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Radiologically isolated syndrome in the spectrum of multiple sclerosis
Abstract
The radiologically isolated syndrome (RIS) currently represents the earliest detectable preclinical phase of multiple sclerosis (MS). Remarkable advancements have been recently made, including the identification of risk factors for disease evolution, revisions to the existing 2009 RIS criteria, and our understanding of the impact of early disease-modifying therapy use in the prevention/delay of symptomatic MS from two randomized clinical trials. Here, we discuss RIS in the context of the spectrum of MS, implications in the clinical management of individuals, and provide insights into future opportunities and challenges given the anticipated inclusion of asymptomatic MS in the formal definition of MS.
... Various recognized risk factors contribute to the conversion of CIS to clinically definite MS, including age, gender, schooling, motor symptoms, imaging findings (infratentorial and periventricular lesions), and oligoclonal bands in the cerebrospinal fluid [38,40]. Additionally, radiologically isolated syndrome (RIS) patients may show no apparent neurological symptoms but display MRI signs of ongoing demyelination in the CNS [41]. Identified risk factors for the occurrence of a first clinical event in RIS patients include specific lesion patterns (the presence of infratentorial, spinal cord, or gadolinium-enhancing lesions) and cerebrospinal fluid-specific oligoclonal bands [42]. ...
Primary demyelinating disorders of the central nervous system (CNS) include multiple sclerosis and the orphan conditions neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein IgG-associated disease (MOGAD). Curative technologies under development aim to selectively block autoimmune reactions against specific autoantigens while preserving the responsiveness of the immune system to other antigens. Our analysis focused on target patient selection for such developments, carefully considering the relevant clinical, regulatory, and market-related aspects. We found that the selection of patients with orphan conditions as target populations offers several advantages. Treatments for orphan conditions are associated with limited production capacity, qualify for regulatory incentives, and may require significantly shorter and lower-scale clinical programs. Furthermore, they may meet a higher acceptable cost-effectiveness threshold in order to compensate for the low numbers of patients to be treated. Finally, curative technologies targeting orphan indications could enter less competitive markets with lower risk of generic price erosion and would benefit from additional market protection measures available only for orphan products. These advantages position orphan conditions and subgroups as the most attractive target indications among primary demyelinating disorders of the CNS. The authors believe that after successful proof-of-principle demonstrations in orphan conditions, broader autoimmune patient populations may also benefit from the success of these pioneering developments.
Background and purpose
Differentiating between multiple sclerosis (MS) and small vessel disease (SVD) lesions represents a key challenge in the day-to-day management of patients. We aimed to distinguish between MS and SVD by identifying the dynamics of lesion movement patterns between enlarging and contracting foci from two MRI time points.
Methods
Standardized 3-Tesla 3-dimensional brain magnetic resonance imaging (MRI) studies were performed at two time points on enrolled MS and SVD patients. Selected supratentorial lesions were segmented and longitudinal changes in the direction of lesion displacement and magnitude along with the evolution of contracting and expanding T1-weighted and T2-weighted MS lesions were quantified based on lesion centroid positioning. Bayesian linear mixed effects regression models were constructed to evaluate associations between changes in lesion transitions and disease state.
Results
A total of 420 lesions were analyzed from 35 MS (female (F):22 (62.9%); median age (range):38 years (y) (22–61), median disease duration:7.38y (0.38–20.99)) and 12 SVD patients (F:11 (100%); 54y (40–66)). MS T2-weighted lesions that increased in volume between MRI time points demonstrated movement toward the cortex (p = 0.01), whereas those that decreased in volume moved toward the center (p < 0.0001). Lesion volume changes related to SVD demonstrated no effect on movement direction over time. Both expanding (p = 0.03) and contracting (p = 0.01) MS lesions demonstrated greater distances between centroids when compared to SVD.
Conclusion
Lesion dynamics may reveal distinct characteristics associated with the biology of disease while providing further insights into the behavior of inflammatory CNS disorders.
Purpose of review
This review presents a comprehensive analysis of the current high-efficacy disease-modifying therapies (DMTs) available for treatment of multiple sclerosis (MS). We discuss the existing approved and emerging therapeutics in patients with relapsing and progressive forms of MS using data from clinical trials and observational studies. Treatment considerations in pediatric and pregnant populations are also reviewed. Finally, we discuss the treatment paradigms of the escalation and early aggressive approaches to treatment of MS, with review of ongoing clinical trials to compare these approaches.
