MRI detection of brain gadolinium retention in multiple sclerosis: Magnetization transfer vs. T1-weighted imaging.

BACKGROUND AND PURPOSE: Evidence of brain gadolinium retention has affected gadolinium-based contrast agent usage. It is, however, unclear to what extent macrocyclic agents are retained and whether their in vivo detection may necessitate nonconventional MRI. Magnetization transfer (MT) could prove suitable to detect gadolinium-related signal changes since dechelated gadolinium ions bind to macromolecules. Therefore, this study aimed to investigate associations of prior gadolinium administrations with MT and T1 signal abnormalities. METHODS: A cohort of 23 persons with multiple sclerosis (MS) (18 females, 5 males, 57 ± 8.0 years) with multiple past gadolinium administrations (median 6, range 3-12) and 23 age- and sex-matched healthy controls underwent 1.5 Tesla MRI with MT, T1-weighted 2-dimensional spin echo, and T1-weighted 3-dimensional gradient echo. The signal intensity index was assessed by MRI in gadolinium retention predilection sites. RESULTS: There were dose-dependent associations of the globus pallidus signal on gradient echo (r = .55, p < .001) and spin echo (r = .38, p = .013) T1-weighted imaging, but not on MT. Relative to controls, MS patients had higher signal intensity index in the dentate nucleus on T1-weighted gradient echo (1.037 ± 0.040 vs. 1.016 ± 0.023, p = .04) with a similar trend in the globus pallidus on T1-weighted spin echo (1.091 ± 0.034 vs. 1.076 ± 0.014, p = .06). MT detected no group differences. CONCLUSIONS: Conventional T1-weighted imaging provided dose-dependent associations with gadolinium administrations in MS, while these could not be detected with 2-dimensional MT. Future studies could explore newer MT techniques like 3D and inhomogenous MT. Notably, these associations were identified with conventional MRI even though most patients had not received gadolinium administrations in the preceding 9 years, suggestive of long-term retention.

Like a Wave in Its Variable Shape, Breadth, and Depth: A Qualitative Interview Study of Experiences of Daytime Sleepiness in People with Parkinson's Disease.

Introduction: Daytime sleepiness is a common nonmotor symptom in Parkinson's disease (PD) which is associated with decreased quality of life and perceived health. However, experiences of daytime sleepiness in people with PD have not been explored. The aim of this qualitative study was to explore experiences of daytime sleepiness in people with PD. Materials and Methods: Five women and seven men (42-82 years) with PD for 1.5 to 21 years and excessive daytime sleepiness (i.e., a score of >10 on the Epworth Sleepiness Scale) participated in the study. Data were collected through individual, semistructured, face-to-face interviews and analyzed with qualitative content analysis. Results: Three themes of the experience of daytime sleepiness were revealed: (1) not an isolated phenomenon, (2) something to struggle against or accept, and (3) something beyond sleepiness. Conclusion. Daytime sleepiness is a complex nonmotor symptom in PD which manifests itself in several ways. Some experiences are similar, for instance, the attribution of daytime sleepiness to PD and its medical treatment. Differences depend on how sleepiness manifests itself, affects the person, and impacts daily life, as well as whether it causes feelings of embarrassment. Some participants needed to struggle against daytime sleepiness most of the time, and others had found a way to handle it, for example, with physical activity. However, sleepiness may also be used to benefit the person, for example, if they allow themselves to take a power nap to regain energy. The health care professionals can easily underestimate or misinterpret the prevalence and burden of daytime sleepiness because people with PD may describe daytime sleepiness as tiredness, drowsiness, or feeling exhausted, not as sleepiness.

Narcolepsy among first- and second-generation immigrants in Sweden: A study of the total population.

AIMS: To study incident narcolepsy in first- and second-generation immigrant groups using Swedish-born individuals and native Swedes as referents. METHODS: The study population included all individuals registered and alive in Sweden at baseline. Narcolepsy was defined as having at least one registered diagnosis of narcolepsy in the Swedish National Patient Register. The incidence of narcolepsy in different immigrant groups was assessed by Cox regression, with hazard ratios (HRs) and 95% confidence intervals (CI). The models were stratified by sex and adjusted for age, geographical residence in Sweden, educational level, marital status, co-morbidities, and neighbourhood socioeconomic status. RESULTS: In the first-generation study, 1225 narcolepsy cases were found; 465 males and 760 females, and in the second-generation study, 1710 cases, 702 males and 1008 females. Fully adjusted HRs (95% CI) in the first-generation study was for males 0.83 (0.61-1.13) and females 0.83 (0.64-1.07), and in the second-generation study for males 0.76 (0.60-0.95) and females 0.91 (95% CI 0.76-1.09). Statistically significant excess risks of narcolepsy were found in first-generation males from North America, and second-generation males with parents from North America, and second-generation females with parents from Latin America. CONCLUSIONS: There were only significant differences in incident narcolepsy between native Swedes and second-generation male immigrants. The observed differences can partly be explained by differences in Pandemrix® vaccinations and are probably not attributable to genetic differences between immigrants and natives.

