Diagnostic Criteria For Multiple Sclerosis Research Articles

Incorporating the Central Vein Sign Into the Diagnostic Criteria for Multiple Sclerosis

This Viewpoint discusses incorporating the central vein sign into the diagnostic criteria for multiple sclerosis.

Performance of McDonald 2017 multiple sclerosis diagnostic criteria and evaluation of genetic ancestry in patients with a first demyelinating event in Argentina

Background: Information on performance of multiple sclerosis (MS) diagnostic criteria is scarce for populations from Latin America, Asia, or the Caribbean. Objective: To assess performance of revised 2017 McDonald criteria as well as evaluate genetic ancestry in a group of MS patients from Argentina experiencing a debut demyelinating event. Methods: Demographic and clinical characteristics, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) findings and new T2 lesions were recorded at baseline and during relapses. Diagnostic accuracy in predicting conversion to clinically defined MS (CDMS) based on initial imaging applying revised 2017 criteria was evaluated and genetic ancestry-informative markers analyzed. Results: Of 201 patients experiencing their first demyelinating event (median follow-up 60 months), CDMS was confirmed in 67. We found 2017 diagnostic criteria were more sensitive (84% vs 67%) and less specific (14% vs 33%) than 2010 criteria, especially in a group of patients revised separately, presenting positive oligoclonal bands (88% vs 8%). Genetic testing performed in 128 cases showed 72% of patients were of European ancestry and 27% presented genetic admixture. Conclusion: 2017 McDonald criteria showed higher sensitivity and lower specificity compared with 2010 criteria, shortening both time-to-diagnosis and time-to-treatment implementation.

T1 /T2 ratio from 3T MRI improves multiple sclerosis cortical lesion contrast.

Cortical demyelinated lesions are prevalent in multiple sclerosis (MS), associated with disability, and have recently been incorporated into MS diagnostic criteria. Presently, advanced and ultrahigh-field MRIs-not routinely available in clinical practice-are the most sensitive methods for detection of cortical lesions. Approaches utilizing MRI sequences obtainable in routine clinical practice remain an unmet need. We plan to assess the sensitivity of the ratio of T1 -weighted and T2 -weighted (T1 /T2 ) signal intensity for focal cortical lesions in comparison to other high-field imaging methods. 3-Tesla and 7-Tesla MRI collected from 10 adults with MS were included in the study. T1 /T2 images were calculated by dividing 3T T1 -weighted (T1 w) images by 3T T2 -weighted (T2 w) fluid-attenuated inversion recovery images for each participant. A total of 614 cortical lesions were identified using 7T T2 *w and T1 w images and corresponding voxels were assessed on registered 3T images. Signal intensities were compared across 3T imaging sequences, including T1 /T2 , T1 w, T2 w, and inversion recovery susceptibility-weighted imaging with enhanced T2 weighting (IR-SWIET) images. T1 /T2 images demonstrated a larger contrast between median lesional and nonlesional cortical signal intensity (median ratio=1.29, range: 1.19-1.38) when compared to T1 w (1.01, 0.97-1.10, p<.002), T2 w (1.17, 1.07-1.26, p<.002), and IR-SWIET (1.21, 1.01-1.29, p<.03). T1 /T2 images are sensitive to cortical lesions. Approaches incorporating T1 /T2 could improve the accessibility of cortical lesion detection in research settings and clinical practice.

Objectively-captured Changes in Trigeminal Fibers before and after Microvascular Decompression Using 3D T2-SPACE MRI Might Relate to Eventual Residual Symptoms.

Although microvascular decompression (MVD) is a reliable treatment for trigeminal neuralgia (TN), neurosurgeons sometimes encounter patients whose symptoms do not improve postoperatively or who experience good treatment efficacy but develop other sensory disturbances. This study aims to objectively identify changes in nerve fibers before and after surgery by MRI and to clarify the relationship between the changes and residual postoperative symptoms. We retrospectively analyzed data from 36 consecutive patients who underwent MVD for classical TN at our hospital between November 2019 and November 2020. Cases that fulfilled the diagnostic criteria for multiple sclerosis were excluded. We confirmed the changes on the brainstem side of the trigeminal nerve preoperatively and at seven days postoperatively using 3D T2-SPACE MRI, in which the patients were divided into three groups: preoperative T2 high intensity positive (A), postoperative T2 high intensity positive (B), and no T2 high-intensity region (C). The primary outcome measures were therapeutic efficacy and frequency of postoperative numbness. The results of MVD surgery were evaluated one year postoperatively. The percentage of cases in which treatment outcomes were rated as excellent or good at one year: group A: 0 (0%), group B: 6 (100%), and group C: 25 (96.2%) (p < 0.05); the frequency of numbness: 2 (50%) in group A, 3 (50%) in group B, and 1 (3.8%) in group C, indicating significant differences between the three groups (p < 0.05). 3D T2-SPACE MRI sequences can be used to identify changes in trigeminal nerve fibers before and after MVD, which might correlate with eventual residual symptoms.

