subjects completed an autonomic symptom (COMPASS-31), quality of life (MSQOL-54) and fatigue (FSS) questionnaire at their routine MS clinic follow-up. Demographic and clinical data were collected from the medical record. Pearson correlations were assessed between autonomic symptoms and fatigue, quality of life, disability and disease duration. Results One-hundred subjects completed the study (mean age 48 years; 78% female; 84% relapsing-remitting), mean disease duration was 14.7 years and mean EDSS 2.5. MSQOL-54 composite scores were 58 physical and 65 mental. COMPASS-31 correlated with MSQOL-54 (Physical R = −0.60; Mental −0.54; p R =0.51; p R =0, p =0.97) or disease duration ( R = −0.02, p =0.84). Conclusions Autonomic symptom burden is correlated with decreased quality of life and increased fatigue. Autonomic symptoms are present early in the disease and at low disability and may reflect aspects of disease burden that are not well-captured by current disability measures.
TL;DR: A utility for online research platforms, which allow for rapid generation of hypotheses that then require validation in clinical settings, is highlighted, as postmenopausal patients in this study reported worse MS disease severity.
Abstract: Background Many women with multiple sclerosis (MS) are postmenopausal, yet the impact of menopause on MS symptoms is unknown. Objective To investigate patient-reported impact of menopause in a large online research platform, PatientsLikeMe (PLM). Methods A detailed reproductive history survey was deployed to PLM members, and responses were linked to PLM׳s prospectively collected patient-reported severity score (MS Rating Scale, MSRS). The MSRS has previously shown good correlation with physician-derived EDSS scores. Results Of the 513 respondents, 55% were postmenopausal; 54% of these reported induced menopause. Median age at natural menopause was 51. Surgical menopause occurred at an earlier age ( p p =0.02) than natural menopause. Postmenopausal status, surgical menopause, and earlier age at menopause were all associated with worse MSRS scores ( p ≤0.01) in regressions adjusting for age, disease type and duration. Conclusion Postmenopausal patients in this study reported worse MS disease severity. Further, this study highlights a utility for online research platforms, which allow for rapid generation of hypotheses that then require validation in clinical settings.
TL;DR: Comorbidity is associated with pain in persons with MS and closer examination of these associations may provide guidance for better management of this disabling symptom in MS.
Abstract: Background Comorbidities are common in multiple sclerosis (MS). The high prevalence of pain in MS is well-established but the influence of comorbidities on pain, specifically, pain-related interference in activity is not. Objective To examine the relationship between comorbidity and pain in MS. Methods We recruited 949 consecutive patients with definite MS from four Canadian centres. Participants completed the Health Utilities Index (HUI-Mark III) and a validated comorbidity questionnaire at 3 visits over 2 years. The HUI's pain scale was dichotomized into two groups: those with/without pain that disrupts normal activities. We used logistic regression to assess the association of pain with each comorbidity individually at baseline and over time. Results The incidence of disruptive pain over two years was 31.1 per 100 persons. Fibromyalgia, rheumatoid arthritis, irritable bowel syndrome, migraine, chronic lung disease, depression, anxiety, hypertension, and hypercholesterolemia were associated with disruptive pain (p Conclusion Comorbidity is associated with pain in persons with MS. Closer examination of these associations may provide guidance for better management of this disabling symptom in MS.
TL;DR: A case of a young woman with relapsing MS who developed acute liver injury after the second infusion of natalizumab is described, which demonstrated a mixed pattern of medication-induced injury or partially treated auto-immune hepatitis.
Abstract: Natalizumab is an α4-integrin monoclonal antibody used for treatment of relapsing multiple sclerosis (MS). At least and nearly 30 cases of liver failure in natalizumab-treated patients are listed in the post-marketing FDA adverse event reporting system (FAERS) and twelve patients with severe liver injury, including several after the first infusion, have been reported (Lisotti et al., 2012; Bezabeh et al., 2010; Martinez-Lapiscina et al., 2013; Michael et al., 2007; Hillen et al., 2015). Herein, we describe a case of a young woman with relapsing MS who developed acute liver injury after the second infusion of natalizumab. Liver biopsy demonstrated a mixed pattern of medication-induced injury or partially treated auto-immune hepatitis. Liver function normalized after natalizumab discontinuation and a subsequent liver biopsy showed resolution of hepatitis. The patient's MS has since been successfully treated with rituximab for over a year. We review the published cases of liver injury associated with natalizumab and those in the post-marketing FDA adverse event reporting system (FAERS).