Picornavirus May Be Linked to Parkinson's Disease through Viral Antigen in Dopamine-Containing Neurons of Substantia Nigra.

Parkinson's disease (PD) is a neurodegenerative disease linked with the loss of dopaminergic neurons in the brain region called substantia nigra and caused by unknown pathogenic mechanisms. Two currently recognized prominent features of PD are an inflammatory response manifested by glial reaction and T-cell infiltration, as well as the presence of various toxic mediators derived from activated glial cells. PD or parkinsonism has been described after infection with several different viruses and it has therefore been hypothesized that a viral infection might play a role in the pathogenesis of the disease. We investigated formalin-fixed post-mortem brain tissue from 9 patients with Parkinson's disease and 11 controls for the presence of Ljungan virus (LV) antigen using a polyclonal antibody against the capsid protein of this recently identified picornavirus with neurotropic properties, suspected of being both a human and an animal pathogen. Evidence of viral antigen was found in 7 out of 9 Parkinson's disease cases and in only 1 out of 11 controls (p = 0.005). The picornavirus antigen was present in dopamine-containing neurons of the substantia nigra. We propose that LV or an LV-related virus initiates the pathological process underlying sporadic PD. LV-related picornavirus antigen has also been reported in patients with Alzheimer's disease. Potentially successful antiviral treatment in Alzheimer's disease suggests a similar treatment for Parkinson's disease. Amantadine, originally developed as an antiviral drug against influenza infection, has also been used for symptomatic treatment of patients with PD for more than 50 years and is still commonly used by neurologists today. The fact that amantadine also has an antiviral effect on picornaviruses opens the question of this drug being re-evaluated as potential PD therapy in combination with other antiviral compounds directed against picornaviruses.

Amyotrophic lateral sclerosis (ALS) among immigrant groups and Swedish-born individuals: a cohort study of all adults 18 years of age and older in Sweden.

BACKGROUND: There is a lack of studies of amyotrophic lateral sclerosis (ALS) in immigrants. OBJECTIVE: The objective is to study the association between country of birth and incident ALS in first-generation immigrants versus Swedish-born individuals, and in second-generation immigrants versus native Swedes. METHODS: Study populations included all adults aged 18 years and older in Sweden, in the first-generation study 6,128,698 individuals (2,975,141 men, 3,153,557 women) with 5,344 ALS cases (3017 men, 2327 women), and in the second-generation study 4,588,845 individuals (2,346,855 men and 2,241,990 women) with 3,420 cases (2027 men and 1393 women). ALS was defined as having at least one registered diagnosis of ALS in the National Patient Register 1998-2017. The incidence of ALS in different first-generation immigrant groups versus Swedish-born individuals was assessed by Cox regression, expressed as hazard ratios (HRs) with 95% confidence intervals (CI). The models were stratified by sex and adjusted for age, geographical residence in Sweden, educational level, marital status, and neighbourhood socioeconomic status. RESULTS: After adjusting for potential confounders, the HRs were lower in foreign-born men, 0.71 (95% CI 0.63-0.81), and women, 0.80 (95% CI 0.70-0.92). The ALS risk was lower among men and women from most Western countries (Europe outside Nordic countries, and North America), and from other regions of the world (Africa, Asia, and Latin America). Among men and women with foreign-born parents, the risk of ALS did not differ significantly from native Swedes. SIGNIFICANCE: In general, the risk of ALS was lower in first-generation men and women but did not differ in second-generation individuals.

Associations Between Fluctuations in Daytime Sleepiness and Motor and Non-Motor Symptoms in Parkinson's Disease.

