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.

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.

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.

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.

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.

Corpus callosum atrophy is strongly associated with cognitive impairment in multiple sclerosis: Results of a 17-year longitudinal study.

BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS) and may be subtle. The corpus callosum is essential for connectivity-demanding cognitive tasks and is significantly affected in MS, therefore it may serve as a marker for cognitive function. OBJECTIVE: The objective of this paper is to longitudinally study the normalized corpus callosum area (nCCA) as a marker of cognitive function and disability in MS. METHODS: Thirty-seven MS patients were followed from 1996 with follow-ups in 2004 and 2013. A healthy matched control group was recruited. The Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT) were assessed. The nCCA was measured on T2-weighted images. Volumetry was performed with FreeSurfer. RESULTS: Disease duration spanned five decades (1.6-46 years). Annual corpus callosal atrophy rate decreased with disease duration. nCCA was strongly correlated with SDMT (r = 0.793, p < 0.001) and moderately correlated with EDSS (r = -0.545, p < 0.001) after adjusting for disease duration, age and sex. The correlations of brain parenchymal fraction, white matter fraction, gray matter fraction and normalized lesion volume were less strong. CONCLUSIONS: The nCCA correlates well with physical and cognitive disability in time perspectives close to two decades, outperforming volumetric measurements. The nCCA is fast and could be feasible for clinical implementation where it may help identify patients in need of neuropsychological evaluation.

Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience.

BACKGROUND: Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS. METHODS: Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months. RESULTS: At 5 years, relapse-free survival was 87%; MRI event-free survival 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%). CONCLUSIONS: HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres.

Interferon ß for secondary progressive multiple sclerosis: a systematic review.

BACKGROUND: It is unclear whether recombinant ß interferons (IFNß) can be effective in secondary progressive multiple sclerosis (SPMS). The aim was to determine whether IFNß can reduce the risk of disability and cognitive impairment progression in SPMS. METHODS: Using Cochrane methodology, we reviewed all randomised placebo controlled trials of IFNß in SPMS patients (1995-March 2012). RESULTS: 5 trials (3082 patients) were included. After 3 years, interferons did not reduce disability progression, confirmed at 6 months (RR 0.98, 95% CI 0.82 to 1.16). A small reduction in the number of patients who had relapses during the first 3 years of treatment (RR 0.91, 0.84 to 0.97) was found. No analysis of cognitive data was possible. More treated than placebo patients dropped out for adverse events. CONCLUSION: 3 year treatment with IFNß does not delay permanent disability in SPMS but reduces relapse risk, indicating that the anti-inflammatory effect of IFNß is unable to prevent MS progression once it has become established.

Radiologically isolated syndrome--incidental magnetic resonance imaging findings suggestive of multiple sclerosis, a systematic review.

With increasing availability of magnetic resonance imaging (MRI), there is also an increase in incidental abnormal findings. MRI findings suggestive of multiple sclerosis in persons without typical multiple sclerosis symptoms and with normal neurological findings are defined as radiologically isolated syndrome (RIS). Half of the persons with RIS have their initial MRI because of headache, and some have a subclinical cognitive impairment similar to that seen in multiple sclerosis. Radiological measurements also show a similarity between RIS and multiple sclerosis. Approximately two-thirds of persons with RIS show radiological progression and one-third develop neurological symptoms during mean follow-up times of up to five years. Cervical cord lesions are important predictors of clinical conversion. Management has to be individualised, but initiation of disease modifying therapy is controversial and not recommended outside of clinical trials since its effects have not been studied in RIS. Future studies should try to establish the prevalence and long-term prognosis of RIS, its impact on quality of life, and define the role of disease modifying therapy in RIS.

Differences between users and non-users of complementary and alternative medicine among people with multiple sclerosis in Denmark: a comparison of descriptive characteristics.