Recent findings
Natalizumab has shown promising data on efficacy in not only randomized trials but also observational studies when compared with placebo, the injectable DMTs, and fingolimod. The anti-CD20 B cell depleting therapies (rituximab, ocrelizumab, and ofatumumab) have also demonstrated superiority in randomized clinical trials compared to their comparator group (placebo, interferon, and teriflunomide, respectively) and rituximab has shown in observational studies to be more effective than older injectable therapies and some of the oral therapies. Alemtuzumab has shown good efficacy in randomized controlled trials and observational studies yet has several potentially severe side effects limiting its use. Mitoxantrone has similarly demonstrated significant reduction in new disease activity compared to placebo but is rarely used due to its severe side effects. Cladribine is an oral DMT often grouped in discussion with other higher efficacy DMTs but may be slightly less effective than the other therapies described in this review. Many emerging targets for therapeutic intervention are currently under investigation that may prove to be beneficial in early aggressive MS, including autologous hematopoietic stem cell transplantation.
Summary
Traditionally, MS has been treated with an escalation approach, starting patients on a modestly effective DMT and subsequently escalating to a higher efficacy DMT when there is evidence of clinical and/or radiologic breakthrough activity. With the development of higher efficacy therapies and emerging data showing the potential positive long-term impact of these therapies when started earlier in the disease course, many clinicians have shifted to an early aggressive treatment approach in which patients are initially started on a higher efficacy DMT. Two clinical trials, the TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) trial and the Determining the Effectiveness of earLy Intensive Versus Escalation approaches for the treatment of Relapsing-remitting MS (DELIVER-MS) trial, aim to directly compare these treatment strategies and their impact on clinical and radiologic outcomes.
The accurate recognition of multiple sclerosis (MS) lesions is challenged by the high sensitivity and imperfect specificity of MRI. To examine whether longitudinal changes in volume, surface area, 3-dimensional (3D) displacement (i.e. change in lesion position), and 3D deformation (i.e. change in lesion shape) could inform on the origin of supratentorial brain lesions, we prospectively enrolled 23 patients with MS and 11 patients with small vessel disease (SVD) and performed standardized 3-T 3D brain MRI studies. Bayesian linear mixed effects regression models were constructed to evaluate associations between changes in lesion morphology and disease state. A total of 248 MS and 157 SVD lesions were studied. Individual MS lesions demonstrated significant decreases in volume < 3.75mm³ (p = 0.04), greater shifts in 3D displacement by 23.4% with increasing duration between MRI time points (p = 0.007), and greater transitions to a more non-spherical shape (p < 0.0001). If 62.2% of lesions within a given MRI study had a calculated theoretical radius > 2.49 based on deviation from a perfect 3D sphere, a 92.7% in-sample and 91.2% out-of-sample accuracy was identified for the diagnosis of MS. Longitudinal 3D shape evolution and displacement characteristics may improve lesion classification, adding to MRI techniques aimed at improving lesion specificity.
Multiple sclerosis (MS) diagnostic criteria are based upon clinical presentation and presence of white matter hyperintensities on two-dimensional magnetic resonance imaging (MRI) views. Such criteria, however, are prone to false-positive interpretations due to the presence of similar MRI findings in non-specific white matter disease (NSWMD) states such as migraine and microvascular disease. The coexistence of age-related changes has also been recognized in MS patients, and this comorbidity further poses a diagnostic challenge. In this study, we investigated the physiologic profiles within and around MS and NSWMD lesions and their ability to distinguish the two disease states. MS and NSWMD lesions were identified using three-dimensional (3D) T2-FLAIR images and segmented using geodesic active contouring. A dual-echo functional MRI sequence permitted near-simultaneous measurement of blood-oxygen-level-dependent signal (BOLD) and cerebral blood flow (CBF). BOLD and CBF were calculated within lesions and in 3D concentric layers surrounding each lesion. BOLD slope, an indicator of lesion metabolic capacity, was calculated as the change in BOLD from a lesion through its surrounding perimeters. We observed sequential BOLD signal reductions from the lesion towards the perimeters for MS, while no such decreases were observed for NSWMD lesions. BOLD slope was significantly lower in MS compared to NSWM lesions, suggesting decreased metabolic activity in MS lesions. Furthermore, BOLD signal within and around lesions significantly distinguished MS and NSWMD lesions. These results suggest that this technique shows promise for clinical utility in distinguishing NSWMD or MS disease states and identifying NSWMD lesions occurring in MS patients.