BACKGROUND: Non-motor fluctuations are a major concern in Parkinson's disease (PD), and they have been categorized into neuropsychiatric, autonomic and sensory fluctuations. However, this categorization does not include sleep and sleep-related features, and the association between daytime sleepiness and other motor and/or non-motor fluctuations in PD remains to be elucidated. OBJECTIVE: To investigate the relationship between daytime sleepiness and other non-motor and motor fluctuations in people with PD. METHODS: A three-day home diary recording daytime sleepiness, mood, anxiety, and motor symptoms was used along with the Karolinska Sleepiness Scale (KSS) and 6 days of accelerometer (Parkinson's KinetiGraph™; PKG™) registration to detect motor fluctuations among people with a DaTSCAN verified clinical PD diagnosis (32 men; mean PD duration, 8.2 years). Participants were categorized as motor fluctuators or non-fluctuators according to the UPDRS part IV and/or the presence of motor and non-motor fluctuations. RESULTS: Fifty-two people with PD participated. Daytime sleepiness correlated significantly with motor symptoms, mood and anxiety among those classified as motor fluctuators (n = 28). Motor fluctuators showed stronger correlations between the individual mean level of all diary variables (daytime sleepiness, anxiety, mood and motor symptoms) when compared to the non-fluctuators (n = 24). Stronger positive within-individual correlations were found among fluctuators in comparison to non-fluctuators. In general, PKG data did not correlate with diary data. CONCLUSION: Episodes of daytime sleepiness, as reported by home diaries, were associated with other self-reported non-motor and motor fluctuations, but were not supported by PKG data.

Huntington's disease among immigrant groups and Swedish-born individuals: a cohort study of all adults 18 years of age and older in Sweden.

BACKGROUND: There is a lack of studies of Huntington's disease (HD) in immigrants. OBJECTIVE: To study the association between country of birth and incident HD in first-generation immigrants versus Swedish-born individuals and in second-generation immigrants versus Swedish-born individuals with Swedish-born parents. METHODS: Study populations included all adults aged 18 years and older in Sweden, i.e., in the first-generation study 6,042,891 individuals with 1034 HD cases and in the second-generation study 4,860,469 individuals with 1001 cases. HD was defined as having at least one registered diagnosis of HD in the National Patient Register. The incidence of HD in different first-generation immigrant groups versus Swedish-born individuals was assessed by Cox regression, expressed as hazard ratios (HRs) and 95% confidence intervals (CI). The models were stratified by sex and adjusted for age, geographical residence in Sweden, educational level, marital status, and neighborhood socioeconomic status. RESULTS: Mean age-standardized incidence rates per 100,000 person-years were for all Swedish-born 0.82 and for all foreign born 0.53 and for all men 0.73 and for all women 0.81, with the highest incidence rates for the group 80-84 years of age. After adjusting for potential confounders, the HRs were lower in women in the first- and second-generation, i.e., 0.49 (95% CI 0.36-0.67) and 0.63 (95% 0.45-0.87), respectively, and also among women from Finland or with parents from Finland. SIGNIFICANCE: In general, the risk of HD was lower in first-generation and second-generation immigrant women but not among male immigrants.

Telephone validation of an Urdu translated version of the extended disability severity scale in multiple sclerosis patients.

BACKGROUND: Expanded Disability Status Scale (EDSS) is a commonly used tool to assess the extent of functional impairment in multiple sclerosis (MS) patients for clinical and research purposes. EDSS is traditionally conducted in a face-to-face setting, however, routine in-person EDSS assessments are often difficult to perform in developing countries due to the various reasons patients are unable to access healthcare and maintain clinic visits. Hence validating a locally translated telephone-based EDSS (T-EDSS) could be potentially useful to both physicians and patients by removing the need to commute to healthcare centers for disability assessment and could lead to overall improved care for MS patients. METHODS: Firstly, the EDSS scale was translated and culturally adapted into Urdu. On enrolment, EDSS was conducted during scheduled clinic visits and forty-seven subjects with MS were henceforth included in the study. Same patients were contacted via telephone following two weeks by a different neurologist to carry out the telephone-EDSS assessment. The patients' baseline EDSS scores at enrolment were blinded to prevent interviewer bias. RESULTS: Kappa value for agreement between the two assessments for EDSS scores of more than 6 was 0.73, whereas the kappa value for EDSS score of less than 4.5 was 0.35. The intraclass correlation coefficient (ICC) for T-EDSS score < 4.5 was 1.7, and for a score > 4.5 was 4.9, with the overall ICC being 0.64. Cronbach's alpha value for T-EDSS score < 4.5 was 0.59 and for the score > 4.5 was 0.79. CONCLUSIONS: This study shows that there exists a positive correlation and substantial level of agreement between in-person EDSS and T-EDSS, especially in MS patients with higher baseline EDSS scores. Hence a locally translated T-EDSS can be used in Pakistani MS patients with reasonable confidence. T-EDSS may be more useful in MS patients with moderate to severe disability.

