Clinical Characteristics and Disability Progression of Early- and Late-Onset Multiple Sclerosis Compared to Adult-Onset Multiple Sclerosis

Background: Compared to the adult onset of multiple sclerosis (AOMS), both early-onset (EOMS) and late-onset (LOMS) are much less frequent, but are often under- or misdiagnosed. The aims of the present study were: 1. To compare demographic and clinical features of individuals with EOMS, AOMS and LOMS, and 2. To identify predictors for disability progression from relapsing remitting MS (RRMS) to secondary progressive MS (SPMS). Method: Data were taken from the Isfahan Hakim MS database. Cases were classified as EOMS (MS onset ≤ 18 years), LOMS (MS onset >50 years) and AOMS (MS >18 and ≤ 50 years). Patients’ demographic and clinical (initial symptoms; course of disease; disease patterns from MRI; disease progress) information were gathered and assessed. Kaplan–Meier and Cox proportional hazard regressions were conducted to determine differences between the three groups in the time lapse in conversion from relapsing remitting MS to secondary progressive MS. Results: A total of 2627 MS cases were assessed; of these 127 were EOMS, 84 LOMS and 2416 AOMS. The mean age of those with EOMS was 14.5 years; key symptoms were visual impairments, brain stem dysfunction, sensory disturbances and motor dysfunctions. On average, 24.6 years after disease onset, 14.2% with relapsing remitting MS (RRMS) were diagnosed with secondary progressive MS (SPMS). The key predictor variable was a higher Expanded Disability Status Scale (EDSS) score at disease onset. Compared to individuals with AOMS and LOMS, those with EOMS more often had one or two relapses in the first two years, and more often gadolinium-enhancing brain lesions. For individuals with AOMS, mean age was 29.4 years; key symptoms were sensory disturbances, motor dysfunctions and visual impairments. On average, 20.5 years after disease onset, 15.6% with RRMS progressed to SPMS. The key predictors at disease onset were: a higher EDSS score, younger age, a shorter inter-attack interval and spinal lesions. Compared to individuals with EOMS and LOMS, individuals with AOMS more often had either no or three and more relapses in the first two years. For individuals with LOMS, mean age was 53.8 years; key symptoms were motor dysfunctions, sensory disturbances and visual impairments. On average, 14 years after disease onset, 25.3% with RRMS switched to an SPMS. The key predictors at disease onset were: occurrence of spinal lesions and spinal gadolinium-enhancement. Compared to individuals with EOMS and AOMS, individuals with LOMS more often had no relapses in the first two years, and higher EDSS scores at disease onset and at follow-up. Conclusion: Among a large sample of MS sufferers, cases with early onset and late onset are observable. Individuals with early, adult and late onset MS each display distinct features which should be taken in consideration in their treatment.

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Older Age at Multiple Sclerosis Onset Is an Independent Factor of Poor Prognosis: A Population-Based Cohort Study

Neuroepidemiology ◽

10.1159/000479516 ◽

2017 ◽

Vol 48 (3-4) ◽

pp. 179-187 ◽

Cited By ~ 19

Author(s):

Francis Guillemin ◽

Cédric Baumann ◽

Jonathan Epstein ◽

Philippe Kerschen ◽

Teresa Garot ◽

...

Keyword(s):

Multiple Sclerosis ◽

Poor Prognosis ◽

Cox Regression ◽

Late Onset ◽

Disease Onset ◽

Population Based ◽

Male Gender ◽

Disability Progression ◽

Relapsing Remitting ◽

Short Time

Background: Late-onset multiple sclerosis (LOMS) frequently features a primary progressive (PP) course, strongly predicting severe disability. In this population-based cohort, we estimated the prognostic role of age at multiple sclerosis (MS) onset, independent of PP course, on disability progression. Methods: The association of age at disease onset (adult, <50 years [AOMS], vs. late, ≥50 years [LOMS]) and time to Expanded Disability Status Scale (EDSS) score 4 and 6 was estimated by Cox regression modelling. Results: Among 3,597 patients, 245 had LOMS. Relapsing-remitting (RR) disease was less frequent with LOMS than AOMS (51.8 vs. 90.8%, p < 0.0001). PP course, LOMS and male gender predicted short time to EDSS 4 and 6. Worse outcome with LOMS (time to EDSS 4 and 6, HR 2.0 [95% CI 1.7-2.4] and 2.3 [1.9-2.9]) was independent of PP course or male gender. LOMS had greater impact on RR than PP disease (time to EDSS 4 and 6, HR 3.1 [2.3-4.0] and 4.0 [2.9-5.6]). Only LOMS predicted time from EDSS 4 to 6 (p < 0.0001). Conclusions: Late onset MS was strongly associated with poor prognosis, independent of initial disease course, in predicting the disability progression along time.