Lesion location across diagnostic regions in multiple sclerosis

BackgroundLesions in the periventricular, (juxta)cortical, and infratentorial region, as visible on brain MRI, are part of the diagnostic criteria for Multiple sclerosis (MS) whereas lesions in the subcortical region are currently only a marker of disease activity. It is unknown whether MS lesions follow individual spatial patterns or whether they occur in a random manner across diagnostic regions. AimFirst, to describe cross-sectionally the spatial lesion patterns in patients with MS. Second, to investigate the spatial association of new lesions and lesions at baseline across diagnostic regions. MethodsExperienced neuroradiologists analyzed brain MRI (3D, 3T) in a cohort of 330 early MS patients. Lesions at baseline and new solitary lesions after two years were segmented (manually and by consensus) and classified as periventricular, (juxta)cortical, or infratentorial (diagnostic regions) or subcortical—with or without Gadolinium-enhancement. Gadolinium enhancement of lesions in the different regions was compared by Chi square test. New lesions in the four regions served as dependent variable in four zero-inflated Poisson models each with the six independent variables of lesions in the four regions at baseline, age and gender. ResultsAt baseline, lesions were most often observed in the subcortical region (mean 13.0 lesions/patient), while lesion volume was highest in the periventricular region (mean 2287 µl/patient). Subcortical lesions were less likely to show gadolinium enhancement (3.1 %) than juxtacortical (4.3 %), periventricular (5.3 %) or infratentorial lesions (7.2 %). Age was inversely correlated with new periventricular, juxtacortical and subcortical lesions. New lesions in the periventricular, juxtacortical and infratentorial region showed a significant autocorrelative behavior being positively related to the number of lesions in the respective regions at baseline. New lesions in the subcortical region showed a different behavior with a positive association with baseline periventricular lesions and a negative association with baseline infratentorial lesions. ConclusionAcross regions, new lesions do not occur randomly; instead, new lesions in the periventricular, juxtacortical and infratentorial diagnostic region are associated with that at baseline. Lesions in the subcortical regions are more closely related to periventricular lesions. Moreover, subcortical lesions substantially contribute to lesion burden in MS but are less likely to show gadolinium enhancement (than lesions in the diagnostic regions).

In Silico Structural Analysis Predicting the Pathogenicity of PLP1 Mutations in Multiple Sclerosis.

The X chromosome gene PLP1 encodes myelin proteolipid protein (PLP), the most prevalent protein in the myelin sheath surrounding the central nervous system. X-linked dysmyelinating disorders such as Pelizaeus-Merzbacher disease (PMD) or spastic paraplegia type 2 (SPG2) are typically caused by point mutations in PLP1. Nevertheless, numerous case reports have shown individuals with PLP1 missense point mutations which also presented clinical symptoms and indications that were consistent with the diagnostic criteria of multiple sclerosis (MS), a disabling disease of the brain and spinal cord with no current cure. Computational structural biology methods were used to assess the impact of these mutations on the stability and flexibility of PLP structure in order to determine the role of PLP1 mutations in MS pathogenicity. The analysis showed that most of the variants can alter the functionality of the protein structure such as R137W variants which results in loss of helix and H140Y which alters the ordered protein interface. In silico genomic methods were also performed to predict the significance of these mutations associated with impairments in protein functionality and could suggest a better definition for therapeutic strategies and clinical application in MS patients.