AIMS: The aim of this study was to investigate differences in socio-economic characteristics between CAM users and CAM non-users among people with MS in Denmark as well as differences in characteristics related to the use of CAM among CAM users and the use of conventional treatments among CAM non-users. METHODS: An internet-based questionnaire was used to collect data from 3361 patient members of the Danish MS society. A letter with a personal code was sent to all respondents, asking them to fill out the questionnaire online. Reminders to non-respondents were sent twice and the final response rate was 55.5%. Statistical associations were presented as odds ratios and with respective 95% confidence intervals. RESULTS: People with MS in Denmark use a wide range of CAM treatments for a variety of reasons. CAM users were more likely to be of female gender, 18-40 years of age, educated at bachelor level or above, and have a high income compared to CAM non-users (p < 0.05). CAM users more often addressed non-specific/preventive treatment purposes through their use of CAM treatments, they communicated less often with a medical doctor about the CAM treatments used, and they experienced less side effects as well as less positive effects from the CAM treatments used when compared with the use of conventional treatments among CAM non-users (p < 0.05). CONCLUSIONS: People with MS in Denmark reported use of a large range of CAM treatments. CAM users differed from CAN non-users in relation to socio-economic factors as well as treatment characteristics.

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.

Interferon beta for secondary progressive multiple sclerosis.

BACKGROUND: Therapy with either recombinant beta-1a or beta-1b interferons (IFNs) is worldwide approved for Relapsing Remitting Multiple Sclerosis (RRMS). A major unanswered question is whether this treatment is able to safely reverse or retard the progressive phase of the disease. OBJECTIVES: The main objective was to verify whether IFNs treatment in Secondary Progressive Multiple Sclerosis (SPMS) is more effective than placebo in reducing the number of patients who experience disability progression. SEARCH METHODS: We searched the Cochrane Multiple Sclerosis Group's Trials Register (1995 to 15 February 2011), the reference lists of relevant articles and conference proceedings. Regulatory agencies were used as additional sources of information. SELECTION CRITERIA: We included all randomised, double or single blind, placebo-controlled trials (RCTs) evaluating the efficacy of IFNs versus placebo in SPMS patients. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed all reports retrieved from the search. They independently extracted clinical, safety and MRI data, using a predefined data extraction form, resolving disagreements after discussion with a third reviewer. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using Risk Ratio (RR) with 95% confidence intervals (CI) for the binary outcomes and Standard Mean Difference with 95% CI for the continuous outcomes. MAIN RESULTS: Five RCTs met the inclusion criteria, from which 3122 (1829 IFN and 1293 placebo) treated patients contributed to the analysis. Included population was heterogeneous in terms of baseline clinical characteristics of the disease, in particular the percentage of patients affected by secondary progression with superimposed relapse ranging from 72% to 44%. IFN beta 1a and 1b did not decrease the risk of progression sustained at 6 months (RR, 95% CI: 0.98, [0.82-1.16]) after three years of treatment. A significant decrease of the risk of progression sustained at 3 months (RR, 95% CI: 0.88 [0.80, 0.97]) and of the risk of developing new relapses at three years (RR 0.91, [0.84-0.97]) were found. The risk of developing new active brain lesions decreased over time but this data was obtained from single studies on Magnetic Resonance Imaging (MRI), performed in subgroups of patients; in spite of no effect on progression, the radiological data supported an effect on MRI parameters. The safety profile reflects what is commonly reported in MS IFN-treated patients. AUTHORS' CONCLUSIONS: Well designed RCTs, evaluating a high number of patients were included in the review. Recombinant IFN beta does not prevent the development of permanent physical disability in SPMS. We were unable to verify the effect on cognitive function for the lack of comparable data. This treatment significantly reduces the risk of relapse and of short -term relapse-related disability.Overall, these results show that IFNs' anti-inflammatory effect is unable to retard progression, when established. In the future, no new RCTs for IFNs versus placebo in SPMS will probably be undertaken, because research is now focusing on innovative drugs. We believe that this review gives conclusive evidence on the clinical efficacy of IFNs versus placebo in SPMS.

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.

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.

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.

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.

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.

Health-related quality of life in relapsing remitting multiple sclerosis patients during treatment with glatiramer acetate: a prospective, observational, international, multi-centre study.