Multiple sclerosis in Pakistan: Current status and future perspective.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) which commonly leads to disability. We reviewed articles on MS from Pakistan using PubMed, Google Scholar and Pak Medinet to present different aspects of the disease and the status of disease modifying treatments in Pakistan and South Asia. MS is not as uncommon in Pakistan as it has been previously thought to be. Estimated prevalence of MS in Pakistan may be 10 per 100,000 population. Data suggests that most features of MS found in Pakistan are similar to those found in the West. These features include a female preponderance, mean age of onset in the third decade of life and similar risk factors including viral infections, smoking, and vitamin D deficiency, as well as genetic risk factors. Relapsing-remitting multiple sclerosis (RRMS) is the most common disease pattern seen in Pakistan which is also consistent with data from other regions. Treatment modalities in Pakistan include immunomodulatory and immunosuppressive drugs. In order to improve care for MS patients in Pakistan, it is extremely important to obtain a population-based prevalence of MS in the country and a national MS registry, along with implementing programs for patients' awareness and the training of doctors, especially internists. There are many disease modifying therapies (DMT) available in Pakistan but no data is available on the utilization and impact of these DMTs.

Multiple sclerosis among first- and second-generation immigrant groups in Sweden.

OBJECTIVES: Risk of multiple sclerosis (MS) is low among first-generation immigrants in Sweden. We aimed to study incident MS in first- and second-generation immigrant groups. MATERIALS & METHODS: We included adults aged 18 years and older in Sweden in first-generation (n = 6 042 891) and second-generation (n = 4 860 469) sub-studies. MS was defined via two diagnoses in the Swedish National Patient Register. MS risk was estimated by Cox regression, with hazard ratios (HRs) and 95% confidence intervals (CI), in different immigrant groups, using Swedish-born as referents in first-generation sub-study, and individuals with Swedish-born parents in the second-generation. Full models were adjusted for age, geographic residence in Sweden, educational level, marital status, neighborhood socioeconomic status, and co-morbidity. RESULTS: MS was diagnosed among 10 746 individuals in the first-generation sub-study, (men 3055 and women 7691), and 11 737 in the second-generation sub-study (men 3549 and women 8188) in the period 1998-2015. The annual incidence rate was higher in Swedish-born compared to foreign-born, 11.5 vs 6.3 per 100 000 person-years (age-standardized to the European standard population). Fully adjusted HRs were lower in first-generation immigrant men (HR 0.72, 0.64-0.82) and women (HR 0.67, 0.62-0.73), and in second-generation immigrant men (HR 0.88, 0.79-0.97) and women (HR 0.79; 0.73-0.84). Among first-generation immigrants, lower HRs were found in most groups. SIGNIFICANCE: The MS risk was lower in first- and second-generation immigrants compared to Swedish-born or individuals with Swedish-born parents.

Parkinson's Disease Among Immigrant Groups and Swedish-Born Individuals: A Cohort Study of All Adults 50 Years of Age and Older in Sweden.

BACKGROUND: There is a lack of studies of Parkinson's disease (PD) in immigrants. OBJECTIVE: To study the association between country of birth and incident PD in immigrants in Sweden versus Swedish-born individuals. METHODS: Study population included all adults aged 50 years and older in Sweden (n = 2775736). PD was defined as having at least one registered diagnosis of PD in the National Patient Register. The incidence of PD in different first-generation immigrant groups versus Swedish-born individuals was assessed by Cox regression, expressed as hazard ratios (HRs) and 95% confidence intervals (CI). The models were stratified by sex and adjusted for age, geographical residence in Sweden, educational level, marital status, neighbourhood socioeconomic status and co-morbidity. RESULTS: Totally 35833 individuals had an incident diagnosis of PD (20401 men and 15432 women). Incidence rates per 100,000 person-years were for all Swedish-born 95.9 and for all foreign-born 60.1; for all men 112.3 and for all women 73.4, with a male to female ratio of 1.53, with the highest incidence rates for the group 80-84 years of age. After adjusting for potential confounders, the overall relative risk of PD was lower in immigrant men (HR 0.78; 95% CI 0.74-0.82) and women (HR 0.92; 95% CI 0.87-0.98). Among immigrant subgroups, a higher risk of PD was found among women from Finland (HR 1.13; 95% CI 1.05-1.23). CONCLUSION: In general, the risk of PD was lower in first-generation immigrant men and women compared to Swedish-born. The only group with a higher risk of PD was women from Finland.