TL;DR: The study provides class III evidence that improvement in adherence to DMT for MS is associated with improved clinical outcomes as measured by relapse reduction, and the proportion of participants remaining relapse-free for 24 months increased with increasing MPR.
Abstract: Objectives The objective of the Therapy Optimization in MS (TOP MS) Study was to prospectively assess the relationship between MS disease-modifying therapy (DMT) adherence and MS relapse risk over 2 years. Methods Potential participants were recruited for TOP MS by specialty pharmacies who dispensed glatiramer acetate and beta interferons for MS nationwide. Signed IRB-approved informed consents were returned to the pharmacies. TOP MS used electronic data capture with monthly patient entries. Adherence, measured by medication possession ratio (MPR), was derived from pharmacy shipment records. Logistic regression examined the association between protocol-defined relapses and DMT MPR ( 0.5– 0.9). Results TOP MS enrolled 3151 persons with MS, and 2410 completed the full 2 years. Across all therapies, the mean MPR for the 2-year completer cohort of 2049 who maintained the same DMT was 0.9+0.2 (range: 0.1–1.0), with 63.8% reaching a 2-year MPR >0.9. Evaluated by categories of MPR, the proportion of participants remaining relapse-free for 24 months increased with increasing MPR, and the proportion with >1 relapses declined with increasing levels of MPR ( p 0.9 MPR group was 64% that of a patient in the MPR p =0.02). Use of >1 DMT prior to the current one was an independent predictor of relapse. Conclusions The study provides class III evidence that improvement in adherence to DMT for MS is associated with improved clinical outcomes as measured by relapse reduction.
TL;DR: A systematic review and meta-analysis to compare the proportion of patients with multiple sclerosis that would be diagnosed with cardiovascular dysautonomia using a definition of at least one abnormal cardiac autonomic test vs. at least two abnormal studies found a wide variation.
Abstract: Background and objective: The definition of cardiovascular autonomic dysfunction in patients with multiple sclerosis is controversial Thus, its true prevalence is unknown We performed a systematic review and meta-analysis to compare the proportion of patients with multiple sclerosis that would be diagnosed with cardiovascular dysautonomia using a definition of at least one abnormal cardiac autonomic test vs at least two abnormal studies Methods: We searched PubMed, Embase, and Scopus from 1980 to December 2013 for publications reporting abnormal autonomic tests in patients with multiple sclerosis We performed random-effects meta-analyses for calculating the proportion of patients diagnosed with autonomic dysfunction with both definitions Results: We included 16 studies comprising 611 patients with multiple sclerosis, assessing Z3 cardiovascular autonomic tests The proportion of patients with autonomic dysfunction was two-fold higher (p=0006) when using the definition of only one abnormal autonomic test (421%) compared to that using at least two abnormal results (188%) Conclusions: We found a wide variation in the proportion of patients with multiple sclerosis diagnosed with cardiovascular dysautonomia by using the two definitions Consensus is needed to define autonomic dysfunction in patients with multiple sclerosis In the meantime, we
TL;DR: The aim of this study was to gather and analyze surveys on prevalence conducted in Brazil, noting its variability in different regions.
Abstract: Epidemiological studies of multiple sclerosis (MS) conducted in Latin America have revealed prevalence rates of this disease from low to medium. The aim of this study was to gather and analyze surveys on prevalence conducted in Brazil, noting its variability in different regions. Systematic review was held in electronic databases and manual search in abstracts concerning ECTRIMS, LACTRIMS and Brazilian Congress of Neurology. Nineteen studies made reference to prevalence rates that ranged from 1.36/100,000 to 27.2/100.000 inhabitants. More studies on the epidemiology of MS in Brazil will be needed for a better assessment of its prevalence and profile.
TL;DR: The role of local melatonin and its precursors, N-acetylserotonin and serotonin, in MS is reviewed to suggest that its local regulation in white matter astrocytes by serotonin availability and apolipoprotein E4, among other potential factors, will be important in the etiology, course and treatment of MS.
