Article

Seasonal patterns in optic neuritis and multiple sclerosis: A meta-analysis

Authors:
  • Carlos III Institute of Health, National Centre of Epidemiology, Madrid
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Abstract

To quantify and characterize seasonal variation in monosymptomatic optic neuritis (MON) onsets, multiple sclerosis (MS) onsets and MS exacerbations (MSE), a meta-analysis was performed, using established methods and pooling weighted information obtained from nine reports on MON, six reports on MS onsets and nine reports on MSE, which fulfilled specific criteria for report quality and data homogeneity. The results suggested that MON, MS onsets and MSE in the Northern hemisphere present a similar pattern with highest frequencies in spring and lowest in winter. These differences were highest for MS onsets, 45% with 95% CI 36-55%, and lowest for MSE, 10% with 95% CI 7-13%, statistically significant and robust, insensitive to an alternative seasonal definition, not unduly influenced by any single primary study, and supported by fail-safe N calculations. Random variation, misclassification and publication bias were less likely to account for the reported generalized seasonal patterns.

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... Higher prevalence of MS attacks has been reported in late spring and early summer in both hemispheres (northern of Europe and Oceania) (Tremlett et al., 2008;Harding et al., 2017;Jin et al., 2000;Pelman et al., 2014). However, seasonality and monthly NMOSD attack frequency has not been reported in Argentina and scarce data with distinct result have been published in UK, China, Japan, Australia/New Zealand and Brazil. ...
... However, a statistical trend (P = 0.06) toward fewer attacks in February-April compared to November-January (mid-spring and summer; potential peak risk of attack) was found. This is in line with the pattern found in MS for this part of the world (Tremlett et al., 2008;Harding et al., 2017;Jin et al., 2000;Pelman et al., 2014). Most recently, a Japanese study (kaishi et al., 2020) reported that seropositive NMOSD patients with an initial attack had a higher NMOSD attack frequency in spring and summer seasons, as previously published for China and Oceania studies Khalilidehkordi et al., 2020). ...
... In addition, the evidence suggests that there may be a risk of vaccination-associated attacks in untreated NMOSD patients, but immunosuppressive treatment at time of vaccine may abort the risk (Mealy et al., 2018). Notably, we did not find a seasonal variation in MS patients in Argentina, but a higher prevalence of MS attacks was observed during spring and summer, in line with other studies (Tremlett et al., 2008;Harding et al., 2017;Jin et al., 2000;Pelman et al., 2014;Farez et al., 2015). Sunlight and ultraviolet levels have been reported as influencing different seasonal patterns in these patients (Harding et al., 2017). ...
Article
Background: Identification of triggers that potentially instigate attacks in neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) has remained challenging. We aimed to analyze the seasonality of NMOSD and MS attacks in an Argentinean cohort seeking differences between the two disorders. Methods: A retrospective study was conducted in a cohort of NMOSD and MS patients followed in specialized centers from Argentina and enrolled in RelevarEM, a nationwide, longitudinal, observational, non-mandatory registry of MS/NMOSD patients. Patients with complete relapse data (date, month and year) at onset and during follow-up were included. Attack counts were analyzed by month using a Poisson regression model with the median monthly attack count used as reference. Results: A total of 551 patients (431 MS and 120 NMOSD), experiencing 236 NMOSD-related attacks and 558 MS-related attacks were enrolled. The mean age at disease onset in NMOSD was 39.5 ±5.8 vs. 31.2 ±9.6 years in MS (p<0.01). Mean follow-up time was 6.1 ±3.0 vs. 7.4 ±2.4 years (p<0.01), respectively. Most of the included patients were female in both groups (79% vs. 60%, p<0.01). We found a peak of number of attacks in June (NMOSD: 28 attacks (11.8%) vs MS: 33 attacks (5.9%), incidence rate ratio 1.82, 95%CI 1.15–2.12, p = 0.03), but no differences were found across the months in both disorders when evaluated separately. Strikingly, we observed a significant difference in the incidence rate ratio of attacks during the winter season when comparing NMOSD vs. MS (NMOSD: 75 attacks (31.7%) vs MS: 96 attacks (17.2%), incidence rate ratio 1.82, 95%CI 1.21–2.01, p = 0.02) after applying Poisson regression model. Similar results were observed when comparing the seropositive NMOSD (n=75) subgroup vs. MS. Conclusions: Lack of seasonal variation in MS and NMOSD attacks was observed when evaluated separately. Future epidemiological studies about the effect of different environmental factors on MS and NMOSD attacks should be evaluated prospectively in Latin America population.
... Previous studies have demonstrated that the incidence of autoimmune diseases varied from season to season, including systemic and neurological immune-mediated diseases (Watad et al., 2017;Jeanjean et al., 2018;Jin et al., 2000;Chroni et al., 2004). Seasonal variation in the onset of autoimmune diseases may reflect changes of external environmental factors, some of which hold the potential to trigger or modulate pathogenic processes involved in autoimmunity (Watad et al., 2017). ...
... The seasonal variation being more prominent in anti-NMDAR and anti-LGI1 encephalitis could likely be attributed to a higher incidence of the 2 subtypes of AE. Our result extends the conception on the seasonality of autoimmune diseases affecting the central nervous system, such as multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein-antibody associated disease (MOGAD), and diseases affecting peripheral nervous system, such as Guillain-Barré syndrome (Jeanjean et al., 2018;Jin et al., 2000;Chroni et al., 2004;Akaishi et al., 2020;Matsui et al., 2018). The result of a meta-analysis suggested that onsets and exacerbations of MS presented with a similar pattern, with highest frequencies in spring and lowest in winter (Jin et al., 2000). ...
... Our result extends the conception on the seasonality of autoimmune diseases affecting the central nervous system, such as multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein-antibody associated disease (MOGAD), and diseases affecting peripheral nervous system, such as Guillain-Barré syndrome (Jeanjean et al., 2018;Jin et al., 2000;Chroni et al., 2004;Akaishi et al., 2020;Matsui et al., 2018). The result of a meta-analysis suggested that onsets and exacerbations of MS presented with a similar pattern, with highest frequencies in spring and lowest in winter (Jin et al., 2000). Previous studies have found that onset of NMOSD was more frequent in the spring-summer period (Akaishi et al., 2020;Matsui et al., 2018;Qiu et al., 2020), and relapses were also more common in spring-summer time (Qiu et al., 2020;Khalilidehkordi et al., 2020). ...
Article
Objective The aim of this study was to examine the seasonal distribution in clinical onset of AE in a multi-center cohort in China. Methods This retrospective study consecutively recruited patients with new-onset definite neuronal surface antibody-associated AE between January 2015 and December 2020 from 3 tertiary hospitals. Demographic and clinical characteristics of the participants were comprehensively collected. Statistical analyses were performed using R. Results Of the 184 patients of AE in our database, 149 (81.0%) were included in the final analysis. The median age of onset was 40.0 years, and 66 (44.3%) patients were female. AE predominantly started in autumn (47, 31.5%) and summer (43, 28.9%) months. Summer-autumn predominance of the clinical onsets was also present in the anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis group (54, 60.0%) and anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis group (20, 76.9%). No obvious seasonal variations were observed among gender, onset age, disease duration, prodromal symptoms, clinical type of initial symptoms, and disease severity by the time of admission. Conclusion This study suggested summer-autumn predominance of the clinical onsets in patients with AE, especially anti-NMDAR and anti-LGI1 encephalitis. Therefore, clinicians should have a high index of suspicion for AE in encephalopathy patients in summer and autumn period.
... Seasonal variation. Based on a Medline search of articles published between 1966 and 2000, a meta-analysis integrated data from ten studies which examined the seasonal variation of MS relapses (Jin et al., 2000). The ratio of highest to lowest seasonal proportions was calculated as 1.10 (95% CI, 1.07-1.13) ...
... The ratio of highest to lowest seasonal proportions was calculated as 1.10 (95% CI, 1.07-1.13) with the highest proportion of relapses occurring in spring and the lowest in winter (Jin et al., 2000). ...
... There appears to be a period of increased risk of a relapse surrounding the time of infection with most studies exploring the two weeks before and five weeks after infection as 'at risk' periods (Sibley et al., 1985;Correale et al., 2006;Andersen et al., 1993;Buljevac et al., 2002Buljevac et al., , 2003Panitch, 1994). Some also reported a seasonal trend in relapse rates; possibly mediated through seasonal variation in vitamin D/ sunlight levels as well as infection rates, although findings were not always consistent (Jin et al., 2000;Tremlett et al., 2008;Ogawa et al., 2004;Fonseca et al., 2009;Koch et al., 2008;Panitch, 1994;Buljevac et al., 2002). Preliminary work has suggested that parasitic gut infections might alter the risk of a relapse as well as possibly longer-term disability outcomes (Correale and Farez, 2007). ...
Article
Multiple sclerosis (MS) is a chronic disease of the central nervous system with an unidentified etiology. We systematically reviewed the literature on the possible risk factors associated with MS disease onset, relapses and progression from 1960-2012 by accessing six databases and including relevant systematic reviews, meta-analyses, case-control or cohort studies. The focus was on identifying modifiable risk factors. Fifteen systematic reviews and 169 original articles were quality assessed and integrated into a descriptive review. Best evidence, which included one or more prospective studies, suggested that lower exposure to sunlight and/or lower serum vitamin D levels were associated with an increased risk of developing MS onset and subsequent relapses, but a similar quality of evidence was lacking for disease progression. Prospective studies indicated that cigarette smoking may increase the risk of MS as well as accelerate disease progression, but whether smoking altered the risk of a relapse was largely unknown. Infections were implicated in both risk of developing MS and relapses, but data for progression were lacking. Specifically, exposure to the Epstein-Barr virus, particularly if this manifested as infectious mononucleosis during adolescence, was associated with increased MS risk. Upper respiratory tract infections were most commonly associated with an increase in relapses. Relapse rates typically dropped during pregnancy, but there was no strong evidence to suggest that pregnancy itself altered the risk of MS or affected long-term progression. Emerging research with the greatest potential to impact public health was the suggestion that obesity during adolescence may increase the risk of MS; if confirmed, this would be of major significance.
... Environmental factors play an important role and seem to underlie seasonal variations found in MS [1,2]. Increased disease activity has been observed in different regions of the world during warmer months [1,3]. Nonetheless, few studies investigated the seasonal variation of immunological activity in MS. ...
... Seasonal recurrence of biological processes (phenology) is acknowledged as an important scientific and public concern [7]. Circannual rhythms have been previously described in humans and cyclic variations in clinical manifestations have been also observed in immune mediated diseases [1,[3][4][5][6]8]. We found a significant increase from spring to summer of all cytokine production analyzing all individuals, of IFN-γ and TNF-α production in RRMS patients, and also of TNF-α in the controls. ...
... In accordance, we found higher levels of pro-inflammatory cytokines during autumn. On the other hand, several studies have found an increased disease activity, as measured by clinical relapses or subclinical MRI activity, during warmer months in European countries, Japan and the US [1,3,9]. Likewise in Brazil, we previously observed increased MS exacerbations in the spring/summer transition [6]. ...
Article
Higher MS relapse frequency is observed during warmer months in different regions, but evidence for an underlying immunological variation is lacking. Therefore, we investigated seasonal variations of cytokine production in relapsing-remitting MS patients. Twenty-one patients and eight controls had blood samples drawn in each season, evaluating for IL-10, IL-6, TNF-α and IFN-γ. The lowest levels of cytokine production were observed in spring samples, with a significant increase from spring to summer for most cytokines, and especially IFN-γ and TNF-α. This phenomenon may underlie the higher prevalence of clinical and subclinical MS activity observed in warmer months.