Validation of Rapid Magnetic Resonance Myelin Imaging in Multiple Sclerosis.

OBJECTIVE: Magnetic resonance imaging (MRI) is essential for multiple sclerosis diagnostics but is conventionally not specific to demyelination. Myelin imaging is often hampered by long scanning times, complex postprocessing, or lack of clinical approval. This study aimed to assess the specificity, robustness, and clinical value of Rapid Estimation of Myelin for Diagnostic Imaging, a new myelin imaging technique based on time-efficient simultaneous T1 /T2 relaxometry and proton density mapping in multiple sclerosis. METHODS: Rapid myelin imaging was applied using 3T MRI ex vivo in 3 multiple sclerosis brain samples and in vivo in a prospective cohort of 71 multiple sclerosis patients and 21 age/sex-matched healthy controls, with scan-rescan repeatability in a subcohort. Disability in patients was assessed by the Expanded Disability Status Scale and the Symbol Digit Modalities Test at baseline and 2-year follow-up. RESULTS: Rapid myelin imaging correlated with myelin-related stains (proteolipid protein immunostaining and Luxol fast blue) and demonstrated good precision. Multiple sclerosis patients had, relative to controls, lower normalized whole-brain and normal-appearing white matter myelin fractions, which correlated with baseline cognitive and physical disability. Longitudinally, these myelin fractions correlated with follow-up physical disability, even with correction for baseline disability. INTERPRETATION: Rapid Estimation of Myelin for Diagnostic Imaging provides robust myelin quantification that detects diffuse demyelination in normal-appearing tissue in multiple sclerosis, which is associated with both cognitive and clinical disability. Because the technique is fast, with automatic postprocessing and US Food and Drug Administration/CE clinical approval, it can be a clinically feasible biomarker that may be suitable to monitor myelin dynamics and evaluate treatments aiming at remyelination. ANN NEUROL 2020;87:710-724.

Epilepsy in immigrants and Swedish-born: A cohort study of all adults 18 years of age and older in Sweden.

PURPOSE: We aimed to study the association between country of birth and incident epilepsy in several immigrant groups using Swedish-born individuals as referents. METHOD: The study population included all adults aged 18 years and older in Sweden, living and deceased, 6,690,598 in the first-generation and 6,683,125 in the second-generation sub-study. Epilepsy was defined as having at least one registered diagnosis of epilepsy in the National Patient Register. The incidence of epilepsy in different immigrant groups, using Swedish-born as referents, was assessed by Cox regression, expressed as hazard ratios (HRs) and 95 % confidence intervals (CI). The models were stratified by sex and adjusted for age, geographical residence in Sweden, educational level, marital status, and neighbourhood socioeconomic status. RESULTS: In the first-generation sub-study, totally 76,541 individuals had at least one registered diagnosis of epilepsy (1.14 % in total; men 1.22 % and women 1.07 %), and in the second-generation study 72,545 (1.09 %; men 1.18 % and women 0.99 %). After adjusting for confounders, in first-generation immigrants compared to their Swedish-born counterparts the incidence was somewhat lower among both men (HR 0.92, 0.90-0.96) and women (HR 0.93, 0.90-0.96), and in the second-generation immigrants among women (HR 0.95, 0.92-0.99) but not men (HR 0.99; 0.96-1.02). Among immigrant groups, a higher incidence of epilepsy was observed among first-generation women from Africa and Iraq, and second-generation men and women from Bosnia, and women from Finland. CONCLUSIONS: Risk of epilepsy was lower in immigrants in general compared to the Swedish-born population; but with higher incidence in some specific groups.

A 10-Year Follow-Up of Excessive Daytime Sleepiness in Parkinson's Disease.

INTRODUCTION: The aim of this prospective study was to investigate excessive daytime sleepiness (EDS) over time and in relation to other PD symptoms among people with Parkinson's disease (PD). METHODS: Thirty participants younger than 65 years with PD were randomly selected. At inclusion, mean (SD) disease duration was 6.2 (4.8) years and median (min-max) severity of PD was classified as stage II (stages I-III) according to Hoehn and Yahr. Participants were followed annually for 10 years with clinical assessments of their PD status, medications, comorbidities, and a standardized interview about their sleep habits and occurrence of daytime sleepiness. EDS was assessed by the self-reported Epworth Sleepiness Scale (ESS). Seventeen participants completed the 10-year longitudinal follow-up. RESULTS: Fifteen of 30 persons were classified to suffer from EDS (ESS > 10) at baseline. At the group level, EDS remained stable over 10 years and did not deteriorate in parallel with worsening of motor symptoms. Furthermore, EDS was associated with sleep quality, fatigue, anxiety, depression, and axial/postural/gait impairments. CONCLUSIONS: EDS did not worsen over 10 years, although other PD aspects did. EDS in PD seems to be a complex nonmotor symptom that is unrelated to deterioration of motor symptoms in PD.

