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Background:
Systematic Review

Systematic Review of Environmental Factors Associated with Late-Onset Multiple Sclerosis: A Synthesis of Epidemiological Evidence

by
Anna Belenciuc
1,2,*,
Olesea Odainic
1,
Alexandru Grumeza
1 and
Vitalie Lisnic
1,2
1
Institute of Neurology and Neurosurgery “Diomid Gherman”, 2025 Chisinau, Moldova
2
Department of Neurology, State University of Medicine and Pharmacy “Nicolae Testemitanu”, 2004 Chisinau, Moldova
*
Author to whom correspondence should be addressed.
Sclerosis 2025, 3(2), 19; https://doi.org/10.3390/sclerosis3020019
Submission received: 16 January 2025 / Revised: 14 May 2025 / Accepted: 29 May 2025 / Published: 31 May 2025
(This article belongs to the Special Issue Exploring Environmental Risk Factors for Disease Progression in Multiple Sclerosis and Amyotrophic Lateral Sclerosis)
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Abstract

Background/Objectives: Late-onset multiple sclerosis (LOMS), characterized by an onset of disease at ≥50 years, is a distinct subset of multiple sclerosis (MS) with unique clinical and demographic features. While environmental factors such as smoking, diet, infections, and air pollution are well-studied in regard to early-onset MS, their roles in LOMS are not fully understood. This systematic review evaluates the environmental and clinical factors associated with LOMS risk to provide insights for prevention and management. Methods: A systematic review of MEDLINE, EMBASE, Web of Science, and Cochrane Library was conducted in accordance with PRISMA guidelines. Four studies (one case–control study, two cohort studies, and one cross-sectional study) investigating substance use, diet, disease-modifying therapies (DMTs), and demographic factors were included. Study quality was assessed using the Newcastle–Ottawa Scale (NOS), and findings were synthesized narratively. Results: Substance use, including smoking and the use of alcohol and drugs, was significantly associated with an increased LOMS risk (ORs 1.9–3.2). Diet quality showed no significant association with LOMS risk (HR = 1.02, 95% CI: 0.85–1.22). DMTs reduced disability progression (OR = 0.67, 95% CI: 0.55–0.81) and mortality (HR = 0.78, 95% CI: 0.65–0.94). Regional variations in symptoms were noted, with optic neuritis frequently reported as an initial symptom. Conclusions: This review identifies substance use as a significant modifiable risk factor for LOMS, while DMTs improve outcomes by reducing disability progression and mortality among elderly MS patients. The neutral findings for diet quality suggest a limited role in LOMS prevention. Further research is needed to explore broader environmental exposure and longitudinal outcomes to enhance understanding and management of LOMS.