Improvement in time to multiple sclerosis diagnosis: 25-year retrospective analysis from New York State MS Consortium (NYSMSC)

Judicious multiple sclerosis (MS) diagnosis and early start of disease modifying therapy significantly improves long-term disability outcomes in persons with MS (pwMS). Retrospective analysis based on 25-year New York State MS Consortium (NYSMSC) data determined the effect of changes in the respective diagnostic criteria in shortening the time between symptom onset to MS diagnosis. Based on 9378 current and historical MS cases, there was a significant decrease in time to diagnosis in pwMS from 1982–2001 to >2017 periods (average 4.2 vs. 1.1 years, p < 0.001). Additional improvements and better implementation of the MS diagnostic criteria can further decrease the diagnosis lag.

Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A consensus statement

Cerebrospinal fluid (CSF) analysis is of utmost importance for diagnosis and differential diagnosis of patients with suspected multiple sclerosis (MS). Evidence of intrathecal immunoglobulin G (IgG) synthesis proves the inflammatory nature of the disease, increases diagnostic certainty and substitutes for dissemination in time according to current diagnostic criteria. The gold standard to determine intrathecal IgG synthesis is the detection of CSF-restricted oligoclonal bands (OCBs). However, advances in laboratory methods brought up κ-free light chains (FLCs) as a new biomarker, which are produced in excess over intact immunoglobulins and accumulate in CSF in the case of central nervous system-derived inflammation. Overwhelming evidence showed a high diagnostic accuracy of intrathecal κ-FLC synthesis in MS with sensitivity and specificity of approximately 90% similar to OCB. κ-FLCs have advantages as its detection is fast, easy, cost-effective, reliable, rater-independent and returning quantitative results which might also improve the value of predicting MS disease activity. An international panel of experts in MS and CSF diagnostics developed a consensus of all participants. Six recommendations are given for establishing standard CSF evaluation in patients suspected of having MS. The panel recommended to include intrathecal κ-FLC synthesis in the next revision of MS diagnostic criteria as an additional tool to measure intrathecal immunoglobulin synthesis.

Multiple Sclerosis – Challenges in Diagnosis

Multiple Sclerosis is an inflammatory demyelinating disease that affects the central nervous system, and is uncommon among the Asian population. It can present with a variety of symptoms, depending on the location of the demyelinating plaques, which could also potentially mimic a range of neurological and non-neurological disorders. We report a 24-year-old woman who presented with recurrent non-specific lower limb numbness, without any other neurological symptoms or signs. The symptoms were presumed to be nonspecific, but they re-occurred eight months later, leading to a more extensive investigation, including whole spine and brain MRI. The MRI showed multiple white matter lesions that are hyperintense on T2W/FLAIR, seen at the right corona radiata, bilateral parietal lobes, right periventricular region and spinal cord, with a simultaneous presence of gadolinium-enhancing and nonenhancing lesions, fulfilling 2017 Mc Donald’s diagnostic criteria for multiple sclerosis. After the careful exclusion of differential diagnoses, she was given pulsed IV methylprednisolone for 5 days, followed by oral teriflunomide. She improved partially, and at 2 months following discharge, she was tolerating the medication well with no further relapses.

Multiple Sclerosis – Challenges in Diagnosis

Multiple Sclerosis is an inflammatory demyelinating disease that affects the central nervous system, and is uncommon among the Asian population. It can present with a variety of symptoms, depending on the location of the demyelinating plaques, which could also potentially mimic a range of neurological and non-neurological disorders. We report a 24-year-old woman who presented with recurrent non-specific lower limb numbness, without any other neurological symptoms or signs. The symptoms were presumed to be nonspecific, but they re-occurred eight months later, leading to a more extensive investigation, including whole spine and brain MRI. The MRI showed multiple white matter lesions that are hyperintense on T2W/FLAIR, seen at the right corona radiata, bilateral parietal lobes, right periventricular region and spinal cord, with a simultaneous presence of gadolinium-enhancing and nonenhancing lesions, fulfilling 2017 Mc Donald’s diagnostic criteria for multiple sclerosis. After the careful exclusion of differential diagnoses, she was given pulsed IV methylprednisolone for 5 days, followed by oral teriflunomide. She improved partially, and at 2 months following discharge, she was tolerating the medication well with no further relapses.

Diagnosis of Multiple Sclerosis.