Background
Steps towards the development of diagnostic criteria are needed for children with the radiologically isolated syndrome to identify children at risk of clinical demyelination.
Objectives
To evaluate the 2005 and 2016 MAGNIMS magnetic resonance imaging criteria for dissemination in space for multiple sclerosis, both alone and with oligoclonal bands in cerebrospinal fluid added, as predictors of a first clinical event consistent with central nervous system demyelination in children with radiologically isolated syndrome.
Methods
We analysed an international historical cohort of 61 children with radiologically isolated syndrome (≤18 years), defined using the 2010 magnetic resonance imaging dissemination in space criteria (Ped-RIS) who were followed longitudinally (mean 4.2 ± 4.7 years). All index scans also met the 2017 magnetic resonance imaging dissemination in space criteria.
Results
Diagnostic indices (95% confidence intervals) for the 2005 dissemination in space criteria, with and without oligoclonal bands, were: sensitivity 66.7% (38.4–88.2%) versus 72.7% (49.8–89.3%); specificity 83.3% (58.6–96.4%) versus 53.9% (37.2–69.9%). For the 2016 MAGNIMS dissemination in space criteria diagnostic indices were: sensitivity 76.5% (50.1–93.2%) versus 100% (84.6–100%); specificity 72.7% (49.8–89.3%) versus 25.6% (13.0–42.1%).
Conclusions
Oligoclonal bands increased the specificity of magnetic resonance imaging criteria in children with Ped-RIS. Clinicians should consider testing cerebrospinal fluid to improve diagnostic certainty. There is rationale to include cerebrospinal fluid analysis for biomarkers including oligoclonal bands in planned prospective studies to develop optimal diagnostic criteria for radiologically isolated syndrome in children.
The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.
Objective
To describe clinical and radiologic outcomes of children with incidental findings on neuroimaging suggestive of CNS demyelination (termed “radiologically isolated syndrome” or RIS).
Methods
Clinical and radiologic data were obtained from a historical cohort of children with no symptoms of demyelinating disease who had MRI scans that met the 2010 MRI criteria for dissemination in space for MS.
Results
We identified 38 children (27 girls and 11 boys) with RIS now being prospectively followed at 16 sites in 6 countries. The mean follow-up time was 4.8 ± 5.3 years. The most common reason for initial neuroimaging was headache (20/38, 53%). A first clinical event consistent with CNS demyelination occurred in 16/38 children (42%; 95% confidence interval [CI]: 27%–60%) in a median of 2.0 years (interquartile range [IQR] 1.0–4.3 years). Radiologic evolution developed in 23/38 children (61%; 95% CI: 44%–76%) in a median of 1.1 years (IQR 0.5–1.9 years). The presence of ≥2 unique oligoclonal bands in CSF (hazard ratio [HR] 10.9, 95% CI: 1.4–86.2, p = 0.02) and spinal cord lesions on MRI (HR 7.8, 95% CI: 1.4–43.6, p = 0.02) were associated with an increased risk of a first clinical event after adjustment for age and sex.
Conclusions
We describe the clinical characteristics and outcomes of children with incidental MRI findings highly suggestive of CNS demyelination. Children with RIS had a substantial risk of subsequent clinical symptoms and/or radiologic evolution. The presence of oligoclonal bands in CSF and spinal cord lesions on MRI were associated with an increased risk of a first clinical event.
Over the past few years, MRI has become an indispensable tool for diagnosing multiple sclerosis (MS). However, the current MRI criteria for MS diagnosis have imperfect sensitivity and specificity. The central vein sign (CVS) has recently been proposed as a novel MRI biomarker to improve the accuracy and speed of MS diagnosis. Evidence indicates that the presence of the CVS in individual lesions can accurately differentiate MS from other diseases that mimic this condition. However, the predictive value of the CVS for the development of clinical MS in patients with suspected demyelinating disease is still unknown. Moreover, the lack of standardization for the definition and imaging of the CVS currently limits its clinical implementation and validation. On the basis of a thorough review of the existing literature on the CVS and the consensus opinion of the members of the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative, this article provides statements and recommendations aimed at helping radiologists and neurologists to better understand, refine, standardize and evaluate the CVS in the diagnosis of MS.