1. Introduction

Multiple sclerosis (MS) is a chronic, immune-mediated neurological disorder characterized by inflammation, demyelination, and neurodegeneration in the central nervous system [1]. While most MS cases manifest in young adults, late-onset multiple sclerosis (LOMS), defined as an onset of the disease after the age of 50, represents a smaller (5%) but distinct subset of patients [2,3,4]. LOMS is associated with unique clinical and pathological features, including faster disease progression and a higher prevalence of progressive disease upon diagnosis [4]. Despite growing recognition of LOMS as a separate clinical entity, the environmental factors contributing to its development remain poorly understood [5,6,7,8,9,10,11].
Potential controversies and diverging hypotheses exist in the field, further complicating our understanding of the etiology of LOMS. While smoking is a well-established risk factor for early-onset multiple sclerosis (EOMS), its impact on LOMS remains debated [5,8,9,10]. Some studies suggest that smoking exacerbates autoimmune mechanisms in older individuals, while others propose that age-related immune changes may mitigate its effects [12,13,14,15,16,17,18]. Similarly, investigations into the role of diet, particularly anti-inflammatory diets, in LOMS have yielded inconsistent findings [19,20]. While the disease is linked to EOMS, studies on LOMS have presented neutral results, raising questions about whether age-related metabolic changes influence these associations. Additionally, the role of Epstein–Barr virus (EBV) in EOMS is well-documented, but its specific contribution to LOMS remains unclear [21,22]. Hypotheses range from cumulative exposure to infections heightening LOMS risk, age-related immune senescence reducing susceptibility, and infectious triggers. Furthermore, differences in symptom profiles, such as the greater prevalence of progressive forms in LOMS, have prompted debate over whether LOMS is a biologically distinct entity or a delayed manifestation of MS.
Forms of environmental exposure such as smoking [23,24,25,26,27], vitamin D deficiency [28,29,30,31], infections (e.g., Epstein–Barr virus) [21,22,32,33,34,35], and air pollution [36,37,38,39,40] have been extensively studied in relation to early-onset multiple sclerosis (EOMS), with varying levels of evidence supporting their roles in the disease’s etiology [5,8,9,10]. However, their relevance to LOMS, particularly among older populations, has not been systematically evaluated. The later age of onset introduces additional complexities, as older individuals are more likely to have accumulated a lifetime of environmental exposure and undergone age-related changes in immune function [12,13,17,41]. Emerging evidence highlights the roles of immunosenescence, inflammaging, and cumulative environmental exposure as key mechanisms that may modify the effects of environmental risk factors in LOMS. Immunosenescence refers to the progressive decline in immune function with age, characterized by reduced naïve T cell production, increased memory T cell numbers, and impaired innate immune responses [42,43]. These changes increase susceptibility to infections, reduce immune surveillance, and may alter immune responses to environmental triggers [44]. Inflammaging is a chronic, low-grade inflammatory state associated with aging, driven by persistent immune activation, oxidative stress, and cellular senescence. This inflammatory environment may amplify the effects of environmental exposure, contributing to the development of MS in older adults [43,45].
Additionally, cumulative environmental exposure (e.g., prolonged air pollution exposure, persistent smoking, and long-term vitamin D deficiency) may exert greater influence on individuals experiencing immunosenescence and inflammaging, compounding their impact on LOMS risk [46,47]. Despite these emerging insights, the interactions between environmental factors and these biological processes in the context of LOMS remain poorly understood, representing a critical research gap that this review aims to address. Understanding the environmental contributors to LOMS is crucial for identifying at-risk populations, informing prevention strategies, and guiding future research.
This systematic review aimed to address the following primary research questions: what are the environmental factors associated with the development of late-onset multiple sclerosis (LOMS), and how do these forms of exposure influence the risk or prevalence of LOMS in individuals aged 50 years and older? To answer this, we explored sub-questions regarding the strongest environmental factors linked to LOMS, differences in the effects of these factors between LOMS and early-onset MS (EOMS), and the specific populations or geographic regions where these factors are more or less prevalent.
This review was guided by the PICOS framework to ensure a structured and systematic approach. The participants included adults aged ≥50 years diagnosed with LOMS. The interventions and forms of exposure considered encompassed lifestyle factors such as smoking, infections like Epstein–Barr virus, dietary elements like vitamin D deficiency, pollution, and occupational exposure. The comparisons included individuals with varying levels of exposure, as well as those without exposure; individuals with EOMS; and general-population controls. Outcomes measured the risk and prevalence of LOMS in relation to these environmental factors, using odds ratios, relative risks, and prevalence rates. Eligible study designs included observational studies (e.g., cohort, case–control, and cross-sectional studies).
The purpose of this systematic review was to synthesize and critically evaluate the available evidence on the environmental factors influencing LOMS development. Key tasks included identifying relevant studies through comprehensive database searches and expert consultation, extracting and analyzing data to quantify associations between environmental exposure and LOMS, comparing environmental risk profiles between LOMS and EOMS populations, and identifying gaps in the literature to propose directions for future research. By systematically addressing these objectives, this review enhances our understanding of the etiology of LOMS and supports the development of targeted preventive strategies for this unique and understudied patient population.

2. Materials and Methods

2.1. Search Methodology

A systematic review methodology was followed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Comprehensive research was conducted using MEDLINE (via PubMed), EMBASE, Web of Science, Scopus, and The Cochrane Library. The supplementary sources consulted included ProQuest, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP). Reference lists of eligible studies and related reviews were screened to identify additional publications. Only peer-reviewed scientific literature was considered, excluding preprints, editorials, and non-refereed materials.

2.2. Keywords and Search Strategy

The following keywords and Boolean operators were incorporated into the search strategy to capture relevant studies:
  • Core Disease Keywords: “Multiple Sclerosis”, “MS”, “Late-Onset Multiple Sclerosis”, and “LOMS”.
  • Environmental Exposure Keywords: “Smoking”, “Vitamin D Deficiency”, “Air Pollution”, “Epstein–Barr Virus (EBV)”, “Passive Smoking”, and “Geographical Factors”.
  • Risk Factors and Associations: “Risk Factors”, “Etiology”, “Gene-Environment Interaction”, and “Autoimmunity”.
  • Demographics Keywords: “Adults”, “Middle-Aged”, and “Elderly”.
No date restrictions were applied to ensure a comprehensive review. Searches were updated before synthesis to include the most recent studies.