... A link between seasons and increased relapse risk was subsequently described by other groups conducting independent studies in multiple countries including the US (11), Switzerland (12), and Japan (13), and was further established by data that demonstrated that seasonal transitions were associated with fluctuations in gadolinium-enhancing MRI activity in MS patients (14). While not all studies reported that MS relapse is dependent on seasonality, a meta-analysis study by Jin et al. has provided compelling evidence demonstrating that during the course of a year increases in MS relapses show a seasonal preference, particularly for spring (15). These results have recently been confirmed by a large multi-investigator study, which queried International MSBase Registry data pertaining to over 32,000 relapses from >9,000 patients. ...
... In lieu of this hypothesis, it is noteworthy that rhinovirus infections exhibit a biannual peak in incidence, with a small increase in infections occurring during spring months, then the majority of infections occurring during the autumn months (26,27). Yet data obtained from the meta-analysis by Jin et al. as well as the MSBase Registry clearly demonstrate that the major increase in MS relapse rate occurs during the months that do not completely overlap with the time frame during which rhinoviral incidence would be expected to peak (15,16). However, the seasonality for all viral infections of the upper-respiratory system is not temporally conserved. ...
... On the other hand, if the occurrence of any upper-respiratory viral infection contributes to MS relapse risk, it would be anticipated that the increased exacerbation risk time frame would correspond to the cumulative increased incidence in upper-respiratory infections caused by all viruses that infect the upper-respiratory tract. In this regard, it is noteworthy that results from multiple epidemiological studies indicate that over the course of a year, the high-risk time frame for obtaining any upper-respiratory viral infection is very similar to the time frame that corresponds to increased relapse risk in MS patients (15,16,28). Moreover, a recent prospective analysis conducted by Tremlett et al. demonstrated that annual MS relapse rates were positively associated with the occurrence of upper-respiratory tract infection and negatively associated with serum 25(OH)D levels (29). ...
Article
Full-text available
Over the past several decades, significant advances have been made in identifying factors that contribute to the pathogenesis of multiple sclerosis (MS) and have culminated in the approval of some effective therapeutic strategies for disease intervention. However, the mechanisms by which environmental factors, such as infection, contribute to the pathogenesis and/or symptom exacerbation remain to be fully elucidated. Relapse frequency in MS patients contributes to neurological impairment and, in the initial phases of disease, serves as a predictor of poor disease prognosis. The purpose of this review is to examine the evidence that supports a role for peripheral infection in modulating the natural history of this disease. Evidence supporting a role for infection in promoting exacerbation in animal models of MS is also reviewed. Finally, a few mechanisms by which infection may exacerbate symptoms of MS and other neurological diseases are discussed. Those who comprise the majority of MS patients acquire approximately two upper-respiratory infections per year; furthermore, this type of infection doubles the risk for MS relapse, underscoring the contribution of this relationship as being potentially important and particularly detrimental.
... Thus, based on the reported anti-inflammatory effects of vitamin D (Correale et al., 2009) (Ascherio et al., 2010), MS relapse occurrence is predicted to peak during autumn and winter. However, several studies, including a metaanalysis (Jin et al., 2000) and a recent multicentric study (Spelman et al., 2014) found that MS disease activity is higher in spring and summer, suggesting that additional factors play a role in MS relapse seasonality. ...
... P=0.02). Hence, the MS patient cohort used in this study shows the seasonality of MS relapses previously described for other cohorts (Jin et al., 2000;Spelman et al., 2014). ...
... Strikingly, vitamin D levels are higher during spring and summer, when relapse occurrence in MS patients peaks. Thus, the observation of a lower occurrence of relapses in seasons characterized by lower vitamin D levels represents a "seasonal paradox": relapses should be less frequent in spring and summer when vitamin D levels are higher, yet the opposite is found in most studies (Jin et al., 2000;Spelman et al., 2014), with a few exceptions (Løken-Amsrud et al., 2012). Our data may solve this paradox by identifying melatonin, whose levels are regulated by seasonal fluctuations in day length, as an additional regulator of the immune response in MS. ...
Article
Seasonal changes in disease activity have been observed in multiple sclerosis, an autoimmune disorder that affects the CNS. These epidemiological observations suggest that environmental factors influence the disease course. Here, we report that melatonin levels, whose production is modulated by seasonal variations in night length, negatively correlate with multiple sclerosis activity in humans. Treatment with melatonin ameliorates disease in an experimental model of multiple sclerosis and directly interferes with the differentiation of human and mouse T cells. Melatonin induces the expression of the repressor transcription factor Nfil3, blocking the differentiation of pathogenic Th17 cells and boosts the generation of protective Tr1 cells via Erk1/2 and the transactivation of the IL-10 promoter by ROR-α. These results suggest that melatonin is another example of how environmental-driven cues can impact T cell differentiation and have implications for autoimmune disorders such as multiple sclerosis.
... A thorough study in mouse and human cells led them to the conclusion that melatonin affects the roles of two kinds of cells that are important in MS disease progression: pathogenic T cells that directly attack and destroy tissue and regulatory T cells, which are supposed to keep pathogenic T cells in check. This higher incidence of MS in spring/summer has been verified in different studies such as in the meta-analysis carried out by Jin et al. (2000) who report that the beginnings of monosymptomatic optic neuritis, the first clinical manifestation ucts, NO nitric oxide, MDA malondialdehyde, tG total glutathione, GSSG oxidized glutathione, GPx glutathione peroxidase, GSH reduced glutathione, SIRT3 sirtuin 3, NF-κB factor nuclear kappa B, Nrf2 Factor 2 related to nuclear erythroid 2, ROS reactive oxygen species, iNOS nitric oxide synthase of MS in 20-30% of cases and in its exacerbations, present a similar pattern with higher frequencies in spring and lower in winter (Jin et al. 2000). Similarly, Spelman et al. (2014), determine that relapse onset in MS followed an annual cyclical sinusoidal pattern with peaks in early spring (Spelman et al. 2014). ...
... A thorough study in mouse and human cells led them to the conclusion that melatonin affects the roles of two kinds of cells that are important in MS disease progression: pathogenic T cells that directly attack and destroy tissue and regulatory T cells, which are supposed to keep pathogenic T cells in check. This higher incidence of MS in spring/summer has been verified in different studies such as in the meta-analysis carried out by Jin et al. (2000) who report that the beginnings of monosymptomatic optic neuritis, the first clinical manifestation ucts, NO nitric oxide, MDA malondialdehyde, tG total glutathione, GSSG oxidized glutathione, GPx glutathione peroxidase, GSH reduced glutathione, SIRT3 sirtuin 3, NF-κB factor nuclear kappa B, Nrf2 Factor 2 related to nuclear erythroid 2, ROS reactive oxygen species, iNOS nitric oxide synthase of MS in 20-30% of cases and in its exacerbations, present a similar pattern with higher frequencies in spring and lower in winter (Jin et al. 2000). Similarly, Spelman et al. (2014), determine that relapse onset in MS followed an annual cyclical sinusoidal pattern with peaks in early spring (Spelman et al. 2014). ...
Article
Full-text available
Background Melatonin is an indole hormone secreted primarily by the pineal gland that showing anti-oxidant, anti-inflammatory and anti-apoptotic capacity. It can play an important role in the pathophysiological mechanisms of various diseases. In this regard, different studies have shown that there is a relationship between Melatonin and Multiple Sclerosis (MS). MS is a chronic immune-mediated disease of the Central Nervous System. Aim The objective of this review was to evaluate the mechanisms of action of melatonin on oxidative stress, inflammation and intestinal dysbiosis caused by MS, as well as its interaction with different hormones and factors that can influence the pathophysiology of the disease. Results Melatonin causes a significant increase in the levels of catalase, superoxide dismutase, glutathione peroxidase, glutathione and can counteract and inhibit the effects of the NLRP3 inflammasome, which would also be beneficial during SARS-CoV-2 infection. In addition, melatonin increases antimicrobial peptides, especially Reg3β, which could be useful in controlling the microbiota. Conclusion Melatonin could exert a beneficial effect in people suffering from MS, running as a promising candidate for the treatment of this disease. However, more research in human is needed to help understand the possible interaction between melatonin and certain sex hormones, such as estrogens, to know the potential therapeutic efficacy in both men and women.
... Thus, we hypothesized that respiratory viral infections that exhibit seasonality may be associated with RA development. This hypothesis is supported by studies investigating other autoimmune diseases [9][10][11][12][13][14][15][16][17]. Multiple sclerosis which exhibits seasonal tendencies has been associated with upper respiratory picornavirus, rhinovirus, and influenza infections [9][10][11][12][13][14][15]. ...
... This hypothesis is supported by studies investigating other autoimmune diseases [9][10][11][12][13][14][15][16][17]. Multiple sclerosis which exhibits seasonal tendencies has been associated with upper respiratory picornavirus, rhinovirus, and influenza infections [9][10][11][12][13][14][15]. Influenza virus infections triggered disease in a genetic model of experimental autoimmune encephalomyelitis [16]. ...
Article
Full-text available
Background: We aimed to investigate the effects of ambient respiratory viral infections in the general population on rheumatoid arthritis (RA) development. Methods: Data of weekly incident RA (2012-2013) were obtained from the Korean National Health Insurance claims database, and those of weekly observations on eight respiratory viral infections were obtained from the Korea Centers for Disease Control and Prevention database. We estimated the percentage change in incident RA associated with ambient mean respiratory viral infections using a generalized linear model, after adjusting for time trend, air pollution, and meteorological data. Results: A total of 24,117 cases of incident RA (mean age 54.7 years, 18,688 [77.5%] women) were analyzed. Ambient respiratory viral infections in the population were associated with a higher number of incident RA over time, and its effect peaked 6 or 7 weeks after exposure. Among the 8 viruses, parainfluenza virus (4.8% for 1% respiratory viral infection increase, 95% CI 1.6 to 8.1, P = .003), coronavirus (9.2%, 3.9 to 14.8, P < .001), and metapneumovirus (44%, 2.0 to 103.4, P = .038) were associated with increased number of incident RA. The impact of these respiratory viral infections remained significant in women (3.8%, 12.1%, and 67.4%, respectively, P < .05) and in older patients (10.7%, 14.6%, and 118.2%, respectively, P < .05). Conclusions: Ambient respiratory viral infections in the population were associated with an increased number of incident RA, especially in women and older patients, suggesting that respiratory viral infections can be a novel environmental risk factor for the development of RA.
... In this scenario, the probability of having a relapse should equal 1/12, or 8.3% chance of having a relapses in any given month. However, in our MS database [16], as well as in several other studies [80,81], relapses did not follow a discrete uniform distribution: in fact there was a consistent seasonality of MS relapses, in which fewer than expected relapses occur during fall and winter, and there is a peak during spring and summer (see Fig. 1). ...
... Although a delay of 1 or 2 months can be expected between vitamin D levels and the occurrence of a relapse, a delay in effect of 3 or more months lacks biological plausibility. Therefore, the observation of a lower occurrence of relapses in seasons characterized by lower vitamin D levels represents a "seasonal paradox": relapses should be less frequent in spring and summer when vitamin D levels are higher, yet the opposite is found in most studies [80,81], with a few exceptions [86] (Fig. 1). ...
Article
Melatonin is a hormone with complex roles in the pathogenesis of autoimmune disorders. Over the years, it has become clear that melatonin may exacerbate some autoimmune conditions, whereas it alleviates others such as multiple sclerosis. Multiple sclerosis is an autoimmune disorder characterized by a dysregulated immune response directed against the central nervous system. Indeed, the balance between pathogenic CD4+ T cells secreting IFN-γ (TH1) or IL-17 (TH17); and FoxP3+ regulatory T cells and IL-10+ type 1 regulatory T cells (Tr1 cells) is thought to play an important role in disease activity. Recent evidence suggests that melatonin ameliorates multiple sclerosis by controlling the balance between effector and regulatory cells, suggesting that melatonin-triggered signaling pathways are potential targets for therapeutic intervention. Here, we review the available data on the effects of melatonin on immune processes relevant for MS and discuss its therapeutic potential.
