Environmental factors and their regulation of immunity in multiple sclerosis

Epidemiological and clinical studies have shown that environmental factors such as infections, smoking and vitamin D are associated with the risk of developing multiple sclerosis (MS). Some of these factors also play a role in the MS disease course. We are currently beginning to understand how environmental factors may impact immune function in MS on a cellular and molecular level. Here we review epidemiological, clinical and basic immunological studies on the environmental factors, viral and parasitic infections, smoking, and vitamin D and relate epidemiological findings with their likely pathophysiology in MS.     

Environmental risk factors in multiple sclerosis

Objectives –  Multiple sclerosis (MS) likely results from an interaction between genetic and exogenous factors. While genetics shapes the overall population MS susceptibility, observed epidemiological patterns strongly suggest a role for the environment in disease initiation and modulation.
Results –  Findings from studies on seasonality in MS patients' birth, disease onset and exacerbations, as well as apparent temporal trends in incidence and gender ratio support an influential effect of viruses, metabolic and lifestyle factors on MS risk. Epstein–Barr virus, vitamin D status, and smoking are factors that may explain such epidemiological patterns.
Conclusions –  Further epidemiological investigations are encouraged and opportunities to use data from existing cohort studies as well as the design of new studies should be pursued. In particular, the development of new large multicentre population-based case-control studies which incorporate the study of the role of environment and genetics, including epigenetic mechanisms, in determining MS risk is proposed.     

Epidemiology of multiple sclerosis: from risk factors to prevention

Although genetic susceptibility explains the clustering of multiple sclerosis (MS) within families and the sharp decline in risk with increasing genetic distance, it cannot fully explain the geographical variations in MS frequency and the changes in risk that occur with migration, which support the action of strong environmental factors. Among these, vitamin D status, infection with the Epstein-Barr virus, and cigarette smoking are emerging as the most consistent predictors of MS risk. In this article, we review the epidemiological data, critically discuss the evidence for causality of these associations, and briefly discuss the possibility of interventions to reduce MS risk.     

Association of smoking with risk of multiple sclerosis: a population-based study

Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. Several studies have shown an association between smoking and MS risk. Here, in a population-based Canadian cohort, we investigate the relationship between personal and maternal smoking exposure and the risk of MS. Using the longitudinal Canadian database, 3,157 MS cases and 756 spouse controls were administered questionnaires on active and passive smoking history. Mothers of cases and controls were also asked about their smoking exposure during pregnancy. The MS cases were more likely to have smoked than spouse controls (odds ratio 1.32, 95 % confidence interval 1.10–1.60, p = 0.003). This association was driven by an excess of ever-smokers in male MS cases. No association was seen with maternal active or passive smoking exposure during pregnancy. Ever-smoking is associated with increased MS risk in males. Further work is needed to understand the mechanism underlying this association.     

Seasonal variation in multiple sclerosis relapse

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.     

Epidemiologic studies of environmental exposures in Parkinson's disease

Parkinson's disease (PD) is the most common cause of the parkinsonian syndromes and the most frequent neurodegenerative disease after Alzheimer's disease. Because of the ageing of Western populations, an increasing number of persons will be affected with PD in the future and neither curative treatments nor preventive measures have been identified. PD is considered as a multifactorial disease, resulting from the effect of environmental factors and genetic susceptibility. Increasing age and male sex appear to be associated with an increased risk of PD. In addition, recent epidemiological studies have identified environmental exposures that influence the risk of PD. This review provides an overview of the epidemiologic evidence for environmental etiologies in PD; we will focus on two environmental exposures that have been quite consistently associated with PD -- cigarette smoking and pesticide exposure -- and will summarize briefly the findings for other exposures. Understanding the mechanisms underlying these epidemiological associations is an essential step for the understanding of the etiology of this neurodegenerative condition and, ideally, to develop neuroprotective drugs.     

Epidemiology and natural history of multiple sclerosis: new insights

PURPOSE OF REVIEW: The cause of multiple sclerosis remains elusive. We review recent epidemiological studies of genetic and environmental factors that influence susceptibility to the disease and its clinical course. RECENT FINDINGS: Genetic advances strengthen the association of multiple sclerosis with the human leukocyte antigen (HLA)-DRB1 allele and interferon-gamma polymorphisms and suggest that apolipoprotein E alleles play an important role. In the environmental realm, nested case-control studies show that prior Epstein-Barr virus exposure is overrepresented in multiple sclerosis. Smoking has been associated with both risk of multiple sclerosis and progressive disease. Vitamin D deficiency might tie together environmental clues with higher multiple sclerosis prevalence rates; dietary vitamin supplementation is also associated with reduced multiple sclerosis risk. Natural history studies demonstrated dissociation between relapses and disease progression, facilitated the ability to distinguish neuromyelitis optica and related syndromes from typical multiple sclerosis, and spawned the exploration of large datasets to model long-term disease activity. SUMMARY: Our understanding of the contributions of specific genetic and environmental factors that contribute to multiple sclerosis has improved. Further refinements will eventually allow powerful longitudinal studies to assess genetic and environmental interactions with implications for prediction of individual disease susceptibility, clinical course, and response to therapy.     