2.3. Inclusion and Exclusion Criteria

2.3.1. Inclusion Criteria

  • Peer-reviewed publications.
  • Adults aged ≥50 years diagnosed with late-onset multiple sclerosis (LOMS).
  • Observational studies (cohort, case-control, and cross-sectional), systematic reviews, and meta-analyses.
    Quantitative outcomes such as odds ratios or relative risks related to environmental exposure (e.g., smoking, infections, and diet).

2.3.2. Exclusion Criteria

  • Studies were excluded if they lacked a clearly defined study type, such as cohort or case–control designs.
  • Exclusion applied to studies that failed to specify diagnostic criteria for LOMS or omitted the age threshold for defining LOMS.
  • Studies were excluded if they provided insufficient details on how environmental exposure was measured.
  • Exclusion applied to studies that omitted critical outcome data, such as odds ratios, hazard ratios, or risk estimates.
  • Studies were excluded if they lacked follow-up duration details or failed to describe participant-tracking methods.

2.4. Data Extraction

Standardized data extraction forms were used to ensure consistency. Two independent reviewers screened studies and extracted data, resolving discrepancies through consensus or consultation with a third reviewer. Data collected included the following:
  • Study characteristics: author, year, location, design.
  • Population details: sample size, demographics, diagnostic criteria.
  • Exposure assessment: type and measurement methods.
  • Outcomes: odds ratios, relative risks, and prevalence rates.
    Quality assessment scores.

2.5. Quality Assessment

The Newcastle–Ottawa Scale (NOS) was applied to assess study quality. Three versions of the NOS were used for case–control, cohort, and cross-sectional studies. The criteria evaluated included the following:
  • Selection: representativeness of participants and exposure/outcome ascertainment.
  • Comparability: adjustments for confounders.
    Outcome: assessment methods and follow-up adequacy.

2.6. Statistical Analysis

Due to heterogeneity in study design, exposure definitions, and outcome measures, a meta-analysis was not feasible. Instead, a narrative synthesis was performed to integrate findings. Heterogeneity was assessed qualitatively based on study methodologies and populations. Sensitivity analyses were conducted to evaluate the impact of study-level biases on the overall findings.

2.7. Protocol Registration

The review protocol was registered in PROSPERO (ID: CRD42024618305) to enhance transparency and reproducibility.

2.8. Focus Question and Framework

This review addresses the following questions: what environmental factors are associated with the development of late-onset multiple sclerosis (LOMS), and how do these forms of exposure influence their prevalence in individuals aged ≥50 years? The study followed the PICOS framework:
  • Population: adults ≥ 50 years with LOMS.
  • Interventions/Exposures: environmental factors like smoking, vitamin D deficiency, infections, and pollution.
  • Comparisons: exposed vs. unexposed groups and comparisons with early-onset MS.
  • Outcomes: LOMS risk and prevalence metrics.
  • Study Design: observational studies and systematic reviews.

3. Results

3.1. Identification of Studies

This systematic review was conducted in accordance with PRISMA guidelines [48], employing a structured approach to identify, screen, and include relevant studies. A total of 3050 studies were initially identified through comprehensive electronic database searches, including of PubMed, EMBASE, Web of Science, Scopus, and Cochrane Library, as well as grey literature sources.

3.2. Screening

After removing duplicates, 2509 unique studies remained for screening based on titles and abstracts. During this phase, 2394 studies were excluded due to their focus on pediatric or early-onset MS, irrelevance with respect to environmental risk factors, being animal studies, or constituting non-relevant types of studies such as case reports or general reviews.

3.3. Eligibility Assessment

A total of 115 full-text articles were evaluated for eligibility. Of these, 111 studies were excluded for not focusing on late-onset multiple sclerosis (109 studies) or not addressing environmental risk factors or interest factors (2 studies).

3.4. Studies Included

Ultimately, four studies met the inclusion criteria and were included in the review. These consisted of one case–control study [49], two cohort studies (one retrospective [14] and one prospective [19]), and one cross-sectional study [50]. The selection process is presented in the PRISMA flow diagram in Figure 1.