... To date studies exploring seasonality in relapse timing have been limited to single clinical centers, limiting any inferences regarding seasonal trends in relapse timing to solitary geographical locations and thus unable to explore broader latitudinal influences. [4][5][6][7][8][9][10][11][12][13][14] These studies have been further limited by small sample sizes and sparse relapse data. A 2000 meta-analysis of ten studies from clinical centres in Europe, the United States and Canada, where each study included a minimum of thirty cases reporting the season-of-onset of relapses, described a clear seasonal trend in the timing of relapse onset, with relapses peaking in spring and with a winter trough 4 . ...
... [4][5][6][7][8][9][10][11][12][13][14] These studies have been further limited by small sample sizes and sparse relapse data. A 2000 meta-analysis of ten studies from clinical centres in Europe, the United States and Canada, where each study included a minimum of thirty cases reporting the season-of-onset of relapses, described a clear seasonal trend in the timing of relapse onset, with relapses peaking in spring and with a winter trough 4 . Similar cyclical annual trends in onset have been observed in subsequent, albeit smaller, studies in both Japan 15 and Spain 16 . ...
Article
This report describes a novel Stata-based application of trigonometric regression modelling to 55 years of multiple sclerosis relapse data from 46 clinical centers across 20 countries located in both hemispheres. Central to the success of this method was the strategic use of plot analysis to guide and corroborate the statistical regression modelling. Initial plot analysis was necessary for establishing realistic hypotheses regarding the presence and structural form of seasonal and latitudinal influences on relapse probability and then testing the performance of the resultant models. Trigonometric regression was then necessary to quantify these relationships, adjust for important confounders and provide a measure of certainty as to how plausible these associations were. Synchronization of graphing techniques with regression modelling permitted a systematic refinement of models until best-fit convergence was achieved, enabling novel inferences to be made regarding the independent influence of both season and latitude in predicting relapse onset timing in MS. These methods have the potential for application across other complex disease and epidemiological phenomena suspected or known to vary systematically with season and/or geographic location.
... 5,7,8 Several studies have examined seasonal variation of relapse onset probability in MS, with conflicting results. [9][10][11][12][13][14][15][16][17][18][19] These studies have generally been limited by small numbers of cases and relapses reported. All published studies have reported on single clinical centers. ...
... On an individual basis, they seem to provide conflicting results. However, results of the meta-analysis performed by Jin et al in 2000 9 are confirmed and extended by our multicenter multinational analysis, showing an overall peak in the probability of relapse onset in spring and trough in autumn. The large overall cohort size lends such analyses power to detect significant effects, as does the prospective assessment that avoids recall bias. ...
Article
Objective: Previous studies assessing seasonal variation of relapse onset in multiple sclerosis have had conflicting results. Small relapse numbers, differing diagnostic criteria and single region studies limit the generalizability of prior results. The aim of this study was to determine if there is a temporal variation in onset of relapses in both hemispheres and to determine if seasonal peak relapse probability varies with latitude. Methods: The MSBase international registry was utilized to analyze seasonal relapse onset distribution by hemisphere and latitudinal location. All analyses were weighted for the patient number contributed by each center. A sine regression model was used to model relapse onset and ultra-violet radiation (UVR) seasonality. Linear regression was used to investigate associations of latitude and lag between UVR trough and subsequent relapse peak. Results: 32 ,762 relapses from 9811 patients across 30 countries were analyzed. Relapse onset followed an annual cyclical sinusoidal pattern with peaks in early spring and troughs in autumn in both hemispheres. Every 10 degrees of latitude away from the equator was associated with a mean decrease in ultra-violet radiation trough to subsequent relapse peak lag of 28 .5 days (95 % CI 3 .29 , 53 .71 , p=0 .028 ). Interpretation: We demonstrate for the first time that there is a latitude-dependent relationship between seasonal UVR trough and relapse onset probability peak independent of location-specific UVR levels, with more distal latitude associated with shorter gaps. We confirm prior meta-analyses showing a strong seasonal relapse onset probability variation in the northern hemisphere, and extend this observation to the southern
... Some studies reported a peak in the number of relapses in spring and/or summer (35,38,39). This pattern of seasonal variation is supported by a meta-analysis (40). However, most of these studies were conducted in North America and Europe. ...
Article
Full-text available
Multiple sclerosis (MS) is becoming a global subject of study in which some demographic variations are thought to be correlated with its activity. Relapsing-remitting multiple sclerosis (RRMS) is the most common demyelinating disorder, characterized by periods of exacerbating attacks, followed by partial or complete remission. Several factors might play a role in disease progression and relapse frequency, such as vitamin D, ultraviolet B radiation, estrogen levels, smoking, obesity, and unhealthy lifestyles. In this study, we identified the relationship between seasonal variation and relapse rate and correlated the latter with sex, age, and vitamin D levels in patients with RRMS in Jeddah, Saudi Arabia. We retrospectively collected data from 182 RRMS patients between 2016 and 2021. A total of 219 relapses were documented in 106 patients (58.2 %). The relapse per patient ratio showed a sinusoidal pattern, peaking in January at a rate of 0.49 and troughed in June at a rate of 0.18. There was no difference in relapse rates between men and women (p =0.280). There was a significant negative correlation between vitamin D levels and relapse rate (r = −0.312, p =0.024). Therefore, the relapse rate was higher during the winter and was correlated with low vitamin D levels. However, relapses are likely multifactorial, and more population-based studies are needed to understand the role of environmental variables in MS exacerbation. A better understanding of this relationship will allow for improved treatment and possibly better prevention of relapse.
... The annual incidence of ON is approximately 5 in 100,000, with a prevalence estimated to be 115 in 100,000 (Martínez-Lapiscina et al., 2014). Results from a meta-analysis of ON in the Northern Hemisphere show that rates are higher at higher latitudes, during spring, and in people of Northern European descent (Jin et al., 2000;Toosy et al., 2014). There is also an association between risk factors for MS and causes of ON in areas of the world where MS is common (Toosy et al., 2014). ...
... In Kerman, Iran, Shafa et al. showed that most cases of MS occurred in winter and spring, which may be due to seasonal infections or other factors triggered by certain climatic conditions specific to these periods [62]. Recently, a meta-analysis showed that there is seasonal variation in the rate of MS recurrence, and this supports the role of some environmental and external factors in MS [62,63]. Watad et al. stated that the variations in the recurrence of MS can be due to meteorological parameters, and ambient air pollutant, and also commented that the effect of [47]. ...
Article
Objectives Some studies have shown that environmental risk factors, including air pollution, might be related to the incidence or recurrence of multiple sclerosis (MS). This systematic review was conducted to investigate the relation between air pollution and MS. Methods A systematic search was conducted in PubMed, Scopus, Science Direct, Embase, and Web of Science; until January 2020 with no restrictions. The search strategy was conducted with air pollution key words such as CO, PM 2.5 , PM 10 , SO 2 , and NO 2 , for exposure and the key word “Multiple sclerosis” as the outcome. Results Eventually, after applying the inclusion and exclusion criteria, 17 articles were included. The methodologies and outcomes reported were heterogeneous and different metrics had been used in the results; therefore conducting a meta-analysis was not possible. Eight studies had analyzed the relation between particulate matter (PM) and the prevalence or relapse of MS and had observed a significant relation. NO 2 and NOx were associated with recurrence or prevalence of MS in three studies. But, in three cohort studies, no association was observed between air pollution and recurrence or occurrence of MS. Conclusions The results of this systematic review show that outdoor air pollution, especially PM and nitrogen oxides might be related to the prevalence or relapse of MS.
... Unlike multiple sclerosis (MS), another immune-mediated, neuroinflammatory disease, wherein season of birth is a risk factor [10] and the incidence of relapses peaks in spring and early summer [8,11,12], it is unknown whether seasonal variation exists in AQP4-Ab disease and MOG-Ab disease. We therefore aimed to examine the seasonal distribution of attacks in AQP4-Ab disease and MOG-Ab disease, looking at both total attacks and onset events within each group. ...
Article
Background Seasonal variation in incidence and exacerbations has been reported for neuroinflammatory conditions such as multiple sclerosis and acute disseminated encephalomyelitis (ADEM). It is unknown whether seasonality also influences aquaporin-4 antibody (AQP4-Ab) disease and myelin-oligodendrocyte antibody (MOG-Ab) disease. Objective We examined the seasonal distribution of attacks in AQP4-Ab disease and MOG-Ab disease. Methods Observational study using data prospectively recorded from three cohorts in the United Kingdom. Results There was no clear seasonal variation in AQP4-Ab or MOG-Ab attacks for either the onset attack nor subsequent relapses. In both groups, the proportion of attacks manifesting with each of the main phenotypes (optic neuritis, transverse myelitis, ADEM/ADEM-like) appeared stable across the year. This study is the first to examine seasonal distribution of MOG-Ab attacks and the largest in AQP4-Ab disease so far. Conclusion Lack of seasonal distribution in AQP4-Ab and MOG-Ab disease may argue against environment factors playing a role in the aetiopathogenesis of these conditions.
... Clusters of new MS cases have been reported in many communities around the world including the United States, Canada, Europe, Israel, New Zealand, Australia and Russia [27][28][29][30]. Many studies indicated significant variation in the global distribution of MS patients, where the incidence of this autoimmune disease is relatively uncommon in tropical climates, but is much more common in temperate zones and in the Western Hemisphere [31]. Furthermore, remarkably elevated incidence rates in northern latitudes were reported [32,33]. ...
... Therefore, melatonin immunoregulatory function is at its lowest during spring, thus leading to increased relapse rate [60]. This is also supported by another study that showed a skew in MS onset during spring as compared to the rest of the year (45% [95%CI 35e55%]) with its lowest incidence during winter, probably due to variation in vitamin D and melatonin levels [62]. ...
Article
Autoimmune diseases (ADs) are a heterogeneous groups of diseases that occur as a results of loss of tolerance to self antigens. While the etiopathogeneis remain obscure, different environmental factors were suggested to have a role in the development of autoimmunity, including infections, low vitamin D levels, UV radiation, and melatonin. Interestingly, such factors possess seasonal variation patterns that could influence disease development, severity and progression. Vitamin D levels which reach a nadir during late winter and early spring is correlated with increased disease activity, clinical severity as well as relapse rates in several disease entities including multiple sclerosis (MS), non-cutaneous flares of systemic lupus erythematosus (SLE), psoriasis, and rheumatoid arthritis (RA). Additionally, immunomodulatory actions of melatonin secretion ameliorate the severity of several ADs including MS and SLE. Melatonin levels are lowest during spring, a finding that correlates with the highest exacerbation rates of MS. Further, melatonin is postulated to be involved in the etiopathogenesis of inflammatory bowel diseases (IBD) through it influence on adhesion molecule and therefore transcription factor expression. Moreover, infections can mount to ADs through pro-inflammatory cytokine release and human antigen mimicry. Seasonal patterns of infectious diseases are correlated with the onset and exacerbation of ADs. During the winter, increased incidence of Epstein-Barr virus (EBV) infectious are associated with MS and SLE flares/onset respectively. In addition, higher Rotavirus infections during the winter precedes type 1 diabetes mellitus onset (T1DM). Moreover, Escherichia coli (E. coli) infection prior to primary biliary cirrhosis (PBC) and T1DM disease onset subsequent to Coxachievirus infections are seen to occur during late summer, a finding that correlate with infectious agents' pattern of seasonality. In this review, the effects of seasonality on the onset, relapses and activity of various ADs were discussed. Consideration of seasonal variation patterns of ADs can possibly provide clues to diseases pathogenesis and lead to development of new approaches in treatment and preventative care.