. A subgroup of MS patients present with “euphoria.” Classical authors describe this symptom as the predominant mood state of these patients, while contemporary authors regard it as rare.
Objective
. This study aimed to address these discrepancies and investigate the contributions made by varying operational definitions and measurement instruments.
Methods
. One hundred MS patients and 100 matched controls completed the classical interview of Cottrell and Wilson and the modern Neuropsychiatric Inventory in a once-off interview.
Results
. The MS group demonstrated high frequencies of euphoria using the classical measure but low frequencies using the contemporary measure and definition. The matched control group demonstrated significantly higher rates than the MS group using the classical measure and lower rates than the MS group using the contemporary measure.
Conclusion
. The discrepancies in incidence rates of euphoria noted in the literature do not reflect a change in the incidence of euphoria in MS, but rather in the definition and operationalisation of “euphoria.” Furthermore, these results highlight the importance of characterising what represents pathological euphoria as well as the need for better definitions and instruments of measure.
Objective:
To evaluate the pre-progressive phase in subjects with radiologically isolated syndrome (RIS) who evolve to primary progressive MS (PPMS).
Methods:
A multicenter RIS cohort was previously established. Demographic, clinical and radiological characteristics of subjects with RIS that evolved directly to PPMS were compared to those that developed a relapsing from onset disease (clinically isolated syndrome (CIS) or relapsing-remitting MS), and were also compared to two other population-based and clinic-based PPMS cohorts.
Results:
Of the 453 subjects with RIS, 128 evolved to symptomatic MS during the follow-up (113 developed a first acute clinical event consistent with CIS/MS, 15 evolved to PPMS). PPMS prevalence (11.7%) and onset age (mean ± SD; 49.1 ± 12.1) in the RIS group was comparable to other PPMS populations (p>0.05). Median time to PPMS was 3.5 years (range: 1.6-5.4). RIS evolved to PPMS more commonly in men (p=0.005) and at an older age (p<0.001) when compared to CIS/MS, independent of follow-up duration. Subjects who evolved to PPMS had more spinal cord lesions (100%) before symptomatic evolution then those that developed CIS/MS (64%) and those that remained asymptomatic (23%) within the follow-up period (p=0.005). Other MRI characteristics in the pre-progressive phase of PPMS were indistinguishable from CIS/MS.
Interpretation:
Subjects with RIS evolve to PPMS at the same frequency as expected from general MS populations in an age dependent manner. Besides age unequivocal presence of spinal cord lesions and being male predicts evolution to PPMS. Our findings further suggest that RIS is biologically part of the MS spectrum. This article is protected by copyright. All rights reserved.
To report the 5-year risk and to identify risk factors for the development of a seminal acute or progressive clinical event in a multi-national cohort of asymptomatic subjects meeting 2009 RIS Criteria.
Retrospectively identified RIS subjects from 22 databases within 5 countries were evaluated. Time to the first clinical event related to demyelination (acute or 12-month progression of neurological deficits) was compared across different groups by univariate and multivariate analyses utilizing a Cox regression model.
Data were available in 451 RIS subjects (F: 354 (78.5%)). The mean age at from the time of the first brain MRI revealing anomalies suggestive of MS was 37.2 years (y) (median: 37.1 y, range: 11-74 y) with mean clinical follow-up time of 4.4 y (median: 2.8 y, range: 0.01-21.1 y). Clinical events were identified in 34% (standard error = 3%) of individuals within a 5-year period from the first brain MRI study. Of those who developed symptoms, 9.6% fulfilled criteria for primary progressive MS. In the multivariate model, age [hazard ratio (HR): 0.98 (95% CI: 0.96-0.99); p = 0.03], sex (male) [HR: 1.93 (1.24-2.99); p = 0.004], and lesions within the cervical or thoracic spinal cord [HR: 3.08 (2.06-4.62); p = <0.001] were identified as significant predictors for the development of a first clinical event.