RebiQoL: A randomized trial of telemedicine patient support program for health-related quality of life and adherence in people with MS treated with Rebif.

RebiQoL was a phase IV multicenter randomized study to assess the impact of a telemedicine patient support program (MSP) on health-related quality of life (HRQoL) in patients with relapsing-remitting MS (RRMS) being administered with Rebif with the RebiSmart device. The primary endpoint was to assess the impact of MSP compared to patients only receiving technical support for RebiSmart on HRQoL at 12 months, using the psychological part of Multiple Sclerosis Impact Scale (MSIS-29), in patients administered with Rebif. A total of 97 patients diagnosed with RRMS were screened for participation in the study of which 3 patients did not fulfill the eligibility criteria and 1 patient withdrew consent. Of the 93 randomized patients, 46 were randomized to MSP and 47 to Technical support only. The demographic characteristics of the patients were well-balanced in the two arms. There were no statistical differences (linear mixed model) in any of the primary (difference of 0.48, 95% CI: -8.30-9.25, p = 0.91) or secondary outcomes (p>0.05). Although the study was slightly underpowered, there was a trend towards better adherence in the MSP group (OR 3.5, 95% CI 0.85-14.40, p = 0.08) although not statistically significant. No unexpected adverse events occurred. This study did not show a statistically significant effect of the particular form of teleintervention used in this study on HRQoL as compared to pure technical support, for MS patients already receiving Rebif with the RebiSmart device. Trial Registration: ClinicalTrials.gov: NCT01791244.

Lesion accumulation is predictive of long-term cognitive decline in multiple sclerosis.

OBJECTIVE: To investigate the long-term progression of cognitive dysfunction and its neuroanatomical correlates and predictors in multiple sclerosis (MS). METHODS: A cohort of 37 MS patients reflecting five decades of disease duration and all subtypes was followed over 17.5 years. Matched controls were recruited at the last follow-up. Global cognitive functioning was assessed using a principal component cognitive index based on comprehensive neuropsychological testing. During the last 8.5 years of the study, brain MRI was performed to analyze normalized volumetrics of three global tissue compartments (white and gray matter, lesions) and strategic regions (corpus callosum, thalamus, hippocampus). RESULTS: Cognitive decline progressed continuously throughout the study paralleled by atrophy and lesion accumulation. The cognitive index partly correlated with Expanded Disability Status Scale (ρ = -0.47, p < 0.001) and was mainly associated with the lesion fraction (ß = -0.48, p < 0.001) and callosal fraction (ß = 0.39, p = 0.002) in multiple linear regression analysis. The lesion fraction was an independent predictor of the cognitive performance 8.5 years later (ß = -0.35, p = 0.008). Symbol Digit Modalities Test was most frequently abnormal (40%), while Rey-Osterrieth Complex Figure Test was more sensitive to detect cognitive decline. CONCLUSIONS: Cognitive impairment progresses continuously in MS, associated with atrophy and lesion accumulation, suggesting that interventions targeting these processes could be beneficial at all disease stages. Widespread cognitive functions are more profoundly affected, associated with lesions and corpus callosal atrophy, supporting the idea of an underlying disconnection mechanism for cognitive decline in MS.

Treatment with disease-modifying drugs for people with a first clinical attack suggestive of multiple sclerosis.