... This pattern is most apparent in younger patients with relapsing-remitting disease and is associated with monthly hours of sunshine. However, this does not A seasonal pattern in MS relapses has previously been noted, with most studies reporting a solitary peak in spring and/or summer months in both northern [2,17,23,26,31] and southern hemispheres [7,26], a pattern which has also been borne out by meta-analysis [11]. Fewer studies have detected a nadir in relapse rates, but in studies that have been able to detect this, the nadir tends to occur in late summer or autumn [9,23,26,29,31]. ...
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Relapses are a characteristic clinical feature of multiple sclerosis (MS), but an appreciation of factors that cause them remains elusive. In this study, we have examined seasonal variation of relapse in a large population-based MS cohort and correlated observed patterns with age, sex, disease course, and climatic factors. Relapse data were recorded prospectively in 2076 patients between 2005 and 2014. 3902 events were recorded in 1158 patients (range 0–24). There was significant seasonal variation in relapse rates (p < 0.0001) and this was associated with monthly hours of sunshine (odds ratio OR 1.08, p = 0.02). Relapse rates were highest in patients under the age of 30 (OR 1.42, p = 0.0005) and decreased with age. There was no evidence of different relapse rates for males compared to females (OR 0.90, p = 0.19). Identification of potentially modifiable environmental factors associated with temporal variation in relapse rates may allow alteration of risk on a population basis and alteration of outcome of established disease once established. Future epidemiological studies should examine dynamic environmental factors with serial prospective measurements and biological sampling. Significant seasonal differences in relapse rates highlight the importance of environmental factors in disease expression and should be taken into account when planning clinical trials in which relapse frequency is an outcome. In addition, identification of potentially modifiable factors associated with this variation may offer unique opportunities for alteration of risk of relapse and long-term outcome on a population level, and suggest putative biological mechanisms for relapse initiation.
... In contrary to the Western study which suggested that optic neuritis occurred more commonly in spring and less commonly in winter [17], our data showed similar occurrence throughout the year except for a peak in April and an absence of cases in May (both of which are in the spring season in Hong Kong). It could The main limitation of this study was its retrospective nature. ...
Article
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Purpose: To review the clinical course of adult patients with acute optic neuritis over 10 years in Hong Kong, and the results were compared with other studies among Asian and Caucasian patients. Methods: This study retrospectively analysed the clinical features of 38 adult patients (51 eyes) presented with optic neuritis in a Hong Kong hospital over 10 years (2001-2010). Results: Optic neuritis had a female predominance (68%). The mean age of presentation was 40 years old. Disc swelling (39%) was more common compared to the optic neuritis treatment trial (ONTT). The recovery time ranged from no recovery to 5 years, with a mean of 6.0 months. However, vision continued to deteriorate despite initial improvement in 45% of patients. Only 11.8% of the eyes attained final visual acuity (VA) of 1.0 or better, while 31.4% had VA 0.1 or worse. Multiple sclerosis or neuromyelitis optica only occurred in 10.4% of patients. Three of our patients who did not receive any treatment showed faster recovery than the average. Conclusions: Optic neuritis in Hong Kong is mostly a clinically isolated syndrome. Our patients presented at a later age and showed a worse visual outcome. Corticosteroid according to ONTT protocol remained our mainstay of treatment although it did not benefit our patients as much as ONTT study. More work on the long-term prognosis and treatment strategies is worthwhile among Chinese optic neuritis patients.
... A cohort study by Farez et al. [258] demonstrated seasonality of MS relapses, specifically, a 32% reduction in the number of MS relapses occurring during fall and winter, in accordance with Jin et al. [259] and Spelman et al. [260]. Treatment with melatonin ameliorates disease in an EAE mouse model [258]. ...
... First, the clinical disease expression and course are highly variable, which hampers defining a uniform concept of disability in MS [5][6][7]. There is wide variation between patients concerning relapse frequency (including seasonal variation [8]) and accrual of (relapserelated) disability. Also, patients may present with virtually all neurological symptoms that exhibit an age-dependent distribution (Table 1) [7]. ...
Article
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Due to the heterogeneous nature of the disease, it is a challenge to capture disease activity of multiple sclerosis (MS) in a reliable and valid way. Therefore, it can be difficult to assess the true efficacy of interventions in clinical trials. In phase III trials in MS, the traditionally used primary clinical outcome measures are the Expanded Disability Status Scale and the relapse rate. Secondary outcome measures in these trials are the number or volume of T2 hyperintense lesions and gadolinium-enhancing T1 lesions on magnetic resonance imaging (MRI) of the brain. These secondary outcome measures are often primary outcome measures in phase II trials in MS. Despite several limitations, the traditional clinical measures are still the mainstay for assessing treatment efficacy. Newer and potentially valuable outcome measures increasingly used or explored in MS trials are, clinically, the MS Functional Composite and patient-reported outcome measures, and on MRI, brain atrophy and the formation of persisting black holes. Several limitations of these measures have been addressed and further improvements will probably be proposed. Major improvements are the coverage of additional functional domains such as cognitive functioning and assessment of the ability to carry out activities of daily living. The development of multidimensional measures is promising because these measures have the potential to cover the full extent of MS activity and progression. In this review, we provide an overview of the historical background and recent developments of outcome measures in MS trials. We discuss the advantages and limitations of various measures, including newer assessments such as optical coherence tomography, biomarkers in body fluids and the concept of ‘no evidence of disease activity’.
... The frequency of relapses increases in the spring and slightly reduces during winter months. In the recent years, this seasonal relationship is postulated to be associated with serum vitamin D levels (23). Data coming from relevant studies show that lower vitamin D levels are associated with more frequent relapses (24,25). ...
Article
Relapse in multiple sclerosis (MS) is defined as a neurologic deficit associated with an acute inflammatory demyelinating event that lasts at least 24 hours in the absence of fever and infection. Myelinoclasis and axonal transection occur in relapses. Diagnosis, prognosis, treatment, and many other features of the disease are directly related to the relapses. MS starts as the relapsing-remitting (RRMS) form in 85% of patients. A large number of relapses in the first years, polysymptomatic relapses, and pyramidal system, brain stem, and spinal cord involvement are signs of a poor outcome. The average frequency of relapses is approximately one per year during the first years of RRMS. The frequency of relapses increases during systemic infections, psychological stress, and in the first 3 months after birth. Seventy-five percent of relapses are monosymptomatic. Pseudo-relapses and paroxysmal symptoms are distinguished from relapses by their sudden onset, sudden termination, and shorter duration. Contrast enhancement is valuable in imaging, but undetectable in most relapses. The regression in the first few weeks of relapses is explained by reduction of the edema, and by remyelination in the following months. Relapses and their features are also among the main determinants of treatment. High-dose methylprednisolone and early treatment with adrenocorticotropic hormone reduce post-relapse disability and shorten the duration of relapses. Plasmapheresis is a good option for patients who do not respond to steroid treatment. Identification of relapses by patients and physicians, distinguishing them from imitators, proper evaluation, treatment when necessary, and monitoring the results are of great importance for patients with MS. The educational levels of patients and physicians regarding these parameters should be increased. Well-designed studies that evaluate the long-term effect of relapse treatment on disability are needed. © Turkish Journal of Neurology, Published by Galenos Publishing House.
... In 2000, Jin et al. performed a meta-analysis examining the relationship between season and mono-symptomatic optic neuritis (a known symptom of MS [48]), MS onset and MS exacerbations. The researchers concluded that there is a peak in incidence during spring and a nadir during winter months in the northern hemisphere in all three parameters, which was highest with respect to MS onset (45 % with 95 % CI 36-55 %), and lowest with respect to its relapses (10 % with 95 % CI 7-13 %) [49]. A large, global multicenter study conducted in 2014 by Spelman et al. further demonstrated a latitude dependent effect. ...
Article
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Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system. MS is causing progressive and relapsing neurological disability, due to demyelination and axonal damage. The etiopathogenesis of MS is poorly understood. A number of environmental factors have been previously suggested, including: month of birth, vitamin D levels, smoking and viral infections. Previous studies assessing seasonal variation of relapses in multiple sclerosis have had conflicting results. The aim of this review is to assess the association between seasonal factors and MS, in terms of disease onset, relapses and activity.
... Diğer nedenler tartışmalıdır. Atak sıklığı ilkbaharda artarken kış aylarında hafif azalır (23). Bu durum özellikle son yıllarda serum D vitamini düzeyleri ile ilişkilendirilmektedir. ...
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Arch Neurol 1997;57:1169- 1170. Yazışma Adresi Yrd.Doç.Dr. Handan Işın Özışıkİnönü Üniversitesi Turgut Özal Tıp Merkezi Nöroloji AD, Malatya Tel : 422 3410660-4908 E-Posta : handanisin@yahoo.com hozisik@inonu.edu.tr
... However, recent work from the MSBase international registry examining 32,762 relapses from 9811 patients across 30 countries from both hemispheres found a strong seasonal variation in onset of relapses with peaks in early spring (after a period of decreased sun exposure) and troughs in autumn in both hemispheres [18]. This confirmed a prior meta-analysis with similar findings from the northern hemisphere [19]. There has been a long delay in testing the effects of vitamin D supplementation on disease course in MS, presumably due to little commercial incentive to test this nonpatentable naturally occurring agent, however a number of large international studies are now underway to examine this issue. ...
Article
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A growing evidence base implicates vitamin D, sun exposure and latitude in the aetiology of multiple sclerosis (MS), however there are less data on the associations of these variables with disease outcomes. We undertook a cross-sectional survey of over 2000 people with MS recruited through internet platforms, seeking self-reported data on geographical location, intentional sun exposure for health, and supplementation with vitamin D, among other lifestyle variables. We also requested data on health-related quality of life (MSQOL-54), self-reported doctor-diagnosed relapse rate, and disability (Patient Determined Disease Steps). Bivariate and multivariate analyses were used for comparisons, including multiple linear regression modeling. Of 2301 participants, 82.3 % were female, median age was 45 years (IQR 38-53 years), with a median time since diagnosis of 6 years (IQR 3-12 years), the majority (61.6 %) having relapsing-remitting MS. Nearly two-thirds (64.6 %) lived in the Northern hemisphere, mostly in developed countries. Most (66.8 %) reported deliberate sun exposure to raise their vitamin D level, and the vast majority (81.8 %) took vitamin D supplements, mostly 2000-5000 IU a day on average. Unadjusted regression modeling incorporating deliberate sun exposure, latitude and vitamin D supplementation showed strong associations of sun exposure with HRQOL which disappeared when controlling for gender, age, disability, physical activity, and fish consumption. In contrast, associations between vitamin D supplementation and HRQOL were maintained adjusting for these variables, with a dose-response effect. Only latitude had significant adjusted associations with disability, with an increase of latitude by one degree (further from the equator) predicting increased odds of moderate disability (OR 1.02 (95 % CI 1.01-1.04)) or high disability (OR 1.03 (95 % CI 1.01-1.05)) compared to no/mild disability. Similarly, latitude was related to relapse rate, with increase in latitude of 1 degree associated with increased odds of having more relapses over the previous year (1.01 (1.00-1.02)). We detected significant associations between latitude, deliberate sun exposure and vitamin D supplementation and health outcomes of this large group of people with MS. Vitamin D is likely to have a key role in these associations and its role in the health outcomes of people with MS urgently requires further study.