These data provide supportive evidence that a meaningful number of RIS subjects evolve to a first clinical symptom. An age <37 y, male sex, and spinal cord involvement appear to be the most important independent predictors of symptom onset.
Benign lymphadenopathy is a common biopsy finding, and may often be confused with malignant lymphoma. It may be separated into major morphologic patterns, each with its own differential diagnosis with certain types of lymphoma. Most cases of reactive follicular hyperplasia is easy to diagnosis, but some cases may be confused with follicular lymphoma, but key morphologic, immunohistochemical, and molecular findings may usually distinguish between the two, particularly assessment of bcl-2 staining. Molecular studies to demonstrate B-cell clonality, as well as the t(14;18), may also be of great use in difficult cases. IgG4-associated sclerosing disease is discussed, as one recently described example of a specific type of reactive follicular hyperplasia in which the etiology may be suggested based on pathologic studies. While overlapping with the other types of hyperplasia, a high index of suspicion as well as IgG and IgG4 immunostains will help raise the possibility of the diagnosis that can be confirmed by further clinical studies. Reactive paracortical/interfollicular hyperplasia is another pattern of reactive hyperplasia, which may easily be confused with Hodgkin and non-Hodgkin lymphoma, particularly T-cell lymphoma. Epstein-Barr virus-associated infectious mononucleosis is an example of reactive paracortical/interfollicular hyperplasia, which may often simulate a malignant lymphoma. Attention to clinical findings, as well as a combination of immunohistochemical stains and in situ hybridization studies for Epstein-Barr early RNA (EBER) will usually allow a definitive diagnosis. In addition, lymph nodes with extensive necrosis may simulate malignant lymphoma. Kikuchi necrotizing histiocytic lymphadenitis is an example of a benign process with extensive necrosis, which may easily be confused with non-Hodgkin lymphoma. Clinical and morphologic features, particularly the presence of abundant karyorrhectic debris along with a paucity of granulocytes, as well as immunohistochemical studies to rule out lymphoma, are most helpful in establishing the correct diagnosis.
BG-12 (dimethyl fumarate) was shown to have antiinflammatory and cytoprotective properties in preclinical experiments and to result in significant reductions in disease activity on magnetic resonance imaging (MRI) in a phase 2, placebo-controlled study involving patients with relapsing-remitting multiple sclerosis.
We conducted a randomized, double-blind, placebo-controlled phase 3 study involving patients with relapsing-remitting multiple sclerosis. Patients were randomly assigned to receive oral BG-12 at a dose of 240 mg twice daily, BG-12 at a dose of 240 mg three times daily, or placebo. The primary end point was the proportion of patients who had a relapse by 2 years. Other end points included the annualized relapse rate, the time to confirmed progression of disability, and findings on MRI.
The estimated proportion of patients who had a relapse was significantly lower in the two BG-12 groups than in the placebo group (27% with BG-12 twice daily and 26% with BG-12 thrice daily vs. 46% with placebo, P<0.001 for both comparisons). The annualized relapse rate at 2 years was 0.17 in the twice-daily BG-12 group and 0.19 in the thrice-daily BG-12 group, as compared with 0.36 in the placebo group, representing relative reductions of 53% and 48% with the two BG-12 regimens, respectively (P<0.001 for the comparison of each BG-12 regimen with placebo). The estimated proportion of patients with confirmed progression of disability was 16% in the twice-daily BG-12 group, 18% in the thrice-daily BG-12 group, and 27% in the placebo group, with significant relative risk reductions of 38% with BG-12 twice daily (P=0.005) and 34% with BG-12 thrice daily (P=0.01). BG-12 also significantly reduced the number of gadolinium-enhancing lesions and of new or enlarging T(2)-weighted hyperintense lesions (P<0.001 for the comparison of each BG-12 regimen with placebo). Adverse events associated with BG-12 included flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain, as well as decreased lymphocyte counts and elevated liver aminotransferase levels.
In patients with relapsing-remitting multiple sclerosis, both BG-12 regimens, as compared with placebo, significantly reduced the proportion of patients who had a relapse, the annualized relapse rate, the rate of disability progression, and the number of lesions on MRI. (Funded by Biogen Idec; DEFINE ClinicalTrials.gov number, NCT00420212.).
BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate).
In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate.
At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12.
In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).
Individuals can be deemed to have radiologically isolated syndrome (RIS) if they have incidental demyelinating-appearing lesions in their brain or spinal cord that are highly suggestive of multiple sclerosis but their clinical history does not include symptoms consistent with multiple sclerosis. Data from international longitudinal cohorts indicate that around half of people with RIS will develop relapsing or progressive symptoms of multiple sclerosis within 10 years, suggesting that in some individuals, RIS is a presymptomatic stage of multiple sclerosis. Risk factors for progression from RIS to clinical multiple sclerosis include younger age (ie, <35 years), male sex, CSF-restricted oligoclonal bands, spinal cord or infratentorial lesions, and gadolinium-enhancing lesions. Other imaging, biological, genetic, and digital biomarkers that might be of value in identifying individuals who are at the highest risk of developing multiple sclerosis need further investigation. Two 2-year randomised clinical trials showed the efficacy of approved multiple sclerosis immunomodulatory medications in preventing the clinical conversion to multiple sclerosis in some individuals with RIS. If substantiated in longer-term studies, these data have the potential to transform our approach to care for the people with RIS who are at the greatest risk of diagnosis with multiple sclerosis.
Background
Psychiatric morbidity is common after an MS diagnosis. However, little is known about psychiatric morbidity during the prodromal phase (before MS onset).
Objectives
To compare the prevalence and relative burden of psychiatric morbidity in individuals with MS versus matched controls before MS onset.
Methods
Using linked administrative and clinical data from British Columbia, Canada, we identified MS cases via a validated algorithm or from neurologist-diagnosed MS clinic attendees. Cases were matched by age, sex, and geographical location with up to 5 general population controls. We identified psychiatric morbidity through a validated definition and determined its prevalence in cases/controls in the 5 years before MS cases’ first demyelinating claim (‘administrative cohort’) or symptom onset (‘clinical cohort’), and estimated case/control prevalence ratios with 95%CIs. We also compared the yearly number of physician visits for psychiatric morbidity, visits to psychiatrists, psychiatric-related admissions, and psychotropic dispensations pre-MS onset in cases/controls regardless of whether psychiatric morbidity algorithm was fulfilled using negative binomial regression fitted via generalised estimating equations; results reported as adjusted rate ratios with 95%CIs. We assessed yearly trends via interaction terms between cases/controls and each year pre-MS onset.
Results
The administrative cohort comprised 6,863/31,865 cases/controls; the clinical cohort 966/4,534 cases/controls. Over the entire 5-year period pre-MS onset, 28.0% (1,920/6,863) of cases and 14.9% (4,738/31,865) of controls (administrative cohort) had psychiatric morbidity, as did 22.0% (213/966) of clinical cases and 14.1% (638/4,534) controls. Psychiatric morbidity prevalence ratios ranged from 1.58; 95%CI:1.38-1.81 (clinical cohort) to 1.91; 95%CI:1.83-2.00 (administrative cohort). In the administrative cohort, healthcare use was higher for cases in each year pre-MS onset (all 95%CIs >1); physician visits were 78% higher in year 5 pre-MS onset and 124% 1 year prior; visits to psychiatrists were 132% higher in year 5 and 146% in year 1; hospitalizations were 129% higher in year 5 and 197% in year 1; and prescription dispensations were 72% higher in year 5 and 100% in year 1. Results were not significant in the clinical cohort.
Conclusion
Psychiatric morbidity represents a significant burden before MS onset and may be a feature of the MS prodrome.
Importance:
Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance imaging (MRI) white matter anomalies within the central nervous system.
Objective:
To determine the time to onset of symptoms consistent with MS.
Design, setting, and participants:
From September 2017 to October 2022, this multicenter, double-blind, phase 3, randomized clinical trial investigated the efficacy of teriflunomide in delaying MS in individuals with RIS, with a 3-year follow-up. The setting included referral centers in France, Switzerland, and Turkey. Participants older than 18 years meeting 2009 RIS criteria were randomly assigned (1:1) to oral teriflunomide, 14 mg daily, or placebo up to week 96 or, optionally, to week 144.