Prognostic criteria in an epidemiological group of patients with multiple sclerosis: an exploratory study

Summary Demographic and clinical features and data on medical history and prior environmental exposure collected during an epidemiological long-term study of multiple sclerosis (MS) were tested for their possible prognostic value. Fifty-two benign MS patients were compared with 29 patients having a malignant course. A primary or secondary progressive course and cerebellar/lower brain-stem symptoms at onset indicated an unfavourable course, whereas no predictive value of sex or of any other type of onset symptomatology was found. Age at onset per se had no influence on prognosis but was associated with more rapid progession only by its relationship with a chronic progressiv type of course. Prior illness, surgery, trauma and childhood exposure to defined environmental factors could not be identified as relevant for prognosis.Presented in part at the 2nd ENS Meeting, Brighton 1990     

The environment and Parkinson's disease: is the nigrostriatal system preferentially targeted by neurotoxins?

Recent epidemiological and experimental studies have renewed interest in the hypothesis that the environment has a role in the pathogenesis of Parkinson's disease (PD). Epidemiological studies have identified protective associations (eg, smoking) as well as adverse risk factors (eg, pesticide exposure) for PD. The concordance rate of PD in pairs of dizygotic twins is similar to that in pairs of monozygotic twins, supporting a role of non-genetic risk factors. New models of selective nigrostriatal damage--such as neurotoxicity induced by rotenone or paraquat--have emphasised that environmental agents may contribute to the neurodegenerative process in PD. Toxins interact, in vitro and in vivo, with alpha-synuclein, an endogenous protein that is implicated in pathology of PD. Similarities between clinical and experimental findings, such as the role of pesticide exposure as a potential environmental risk factor, highlight the importance of a multidisciplinary approach to the aetiology of PD.     

Multiple sclerosis and birth order: a longitudinal cohort study

BACKGROUND: Genetic epidemiological studies suggest both genetic and environmental factors have a role in multiple sclerosis (MS). Environmental effects are strongly suggested from geographical gradients, migration data, and discordance rates in twins. In epidemiological studies, risk of MS in offspring of small families and in those with an early birth-order position has been reported and interpreted in the context of the hygiene hypothesis, which is that infections at an early age, introduced by older siblings, are protective. We aimed to study the effect of birth order on MS risk. METHODS: A longitudinal, population-based sample of individuals with MS and their healthy siblings were identified from the Canadian Collaborative Project on Genetic Susceptibility to MS. Data were grouped according to single (simplex) or multiple (multiplex) siblings with MS in a sibship. Separate analyses were done for each sibship size. FINDINGS: We studied 10 995 individuals with MS and 26 336 healthy siblings, and found no relation between MS risk and birth-order position. In simplex sibships of at least seven siblings, slightly more siblings who were born late in the birth order had MS; the same was found for the first-born sibling with MS in a multiplex sibship. Siblings with MS were slightly younger (p<0.0001) than those without MS, contrary to the expected age at onset bias. INTERPRETATION: These findings do not support the hygiene hypothesis and could be due to a cohort effect resulting from increasing MS incidence. Birth order has no effect on MS risk in most families, and there is no support for the hypothesis that having older siblings protects against MS.     

Test-retest repeatability of self-reported environmental exposures in Parkinson's disease cases and healthy controls

There is substantial disagreement among published epidemiological studies regarding environmental risk factors for Parkinson's disease (PD). Differences in the quality of measurement of environmental exposures may contribute to this variation. The current study examined the test-retest repeatability of self-report data on risk factors for PD obtained from a series of 32 PD cases recruited from neurology clinics and 29 healthy sex-, age- and residential suburb-matched controls. Exposure data were collected in face-to-face interviews using a structured questionnaire derived from previous epidemiological studies. High repeatability was demonstrated for 'lifestyle' exposures, such as smoking and coffee/tea consumption (kappas 0.70-1.00). Environmental exposures that involved some action by the person, such as pesticide application and use of solvents and metals, also showed high repeatability (kappas>0.78). Lower repeatability was seen for rural residency and bore water consumption (kappa 0.39-0.74). In general, we found that case and control participants provided similar rates of incongruent and missing responses for categorical and continuous occupational, domestic, lifestyle and medical exposures.     

Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors

As discussed in Part I of this review, the geographic distribution of multiple sclerosis (MS) and the change in risk among migrants provide compelling evidence for the existence of strong environmental determinants of MS, where "environmental" is broadly defined to include differences in diet and other behaviors. As we did for infections, we focus here primarily on those factors that may contribute to explain the geographic variations in MS prevalence and the change in risk among migrants. Among these, sunlight exposure emerges as being the most likely candidate. Because the effects of sun exposure may be mediated by vitamin D, we also examine the evidence linking vitamin D intake or status to MS risk. Furthermore, we review the evidence on cigarette smoking, which cannot explain the geographic variations in MS risk, but may contribute to the recently reported increases in the female/male ratio in MS incidence. Other proposed risk factors for MS are mentioned only briefly; although we recognize that some of these might be genuine, evidence is usually sparse and unpersuasive.     

Genetic and environmental factors and the distribution of multiple sclerosis in Europe

Background: The observation that the incidence of multiple sclerosis (MS) increases further from the equator has prompted considerable interest in the factors that might underlie this latitude gradient. Potential candidates include population frequencies of disease‐associated Human Leukocyte Antigen (HLA) alleles which are the major genetic component of MS susceptibility. Ultraviolet (UV) exposure and smoking have also been implicated as key environmental risk factors. Methods: We used multiple sources of published data on MS prevalence, HLA allele frequencies, UV index and cigarette smoking to assess the contributions of both nature and nurture to the distribution of MS within Europe. Results: We observed that HLA alleles unequivocally interact with a population‐wide level to determine disease risk. The UV index and smoking behaviour was also shown to correlate with disease distribution in Europe. For countries with HLA, UV and smoking data, these three factors were shown to account for 75% of the variance in MS prevalence. Conclusions: Genetic (HLA) and environmental (UV and smoking) risk factors thus interact in a complex manner with each other to determine a large proportion of MS susceptibility within Europe.     

Environmental studies of schizophrenia through the prism of epigenetics

Traditionally, etiological research of schizophrenia has been focused on elucidating predisposing genes and environmental risk factors. While numerous putative environmental hazards have been suggested, inconsistencies and methodological limitations of epidemiological studies have made it difficult to identify even a single exogenous cause of schizophrenia. Furthermore, there is increasing evidence that environmental risk factors may not play as much of a significant role in schizophrenia as previously suspected. In this article, we argue that molecular epigenetic studies can overcome the complexities of traditional epidemiological studies and may become a productive line of research in understanding the nongenetic mechanisms of schizophrenia.     

Epidemiology of primary blepharospasm.

We review epidemiological data on primary blepharospasm (BSP). There is a large variation in the stated prevalence of BSP, with crude estimates ranging from 16 to 133 per million in different studies. A large proportion of this variability may be the result of differences in physician education on BSP. Age and female gender may increase the risk of developing BSP. The few case-control studies focusing on adult dystonias including BSP showed an increased risk in association with family history of dystonia and/or postural tremor, prior head and face trauma, and prior eye disease (e.g., blepharitis and keratoconjunctivitis), and a decreased risk associated with cigarette smoking. No association was found with age-related medical conditions such as hypertension and diabetes, family history of parkinsonism, and a history of anxiety or depression. Broocks et al. [Am J Psychiatry, 1998;155:555-557] found a significantly higher frequency of obsessive-compulsive symptoms in BSP than hemifacial spasm despite the clinical similarity. Among putative risk factors for BSP, age at onset, female gender, and prior head or face trauma may affect spread of dystonia to adjacent body regions. While limited, the body of epidemiological data support the idea that environmental and familial, possibly genetic, factors may both be important in the etiology of BSP.     