The diagnosis of multiple sclerosis (MS) can be made based on clinical symptoms and signs alone or a combination of clinical and paraclinical features. Diagnostic criteria for MS have evolved over time, and the latest version facilitates earlier diagnosis of MS in those presenting with typical clinical syndromes. This article summarizes the current diagnostic criteria for MS, typical and atypical presentations of MS, and when diagnostic criteria should be applied with caution. The most recent version of the MS diagnostic criteria has the benefits of simplicity and greater sensitivity in comparison to previous iterations. However, misdiagnosis remains a significant issue in MS clinical care, even at MS specialty centers. It is, therefore, evident that careful clinical application of the current version of the diagnostic criteria is necessary and that tools improving the diagnostic accuracy of MS would be of substantial clinical utility. Emerging diagnostic biomarkers that may be useful in this regard, including the central vein sign, paramagnetic rim lesions, and fluid biomarkers, are discussed. Current MS diagnostic criteria facilitate the early diagnosis of MS in people presenting with typical clinical syndromes but should be used cautiously in those presenting with atypical syndromes and in special populations. Clinical judgment and existing paraclinical tools, including sequential MRIs of the neuraxis and laboratory tests, are useful in minimizing misdiagnosis and facilitating the accurate diagnosis of MS. Diagnostic biomarkers that may facilitate or refute a diagnosis of MS in these settings, and emerging imaging and fluid biomarkers may eventually become available for use in clinical settings.

Psychometrics of the Multiple Sclerosis and Magnetic Resonance Imaging Knowledge Patient Questionnaire: A Pilot Study.

BACKGROUND: In the last few decades, the revised diagnostic criteria for multiple sclerosis (MS) and the development of numerous new MS therapies have created the possibility of early diagnosis and opportune MS management. However, these changes, and the mounting emphasis on patient choice and shared decision making, have not been accompanied by improvements in information provided to patients with MS (PwMS). Information provision for PwMS increases disease-related knowledge that may assist them in decision making and quality of life. The purpose of this study was to validate the Multiple Sclerosis and Magnetic Resonance Imaging Knowledge Questionnaire (MSMRIKQ) to improve patients' shared decision-making capabilities. METHODS: In this methodological study, the instrument development process was completed in 4 stages using principles of measurement theory: (1) establishing a pool of items after patient and clinician panels' review, (2) evaluating the validity of the scale-both face and content validity, (3) pilot testing the scale, and (4) post-pilot testing statistical analysis of items and scale reliability and validity. RESULTS: The 20-item instrument was finalized based on a panel of MS experts' and patients' comments. The final version of the MSMRIKQ was pilot tested with a sample of 46 PwMS. Face validity was established on all MSMRIKQ items. Individual item-level and scale-level content validity indices for universal agreement estimates were acceptable at item-level content validity index = 1 and scale-level content validity index = 1 for the 20 items. The Kuder-Richardson 20 reliability estimate for the entire scale was 0.58; the Kuder-Richardson 20 estimates for the subscales of MS and magnetic resonance imaging knowledge were 0.35 and 0.51, respectively. The split-half reliability with Spearman-Brown correction for the total scale was 0.60. The Poisson regression model was significant for predicting MS knowledge within this population. CONCLUSION: The MSMRIKQ is a basic knowledge instrument for clinical and research use.

Serum MOG-IgG in children meeting multiple sclerosis diagnostic criteria

Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is now recognized as distinct from multiple sclerosis (MS). Objective: To evaluate the importance of considering myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin-G (IgG) serology when applying MS diagnostic criteria in children. Methods: Within a prospective cohort of children meeting MS criteria (median follow-up = 6 years, interquartile range (IQR) = 4–9), we measured MOG-IgG in serial archived serum obtained from presentation, and compared imaging and clinical features between seropositive and seronegative participants. Results: Of 65 children meeting MS criteria (median age = 14.0 years, IQR = 10.9–15.1), 12 (18%) had MOG-IgG at disease onset. Seropositive participants were younger, had brain magnetic resonance imaging (MRI) features atypical for MS, rarely had cerebrospinal fluid (CSF) oligoclonal bands (2/8, 25%), and accumulated fewer T2 lesions over time. On serial samples, 5/12 (42%) were persistently seropositive, 5/12 (42%) became seronegative, and 2/12 (17%) had fluctuating results. All 12 children experienced a disease course different from typical MS. Conclusion: While children with MOG-IgG can have clinical, CSF, and MRI features conforming to MS criteria, the presence of MOG-IgG is associated with atypical features and predicts a non-MS disease course. Given MOG-IgG seropositivity can wane over time, testing at first attack is of considerable importance for the diagnosis of MOGAD.