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Should We Use Clinical Tools to Identify Disease Progression?

Frontiers in Neurology ◽

10.3389/fneur.2020.628542 ◽

2021 ◽

Vol 11 ◽

Author(s):

Hernan Inojosa ◽

Undine Proschmann ◽

Katja Akgün ◽

Tjalf Ziemssen

Keyword(s):

Multiple Sclerosis ◽

Clinical Markers ◽

Disability Progression ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Secondary Progressive ◽

Disability Status ◽

Relapsing Remitting ◽

Clinical Tools

The presence of disability progression in multiple sclerosis (MS) is an important hallmark for MS patients in the course of their disease. The transition from relapsing remitting (RRMS) to secondary progressive forms of the disease (SPMS) represents a significant change in their quality of life and perception of the disease. It could also be a therapeutic key for opportunities, where approaches different from those in the initial phases of the disease can be adopted. The characterization of structural biomarkers (e.g., magnetic resonance imaging or neurofilament light chain) has been proposed to differentiate between both phenotypes. However, there is no definite threshold between them. Whether the risk of clinical progression can be predicted by structural markers at early disease phases is still a focus of clinical research. However, several theories and pathological evidence suggest that both disease phenotypes are part of a continuum with common pathophysiological mechanisms. In this case, the clinical evaluation of the patients would play a preponderant role above destruction biomarkers for the early identification of disability progression and SPMS. For this purpose, the use of clinical tools beyond the Expanded Disability Status Scale (EDSS) should be considered. Besides established functional tests such as the Multiple Sclerosis Functional Composite (MSFC), patient's neurological history or digital resources may help neurologists in the decision-taking. In this article, we discuss arguments for the use of clinical markers in the detection of secondary progressive MS and the characterization of progressive disease activity.

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Age at onset as a determinant of presenting phenotype and initial relapse recovery in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458511417479 ◽

2011 ◽

Vol 18 (1) ◽

pp. 45-54 ◽

Cited By ~ 52

Author(s):

M Cossburn ◽

G Ingram ◽

C Hirst ◽

Y Ben-Shlomo ◽

TP Pickersgill ◽

...

Keyword(s):

Multiple Sclerosis ◽

Late Onset ◽

Age At Onset ◽

Disease Onset ◽

Complete Recovery ◽

Population Based ◽

Disease Course ◽

Index Event ◽

Relapsing Remitting ◽

Age Dependent

Background: Age at onset modifies prognosis in multiple sclerosis (MS) and may also exert an effect on the characteristics of disease ignition. Understanding how age influences presentation informs disease management and may allow differentiation of distinct clinical sub-groups. Objectives: To determine the nature of age-specific presentations of relapsing–remitting MS (RRMS) with respect to onset symptoms, gender ratios and index event outcomes. Methods: In a prospective, population-based sample of 1424 patients in South-East Wales we examined associations between age at onset, clinical features and outcome of the onset event, making specific comparisons between paediatric, adolescent and late-onset MS. Results: Age at onset varied significantly between sexes (Male 31.2, Female 29.3, p = 0.002), 0.7% had paediatric onset, 2.7% adolescent onset and 2.8% late-onset MS (>50 years). Optic neuritis was common in younger patients and declined after age 30. Lower limb motor, facial sensory, sexual and sphincteric symptoms rose with age independent of sex and disease course. F:M ratios were highest <16 years of age and declined with increasing age, with a male excess in those over 50. Probability of complete recovery from index event declined with age from 87.4% in the youngest group to 68% in the eldest ( p = 0.009). Conclusions: Age at disease onset in RRMS exerts a significant effect on gender ratios and presenting phenotype, and allows identification of specific clinical sub-groups. In addition, ability to recover from initial relapse declines with age, suggesting accumulation of disability in MS is an age-dependent response to relapse.