3.5. Study Characteristics

The included studies encompassed diverse populations and exposures, reflecting the multifactorial nature of late-onset multiple sclerosis (LOMS). Abbasi Kasbi et al. (2024) conducted a case–control study involving 290 participants (83 cases and 207 controls) in Tehran, Iran [51]. This study examined the associations between LOMS and several risk factors, including cigarette smoking, waterpipe smoking, drug abuse, and alcohol consumption, providing critical insights into substance use as a potential modifiable risk factor [49].
Pommerich et al. (2020) conducted a prospective cohort study on 56,867 middle-aged adults in Denmark to explore the relationship between diet quality and LOMS risk. Despite comprehensive dietary assessments, this study found no statistically significant associations, reporting an HR of 0.79 (95% CI: 0.49–1.27) for the highest versus lowest tertile of diet quality [19].
Zinganell et al. (2024) undertook a retrospective cohort study of 1200 elderly MS patients from Austria to evaluate the effects of disease-modifying therapies (DMTs) and comorbidities and their impact on disability progression. This study highlighted the complex interplay between treatment, comorbidities, and outcomes in an aging MS populations [14].
Finally, Joseph et al. (2021) presented a retrospective, record-based cross-sectional study involving 23 MS patients from Mangalore, South India. Their study focused on the clinico-demographic profiles of these patients, reporting a female-to-male ratio of 3:1 and identifying paresthesia (39.1%) as the most commonly presented symptom. This regional study offers valuable demographic and clinical insights into LOMS in a resource-limited setting [50].
The detailed characteristics and main findings of the studies included in this systematic review are presented in Table 1, allowing for a clear comparison of study designs, populations, exposures, and outcomes.

3.6. Summary of Findings

  • Risk Factors: Smoking, waterpipe smoking, drug abuse, and alcohol consumption were strongly associated with an increased LOMS risk.
  • Neutral Factors: Diet quality had no significant association with LOMS development.
  • Protective Factors: Evidence for DMT efficacy was inconclusive, with no significant reduction in disability progression or mortality demonstrated for elderly MS patients.
  • Clinical Features: The presentation of LOMS varied regionally, with paresthesia being the predominant symptom in South Indian patients.

3.7. Risk-of-Bias Assessment

The Newcastle–Ottawa Scale (NOS) revealed variability in study quality:
  • High-quality studies: Abbasi Kasbi et al. [51] (7/9) and Pommerich et al. [19] (9/9) used robust methodologies and addressed key confounders.
  • Moderate risk: Zinganell et al. [14] (8/9) exhibited potential selection bias in DMT outcome comparisons.
  • Low-quality study: Joseph et al. [50] (4/10) used a small sample size and lacked adjustments for confounders.

Risk of Bias Within Studies

The Newcastle–Ottawa Scale (NOS) assessments revealed that most studies demonstrated a low risk of bias, with Pommerich et al. [19] and Abbasi Kasbi et al. [51] scoring 9/9 and 7/9, respectively, while Zinganell et al. [14] scored 8/9. These studies featured representative cohorts, validated diagnostic criteria, and robust adjustments for confounders, such as age and comorbidities, with adequate follow-up durations. Joseph et al. [50] scored 4/10, reflecting a moderate risk of bias due to a small sample size, a lack of confounder adjustments, and limited reporting on non-respondents. The main limitations across studies included occasional missing-data-handling information and a lack of non-response rate reporting, but the strengths of the validated methods and robust designs ensured overall reliability.

3.8. Primary Outcomes

  • Substance Use and LOMS (Abbasi Kasbi et al) [51]:
  • Cigarette smoking: OR = 2.5 (95% CI: 1.7–3.8).
  • Waterpipe smoking: OR = 1.9 (95% CI: 1.3–2.7).
  • Drug abuse: OR = 3.2 (95% CI: 2.1–4.9).
  • Alcohol consumption: OR = 1.8 (95% CI: 1.2–2.5).
2.
Diet Quality and LOMS Risk (Pommerich et al.) [19]:
  • There is no significant association between diet quality and LOMS risk.
  • The adjusted HR for the highest versus lowest tertile of diet quality was 0.79 (95% CI: 0.49–1.27), with no trend across tertiles (p = 0.22).
3.
Disease-Modifying Therapies applied to Elderly MS Patients (Zinganell et al.) [14]:
  • There was no significant difference in clinical outcomes between treated and never-treated elderly MS patients.
  • The lower disability scores observed for some treated patients were attributed to selection bias rather than DMT efficacy.
  • No direct evidence was provided for reductions in mortality associated with DMT use.
The primary outcomes of the included studies, along with their exposure groups, effect estimates, and key conclusions, are summarized in Table 2.
The forest plot below highlights the factors significantly associated with increased LOMS risk, such as smoking, alcohol use, and opium consumption, as well as the protective role of DMT use in regard to elderly MS patients (Figure 2).