Emerging analytes in cerebrospinal fluid (CSF) testing

CSF examination is a useful investigation in the diagnosis, monitoring and prognostication of several neuroimmunological diseases. Traditionally, several biomarkers used in the diagnostic immunopathology laboratory, e.g., the presence of oligoclonal bands by isoelectric focusing, have been included in the diagnostic criteria for multiple sclerosis. Lately, with the emergence of various autoimmune encephalitides, and the growing awareness that not all biomarkers of systemic disease are present in peripheral blood, there has been an active search for clinically useful analytes in the CSF.

Anti-Phosholipid Syndrome Misdiagnosed As Multiple Sclerosis: A Case Report.

Multiple sclerosis (MS) and anti-phospholipid syndrome (APS) are chronic, immune-mediated, relapsing-remitting disorders affecting young adults. APS is characterized by thrombosis and pregnancy mortality associated with anti-phospholipid antibodies. The diagnosis of APS may be difficult, and it is not uncommon for patients with APS to be misdiagnosed with multiple sclerosis. In this case report, we describe a patient who was diagnosed as having multiple sclerosis for eleven-year. Initially, the patient had neurological deficits with relapsing-remitting courses, like MS but he had not classic magnetic resonance imaging appearance of MS and absence of oligoclonal bands in the cerebrospinal fluid. He did not meet the 'dissemination criteria in time and place' specified in the MS diagnostic criteria. Also, he had an acute myocardial infarction and ischemic stroke at different times. The diagnosis of primary APS was made after the patient had thrombotic attacks, seizure and was positive for anti-phospholipid antibodies (aPLs) twice. Our observations raise awareness about the importance of the early and correct diagnosis of APS. When assessing MS patients, clinicians should consider APS, if the MS has atypical features.

Cortical lesions, central vein sign, and paramagnetic rim lesions in multiple sclerosis: Emerging machine learning techniques and future avenues

The current diagnostic criteria for multiple sclerosis (MS) lack specificity, and this may lead to misdiagnosis, which remains an issue in present-day clinical practice. In addition, conventional biomarkers only moderately correlate with MS disease progression. Recently, some MS lesional imaging biomarkers such as cortical lesions (CL), the central vein sign (CVS), and paramagnetic rim lesions (PRL), visible in specialized magnetic resonance imaging (MRI) sequences, have shown higher specificity in differential diagnosis. Moreover, studies have shown that CL and PRL are potential prognostic biomarkers, the former correlating with cognitive impairments and the latter with early disability progression. As machine learning-based methods have achieved extraordinary performance in the assessment of conventional imaging biomarkers, such as white matter lesion segmentation, several automated or semi-automated methods have been proposed as well for CL, PRL, and CVS. In the present review, we first introduce these MS biomarkers and their imaging methods. Subsequently, we describe the corresponding machine learning-based methods that were proposed to tackle these clinical questions, putting them into context with respect to the challenges they are facing, including non-standardized MRI protocols, limited datasets, and moderate inter-rater variability. We conclude by presenting the current limitations that prevent their broader deployment and suggesting future research directions.

Oligoclonal bands: An immunological and clinical approach.

Oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) represent an indicator of IgG and IgM immunoglobulins intrathecal synthesis in the central nervous system (CNS). The techniques and detection methods for their determination have evolved from the beginning to isoelectric focusing on an agarose gel as the gold standard technique and immunodetection as the reference method. The evolution, both in techniques and methods for detection of IgG and IgM OCBs is evaluated in this review. In addition to the significance of the presence of a single band of IgG immunoglobulin in CSF, IgG OCBs within the diagnostic criteria of multiple sclerosis (MS), the prevalence of IgG OCBs and the effect of latitude in MS, as well as the clinical and immunological involvement of OCBs (IgG and IgM) in MS and other neurological diseases.