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Secondary Progressive Multiple Sclerosis: New Insights

Neurology ◽

10.1212/wnl.0000000000012323 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012323

Author(s):

Bruce Anthony Campbell Cree ◽

Douglas L Arnold ◽

Jeremy Chataway ◽

Tanuja Chitnis ◽

Robert J. Fox ◽

...

Keyword(s):

Multiple Sclerosis ◽

Progressive Disease ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Response To Treatment ◽

Disability Progression ◽

Long Term Outcomes ◽

Secondary Progressive ◽

Relapsing Remitting

In most cases, multiple sclerosis (MS) begins with a relapsing–remitting course followed by insidious disability worsening that is independent from clinically apparent relapses and is termed secondary progressive multiple sclerosis (SMPS). Major differences exist between relapsing–remitting MS (RRMS) and SPMS, especially regarding therapeutic response to treatment. This review provides an overview of the pathology, differentiation, and challenges in the diagnosis and treatment of SPMS. We emphasize the criticality of conversion from a relapsing–remitting to a secondary progressive disease course not only because such conversion is evidence of disability progression, but also because, until recently, treatments that effectively reduced disability progression in relapsing MS were not proven to be effective in SPMS. Clear clinical, imaging, immunological, or pathological criteria marking the transition from RRMS to SPMS have not yet been established. Early identification of SPMS will require tools which, together with the use of appropriate treatments, may result in better long-term outcomes for the population of patients with SPMS.

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Elevated sCD40L in Secondary Progressive Multiple Sclerosis in Comparison to Non-progressive Benign and Relapsing Remitting Multiple Sclerosis

Journal of Central Nervous System Disease ◽

10.1177/11795735211050712 ◽

2021 ◽

Vol 13 ◽

pp. 117957352110507

Author(s):

Qi Wu ◽

Qin Wang ◽

Jennifer Yang ◽

Jacob WS Martens ◽

Elizabeth A Mills ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Plasma Levels ◽

Disease Onset ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Secondary Progressive ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

Background: The long-term prognosis of relapsing-remitting multiple sclerosis (RRMS) is usually unfavorable as most patients transition to secondary progressive multiple sclerosis (SPMS) with accumulative disability. A rare form of non-progressive multiple sclerosis (MS) also exists, known as benign MS (BMS or NPMS), which lacks disease progression defined as Expanded Disability Status Scale (EDSS) ≤3 after 15 years of disease onset without treatment. Purpose: Our study aims to identify soluble plasma factors predicting disease progression in multiple sclerosis (MS). Research Design and Study Sample: We utilized Luminex multiplex to analyze plasma levels of 33 soluble factors, comparing 32 SPMS patients to age-, sex-, and disease duration-matched non-progressive BMS patients, as well as to RRMS patients and healthy controls. Results: Plasma levels of EGF, sCD40L, MCP1/CCL2, fractalkine/CX3CL1, IL-13, Eotaxin, TNFβ/LTα, and IL-12p40 were significantly different between the various types of MS. Plasma sCD40L was significantly elevated in SPMS compared to BMS and RRMS. The combination of MCP1/CCL2 and sCD40L discriminated between RRMS and SPMS. MCP1/CCL2 was found to be the most effective classifier between BMS and RRMS, while BMS was most effectively distinguished from SPMS by the combination of sCD40L and IFNγ levels. Conclusions: These differences may facilitate personalized precision medicine and aid in the discovery of new therapeutic targets for disease progression through the improvement of patient stratification.

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Multiple sclerosis in Pakistan

Multiple Sclerosis Journal ◽

10.1177/1352458506072339 ◽

2007 ◽

Vol 13 (5) ◽

pp. 668-669 ◽

Cited By ~ 9

Author(s):