The role of Epstein-Barr virus in multiple sclerosis:from molecular pathophysiology to in vivo imaging

Multiple sclerosis(MS) is a disease of the central nervous system characterized by inflammation, demyelination, and neuronal damage. Environmental and genetic factors are associated with the risk of developing MS, but the exact cause still remains unidentified. Epstein-Barr virus(EBV), vitamin D, and smoking are among the most well-established environmental risk factors in MS. Infectious mononucleosis, which is caused by delayed primary EBV infection, increases the risk of developing MS. EBV may also contribute to MS pathogenesis indirectly by activating silent human endogenous retrovirus-W. The emerging B-cell depleting therapies, particularly anti-CD20 agents such as rituximab, ocrelizumab, as well as the fully human ofatumumab, have shown promising clinical and magnetic resonance imaging benefit. One potential effect of these therapies is the depletion of memory B-cells, the primary reservoir site where EBV latency occurs. In addition, EBV potentially interacts with both genetic and other environmental factors to increase susceptibility and disease severity of MS. This review examines the role of EBV in MS pathophysiology and summarizes the recent clinical and radiological findings, with a focus on B-cells and in vivo imaging. Addressing the potential link between EBV and MS allows the better understanding of MS pathogenesis and helps to identify additional disease biomarkers that may be responsive to B-cell depleting intervention.     

Some contributions of the Department of Veterans Affairs to the epidemiology of multiple sclerosis

The first class 1 treatment trial ever conducted in multiple sclerosis (MS) was a Veterans Administration Cooperative Study. This led us to explore MS in the military-veteran populations of the United States in three main series: Army men hospitalized with final diagnoses of MS in World War II, all veterans of World War II and the Korean Conflict, and veterans of later service up to 1994. In each series, all cases had been matched with pre-illness military peers. These series provide major information on its clinical features, course and prognosis, including survival, by sex and race (white men and women; black men), as well as risk factors for occurrence, course, and survival. They comprise the only available nationwide morbidity distributions of MS in the United States. Veterans who are service-connected for MS by the Department of Veterans Affairs and matched with their military peers remain a unique and currently available resource for further clinical and epidemiological study of this disease.     

The analytical epidemiology of obsessive-compulsive disorder: risk factors and correlates

In this qualitative systematic review, we evaluate studies of the demographic, innate, and environmental risk factors and correlates associated with the development of Obsessive-Compulsive Disorder (OCD) in epidemiological samples. We found that a significant proportion of the studies indicate that late adolescence is a period of increased vulnerability for the development of OCD; that OCD affects predominantly female adults and male children and adolescents; that those who are unmarried or abusing drugs are more likely to present with OCD; that OCD is a familial and genetic disorder, particularly when one considers symptom dimensions instead of categorical diagnosis and when the disorder begins at an early age; and that individuals with OCD from the community, like those seen in clinical settings, may be especially prone to present psychiatric conditions such as mood and anxiety disorders. Although there are plenty of data on the correlates and risk factors of OCD in epidemiological samples, more research is needed on other potential risk factors, including obstetrical and pregnancy problems, pre-morbid neurocognitive functioning, and streptococcal infections, among others.     

Prevention and treatment of MS: studying the effects of vitamin D

Observational studies suggest that adequate vitamin D nutrition may reduce the risk of MS and affect the course of the disease. Inherent limitations in these studies, however, preclude a causal interpretation. Randomized controlled clinical trials are the next step to addressing whether vitamin D prevents MS or can favorably affect the course and progression of MS. Here we briefly review the current literature on vitamin D and MS, both as a risk factor and potential treatment for MS with a focus on the issues and challenges in designing prevention and treatment clinical trials.     

What affects your MS? Responses to an anonymous, Internet-based epidemiological survey

Evolving information technology has raised the possibility of new methods of data collection in multiple sclerosis (MS) research. An anonymous, self-report, Internet-based survey was developed, which asked people with MS their opinion on how various extrinsic factors affected their condition. From September 2001 to July 2002, a total of 2529 people completed the questionnaire. The demographic and clinical profiles of the anonymous respondents indicated that most were likely to have MS. Common factors reported as beneficial were cannabis, cold baths, meditation and dietary factors. Common adverse factors reported were high stress, exposure to high temperatures and viral infections. There was an increasing report of high temperatures as being adverse with increasing respondent age (test for trend, P < 0.001). The adverse report of high temperatures correlated significantly with the report of strong sunlight apparently making MS worse (r = 0.35, P < 0.0001). In Australia, high temperatures were more likely to be reported as adverse in warmer, lower latitude regions. The association between strong sunlight as adverse and age or region did not persist after adjustment for high temperatures. Thus, this apparent adverse factor appeared to relate to solar heat, not solar light. People with MS may risk vitamin D deficiency because of sun avoidance due to heat-related fatigue or intolerance. This is of clinical significance not only for bone health but because vitamin D may have beneficial immunomodulatory properties. The present study provides new information from people with MS on factors that may influence symptoms or clinical course. This information will now be used in the design of formal epidemiological cohort studies.