BACKGROUND: The treatment of multiple sclerosis has changed over the last 20 years. The advent of disease-modifying drugs in the mid-1990s heralded a period of rapid progress in the understanding and management of multiple sclerosis. With the support of magnetic resonance imaging early diagnosis is possible, enabling treatment initiation at the time of the first clinical attack. As most of the disease-modifying drugs are associated with adverse events, patients and clinicians need to weigh the benefit and safety of the various early treatment options before taking informed decisions. OBJECTIVES: 1. to estimate the benefit and safety of disease-modifying drugs that have been evaluated in all studies (randomised or non-randomised) for the treatment of a first clinical attack suggestive of MS compared either with placebo or no treatment;2. to assess the relative efficacy and safety of disease-modifying drugs according to their benefit and safety;3. to estimate the benefit and safety of disease-modifying drugs that have been evaluated in all studies (randomised or non-randomised) for treatment started after a first attack ('early treatment') compared with treatment started after a second attack or at another later time point ('delayed treatment'). SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register, MEDLINE, Embase, CINAHL, LILACS, clinicaltrials.gov, the WHO trials registry, and US Food and Drug Administration (FDA) reports, and searched for unpublished studies (until December 2016). SELECTION CRITERIA: We included randomised and observational studies that evaluated one or more drugs as monotherapy in adult participants with a first clinical attack suggestive of MS. We considered evidence on alemtuzumab, azathioprine, cladribine, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, immunoglobulins, interferon beta-1b, interferon beta-1a (Rebif®, Avonex®), laquinimod, mitoxantrone, natalizumab, ocrelizumab, pegylated interferon beta-1a, rituximab and teriflunomide. DATA COLLECTION AND ANALYSIS: Two teams of three authors each independently selected studies and extracted data. The primary outcomes were disability-worsening, relapses, occurrence of at least one serious adverse event (AE) and withdrawing from the study or discontinuing the drug because of AEs. Time to conversion to clinically definite MS (CDMS) defined by Poser diagnostic criteria, and probability to discontinue the treatment or dropout for any reason were recorded as secondary outcomes. We synthesized study data using random-effects meta-analyses and performed indirect comparisons between drugs. We calculated odds ratios (OR) and hazard ratios (HR) along with relative 95% confidence intervals (CI) for all outcomes. We estimated the absolute effects only for primary outcomes. We evaluated the credibility of the evidence using the GRADE system. MAIN RESULTS: We included 10 randomised trials, eight open-label extension studies (OLEs) and four cohort studies published between 2010 and 2016. The overall risk of bias was high and the reporting of AEs was scarce. The quality of the evidence associated with the results ranges from low to very low. Early treatment versus placebo during the first 24 months' follow-upThere was a small, non-significant advantage of early treatment compared with placebo in disability-worsening (6.4% fewer (13.9 fewer to 3 more) participants with disability-worsening with interferon beta-1a (Rebif®) or teriflunomide) and in relapses (10% fewer (20.3 fewer to 2.8 more) participants with relapses with teriflunomide). Early treatment was associated with 1.6% fewer participants with at least one serious AE (3 fewer to 0.2 more). Participants on early treatment were on average 4.6% times (0.3 fewer to 15.4 more) more likely to withdraw from the study due to AEs. This result was mostly driven by studies on interferon beta 1-b, glatiramer acetate and cladribine that were associated with significantly more withdrawals for AEs. Early treatment decreased the hazard of conversion to CDMS (HR 0.53, 95% CI 0.47 to 0.60). Comparing active interventions during the first 24 months' follow-upIndirect comparison of interferon beta-1a (Rebif®) with teriflunomide did not show any difference on reducing disability-worsening (OR 0.84, 95% CI 0.43 to 1.66). We found no differences between the included drugs with respect to the hazard of conversion to CDMS. Interferon beta-1a (Rebif®) and teriflunomide were associated with fewer dropouts because of AEs compared with interferon beta-1b, cladribine and glatiramer acetate (ORs range between 0.03 and 0.29, with substantial uncertainty). Early versus delayed treatmentWe did not find evidence of differences between early and delayed treatments for disability-worsening at a maximum of five years' follow-up (3% fewer participants with early treatment (15 fewer to 11.1 more)). There was important variability across interventions; early treatment with interferon beta-1b considerably reduced the odds of participants with disability-worsening during three and five years' follow-up (OR 0.52, 95% CI 0.32 to 0.84 and OR 0.57, 95% CI 0.36 to 0.89). The early treatment group had 19.6% fewer participants with relapses (26.7 fewer to 12.7 fewer) compared to late treatment at a maximum of five years' follow-up and early treatment decreased the hazard of conversion to CDMS at any follow-up up to 10 years (i.e. over five years' follow-up HR 0.62, 95% CI 0.53 to 0.73). We did not draw any conclusions on long-term serious AEs or discontinuation due to AEs because of inadequacies in the available data both in the included OLEs and cohort studies. AUTHORS' CONCLUSIONS: Very low-quality evidence suggests a small and uncertain benefit with early treatment compared with placebo in reducing disability-worsening and relapses. The advantage of early treatment compared with delayed on disability-worsening was heterogeneous depending on the actual drug used and based on very low-quality evidence. Low-quality evidence suggests that the chances of relapse are less with early treatment compared with delayed. Early treatment reduced the hazard of conversion to CDMS compared either with placebo, no treatment or delayed treatment, both in short- and long-term follow-up. Low-quality evidence suggests that early treatment is associated with fewer participants with at least one serious AE compared with placebo. Very low-quality evidence suggests that, compared with placebo, early treatment leads to more withdrawals or treatment discontinuation due to AEs. Difference between drugs on short-term benefit and safety was uncertain because few studies and only indirect comparisons were available. Long-term safety of early treatment is uncertain because of inadequately reported or unavailable data.