M. Wasay ◽

S. Ali ◽

I.A. Khatri ◽

A. Hassan ◽

M. Asif ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Duration ◽

Age At Onset ◽

Disease Onset ◽

Severe Disability ◽

Motor Weakness ◽

Secondary Progressive ◽

Male Ratio ◽

Short Disease Duration ◽

Relapsing Remitting

We describe retrospective data from the largest series of patients (n=142) with multiple sclerosis (MS) from Pakistan. Mean age at onset was 27 years, with a female to male ratio of 1.45:1. The disease onset was polysymptomatic in 75% patients. Motor weakness was the most common onset symptom (70%), followed by sensory symptoms (45%). Optico-spinal type of MS was seen in only 3% of patients The courzse was relapsing-remitting (RR) in 81%, primary progressive (PP) in 21%, and secondary progressive (SP) in 4% of patients. Almost three-fourths of the patients were moderately (45%) or severely (31%) disabled at the time of evaluation. Two-thirds of patients with severe disability had a mean disease duration of only 5.2 years. In conclusion, MS is not uncommon in Pakistan, and many patients were found to have severe disability despite short disease duration. Multiple Sclerosis 2007; 13: 668-669. http://msj.sagepub.com

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Diagnostic uncertainty during the transition to secondary progressive multiple sclerosis: Multicenter study in Argentina

Multiple Sclerosis Journal ◽

10.1177/1352458520924586 ◽

2020 ◽

pp. 135245852092458 ◽

Cited By ~ 1

Author(s):

Juan Ignacio Rojas ◽

Liliana Patrucco ◽

Ricardo Alonso ◽

Orlando Garcea ◽

Norma Deri ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Onset ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Multicenter Cohort Study ◽

Diagnostic Uncertainty ◽

Secondary Progressive ◽

Kaplan Meier ◽

Relapsing Remitting ◽

Time Required

Background: A period of diagnostic uncertainty often characterizes the clinical transition from relapsing to secondary progressive multiple sclerosis (SPMS). Objective: The aim of this study was to describe the length of time required to reclassify relapsing-remitting MS (RRMS) patients who have clinically transitioned to SPMS (diagnosis uncertainty). Methods: This is a retrospective multicenter cohort study conducted in Argentina, identifying in every center all patients with diagnosis of MS who transitioned from RRMS to SPMS during the follow-up. We identified the dates of the last definitive RRMS and first definitive SPMS diagnoses for diagnostic uncertainty. The time required to reclassify RRMS who transitioned to SPMS and the time from disease onset to reclassify SPMS were calculated using the Kaplan–Meier method. Results: A total of 170 patients were included, where the mean age at disease onset (first symptom) was 36 ± 6 years; the length of time required to reclassify RRMS patients who transitioned to SPMS was 3.3 ± 1.1 years (range = 1–7 years); and the time from disease onset to classify SPMS was 19.4 ± 8.5 years (range = 16–35 years). Conclusion: A period of diagnostic uncertainty regarding the transition from RRMS to SPMS was present in many of our patients, with a mean time of 3.3 years.

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CCR5Δ32 Polymorphism Associated with a Slower Rate Disease Progression in a Cohort of RR-MS Sicilian Patients

Multiple Sclerosis International ◽

10.1155/2011/153282 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6

Author(s):

Rosalia D'Angelo ◽

Concetta Crisafulli ◽

Carmela Rinaldi ◽

Alessia Ruggeri ◽

Aldo Amato ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Onset ◽

Expanded Disability Status Scale ◽

Ccr5 Gene ◽

Secondary Progressive ◽

Inflammatory Mechanism ◽

Disability Status ◽

Relapsing Remitting ◽

Cc Chemokines ◽

Sicilian Population

Multiple sclerosis (MS) disease is carried through inflammatory and degenerative stages. Based on clinical feaures, it can be subdivided into three groups: relapsing-remitting MS, secondary progressive MS, and primary progressive MS. Multiple sclerosis has a multifactorial etiology with an interplay of genetic predisposition, environmental factors, and autoimmune inflammatory mechanism in which play a key role CC-chemokines and its receptors. In this paper, we studied the frequency of CCR5 gene Δ32 allele in a cohort of Sicilian RR-MS patients comparing with general Sicilian population. Also, we evaluate the association between this commonly polymorphism and disability development and age of disease onset in the same cohort. Our results show that presence of CCR5Δ32 is significantly associated with expanded disability status scale score (EDSS) but not with age of disease onset.

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Disease-modifying drugs can reduce disability progression in relapsing multiple sclerosis

Brain ◽

10.1093/brain/awaa251 ◽

2020 ◽

Vol 143 (10) ◽

pp. 3013-3024

Author(s):

Maria Pia Amato ◽

Mattia Fonderico ◽

Emilio Portaccio ◽

Luisa Pastò ◽

Lorenzo Razzolini ◽

...