BACKGROUND: Glatiramer acetate (GA) and interferon-beta (INFb) are first-line disease modifying drugs for relapsing remitting multiple sclerosis (RRMS). Treatment with INFb is associated with a significant increase in health-related quality of life (HR-QoL) in the first 12 months. It is not known whether HR-QoL increases during treatment with GA. METHODS: 197 RRMS patients, 106 without and 91 with prior immunomodulation/immunosuppression, were studied for HR-QoL (Leeds Multiple Sclerosis-QoL [LMS-QoL] scale, score range 0 - 32), fatigue (Fatigue Impact Scale [FIS]) and depressed mood (Beck Depression Inventory-Short Form [BDI-SF]) at baseline and 6 and 12 months after start of GA treatment. RESULTS: At 6 and 12 months mean LMS-QoL scores were significantly increased in the treatment-naive patient group (p < 0.001), not in the pre-treated group. At month 12 43% of treatment-naïve patients had improved HR-QoL (increase LMS-QoL score 3 or more points) (p < 0.001). Likewise, mean FIS scores were decreased at months 6 and 12 in the treatment-naïve group (p < 0.01), not in the pre-treated group. In both groups mean BDI-SF scores did not change. No demographic or clinical baseline factor was predictive of HR-QoL increase. HR-QoL changes were zero to negative for patients who had discontinued GA before month 12 (28.4% of patients). CONCLUSIONS: In RRMS patients without prior immunomodulation/immunosuppression treatment with GA was associated with an increase in HR-QoL in the first 6 months, that was sustained at 12 months. In 4 out of 10 patients HR-QoL improved. Increase in HR-QoL was associated with decrease in fatigue.

A longitudinal observational study of brain atrophy rate reflecting four decades of multiple sclerosis: a comparison of serial 1D, 2D, and volumetric measurements from MRI images.

INTRODUCTION: Multiple sclerosis (MS) has a variable progression with an early onset of atrophy. Individual longitudinal radiological evaluations (over decades) are difficult to perform due to the limited availability of magnetic resonance imaging (MRI) in the past, patients lost in follow-up, and the continuous updating of scanners. We studied a cohort with widespread disease duration at baseline. The observed individual atrophy rates over time of 10 years represented four decades of disease span. METHODS: Thirty-seven MS patients (age range 24-65 years with disease duration 1-33 years) were consecutively selected and evaluated with MRI at baseline 1995 and in 1996. They were followed up for a decade (mean of 9.25 years, range 7.3-10 years) up to 2003-2005. Brain parenchymal volume and volumes of the supratentorial ventricles were analyzed with semi-automated volumetric measurements at three time points (1995, 1996, and 2003-2005). RESULTS: Volumetric differences were found over shorter periods of time (1-7 months); however, differences vanished by the end of follow-up. A uniform longitudinal decrease in brain volume and increase in ventricle volumes were found. Frontal horn width (1D) correlated strongest to 3D measures. No statistical differences of atrophy rates between MS courses were found. Supratentorial ventricular volumes were associated with disability and this association persisted during follow-up. CONCLUSION: Despite variable clinical courses, the degenerative effects of MS progression expressed in brain atrophy seem to uniformly progress over longer periods of time. These volumetric changes can be detected using 1D and 2D measurements performed on a routine PACS workstation.

The first case history of multiple sclerosis: Augustus d'Esté (1794-1848).

The personal diary of Sir Augustus d'Esté, born 1794 grandson of King George III of England, reveals a medical history strongly suggesting that Augustus suffered from multiple sclerosis (MS). It could well be the first record of a person having this disease. Charcot coined the term sclérose en plaques 20 years after the death of this patient in 1848. The onset of this man's MS seems to have been in 1822 with bilateral optic neuritis, the disease gradually developing in the classic manner with bouts derived from different loci in the central nervous system and eventually a secondary progressive form with paraparesis, sphincter incontinence, urinary problems and impotence. In 1941, Firth highlighted the case of Augustus d'Esté and later wrote a description of the pathology including a discussion on the aetiology of MS. No previous medical records have given such a characteristic picture of MS as this.