Spotlight on the October 26 Issue

#### Notable in Neurology This Week This issue features an article that investigates the effects of changes to multiple sclerosis (MS) diagnostic criteria over time on the treatment and outcome of patients with clinically isolated syndrome; another compares the characteristics of perimenstrual and nonperimenstrual migraine attacks in women with migraine. A review discusses the main epilepsy phenotypes associated with monogenic disorders and treatment options for genetic epilepsies. ### Reflexive Eye Closure in Response to Cone and Melanopsin Stimulation: A Study of Implicit Measures of Light Sensitivity in Migraine Using reflexive eye closure to measure light sensitivity, researchers studied …

Outcomes of pregnancy in Egyptian women with multiple sclerosis in the new treatment era: a multi-center retrospective observational study

BackgroundPregnancy is a recent growing issue in multiple sclerosis (MS) and the update in the diagnostic criteria of MS and introduction of many disease-modifying therapies (DMTs) may cause changes in the relationship between MS, pregnancy, and breastfeeding. This study aimed to investigate the effect of pregnancy and breastfeeding on MS and vice versa. A retrospective observational study was conducted to include MS women with a history of at least one pregnancy during the last 7 years. Data were collected from the archived files in addition to a self-administrating questionnaire. The annualized relapsing rate (ARR) was calculated before, during, and after pregnancy.ResultsWe included 116 successful pregnancies from 93 MS women with mean age 32.74 ± 5.12 years. Interferon-beta was the commonly used DMT during and after pregnancy. Despite the ARR during the two years preceding the conception was 0.36 (95% CI 0.32–0.41), this rate was significantly decreased during first, second, and third trimester (0.07; 95% CI 0.04–0.15, 0.10; 95% CI 0.03–0.17, and 0.15; 95% CI 0.08–0.24, respectively; P-value < 0.001 in all). Furthermore, this ARR was significantly decreased during the first and last three months after delivery (0.27; 95% CI 0.16–0.39; P-value = 0.037, and 0.24; 95% CI 0.17–0.38; P-value = 0.023). Exclusive breastfeeding was associated with deceased risk of postpartum relapse, with HR 0.31 (95% CI 0.12–0.67; P = 0.002).ConclusionsPregnancy is protective from MS relapse, with a significant decrease of ARR from the pre-pregnancy period. Postpartum reactivation of the disease occurs from the third month after labor, rather than the early postpartum period. Exclusive breastfeeding for at least 2 months decreased the risk of postpartum relapse.

Effect of Changes in MS Diagnostic Criteria Over 25 Years on Time to Treatment and Prognosis in Patients With Clinically Isolated Syndrome

To explore whether time to diagnosis, time to treatment initiation, and age to reach disability milestones have changed in patients with clinically isolated syndrome (CIS) according to different multiple sclerosis (MS) diagnostic criteria periods. This retrospective study was based on data collected prospectively from the Barcelona-CIS cohort between 1994 and 2020. Patients were classified into 5 periods according to different MS criteria, and the times to MS diagnosis and treatment initiation were evaluated. The age at which patients with MS reached an Expanded Disability Status Scale (EDSS) score ≥3.0 was assessed by Cox regression analysis according to diagnostic criteria periods. Last, to remove the classic Will Rogers phenomenon by which the use of different MS criteria over time might result in a changes of prognosis, the 2017 McDonald criteria were applied, and age at EDSS score ≥3.0 was assessed by Cox regression. In total, 1,174 patients were included. The median time from CIS to MS diagnosis and from CIS to treatment initiation showed a 77% and 82% reduction from the Poser to the McDonald 2017 diagnostic criteria periods, respectively. Patients of a given age diagnosed in more recent diagnostic criteria periods had a lower risk of reaching an EDSS score ≥3.0 than patients of the same age diagnosed in earlier diagnostic periods (reference category Poser period): adjusted hazard ratio (aHR) 0.47 (95% confidence interval 0.24-0.90) for McDonald 2001, aHR 0.25 (0.12-0.54) for McDonald 2005, aHR 0.30 (0.12-0.75) for McDonald 2010, and aHR 0.07 (0.01-0.45) for McDonald 2017. Patients in the early-treatment group displayed an aHR of 0.53 (0.33-0.85) of reaching age at EDSS score ≥3.0 compared to those in the late-treatment group. Changes in prognosis together with early-treatment effect were maintained after the exclusion of possible bias derived from the use of different diagnostic criteria over time (Will Rogers phenomenon). A continuous decrease in the time to MS diagnosis and treatment initiation was observed across diagnostic criteria periods. Overall, patients diagnosed in more recent diagnostic criteria periods displayed a lower risk of reaching disability. The prognostic improvement is maintained after the Will Rogers phenomenon is discarded, and early treatment appears to be the most likely contributing factor.