Keyword(s):

Multiple Sclerosis ◽

Late Onset ◽

Hazard Ratio ◽

Adjusted Hazard Ratio ◽

Dependent Manner ◽

Adult Onset ◽

Disease Modifying Drugs ◽

Relapsing Remitting ◽

Disease Modifying

Abstract An ever-expanding number of disease-modifying drugs for multiple sclerosis have become available in recent years, after demonstrating efficacy in clinical trials. In the real-world setting, however, disease-modifying drugs are prescribed in patient populations that differ from those included in pivotal studies, where extreme age patients are usually excluded or under-represented. In this multicentre, observational, retrospective Italian cohort study, we evaluated treatment exposure in three cohorts of patients with relapsing-remitting multiple sclerosis defined by age at onset: paediatric-onset (≤18 years), adult-onset (18–49 years) and late-onset multiple sclerosis (≥50 years). We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale (EDSS) evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% conﬁdence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained EDSS of 4.0. The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in paediatric-onset and adult-onset patients [adjusted hazard ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5–17.9) for paediatric-onset and 6.3 (4.9–8.0) for adult-onset, P < 0.0001] showing a trend in late-onset patients [adjusted hazard ratio = 1.9 (0.9–4.1), P = 0.07]. These results were confirmed for a sustained EDSS score of 4.0. We also found that relapses were a risk factor for 12-month confirmed disability worsening in all three cohorts, and female sex exerted a protective role in the late-onset cohort. This study provides evidence that sustained exposure to disease-modifying drugs decreases the risk of disability accumulation, seemingly in a dose-dependent manner. It confirms that the effectiveness of disease-modifying drugs is lower in late-onset patients, although still detectable.

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Longitudinal disability curves for predicting the course of relapsing-remitting multiple sclerosis

Multiple Sclerosis Journal ◽

10.1191/1352458503ms945oa ◽

2003 ◽

Vol 9 (5) ◽

pp. 486-491 ◽

Cited By ~ 18

Author(s):

Anat Achiron ◽

Yoram Barak ◽

Zeev Rotstein

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Disease Onset ◽

Disease Process ◽

Predictive Ability ◽

Rank Test ◽

Clinical Impression ◽

Disability Progression ◽

Relapsing Remitting ◽

Table Analysis

Background: Multiple sclerosis (MS) is a lifelong disease affecting young adults that ultimately can lead to significant neurological disability. Identifying the rate of progression of disability for an individual patient early in the disease process can influence treatment decisions as well as enable monitoring of the disease overtime. Objective: The aims of the present study were to develop longitudinal disability curves to assess disease progression in patients with relapsing -remitting MS. The construction of these disability curves was based on the mean yearly Expanded Disability Status Scale (EDSS) scores, represented as a major percentile group. To determine their predictive ability, validation of the percentile curves was performed. Methods: Using the Multiple Sclerosis C enter computerized database of 1540 patients’ records, we identified 1317 subjects with a definite MS and a relapsing-remitting disease course. Longitudinal disability curves were constructed for a subgroup of relapsing-remitting patients (n=1001) with consecutive (3-6 months) EDSS assessments for a period of up to 10 years since onset. The constructed disability curves were then validated in an additional subgroup of relapsing - remitting MS patients (n=268) with continuous follow-up visits for a period of 10 years. Results: Statistical procedures using parametric and nonparametric regression procedures were applied to the data in two stages. In the first stage, selected major percentiles were generated for up to 10 years from disease onset with a variety of parametric procedures including moving averages. In the second stage, the empirical percentiles were smoothed to obtain the final disability progression curves. The log-rank test for equality demonstrated a significant adjustment between the initial percentile assignment and disability progression (P B-0.001). Life table analysis demonstrated that the probability of deviating from the initially assigned percentile to a higher percentile over time, representing more severe disability than expected, is in the range of 6.5% for the 50th percentile to 10.4% for the 75th percentile. Conclusion: Longitudinal disability curves can be used in MS to assess individual patient disability, can contribute to the overall clinical impression of disease progression and can add to the evaluation of immunomodulating treatment effects overtime.

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