... In 2008 there were in total 6500 patients with MS in Finland. Some of the symptoms of MS are listed in Figure 2. Seasonality can be seen in both the incidence of MS and the occurrence of relapses: according to a meta-analysis of MS incidence studies in the northern hemisphere, the highest frequencies of MS onset are generally detected in the spring, and lowest in the winter (Jin et al 2000). A seasonal climate causes variation in the human immune functions through affecting melatonin production of the pineal gland, which may even have implications for the incidence of MS relapses (Nelson et al 1995). ...
... Most common season of presentation of ADS in the present study was autumn, but it was spring in the studies by Jin et al. and Ghobai et al. (10,11). ...
Article
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Objective: Incidence of CNS acquired demyelinating syndrome (ADS), especially multiple sclerosis (MS) in children, appears to be on the rise worldwide. The objective of this study was to determine prevalence, clinical presentation, neuroimaging features, and prognosis of different types of ADS in Iranian children. Materials & methods: During the period 2002-2012, all the patients (aged 1-18 years) with ADS, such as MS, acute disseminated encephalomyelitis (ADEM), optic neurotic (ON), Devic disease, and transverse myelitis (TM), referred to the pediatric neurology ward, Nemazee Hospital, Shiraz University of Medical Sciences, were included in this study. Demographic data, clinical signs and symptoms, past and family history, preclinical findings, clinical course, and outcome were obtained. Results: We identified 88 patients with ADS in our center. The most prevalent disease was MS with 36.5% (n=32), followed by AEDM 26.1% (n=31), ON 17% (n=13), TM 15.9% (n=14), and Devic disease 4.5% (n=4). MS, ON, TM were more common among females while ADEM was more common in males. Children with ADEM were significantly younger than those with other types of ADS. Family history was positive in 10% of patients with MS. Previous history of recent infection was considerably seen in cases with ADEM. Clinical presentation and prognosis in this study was in accordance with those in previous studies on children. Conclusion: In this study, the most common type of ADS was MS, which was more common in female and older age cases. ADEM was more common in male and younger children. ADEM and ON had the best and Devic disease had the worst prognosis.
Article
Objective Certain neurologic diseases have been noted to vary by season, and this is important for understanding disease mechanisms and risk factors, but seasonality has not been systematically examined across the spectrum of neurologic disease, and methodologic guidance is also lacking. Methods Using nationally representative data from the National Inpatient Sample, a stratified 20% sample of all non-federal acute care hospitalizations in the United States, we calculated the monthly rate of hospitalization for fourteen neurologic diseases from 2016-2018. For each disease, we assessed seasonality of hospitalization using chi-square, Edward, and Walter-Elwood tests and seasonal time series regression models. Statistical tests were adjusted for multiple hypothesis testing using Bonferroni correction. Results Meningitis, encephalitis, ischemic stroke, intracerebral hemorrhage, Guillain-Barre syndrome, and multiple sclerosis had statistically significant seasonality according to multiple methods of testing. Subarachnoid hemorrhage, status epilepticus, myasthenia gravis, and epilepsy had significant seasonality according to Edwards and Walter-Elwood tests but not chi-square tests. Seasonal time series regression illustrated seasonal variation in all fourteen diseases of interest, but statistical testing for seasonality within these models using the Kruskal-Wallis test only achieved statistical significance for meningitis . Interpretation Seasonal variation is present across the spectrum of acute neurologic disease, including some conditions for which seasonality has not previously been described, and can be examined using multiple different methods. This article is protected by copyright. All rights reserved.
Article
Background Multiple Sclerosis (MS) relapses are episodes of transient disease exacerbation. There are contradictory findings regarding seasonal variation in MS relapses. In this systematic review and meta-analysis, we aimed to investigate the seasonal and monthly variation in relapse rates among patients with MS.Methods We systematically queried PubMed, Scopus, and Web of Science for published papers until February 30, 2022.ResultsA total of 24 studies were included in this systematic review and meta-analysis with a total of 29,106 patients with MS. We found that the relapse rate was significantly lower in fall compared to the average relapse rate in other seasons with a risk ratio (RR) of 0.97 (95% CI 0.95–0.98). Furthermore, patients with MS experienced a higher number of relapses in April (RR: 1.06, 95% CI 1.01–1.11) and March (RR: 1.08, 95% CI 1.00–1.16) compared to other months. Also, the risk of relapse was lower in August (RR: 0.92, 95% CI.85–0.98), September (RR: 0.97, 95% CI.94–0.99), October (RR: 0.92, 95% CI.89–0.96), and November (RR: 0.93, 95% CI.89–0.97).Conclusion Our systematic review and meta-analysis confirm the temporal fluctuations in the relapse of MS through a comprehensive review of the existing literature, with a lower relapse rate during late summer and fall and a higher relapse rate during early spring.
Chapter
Affliction of the afferent visual system, in particular acute optic neuritis (AON), is commonly seen in multiple sclerosis (MS) and other inflammatory autoimmune conditions. AON is an inflammatory condition of the optic nerve. The clinical presentation of AON is variable, though most commonly involves pain and impairment or loss of vision in the affected eye. Severity, duration, and resolution of symptoms depend on underlying disease pathology. In the Western world, AON is most commonly seen in the setting of demyelinating conditions such as MS. The spectrum of conditions associated with AON, however, is broad and includes non-MS autoimmune and demyelinating diseases, infections, granulomatous disease, paraneoplastic processes, and rarely, hereditary diseases. Identifying potential “red-flags” or atypical features of AON is important in the consideration of alternative diagnoses to MS as the underlying mechanism. While diagnosis of AON is primarily clinical, utilization of magnetic resonance imaging (MRI) and electrophysiological studies has historically aided AON diagnosis. Utilization of more advanced imaging techniques, such as optical coherence tomography (OCT), has allowed for more specific analyses and monitoring of axonal and neuronal degeneration following AON. The treatment of classic demyelinating, including idiopathic, forms of AON has primarily focused on the use of corticosteroids, although this approach may not actually be supported by evidence. Recovery from AON is largely dependent on the severity and underlying pathology of the AON. Potential neuroprotective and remyelinating strategies (in MS) are in development, and clinical trials are ongoing.
Article
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune inflammatory disorder of the central nervous system (CNS) that is mainly associated with serum autoantibodies against aquaporin-4 (AQP4) in astrocytes. The relapsing clinical course of NMOSD, which can be blinding and disabling due to severe visual impairment, spinal cord lesions and a group of brain syndromes, suggests the importance of accurately evaluating the likelihood and severity of relapse at an early stage of the disease. To date, many risk factors have been revealed in association with relapse, and only some of them are supported by substantial evidence. Furthermore, while the clinical use of conventional immunosuppressants is mostly empirical, an increasing number of emerging therapies for monoclonal antibodies have been confirmed by several randomized placebo-controlled trials to be effective and safe for relapse prevention. In this review, we summarize the reported risk factors that may influence the frequency, symptoms, severity and prognosis of relapse in NMOSD, as well as the efficacy and safety of emerging therapies for relapse prevention. All of these results enable us to better recognize patients who are at higher risk of relapse and suggest more effective monoclonal antibody therapies for use in these patients.
Article
Aims: To analyze the incidence of optic neuritis (ON) in South Korean children and adolescent according to age, gender, etiological underlying disease, and season. Methods: Population-based nationwide database of Korean health insurance review and assessment was used to identify subjects aged 1 year or older but younger than 19 years with diagnosis with ON during the study period (2011-2017). Results: The total number of incident ON cases was 740 (398 females and 342 males) in the South Korean pediatric population during our seven-year study period. Mean annual incidence of ON was 1.04 per 100,000 people (1.17 vs. 0.92 for female vs. male subjects). Average female/male ratio of pediatric ON was 1.27:1. Cumulative incidence of ON was 7.28 per 100,000 from 2011 to 2017. Majority (87%) of patients had no underlying etiological disease, and 10.41% of patients had infectious disease before the diagnosis of ON. The most common etiology of infectious disease was meningitis (24.68%). Incidence rate increased with age (p = .002, p = .006, and p < .0001 for total, males, and females, respectively). The incidence of ON in spring was higher than that in autumn (173 vs. 133 cases respectively, p = .02). Conclusions: We presented the incidence of children and adolescent ON in South Korea. Infectious disease was the most common underlying etiological disease. Incidence of ON increased with age and it showed seasonal variation in South Korean children and adolescents.
Article
Background: To analyse in a population-based setting the clinical features, prognostic factors, and seasonality of patients diagnosed with acute idiopathic optic neuritis (ON). Methods: Retrospective analysis of ophthalmological records, laboratory parameters, and magnetic resonance imaging (MRI) of patients with symptoms suggestive of ON referred to the Helsinki University Hospital (serving a population of 1.53 million in Southern Finland) were analysed between May 1, 2008 and April 14, 2012. Results: Of the 291 patients with suspected ON, 184 (63%) were diagnosed with ON (mean age 34 years, 76% females). Intravenous methylprednisolone treatment was administered in 131 (71%) patients. First ON was diagnosed in 123 patients (67%), 55 (30%) had a previous diagnosis of multiple sclerosis (MS) and two patients with their first ON were diagnosed with neuromyelitis optica. Evolution of best corrected visual acuity (BCVA) was analysed in 132 (72%) patients, who were reviewed median of 38 days after onset. Median and mean BCVAs in these reviewed patients were 0.4 and 0.2 at the time of diagnosis and 1.0 and 0.5 at the time of the review. Recovery was relatively good in the majority of patients; 82% (n = 108) had reached BCVA of ≥0.5 and 70% (n = 92) and BCVA of ≥0.8 at the time of the review, while thirteen (10%) had poor prognosis, BCVA ≤0.1 at review. Accessory clinical features included optic disc swelling (21%), colour vision impairment (75%), and pain with eye movements (65%). Relative afferent pupillary defect was abnormal in 76% of the patients with their first ON. Baseline visual acuity was most strongly associated with visual outcome at review (P < 0.001, linear regression). Optic disc swelling and the presence of lesions in the optic nerve on MRI had a more modest association with poorer recovery (P = 0.033 and P = 0.049, respectively), while age, sex, previous history of ON, and previous diagnosis of multiple sclerosis were not associated with outcome at review. Incidence of ON showed a clear seasonal pattern; there were two times more cases in April to June versus October to December (P = 0.03), confirming previous results from Sweden. Conclusions: Our data suggest that besides baseline visual acuity, optic disc swelling and lesions in the optic nerve on MRI are associated with poorer prognosis. As in previous studies, we observed that diagnostics of ON is difficult, accessory clinical findings such as pain and RAPD are not always present. Although the diagnosis of ON is clinical, the role of MRI should be considered in differential diagnostics and in defining potential prognostic markers.
Article
Purpose of review: This article provides an overview of the clinical and pathologic features of multiple sclerosis (MS) relapses and reviews evidence-based approaches to their treatment. Recent findings: Despite the increasing number and potency of MS treatments, relapses remain one of the more unpredictable and disconcerting disease aspects for many patients with MS, making their accurate recognition and treatment an essential component of good clinical care. The expanding range of relapse treatments now includes oral corticosteroids, comparable in efficacy to IV methylprednisolone at a fraction of the cost. While this development improves access to prompt treatment, it also underscores the importance of recognizing mimics of MS relapses to reduce corticosteroid overuse and its attendant risks. Summary: Like MS itself, MS relapse remains primarily a clinical diagnosis. The treatment options for MS relapse include corticosteroids, adrenocorticotropic hormone (ACTH), plasma exchange, and rehabilitation, used singly or sequentially, with the goal of limiting the duration and impact of associated disability. Even when treated promptly and effectively, clinical or subclinical sequelae of MS relapses frequently remain.