Alemtuzumab Use in Clinical Practice: Recommendations from European Multiple Sclerosis Experts.

Alemtuzumab (Lemtrada™) is a humanized monoclonal antibody approved in more than 50 countries. Within the European Union, alemtuzumab is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS) with active disease defined by clinical or imaging features; in the USA, the indication states that alemtuzumab should generally be reserved for the treatment of patients with relapsing forms of multiple sclerosis who have had an inadequate response to two or more disease-modifying therapies (DMTs). In clinical trials, alemtuzumab demonstrated efficacy in treatment-naïve patients with active RRMS and those relapsing on prior DMTs, with a consistent and manageable safety and tolerability profile. The European Union indication provides physicians with significant flexibility regarding treatment decisions, affording the opportunity for individualized treatment. Thus, alemtuzumab may be an appropriate treatment choice across a broad range of patients with RRMS, including, for example, treatment-naïve patients with active disease, patients with highly active disease, or for patients relapsing on prior DMTs. There are several practicalities to consider when using alemtuzumab, including the unique dosing regimen, administered via intravenous infusion on 5 consecutive days at baseline and on 3 consecutive days 12 months later, and as-needed retreatment (3 consecutive days at least 12 months after the last course) in cases of disease recurrence. Additionally, routine monthly monitoring is required for up to 48 months after the last infusion to promptly identify potentially serious autoimmune adverse events. Given these considerations, it is beneficial to gain insight into how alemtuzumab is being used in the real-world clinical setting. Here, we report recommendations from European multiple sclerosis experts regarding best practices for alemtuzumab treatment, including management of adverse events and compliance with ongoing safety monitoring requirements.

A single-group pilot feasibility study of cognitive behavioural therapy in people with multiple sclerosis with depressive symptoms.

PURPOSE: The aims were to evaluate (a) the feasibility of face-to-face cognitive behavioural therapy (CBT) in people with MS (PwMS) with depressive symptoms; (b) the feasibility of methods and measurements used; and (c) the outcome of the intervention before the conducting of an equivalence study of comparative methods of face-to-face CBT. DESIGN: A single-group pilot feasibility study. PATIENTS: PwMS (n = 15) with sub-threshold to moderate depressive symptoms, recruited at the Karolinska University Hospital, Stockholm, Sweden. METHODS: The intervention consisted of 15-20 sessions of face-to-face CBT. Feasibility outcomes included recruitment rate, recruitment procedure and adverse events. Primary clinical outcome was the Beck Depression Inventory-II (BDI-II). Follow-ups were conducted after 3 weeks and 3 months. An estimated sample size calculation was conducted. RESULTS: The face-to-face CBT intervention, methods and measurements used were feasible. The outcome on BDI-II indicated that face-to-face CBT is an effective method for alleviating sub-threshold to moderate depressive symptoms in PwMS. CONCLUSION: Face-to-face CBT is feasible for use in PwMS aiming at decrease depressive symptoms. For an equivalence study, a screening process for depressive symptoms and two comparative intervention arms including traditional face-to-face CBT and low-intensity face-to-face CBT is recommended. Primary outcomes should include the BDI-II and also assessment of anxiety symptoms. Implications for Rehabilitation Depression is common among people with MS (PwMS), however, depressed PwMS do not always receive adequate treatment for depression which may lead to increased disability and worse health-related quality of life (HRQL). Cognitive behavioural therapy (CBT) is a psychological treatment method that might be beneficial for PwMS with depressive symptoms, but the evidence is still weak and further research is needed. The results from our pilot feasibility study demonstrate that for an effectiveness study of face-to-face CBT for PwMS with sub-threshold to moderate depressive symptoms the following points should be acknowledged. The design of an effectiveness study should be a randomized controlled trial including two treatment arms: traditional face-to-face CBT and a low-intensity face-to-face CBT. To increase the inclusion rate a screening process for depressive symptoms is recommended. Primary outcomes besides the Beck Depression Inventory-II should include the Hospital Anxiety and Depression Scale in order to capture anxiety symptoms and the Multiple Sclerosis Impact Scale-29 to capture HRQL.