Abstract: Multiple sclerosis (MS) is an immune mediated disorder that is under intensive investigation in an attempt to improve on available treatments. Many of the changes occurring in MS, including increased mitochondrial dysfunction, pain reporting and depression may be partly mediated by increased indoleamine 2,3-dioxygenase, which drives tryptophan to the production of neuroregulatory tryptophan catabolites and away from serotonin, N-acetylserotonin and melatonin production. The consequences of decreased melatonin have classically been attributed to circadian changes following its release from the pineal gland. However, recent data shows that melatonin may be produced by all mitochondria containing cells to some degree, including astrocytes and immune cells, thereby providing another important MS treatment target. As well as being a powerful antioxidant, anti-inflammatory and antinociceptive, melatonin improves mitochondrial functioning, partly via increased oxidative phosphorylation. Melatonin also inhibits demyelination and increases remyelination, suggesting that its local regulation in white matter astrocytes by serotonin availability and apolipoprotein E4, among other potential factors, will be important in the etiology, course and treatment of MS. Here we review the role of local melatonin and its precursors, N-acetylserotonin and serotonin, in MS.
TL;DR: Among NARCOMS participants older age at enrollment, male sex and greater disability were associated with increased mortality risk, and this cohort of MS subjects had a lower proportionate mortality from cardiovascular disease and cancer compared to the U.S. population.
Abstract: Background Multiple Sclerosis (MS) is a leading cause of disability among young Americans. Reports suggest that life expectancy (i.e., average age at death) remains reduced as compared to the general population, but underlying causes of death (UCOD) are less well-characterized. Objective To describe the cause-specific mortality among participants enrolled in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry and to compare the profile of these causes by age, sex, race and disability status at entry into NARCOMS, with U.S. mortality data. Methods The underlying cause of death (UCOD), any mention cause of death and proportionate mortality were compared among U.S. NARCOMS participants by age, sex, race and disability status. Results Of the 32,445 participants to be considered for this study, 2,927 had died. Compared to survivors, decedents were older at enrollment and MS diagnosis, more likely to be male, and had less education. UCOD differed markedly by age group. In both sexes, MS as the UCOD was proportionately lower by 20% or more in those aged 25-39 compared to those aged 75 or older. Cancer and cardiovascular causes were more frequent as causes of death with increasing age, but were less than expected at older ages. The effect of disability on mortality was roughly equivalent to the effect of aging on mortality. Conclusions Among NARCOMS participants older age at enrollment, male sex and greater disability were associated with increased mortality risk. This cohort of MS subjects had a lower proportionate mortality from cardiovascular disease and cancer compared to the U.S. population.
TL;DR: More than 50% reported unmet needs relating to MS: suggesting non-pharmacological needs are not optimally addressed, particularly in older, single, rural residents, with greater EDSS and progressive non-relapsing MS.
Abstract: Background There is no evidence that disease modifying therapies (DMTs) are beneficial in progressive (non-relapsing) MS. However, these patients may benefit from multidiscipliniary interventions, and require financial and community support. Non-pharmacological needs of MS patients may be overlooked during fund allocation, and identification of unmet needs is important to optimise care and inform governmental resource distribution. Aim To identify unmet needs of MS patients in 3 areas during an Irish epidemiology study.Patients and methods: Observational study in 3 regions in Ireland: South Dublin SCD (an urban area), Donegal DGL and Wexford WEX (rural counties).A validated Needs Assessment Questionnaire (NAQ) was completed by MS patients at research clinics, or by telephone if unable to attend. Results We identified 632 patients with multiple sclerosis: 23% SCD (urban), 30.8% WEX, and 46.2% DGL.MS subtype was relapsing remitting (RR) in 51.1%, secondary progressive (SP) in 39.7%, and primary progressive (PP) in 9.2%. EDSS was 6.5 in 14%. NAQ was completed by 325 (49.9%).Group A: 155 (47.7%) reported no unmet needs relating to MS.Group B: 170 (52.3%) reported unmet needs relating to MS,including all in a group continuing to use disease-modifying therapy without benefit (EDSS>6.5).Number of unmet needs per patient in group B: 1 need 27%, ≥2 needs 73%, ≥5 24%.Unmet needs overall correlated with EDSS >6.5 ( p p p p p p 0.045) and marital status: 24% single, 13.5% married ( p 0.03).Multivariate analysis: related to rural residence ( p p p 0.003)and increasing age: 52.5 v 45.8y ( p 0.0006).Multivariate analysis: rural, older age, higher EDSS ( p p p p 0.002).Multivariate analysis: related to higher EDSS ( p p 0.001): multivariate analysis: SPMS ( p Discussion More than 50% reported unmet needs relating to MS: suggesting non-pharmacological needs are not optimally addressed, particularly in older, single, rural residents, with greater EDSS and progressive non-relapsing MS. Physiotherapy offers significant benefits, but is the most frequently reported unmet need.These findings highlight the need for increased fund allocation, especially for development of community supports and multidisciplinary/ social services.Identifying unmet needs may help inform health service planning, and emphasises particular need for improved resources in a high-risk group of MS patients.