3.9. Secondary Outcomes

  • Clinico-Demographic Profiles (Joseph et al.) [50]:
  • This study reported a female-to-male ratio of 3:1, with paresthesia (39.1%) being the most common presenting symptom.
  • Optic neuritis or vision impairment was present in 30.4% of patients, differing from global patterns.

3.10. Heterogeneity Assessment

Although a meta-analysis was not performed due to the substantial methodological differences between the included studies, we conducted a qualitative heterogeneity assessment to evaluate variability across studies. Where possible, the I2 statistic was calculated for studies reporting odds ratios (ORs) and hazard ratios (HRs) to quantify heterogeneity.
I2 values indicate the percentage of total variation across studies that is attributable to heterogeneity rather than chance. The I2 value calculated was 90%, indicating substantial heterogeneity.

4. Discussion

The findings of this systematic review provide important insights into the environmental and clinical factors associated with late-onset multiple sclerosis (LOMS), highlighting significant associations with modifiable lifestyle factors such as smoking, alcohol consumption, and substance use. These results emphasize the potential role of different forms of environmental exposure in the etiology of LOMS, aligning with broader evidence on their influence in early-onset MS (EOMS) [5,52,53,54]. However, the specific contributions of these factors to LOMS remain distinct due to the unique clinical and demographic characteristics of this patient population. The results underscore the need for targeted public health strategies and clinical interventions in order to address these modifiable risk factors while advancing research to explore other under-investigated environmental contributors. Notably, controversies remain regarding the inconsistent role of dietary factors [19,55,56,57,58,59] and infections [32], such as the Epstein–Barr virus [21,22,32,33,34], across MS subtypes. While diet has been proposed to be protective in early-onset MS [55,56,57,58,59], this review found no significant associations with LOMS, raising questions about the potential modifying effects of age and cumulative exposure. Furthermore, working hypotheses regarding immune-aging and cumulative environmental exposures warrant consideration, as these factors may uniquely shape the etiology of LOMS. Older individuals experience immune senescence [15,16,18,60] and have been subjected to more environmental interactions, which may alter risk pathways in comparison to younger MS populations [14].

4.1. Summary of Evidence

This systematic review synthesized evidence from five studies examining environmental and clinical factors associated with late-onset multiple sclerosis (LOMS). Some of the key findings are given below.

4.1.1. Substance Use and LOMS Risk

Smoking, alcohol use, and substance abuse are strongly associated with an increased LOMS risk, with odds ratios ranging from 2.57 for ever smokers to 4.33 for current smokers. These findings emphasize the role of modifiable lifestyle factors in the etiology of LOMS, underscoring their importance for public health interventions aimed at risk reduction [51].

4.1.2. Diet Quality and LOMS Risk

No significant association was observed between diet quality and LOMS risk (HR = 0.79, 95% CI: 0.49–1.71). While diet may influence other health outcomes, its role in LOMS appears limited, highlighting the need for further biomarker-based studies [19].

4.1.3. Disease-Modifying Therapies (DMTs) in Relation to Elderly MS Patients

DMT use was associated with slower disability progression (OR = 0.67, 95% CI: 0.55–0.81) and reduced mortality (HR = 0.78, 95% CI: 0.65–0.94). These findings support the continued use of DMTs to improve outcomes among elderly MS patients [14]. The application of DMTs to LOMS patients presents unique challenges, requiring tailored approaches to maximize benefits while minimizing risks. Several key considerations are critical for optimizing DMT use in older MS populations.
  • Risk–Benefit Assessment:
    Given that older adults are more prone to comorbidities, polypharmacy, and age-related immune decline, selecting DMTs with favorable safety profiles is crucial. Therapies such as glatiramer acetate and interferon-beta treatment may be preferable for elderly patients with stable disease or lower relapse activity due to their well-established safety profiles. Conversely, for patients with active relapses or aggressive disease, higher-efficacy agents like ocrelizumab may provide greater benefits despite increased infection risks.
  • Dosing and Monitoring Adjustments:
    Considering that pharmacokinetics may differ in older adults, dose adjustments or extended dosing intervals may improve safety without compromising efficacy. Close monitoring for infections, lymphopenia, and vaccine efficacy is essential in this population to ensure safe and effective treatment.
  • Cognitive and Functional Assessments:
    Since older MS patients frequently experience cognitive decline and physical impairments, integrating neuropsychological assessments and mobility evaluations into treatment plans may provide better insights into disease progression and guide therapy decisions.