Article
Résumé La neurologie environnementale est une approche nouvelle des pathologies neurologiques qui prend en compte l’impact de l’environnement dans leur genèse. Son champ d’intérêt recouvre de multiples disciplines qui s’occupent d’aspects spécifiques de notre environnement. Elle est basée sur une lecture à la fois analytique et globalisante des facteurs de risque environnementaux. Combinant les apports cliniques (histoire naturelle et évolutive de la maladie), à l’épidémiologie (notamment la génétique épidémiologique), à l’exposologie et aux modèles animaux, elle propose des modalités thérapeutiques renouvelées.
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Background: Triggers of multiple sclerosis (MS) relapses are essentially unknown. PM10 exposure has recently been associated with an increased risk of relapses. Objectives: We further explore the short-term associations between PM10, NO2, benzene (C6H6), O3, and CO exposures, and the odds of MS relapses' occurrence. Methods: Using a case-crossover design, we studied 424 MS patients living in the Strasbourg area, France between 2000 and 2009 (1783 relapses in total). Control days were chosen to be ± 35 days relative to the case (relapse) day. Exposure was modeled through ADMS-Urban software at the census block scale. We consider single-pollutant and multi-pollutant conditional logistic regression models coupled with a distributed-lag linear structure, stratified by season ("hot" vs. "cold"), and adjusted for meteorological parameters, pollen count, influenza-like epidemics, and holidays. Results: The single-pollutant analyses indicated: 1) significant associations between MS relapse incidence and exposures to NO2, PM10, and O3, and 2) seasonality in these associations. For instance, an interquartile range increase in NO2 (lags 0-3) and PM10 exposure were associated with MS relapse incidence (OR = 1.08; 95%CI: [1.03-1.14] and OR = 1.06; 95%CI: [1.01-1.11], respectively) during the "cold" season (i.e., October-March). We also observed an association with O3 and MS relapse incidence during "hot" season (OR = 1.16; 95%CI: [1.07-1.25]). C6H6 and CO were not significantly related to MS relapse incidence. However, using multi-pollutant models, only O3 remained significantly associated with the odds of relapse triggering during "hot" season. Conclusion: We observed significant single-pollution associations between the occurrence of MS relapses and exposures to NO2, O3 and PM10, only O3 remained significantly associated with occurrence of MS relapses in the multi-pollutant model.
Article
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Numerous neurobehavioral diseases typically exhibit annual rhythms in the frequency with which they cause flare-ups. A prime example is the seasonal affective disorder syndrome (SADS), in which symptoms usually start to appear in November and disappear in the late winter, after which many patients remain asymptomatic until the following fall. Smaller seasonal variations in mood and behavior are also sometimes noted among patients with Depression, per se, but less so among normal control subjects.
Article
Low 25-hydroxy vitamin D (25-[OH]-D) serum concentrations have been associated with higher disease activity in multiple sclerosis (MS) patients. In a large cross-sectional study we assessed the vitamin D status in MS patients in relation to seasonality and relapse rate. 415 MS-patients (355 relapsing-remitting MS and 60 secondary-progressive, 282 female, mean age 39.1 years) of whom 25-(OH)-D serum concentrations were determined at visits between 2010 and 2013 were included in the study. All clinical data including relapse at visit and expanded disability status scale were recorded in a standardized manner by an experienced neurologist. Seasonal variations of 25-(OH)-D serum concentrations were modelled by sinusoidal regression and seasonal variability in the prevalence of relapse by cubic regression. The mean 25-(OH)-D serum concentration was 24.8 ng/ml (range 8.3–140 ng/ml) with peak levels of 32.2 ng/ml in July/August and nadir in January/February (17.2 ng/ml). The lowest modelled prevalence of relapse was in September/October (28%) and the highest modelled prevalence in March/April (47%). The nadir of 25-(OH)-D serum concentrations preceded the peak in prevalence of relapses by two months. In summary, seasonal variation of 25-(OH)-D serum levels were inversely associated with clinical disease activity in MS patients. Future studies should investigate whether vitamin D supplementation in MS patients may decrease the seasonal risk for MS relapses.
Chapter
Acute optic neuritis is a common inflammatory optic neuropathy that is closely associated with multiple sclerosis (MS). As a clinical syndrome, optic neuritis typically presents with subacute visual loss and periocular pain that often resolve spontaneously. Optic neuritis is frequently the initial manifestation of MS, and also occurs commonly during the course of the disease. Not only does optic neuritis explain some of the visual disability experienced by MS patients, but it also provides unique insight into the pathophysiologic mechanisms underlying the MS disease process. Advancements in ocular and magnetic resonance imaging techniques have provided an exciting opportunity to interrogate optic neuritis as an in vivo model of inflammation, demyelination, and neurodegeneration in the central nervous system. In this chapter, we introduce the relationship between optic neuritis and MS, describe the clinical course of optic neuritis, and review its underlying pathophysiologic concepts.
Article
Purpose of review: The discovery of aquaporin-4 (AQP4) antibodies with high specificity for neuromyelitis optica spectrum disorder (NMOSD) has induced tremendous changes in the approach and management of central nervous system (CNS) neuroinflammatory disorders. Owing to the increasing availability of the AQP4 antibody assay and evolution of diagnostic criteria for multiple sclerosis and NMOSD, recent studies have reevaluated CNS neuroinflammatory disorders. This review describes recent advances in the understanding of CNS neuroinflammatory disorders in Asian/Pacific regions. Recent findings: Although multiple sclerosis prevalence is lower in Asian countries than in Western countries, the overall clinical features of multiple sclerosis are comparable between these countries. Hospital-based studies have reported that the frequency of NMOSD is higher in Asian populations (22-42%) than in white populations (2-26%). Despite improvements in the AQP4 antibody assay, AQP4 antibodies are not detected in certain patients with NMOSD. Recently, myelin oligodendrocyte glycoprotein (MOG) antibodies have been identified in AQP4 antibody-negative patients with the NMOSD phenotype, and the clinical features differ slightly between MOG antibody-positive patients and AQP4 antibody-positive patients. Summary: The understanding of CNS neuroinflammatory disorders in Asian/Pacific regions continues to evolve owing to the discovery of new biological markers and recognition of broader clinical phenotypes.
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Acute necrotizing encephalopathy of childhood (ANEC) is a rare form of encephalopathy characterized by rapid neurological deterioration along with seizures, decreased level of consciousness and coma. We herein report ANEC in a 12-month-old Iranian girl following febrile respiratory illness. She presented with convulsions characterized by upward gaze, spastic posture and sucking movements followed by rapid deterioration of consciousness and hemodynamic instability due to involvement of brainstem. Although several cases have been reported from East Asian countries, it has been rarely reported from Middle East region. This is the third case being reported from Iran. The diagnosis of ANEC should be kept in mind in all children with progressive neurological deterioration following a febrile convulsion. Although neuroradiological findings might be non-specific especially in early course of the disease, brain imaging should be performed when there is suspicion regarding the diagnosis.
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Optic neuritis is one of the most important neuro-ophthalmologic diseases which cause vision loss in young adults. There are obvious differences in the prevalence of optic neuritis in different countries and regions. Through the review of the related literature at home and abroad in recent years, this article summarizes the etiology and epidemiological characteristics of optic neuritis. It is expected to provide reference and comparison for the epidemiological investigation of cross regional, multi-center cooperation.
Article
Optic neuritis is a common optic neuropathy, which typically presents with sudden loss of vision. Visual deficit of optic neuritis varies in severity and generally can be improved spontaneously over several-month duration. The most convincing eight evidences from level I and II evidence of evidence-based medicine(EBM) about the treatment of all the optic neuritis were collected by searching the Cochrane Controlled Trials Register (CENTRAL), MEDLINE, EMBASE and reference lists of identified trial reports since the last decade. At present, the latest findings showed that there is no conclusive evidence of benefit in terms of recovery to normal visual acuity, visual field or contrast sensitivity with either intravenous or oral corticosteroids at the doses evaluated in trials included in this review. Either no treatment or intravenous corticosteroid therapy followed by oral corticosteroids is appropriate, and intravenous corticosteroid may benefit the patient in terms of faster recovery to normal vision. There may be of different treatment of optic neuritis in China compared to Western countries due to geographical, racial and genetic background that may cause different etiology and clinical features of optic neuritis. Therefore, in China, it is imperative to carry out a large randomized control trial (RCT) of optic neuritis as soon as possible to get the best evidence for the management of optic neuritis patients.
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In this chapter, the biology of vitamin D, including its calcemic and especially noncalcemic functions, is reviewed, with a special focus on vitamin D effects on immune function. The newest findings derived from studies on association of vitamin D with MS are also critically discussed. Finally, some issues for future investigation are presented in the concluding remarks.
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Epidemiology is one of the most focused areas of multiple sclerosis research. The emerging statistics serve several purposes. This includes generating etiological hypotheses, establishing healthcare needs in the community, defining the natural history of multiple sclerosis as the basis for understanding the evolving clinical expression of tissue injury, and providing a yardstick against which the results of therapies can be compared. The attempts to formulate reliable hypotheses using the epidemiological evidence are potentially vulnerable. Most sensitive to artifact have been the temporal and geographical trends emerging from comparisons of prevalence between regions and the serial study of individual locations. Incidence, prevalence, and mortality have a close relationship. Incidence describes new events in a defined group over a given period. Prevalence describes the number of affected individuals in a population at risk on a given occasion. Mortality describes the number of individuals dying with or as a result of multiple sclerosis among the at-risk population over a given period. With the decline in autopsy rates and the trend for death certification to reflect administrative needs rather than pathological verification, mortality is a poor statistic for evaluating the epidemiology of multiple sclerosis.
Article
Relapses (episodic exacerbations of neurological signs or symptoms) are a defining feature of relapsing-remitting multiple sclerosis (MS), the most prevalent MS phenotype. While their diagnostic value relates predominantly to the definition of clinically definite MS, their prognostic value is determined by their relatively high associated risk of incomplete remission resulting in residual disability. The mechanisms governing a relapse incidence are unknown, but numerous modifiers of relapse risk have been described, including demographic and clinical characteristics, many of which represent opportunities for improved disease management. Also relapse phenotypes have been associated with patient and disease characteristics and an individual predisposition to certain phenotypic presentations may imply individual neuroanatomical disease patterns. While immunomodulatory therapies and corticosteroids represent the mainstay of relapse prevention and acute management, respectively, their effect has only been partial and further search for more efficient relapse therapies is warranted. Other areas of research include pathophysiology and determinants of relapse incidence, recurrence and phenotypes, including the characteristics of the relapsing and non-relapsing multiple sclerosis variants and their responsiveness to therapies. © 2015 S. Karger AG, Basel.
Article
Background and purposeMultiple sclerosis is a chronic inflammatory disorder of the central nervous system characterized by acute episodes of neurological dysfunction thought to reflect focal areas of demyelination occurring in clinically eloquent areas. These symptomatic relapses are generally considered to be random clinical events occurring without discernible pattern. The hypothesis that relapses may follow a predetermined sequence and may provide insights into underlying pathological processes was investigated.Methods Employing prospective clinical database data from 1482 patients who had experienced one or more consecutive relapses were analysed. Using regression analysis, site and symptom of index event were compared with those of first relapse.ResultsIt is demonstrated that following disease ignition subsequent relapses may not be random events but dependent on characteristics of the index event. All anatomical sites were more likely to be affected in the first relapse if that site had been involved in the index event with a similar association observed when comparing by symptoms.Conclusion These findings have importance in understanding the evolution of the disease and predicting individual disease progression and may aid with patient counselling and management.