TL;DR: The overall objective is to highlight the real possibility of being forced to decide between these two entities in clinical practise, present a reasonable approach to help differentiate them and especially to focus on the possibility of TDLs in order to avoid unnecessary biopsy.
Abstract: Tumefactive demyelinating lesions (TDLs) are not an uncommon manifestation of demyelinating disease but can pose diagnostic challenges in patients without a pre-existing diagnosis of multiple sclerosis (MS) as well as in known MS patients. Brain tumours can also arise in MS patients and can be seen in chronic MS patients as co-morbidities. Delayed diagnosis or unnecessary intervention or treatment will affect the ultimate prognosis of these patients. In this article, we will review some typical cases illustrating the dilemma and review the information that helps to differentiate the two conditions. The intention is not to present an extensive differential diagnosis of both entities, but to examine some typical examples when the decision arises to decide between the two. We take a somewhat different approach, by presenting the cases in "real time", allowing the readers to consider in their own minds which diagnosis they favour, discussing in detail some of the pertinent literature, then revealing later the actual diagnosis. We would urge readers to consider re-visiting their first thoughts about each case after reading the discussion, before reading the follow-up of each case. The overall objective is to highlight the real possibility of being forced to decide between these two entities in clinical practise, present a reasonable approach to help differentiate them and especially to focus on the possibility of TDLs in order to avoid unnecessary biopsy.
TL;DR: In this article, the authors used volumetric T1-weighted brain images to investigate cross-sectional area measures in the uppermost cervical cord and compared them with areas at the standard C2/3 level.
Abstract: Background
In multiple sclerosis (MS), recent work suggests that cervical cord atrophy is more consistently correlated with physical disability than brain white matter lesion load and atrophy. Although spinal cord imaging has not been routinely obtained in many clinical trial and research studies, brain volumetric imaging usually has and includes the upper cervical cord.
Objectives
Using volumetric T1-weighted brain images, we investigated cross-sectional area measures in the uppermost cervical cord and compared them with areas at the standard C2/3 level.
Methods
Using T1-weighted brain scans from 13 controls and 37 people with MS, and an active surface technique, cross-sectional area was measured over 5 mm and 1 mm cord segments at C2/3, below the level of odontoid peg, and 2 cm and 2.5 cm below the pons. Brain volume was also measured.
Results
Cord area measurements were most reliable in a 5 mm segment 2.5 cm below the pons (inter-rater coefficient of variation 1.5%, intraclass correlation coefficient 0.99). Cord area at this level correlated more with that at C2/3 area than with brain volume (r=0.811 with C2/3, r=0.502 with brain volume).
Conclusion
Whereas the standard C2/3 level is often not within the field of view on brain images, the level 2.5 cm below the pons usually is, and measurement at this level may be a good way to investigate upper cervical cord atrophy when only brain images are available.
TL;DR: The data show that employed MS patients report more negative work events and accommodations than employed healthy persons, suggesting the need for cognitive training and specific accommodation strategies in the work place.
Abstract: Background Physical disability and cognitive impairment are significant predictors of unemployment in multiple sclerosis (MS). However, little is known about the frequency of work problems in employed patients, in comparison to employed healthy persons. Objective Use an online monitoring tool to compare the frequency of negative work events in MS patients and healthy controls, and determine a threshold at which the frequency of work problems is clinically meaningful. Methods The sample comprised 138 MS patients and 62 healthy controls. All reported on recent negative work events and accommodations using an online survey. The clinical test battery measured depression, motor and cognitive function. Statistical tests compared the frequency of work problems in MS patients and healthy controls. Clinical neuro-performance scales were then assessed in at-risk patients with many work problems, versus those with no work problems. Results As a group, employed MS patients exhibited deficits in motor ability, verbal memory, and processing speed and were more likely than controls to report negative work events and accommodations. At-risk patients, that is, those reporting more than one negative work event, had more pronounced motor and cognitive deficits than their relatively stable counterparts. Conclusion The data show that employed MS patients report more negative work events and accommodations than employed healthy persons. Those patients deemed at risk for job loss have more cognitive and motor impairment, suggesting the need for cognitive training and specific accommodation strategies in the work place.