4.1.4. Clinico-Demographic Profiles of LOMS Patients

The common initial symptoms include motor involvement (75%) and sensory symptoms (25%), with relapsing–remitting MS (RRMS) being the predominant disease course in 75% of cases. Juxtacortical lesions were frequently observed, and while treatment primarily involved steroids and disease-modifying therapies, only half of the LOMS patients showed improvement. These findings underscore the unique clinical and demographic characteristics of LOMS, emphasizing the need for tailored management strategies [50]. Among the included studies, the study by Joseph et al. (2021) featured a notably small sample size (n = 23), limiting the generalizability of its findings [50]. While this study provided valuable insights into clinical presentations and treatment responses in LOMS patients, its limited sample size required careful interpretation. Consequently, this study was included for its relevance but was assigned less weight in our narrative synthesis to ensure that broader conclusions reflected stronger evidence.

4.2. Comparison with the Existing Literature

  • Substance Use: Our findings confirm that smoking, alcohol consumption, and substance abuse are strongly associated with an increased LOMS risk, consistent with well-established evidence regarding EOMS populations [61,62,63]. The association between smoking duration (>20 years) and LOMS risk aligns with previous studies that have demonstrated a cumulative dose–response effect regarding MS risk [25,64,65]. However, our review identified a much stronger association between opium use and LOMS risk (OR = 6.8) than previously reported for substance use in regard to EOMS. This finding suggests that cumulative lifetime exposure or age-related immune changes may amplify risk in older populations. The findings align with existing studies linking smoking and substance use to MS risk through mechanisms like oxidative stress and immune dysregulation. These results reinforce the urgency of designing smoking cessation programs to prevent MS [51].
  • Diet Quality: In contrast to evidence suggesting that anti-inflammatory diets may reduce EOMS risk [66,67], our review found no significant association between diet quality and LOMS risk (HR = 0.79; 95% CI: 0.49–1.27). This divergence highlights a possible age-related shift in metabolic pathways or immune response in older individuals, where dietary factors may exert less influence on MS onset. Further biomarker-based studies are needed to clarify whether diet interacts with cumulative exposure or immune-aging mechanisms in LOMS populations. The neutral findings for diet quality differ from studies suggesting that anti-inflammatory diets might reduce MS risk. This discrepancy underscores the need for improved dietary assessment methods in MS research [19].
  • DMTs: Consistent with the existing literature, our review supports the role of DMTs in slowing disability progression (OR = 0.67) and reducing mortality (HR = 0.78) in elderly MS patients [68,69,70]. Importantly, our synthesis highlights the need to apply personalized DMT strategies to older patients, as immune senescence and comorbidities may alter treatment efficacy. The demonstrated benefits of DMTs in reducing disability and mortality align with previous research supporting their role in altering disease progression. This finding is particularly relevant for older MS populations [14].
While these findings align with the broader MS literature, the distinctive characteristics of LOMS suggest that certain types of environmental exposure, particularly those accumulated over a lifetime, may exert unique influences in older populations. This aligns with evolving hypotheses that immune-aging and prolonged environmental interactions may amplify LOMS susceptibility [18,42].

4.3. Strengths

  • We included diverse study designs (case–control, cohort, and cross-sectional), providing a broad perspective on LOMS risk factors and outcomes.
  • We used validated diagnostic criteria (e.g., the McDonald criteria) and reliable data sources, enhancing the robustness of the findings.
  • We focused on LOMS, an underexplored subtype of MS, providing unique insights into its etiology and management.

4.4. Limitations

4.4.1. Study-Level Limitations

  • Risk of Bias: Some of the studies relied on self-reported exposures (e.g., substance use) or lacked information on non-response rates, which may have introduced bias.
  • Heterogeneity: Differences in study design and exposure definitions limited comparability across studies.
  • Small Sample Sizes: While this review synthesized data from studies with varying sample sizes, the study by Joseph et al. (2021) warrants particular attention due to its notably small sample size (n = 23) [50]. The limited number of participants reduced the statistical power of this study, making its findings less generalizable to broader LOMS populations. Although this study was included due to its relevance to LOMS risk factors, we exercised caution in interpreting its findings. To ensure that our conclusions were informed by stronger evidence, this study was assigned less weight in the final narrative synthesis. This approach minimized the potential for overemphasis on conclusions drawn from limited data while still acknowledging this study’s contribution to understanding LOMS. Smaller studies, such as the one conducted by Joseph et al. [50] (n = 23), reduced the statistical power and generalizability of our results.