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Studies investigating a proposed association between multiple sclerosis (MS) and migraine have produced conflicting results and a great range in the prevalence rate of migraine in MS patients. By meta-analysing all available data we aimed to establish an overall estimate of any association in order to more accurately inform clinicians and care-givers about a potential association between MS and migraine. Pubmed and EMBASE were searched to identify suitable studies. Studies were included if they were a case-control study or cohort study in which controls were not reported to have another neurological condition, were available in English, and specified migraine as a headache sub-type. The odds ratio (OR) of migraine in MS patients vs. controls was calculated using the inverse variance with random effects model in Review Manager 5.1. Eight studies were selected for inclusion, yielding a total of 1864 MS patients and 261563 control subjects. We found a significant association between migraine and MS (OR = 2.60, 95% CI 1.12-6.04), although there was significant heterogeneity. Sensitivity analysis showed that migraine without aura was associated with MS OR = 2.29 (95% CI 1.14-4.58), with no significant heterogeneity. MS patients are more than twice as likely to report migraine as controls. Care providers should be alerted to ask MS patients about migraine in order to treat it and potentially improve quality of life. Future work should further investigate the temporal relationship of this association and relationship to the clinical characteristics of MS.
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In a retrospective survey of acute optic neuritis 144 cases in adults were found and, of these, 127 were reviewed, five had died of causes related to multiple sclerosis, and 12 were lost to follow-up. There was a statistically significant seasonal variation in the incidence of optic neuritis. When the life-table method of analysis was used, the probability of developing multiple sclerosis rises to 78% 15 years after an episode of optic neuritis. At review, 49 (73%) of the 67 patients with multiple sclerosis were independent and leading active lives.
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Sequential MR imaging frequently shows disease activity (clinically silent new brain lesions) in subgroups of patients with multiple sclerosis and therefore is valuable in monitoring the effects of treatment. Monitoring of disease activity in patients being treated for relapsing-remitting multiple sclerosis will increase in importance as new and safe therapies are developed. We studied sequential enhanced MR images of patients with early relapsing-remitting multiple sclerosis to define the MR features that indicate disease activity in this subgroup of patients and to compare MR imaging and clinical findings for this purpose. Seven patients with relapsing-remitting definite multiple sclerosis were examined monthly for 4-12 months. For each image, a standard repositioning protocol consisting of three images was used to ensure reproducibility of axial (double oblique) image planes, planned according to internal landmarks. A total of 58 unenhanced T2-weighted and enhanced T1-weighted MR images were obtained. MR images showed new enhancing lesions in six of the seven patients. On 25 (43%) of the 58 enhanced T1-weighted MR images, a total of 50 new enhancing lesions were observed, and on one image a reenhancing lesion was seen. The unenhanced T2-weighted images showed corresponding abnormalities for 92% of the new enhancing lesions. At follow-up, most lesions (86%) were enhanced on only one occasion: 4% were enhanced on more than two consecutive monthly MR examinations. Forty-nine percent of the lesions seen on T2-weighted images "disappeared" (beyond the resolution of the imaging system) after a mean follow-up of 3.5 months, especially lesions that were initially smaller than 5 mm. During the study, only five clinical relapses occurred in three patients (all at times when MR images showed contrast-enhancing lesions), and fixed disability did not increase. On 21 additional occasions, MR images showed new enhancing or reenhancing lesions in patients who were clinically stable at the time (4.2 times more clinically silent disease activity). Our results suggest that contrast-enhanced MR imaging is more sensitive than clinical monitoring for detecting new disease activity in patients with relapsing-remitting multiple sclerosis and that MR imaging might be useful in the evaluation of therapeutic regimens.
Article
This book on the use of epidemiologic data deals with the basic concepts and skills needed for the appraisal of published reports or one's own findings. Applications in clinical medicine, public health and community medicine, and research are taken into consideration. The book acts as an introductory manual that deals in a simple way with fundamental epidemiological approaches and procedures; its aim is to produce competence in the ABC's of data interpretation. It is a workbook of short exercises and instructional self-tests that introduces and explains fundamental approaches and procedures in data interpretation and develops competency in working with epidemiological tools. It deals with basic concepts, the step-by-step assessment of data, rates and other simple measures and the appraisal of their accuracy, associations between variables, the appraisal of cause-effect relationships, meta-analysis, and the practical application of epidemiological findings in clinical practice, community medicine and public health, or research. © 1988, 1994, 2001 by Oxford University Press. All rights reserved.
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The objective of our study was to assess the 5-year risk of and prognostic factors for the development of clinically definite multiple sclerosis (CDMS) following optic neuritis. In a prospective cohort study design, 388 patients, who did not have probable or definite MS at study entry enrolled in the Optic Neuritis Treatment Trial between 1988 and 1991, and were followed for the development of CDMS. The 5-year cumulative probability of CDMS was 30% and did not differ by treatment group. Neurologic impairment in the patients who developed CDMS was generally mild. Brain MRI performed at study entry was a strong predictor of CDMS, with the 5-year risk of CDMS ranging from 16% in the 202 patients with no MRI lesions to 51% in the 89 patients with three or more MRI lesions. Independent of brain MRI, the presence of prior nonspecific neurologic symptoms was also predictive of the development of CDMS. Lack of pain, the presence of optic disk swelling, and mild visual acuity loss were features of the optic neuritis associated with a low risk of CDMS among the 189 patients who had no brain MRI lesions and no history of neurologic symptoms or optic neuritis in the fellow eye. The 5-year risk of CDMS following optic neuritis is highly dependent on the number of lesions present on brain MRI. However, even a normal brain MRI does not preclude the development of CDMS. In these patients with no brain MRI lesions, certain clinical features identify a subgroup with a particularly low 5-year risk of CDMS.
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Hypothetical risk factors in multiple sclerosis are reviewed. So far accumulated data how that the most probable of the risk factors is represented by the morbillivirus group.
Article
The difficulties of linking physiological changes in people with weather factors are great. They are increased manyfold when the study is limited to the macroclimate of the approximate geographic environs of a person or group of persons, since the physiological interactions are with the microclimate in immediate contact with the person, rather than with the geographic weather. The macroclimate is considerably modified by factors such as buildings, clothing, activity, etc. The influence of weather on multiple sclerosis has been the subject of frequent discussions. Many writers have expressed the thought that the disease is influenced by climate factors, and Ziegler1 reported that exacerbations of the disease in Minnesota occurred most frequently in the spring. Limburg2 was unable to find statistical evidence to support this contention but felt that his studies supported previous observations that the disease is more frequent in colder climates. He suggested, on the basis of
Article
Since optic neuritis occurs frequently in multiple sclerosis (MS), it has been thought to herald the onset of MS in the young adult where no specific cause can be identified. This study was designed to examine the incidence of optic neuritis in the resident population of Rochester, Minn, in order to clarify the relationship between optic neuritis and MS. Thirteen to fifteen percent of the patients with MS in the Rochester population presented with optic neuritis, and 27% to 37% of the MS patients showed evidence of optic neuritis during the course of their disease. Prospective analysis of idiopathic optic neuritis cases revealed that the chance of its progressing to MS was approximately 17%. The unfavorable prognosis previously associated with idiopathic optic neuritis may be the result of a bias of clinical series.
Article
For any given research area, one cannot tell how many studies have been conducted but never reported. The extreme view of the "file drawer problem" is that journals are filled with the 5% of the studies that show Type I errors, while the file drawers are filled with the 95% of the studies that show nonsignificant results. Quantitative procedures for computing the tolerance for filed and future null results are reported and illustrated, and the implications are discussed. (15 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
Review of the association between optic neuritis (ON) and multiple sclerosis (MS). MS often presents as acute unilateral ON. While it is clear that many patients with ON suffer from a generalized disease of the central nervous system that will go on to clinically definite MS (CDMS), it is also clear that others do not. With more and more well-informed patients and the emerging pharmacotheraphy for MS, the distinction between those patients with ON who have MS and those who do not, has become more important than ever before. Recently, a large randomized clinical trial on patients with ON or other clinically isolated syndromes suggestive of MS and evidence of prior subclinical demyelination on magnetic resonance imaging of the brain, found that treatment with recombinant interferon-beta-1a is beneficial by reducing the development of CDMS. Ophthalmologists should refer their patients with acute ON to a neurologist for MS-directed investigations and decisions regarding early institution of disease modifying therapy.
Article
Eighty-six patients with monosymptomatic optic neuritis of unknown cause were followed prospectively for a median period of 12.9 years. At onset, cerebrospinal fluid (CSF) pleocytosis was present in 46 patients (53%) but oligoclonal immunoglobulin in only 40 (47%) of the patients. The human leukocyte antigen (HLA)-DR2 was present in 45 (52%). Clinically definite multiple sclerosis (MS) was established in 33 patients. Actuarial analysis showed that the cumulative probability of developing MS within 15 years was 45%. Three risk factors were identified: low age and abnormal CSF at onset, and early recurrence of optic neuritis. Female gender, onset in the winter season, and the presence of HLA-DR2 antigen increased the risk for MS, but not significantly. Magnetic resonance imaging detected bilateral discrete white matter lesions, similar to those in MS, in 11 of 25 patients, 7 to 18 years after the isolated attack of optic neuritis. Nine were among the 13 with abnormal CSF and only 2 belonged to the group of 12 with normal CSF (p = 0.01). Normal CSF at the onset of optic neuritis conferred better prognosis but did not preclude the development of MS.
Article
An epidemiological survey of multiple sclerosis (MS) was done in the Padova province. The province is situated in North-East Italy between 45 N and 46 N. After intensive review of all sources of medical information 122 cases of Probable MS were identified. The crude prevalence rate for MS in the Padova province in 1971 was 16.04 cases/100,000 inhabitants. The clinical characteristics of the MS cases were also evaluated and compared with similar studies done in Northern Europe.
Article
A five year retrospective study was undertaken involving 87 patients admitted to the University College Hospital, Galway, with a confirmed diagnosis of multiple sclerosis (MS). The aim of this study was to consider aspects of this disease as it affected this population in the West of Ireland. Age, sex, and social characteristics of the population were examined. Disease characteristics studied included its remittent and progressive forms and the degree of disability it caused. Relapses of disease were considered in greater detail. It was found that: 1. The highest percentage of patients with MS was in the 40–45 year age group. 2. The mean age of onset of the disease was 37.7 years. 3. Females were in the majority (female: male ratio of 1.4:1) and most of these suffered from the progressive form of MS. 4. Males tended to experience the larger percentage of relapses and had a lower annual relapse rate than females. 5. Of the social groups investigated, those involved in the industry had the highest reported average annual relapse rate. 6. Motor symptoms played an important part in exacerbations, either alone or in combination with other symptoms. 7. Relapses occurred in a cyclical fashion with peaks over 2–3 months. 8. The number of relapses did not tend to vary throughout the year.
Article
A neurological surveillance was combined with prospective recording of upper respiratory and gastrointestinal infections and serological diagnosis of five common viral infections in 60 benign multiple sclerosis patients, with a mean follow-up of 31 months. During 4-week at risk (AR) periods encompassing common infections, a significant excess of MS relapses was found in the AR period, with a relative risk of 1.3. A seasonal variation of the MS relapse rate was found with a minimum in summer. There was a significant correlation between the number of AR relapses and the number of common infections per month explaining the periannual distribution of relapses. The non-AR relapses showed no seasonal variation. There was a significant correlation between adenovirus CF titre rises associated with upper respiratory infections and the occurrence of a major MS relapse in the AR period (n = 7), while influenza infections were not followed by a major MS relapse (n = 6). Linear homologies have been demonstrated between adenovirus and basic myelin protein. The epidemiological approach is essential to our understanding of systemic antigens triggering multiple sclerosis activity.