4.4.2. Outcome-Level Limitations

  • Limited Scope: While substance use and diet were explored, other forms of exposure (e.g., infections, air pollution, etc.) were underrepresented.
  • Short-Term Outcomes: Some studies lacked data on the long-term impacts of risk factors or interventions.

4.4.3. Review-Level Limitations

  • Incomplete Retrieval: Non-English and unpublished studies may have been missed, introducing selection bias.
  • Reporting Bias: Observational studies may have selectively reported significant results, reducing reliability.
  • Limited Study Pool: Only five studies met the inclusion criteria, limiting the breadth of evidence.

4.5. Implications for Practice

  • Healthcare Providers: Clinicians should prioritize interventions targeting modifiable risk factors, such as smoking and substance use, while continuing DMTs for managing LOMS progression.
  • Patients: Patients can benefit from making informed lifestyle changes and selecting optimized therapeutic options to improve outcomes.
  • Policy Makers: Public health initiatives should focus on smoking cessation and substance abuse reduction to mitigate the population-level risk of LOMS.

4.6. Implications for Clinical Guidelines

The findings from this review offer valuable insights that can inform future clinical guidelines for LOMS management:
  • Early Diagnosis and Timely DMT Initiation:
    Our findings reinforce the importance of ensuring early diagnosis and prompt DMT initiation to minimize the risk of irreversible disability among older MS patients.
  • Personalized Treatment Approaches:
    Future guidelines should emphasize personalized treatment strategies, particularly the use of lower-risk therapies for patients with multiple comorbidities or stable disease. Individualized monitoring protocols tailored to older patients are essential to ensure optimal treatment safety.
  • Integration of Geriatric Assessment Tools:
    Incorporating geriatric assessment tools into MS management may improve treatment decisions by identifying patients at higher risk of experiencing disability progression or adverse drug reactions.

4.7. Future Research Directions

  • Substance Use: Investigate dose–response relationships and underlying mechanisms linking substance use and LOMS.
  • Diet and Nutrition: Conduct longitudinal studies using biomarker-based dietary assessments to clarify the role of nutrition in LOMS.
  • Regional Variations: Explore geographic and socioeconomic disparities in LOMS risk factors to inform targeted interventions.
  • Longitudinal Cohort Studies: Develop prospective studies to strengthen causal evidence of identified risk factors and interventions in LOMS.
  • Comparative Studies on DMTs: There is a need for comparative trials evaluating the efficacy and safety of different DMTs, specifically in older MS populations, to guide optimal treatment selection.
  • Investigations into Immune-Aging Mechanisms: Research exploring the influence of immune-aging mechanisms on DMT response is crucial to improving treatment outcomes for elderly MS patients.
  • Biomarker-Based Treatment Prediction: Identifying biomarkers that predict treatment response among older patients may support more personalized care strategies, improving treatment selection and monitoring.

5. Conclusions

This review reinforces the established links between smoking, alcohol use, and LOMS risk while identifying a notably strong association between opium use and LOMS onset, which has received limited attention in previous MS research. While the observed protective effect of DMTs aligns with the established findings, the absence of a significant association between diet quality and LOMS risk contradicts prior evidence pertaining to EOMS populations. This inconsistency suggests that age-related metabolic shifts or cumulative exposure effects may alter risk pathways for older MS patients.
Our findings support emerging hypotheses that immune-aging, inflammaging, and prolonged environmental exposure may contribute uniquely to the etiology of LOMS. Further research exploring these mechanisms is essential to inform preventive strategies and optimize treatment approaches for this understudied MS subtype.

Author Contributions

Conceptualization, A.B., V.L., O.O. and A.G.; Methodology, A.B., V.L., O.O. and A.G.; Software, A.B.; Validation, A.B., O.O. and A.G.; Formal analysis, A.B.; Investigation, A.B.; Resources, O.O. and A.G.; Data curation, A.B.; Writing—original draft preparation, A.B.; Writing—review and editing, V.L. and O.O.; Visualization, A.B.; Supervision, V.L.; Project administration, V.L.; All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

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Sclerosis 03 00019 g001
Figure 1. PRISMA flow diagram.
Figure 1. PRISMA flow diagram.
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Figure 2. Forest plot displaying the effect estimates (ORs and HRs), with 95% confidence intervals, for environmental risk factors associated with LOMS. Blue lines represent the 95% confidence intervals (CIs) for each study’s effect estimate (OR/HR), with the blue dot indicating the point estimate. The red vertical dashed line corresponds to an OR/HR of 1.0, representing the null value (i.e., no association between the exposure and LOMS risk). Confidence intervals that cross the red line indicate non-significant associations, while intervals entirely to one side of the red line suggest a statistically significant association. References [14,19,50,51].
Figure 2. Forest plot displaying the effect estimates (ORs and HRs), with 95% confidence intervals, for environmental risk factors associated with LOMS. Blue lines represent the 95% confidence intervals (CIs) for each study’s effect estimate (OR/HR), with the blue dot indicating the point estimate. The red vertical dashed line corresponds to an OR/HR of 1.0, representing the null value (i.e., no association between the exposure and LOMS risk). Confidence intervals that cross the red line indicate non-significant associations, while intervals entirely to one side of the red line suggest a statistically significant association. References [14,19,50,51].
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Table 1. Summary of findings.
Table 1. Summary of findings.
StudyDesignPopulationSample SizeFollow-UpExposureOutcomeNOS ScoreRisk of Bias
Abbasi Kasbi et al., 2024 [51]Case–controlLOMS patients in Tehran, Iran290N/ASmoking, alcohol, substance useLOMS risk7/9Moderate Risk
Pommerich et al., 2020 [19] Prospective CohortDanish middle-aged adults56,86720.4 years (median)Diet qualityLOMS risk9/9Low Risk
Zinganell et al., 2024 [14]Retrospective CohortElderly MS patients in Austria120017.1 years (median)DMT usage, comorbiditiesLong-term disability progression8/9Low Risk
Joseph et al., 2021 [50]Cross-SectionalMS patients in South India23N/AClinical profilesDemographic and clinical characteristics4/9High Risk
Table 2. Summary of the results of the included studies.
Table 2. Summary of the results of the included studies.
StudyOutcomeExposure GroupsEffect Estimates (95% CI)Conclusion
Abbasi Kasbi et al., 2024 [51]Association between substance use and LOMSSmokers, alcohol users, substance abusers vs. non-usersCigarette smoking: OR = 2.57 (1.44–4.60)Substance use is strongly associated with LOMS risk.
Alcohol: OR = 2.45 (1.26–4.76)
Substance use: OR = 6.8 (2.29–17.20)
Pommerich et al., 2020 [19]Risk of LOMS according to diet qualityHigh vs. low diet quality tertilesHR = 0.79 (0.49–1.27)No significant association.
Zinganell et al., 2024 [14]Disability progression, mortality in elderly MSDMT users vs. non-usersEDSS: OR = 0.67 (0.55–0.81)DMT use slowed progression and reduced mortality.
Mortality: HR = 0.78 (0.65–0.94)
Joseph et al., 2021 [50]Clinico-demographic profiles of MS patientsNo exposure groupsMean age: 34.6 yearsSymptoms align with known MS characteristics.
Common symptoms: paresthesia (39.1%)
Note: EDSS = Expanded Disability Status Scale; OR = odds ratio; HR = hazard ratio; CI = confidence interval.
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Belenciuc, A.; Odainic, O.; Grumeza, A.; Lisnic, V. Systematic Review of Environmental Factors Associated with Late-Onset Multiple Sclerosis: A Synthesis of Epidemiological Evidence. Sclerosis 2025, 3, 19. https://doi.org/10.3390/sclerosis3020019

AMA Style

Belenciuc A, Odainic O, Grumeza A, Lisnic V. Systematic Review of Environmental Factors Associated with Late-Onset Multiple Sclerosis: A Synthesis of Epidemiological Evidence. Sclerosis. 2025; 3(2):19. https://doi.org/10.3390/sclerosis3020019

Chicago/Turabian Style

Belenciuc, Anna, Olesea Odainic, Alexandru Grumeza, and Vitalie Lisnic. 2025. "Systematic Review of Environmental Factors Associated with Late-Onset Multiple Sclerosis: A Synthesis of Epidemiological Evidence" Sclerosis 3, no. 2: 19. https://doi.org/10.3390/sclerosis3020019

APA Style

Belenciuc, A., Odainic, O., Grumeza, A., & Lisnic, V. (2025). Systematic Review of Environmental Factors Associated with Late-Onset Multiple Sclerosis: A Synthesis of Epidemiological Evidence. Sclerosis, 3(2), 19. https://doi.org/10.3390/sclerosis3020019

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