Article
We investigated the paraclinical profile of monosymptomatic optic neuritis (ON) and its prognosis for multiple sclerosis (MS). The correct identification of patients with very early MS carrying a high risk for conversion to clinically definite MS is important when new treatments are emerging that hopefully will prevent or at least delay future MS. We conducted a prospective single observer and population-based study of 147 consecutive patients (118 women, 80%) with acute monosymptomatic ON referred from a catchment area of 1.6 million inhabitants between January 1, 1990 and December 31, 1995. Of 116 patients examined with brain MRI, 64 (55%) had three or more high signal lesions, 11 (9%) had one to two high signal lesions, and 41 (35%) had a normal brain MRI. Among 143 patients examined, oligoclonal IgG (OB) bands in CSF only were demonstrated in 103 patients (72%). Of 146 patients analyzed, 68 (47%) carried the DR15,DQ6,Dw2 haplotype. During the study period, 53 patients (36%) developed clinically definite MS. The presence of three or more MS-like MRI lesions as well as the presence of OB were strongly associated with the development of MS (p < 0.001). Also, Dw2 phenotype was related to the development of MS (p = 0.046). MRI and CSF studies in patients with ON give clinically important information regarding the risk for future MS.
Article
One hundred and one of 146 patients presenting with isolated idiopathic optic neuritis, previously reviewed in 1978, were reassessed clinically, and retyped for HLA antigens and Factor B alleles, after a mean follow-up of 11.6 years. Fifty eight patients (57%) had developed multiple sclerosis at the time of reassessment in the present study, of whom 51 (88%) had clinically definite disease. This compared with 40% of the original group, in 1978, of whom 62% then had clinically definite multiple sclerosis. When the life-table method of analysis was used, the probability of developing multiple sclerosis was 75%, 15 years after the initial episode of optic neuritis. The frequencies of HLA-DR2 and the recently defined D-region antigen, DQw1, were significantly increased in patients with isolated optic neuritis and those who subsequently developed multiple sclerosis compared with normal controls, but neither allele appears to influence progression from optic neuritis to multiple sclerosis. Patients with optic neuritis who were HLA-DR3 positive had an increased risk for the development of multiple sclerosis (RR = 2.8) and this risk was further enhanced when DR3 occurred in combination with DR2 (RR = 6.7). The overall increased risk of developing multiple sclerosis for patients with this combination was 26 times that for the normal population. When the patients' original tissue-typing was considered BT 101 no longer influenced conversion of optic neuritis to multiple sclerosis. This may partly be explained by improved methods of tissue-typing, since not all BT 101 patients were subsequently found to be positive for HLA-DR2 or HLA-DQw1 and vice versa and by extended follow-up as multiple sclerosis conversion in HLA-DR2 negative individuals increased with time. All 101 patients were typed for Factor B alleles. No significant differences in frequencies were found between individuals with isolated optic neuritis or those who progressed to multiple sclerosis compared with the control population. Recurrent episodes of optic neuritis were associated with an increased risk for the development of multiple sclerosis in this study.
Article
The prevalence index of multiple sclerosis in Bucharest is 41,26 0/0000 and that of the incidence is of 1,78 0/0000. These figures indicate that our country can be included in the group of 'high risk' countries with regard to this disease. Analysis of the dispersion in the investigated area revealed the following aspects: a lower prevalence in areas where the construction of new buildings has determined a powerful influx of the rural population; and a prevalence higher than the average in the central area of the old city, as well as in the areas with a lower number of inhabitants. The dynamic analysis of hospitalizations of cases with multiple sclerosis in the neurological clinics of Bucharest revealed the existence of some annual characteristics, as well as seasonal changes, suggesting a series of pathogenetic considerations.
Article
In a family study of all patients with multiple sclerosis (MS) in Orkney, the number of inbred among patients, although high for Britain, is not higher than the number among controls, and the inbreeding coefficients appear to eliminate recessive involvement of rare genes from the aetiology. The kinship coefficients show that the ancestries of patients and controls are closely enmeshed, and eliminate from the aetiology involvement of recently introduced genes dominant or codominant in effect. Family histories show that single locus inheritance is unlikely unless penetrance is very low. Multifactorial genetic involvement is much more likely, and it is compatible with all recent findings; on this hypothesis heritability estimates, not altogether satisfactory because of the limited number of patients in the population, suggest that the genetic contribution to the aetiology of the disease in Orkney is only moderate.
Article
One-hundred and forty-six patients who had presented with optic neuritis but without evidence of demyelination elsewhere in the nervous system, and in whom no specific cause could be identified, were reassessed clinically between one month and twenty-three years after the onset. Fifty-eight patients (40 per cent) had developed MS. All 146 patients were HLA-typed. Three factors were identified which were significantly associated with the development of MS: positive typing for the HLA antigen BT 101, winter onset of the initial attack of optic neuritis in BT 101-positive patients only, and recurrent attacks of optic neuritis. The application of these results to the individual patient is of limited use. However, recurrent attacks of optic neuritis should be given the same significance in the clinical classification of MS as episodes of demyelination occurring elsewhere in the central nervous system in a patient with a previous attack of optic neuritis. The results suggest that optic neuritis is caused by two different environmental agents or groups of agents and that the agent which is most common in the winter leads to the development of MS in the genetically susceptible individual. The agent more common in the summer is much less likely to cause MS in either suscetible or non-susceptible individuals. The biological role of the HLA system in the handling of foreign antigens is discussed and it is suggested that the presence of the HLA antigens associated with MS confers a specific disadvantage on individuals in the ability to handle infection by the MS causative agent and that this allows damaging immunological processes to develop.
Article
Evidence is presented pointing to an increased incidence of multiple sclerosis having taken place in South Africa during the period 1964 to 1970 and in Tokyo, Japan, during the period 1966 to 1972. There is a possibility that these changes in incidence point to the introduction during the years immediately after the second world war, of an infective element-probably from a high-risk area-to Tokyo and South Africa. If this is so, it lends support to the theory of an infective basis for multiple sclerosis and that the suspected infection in prepubertal susceptibles may produce the symptoms of multiple sclerosis years later. Other factors relevant to multiple sclerosis such as environmental changes, improved diagnostic techniques, and susceptibility are discussed.
Article
The highly variable clinical course and the lack of a direct measurement of disease activity have made evaluation of experimental therapies in multiple sclerosis (MS) difficult. Recent studies indicate that clinically silent lesions can be demonstrated by magnetic resonance imaging (MRI) in patients with mild relapsing-remitting MS. Thus, MRI may provide a means for monitoring therapeutic trials in the early phase of MS. We studied 12 patients longitudinally for 12 to 21 months with monthly gadolinium (Gd)-enhanced MRIs. The data have been used to identify the most effective design of a clinical trial using Gd-enhanced lesions as the outcome measure. Frequent ( > 1/mo) Gd-enhancing lesions were observed in 9 of the 12 patients, indicating that the disease is active even during the early phase of the illness. The frequency of the lesions was not constant; there was marked fluctuation in lesion number from month to month. However, the magnitude of the peak number of lesions and the frequency of the peaks varied among patients. Because of this variability, the most effective use of Gd-enhancing lesions as an outcome measure in a clinical trial was a crossover design with study arms of sufficient duration to allow accurate estimation of lesion frequency. Monitoring Gd-enhancing lesions may be an effective tool to assist in the assessment of experimental therapies in early MS.
Article
Multiple sclerosis definition is anatomical. Its symptomatology is not specific and 4 main criteria are necessary in order to obtain a diagnosis of certitude or of presumption: 1) dissemination of signs and symptoms in space and time; 2) respect of age; 3) the symptomatology must be the expression of lesions affecting mainly the white matter; 4) elimination of other possible diagnosis. CSF examination, evoked potential and NMR study may help to the diagnosis, but no abnormality is specific of multiple sclerosis.
Article
A study was made of the clinical manifestations of multiple sclerosis (MS) in 106 Russians born in the European part of the USSR, who moved afterwards to Uzbekistan at different times. Analysis of the two patients' groups demonstrated that in those who fell ill in Uzbekistan, MS started at an older age and ran a more malignant course as compared to those who had fallen ill in the European part of the USSR. Therefore, a model has been tried, permitting one to assess the influence of the climatogeographic conditions of the region under study on the clinical polymorphism of MS after exclusion of the populational differences between the examinees.
Article
Forty-five patients with clinically definite multiple sclerosis (DS) with onset in the period studied, were reviewed retrospectively. The time of the first exacerbation after the onset, but not the time of onset exhibited seasonal variation (p = 0.003), as 76% of the exacerbations occurred in the winter months. On review of all 148 cases of clinically definite DS in the department's records, a seasonal variation was found of both the time of onset (p = 0.047) and the time of the next exacerbation (p = 0.0004). In previous studies different seasons of peak disease activity were found. These differences may be caused by different methods or by differences in the local factors, which influence the course of the disease. The seasonal variation of the frequency of the disease manifestations is probably caused by a variation in environmental factors. In this study, the importance of infections could not be evaluated.
Article
A prospective study of the relationship between exacerbations and season in 336 patients with clinically definite multiple sclerosis showed a significant monthly variation as well as a seasonal pattern of exacerbations. The data obtained are compared with earlier studies that have used varying methodologies. The results continue to support the hypothesis that undefined environmental factors influence the course of multiple sclerosis.
Article
Over an 8 year period, 170 patients with multiple sclerosis (MS) and 134 healthy controls were assessed at monthly intervals in order to ascertain environmental factors which might be important in producing exacerbation or progression of the illness, and to compare the frequency of common viral infections in the two groups. During cumulative periods designated "at risk" (2 weeks before the onset of infection until 5 weeks afterwards) annual exacerbation rates were almost 3-fold greater than those during periods not at risk. Approximately 9% of infections were temporally related to exacerbations, whereas 27% of exacerbations were related to infections. Frequency of common infections was approximately 20-50% less in MS patients than controls; it was progressively less in those with greater disability. Even in minimally disabled patients with similar potential for infectious contacts, the infection rate was significantly less than in controls, suggesting that MS patients could have superior immune defences against common viruses.
Article
In an analysis of general practice records the rate of chronic sinusitis was significantly greater in 92 patients with multiple sclerosis (MS) than in matched controls (p less than 0.0001). MS and chronic sinus infection were also significantly associated in the timing of attacks, in the age at which patients suffered their attacks, and in the seasonal pattern of attacks.
Article
Pespite many studies on the rate of conversion of optic neuritis (ON) to multiple sclerosis (MS) the subject remains controversial. There are hardly two studies that have treated the problem in quite the same manner, reflecting the fact that many variables affect the calculated outcome, some beyond the control of individual investigators. Most investigators accept a close relationship since many patients with clinically definite MS have an ON at some point in the course of their disease and many patients with ON have converted to clinically definite MS in follow-up. Frequencies of conversion ranging from 13% to 85% have been reported in the literature.1,2 The longest follow-ups have been in some of the studies with the lowest conversion rates and this has led to isolated ON enjoying a diagnostic status approaching that of a specific disease despite the fact that ON is not a clinical pathologic entity. No
Article
The diagnostic value of the pattern-evoked response has been assessed in 73 patients referred because of suspected multiple sclerosis. Altogether 52 had delayed responses. Fifty-one patients in the group satisfied McAlpine's criteria for diagnosing definite, probable, or possible multiple sclerosis. Of these, all but two had delayed responses in one or both eyes, while only three of the remaining 22 patients had delays. In those patients with multiple sclerosis but without any history of optic neuritis the incidence of delayed responses was only slightly less. Of 51 patients with delayed responses 23 had normal discs. Thus subclinical lesions of the visual pathways can be readily detected with this test. The high incidence of abnormal pattern responses, even in patients with no other ocular signs or symptoms, suggests that the test is of value in establishing the diagnosis.
Article
An epidemiological survey of multiple sclerosis (MS) was done in the Padova province. After intensive review of all sources of medical information 122 cases of probable MS were identified. The crude prevalence rate for MS in the Padova province in 1971 was 16.04 cases/100,000 inhabitants. The clinical characteristics of the MS cases were also evaluated and compared with similar studies done in Northern Europe.