Interventions:
Clinical, MRI, and patient-reported outcomes (PROs) were collected at baseline and yearly until week 96, with an optional third year in the allocated arm if no symptoms have occurred.
Main outcomes:
Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs.
Results:
Among 124 individuals assessed for eligibility, 35 were excluded for declining to participate, not meeting inclusion criteria, or loss of follow-up. Eighty-nine participants (mean [SD] age, 37.8 [12.1] years; 63 female [70.8%]) were enrolled (placebo, 45 [50.6%]; teriflunomide, 44 [49.4%]). Eighteen participants (placebo, 9 [50.0%]; teriflunomide, 9 [50.0%]) discontinued the study, resulting in a dropout rate of 20% for adverse events (3 [16.7%]), consent withdrawal (4 [22.2%]), loss to follow-up (5 [27.8%]), voluntary withdrawal (4 [22.2%]), pregnancy (1 [5.6%]), and study termination (1 [5.6%]). The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, in both the unadjusted (hazard ratio [HR], 0.37; 95% CI, 0.16-0.84; P = .02) and adjusted (HR, 0.28; 95% CI, 0.11-0.71; P = .007) analysis. Secondary imaging end point outcomes including the comparison of the cumulative number of new or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P = .14), new gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P = .09), and the proportion of participants with new lesions (odds ratio, 0.72; 95% CI, 0.25-2.06; P = .54) were not significant.
Conclusion and relevance:
Treatment with teriflunomide resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72%, relative to placebo, in preventing a first clinical demyelinating event. These data suggest a benefit to early treatment in the MS disease spectrum.
Trial registration:
ClinicalTrials.gov Identifier: NCT03122652.
Accurate diagnosis of multiple sclerosis requires careful attention to its differential diagnosis-many disorders can mimic the clinical manifestations and paraclinical findings of this disease. A collaborative effort, organised by The International Advisory Committee on Clinical Trials in Multiple Sclerosis in 2008, provided diagnostic approaches to multiple sclerosis and identified clinical and paraclinical findings (so-called red flags) suggestive of alternative diagnoses. Since then, knowledge of disorders in the differential diagnosis of multiple sclerosis has expanded substantially. For example, CNS inflammatory disorders that present with syndromes overlapping with multiple sclerosis can increasingly be distinguished from multiple sclerosis with the aid of specific clinical, MRI, and laboratory findings; studies of people misdiagnosed with multiple sclerosis have also provided insights into clinical presentations for which extra caution is warranted. Considering these data, an update to the recommended diagnostic approaches to common clinical presentations and key clinical and paraclinical red flags is warranted to inform the contemporary clinical evaluation of patients with suspected multiple sclerosis.
The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the central nervous system within individuals lacking symptoms typical of multiple sclerosis. The RIS criteria have been validated and predict the transition to symptomatic MS reliably. The performance of RIS criteria that require fewer MRI lesions is unknown.
2009-RIS subjects, by definition, fulfill 3-4 of 4 criteria for 2005 dissemination in space [DIS] and subjects fulfilling only 1 or 2 lesions in at least one 2017 DIS location were identified within 37 prospective databases. Univariate and multivariate Cox regression models were used to identify predictors of a first clinical event. Performances of different groups were calculated.
747 subjects (72.2% female, mean age 37.7 ± 12.3 years at the index MRI) were included. The mean clinical follow-up time was 46.8 ± 45.4 months. All subjects had focal T2 hyperintensities suggestive of inflammatory demyelination on MRI; 251 (33.6%) fulfilled 1 or 2 2017 DIS criteria (designated as Group 1 and Group 2, respectively), and 496 (66.4%) fulfilled 3 or 4 2005 DIS criteria representing 2009-RIS subjects. Group 1 and 2 subjects were younger than the 2009-RIS Group and were more likely to develop new T2 lesions over time (p < 0.001). Groups 1 and 2 were similar regarding survival distribution and risk factors for transition to multiple sclerosis.
At five years, the cumulative probability for a clinical event was 29.0% for Groups 1-2 compared to 38.7% for 2009-RIS (p = 0.0241). The presence of spinal cord lesions on the index scan and CSF-restricted oligoclonal bands in Groups 1-2 increased the risk of symptomatic MS evolution at five years to 38%, comparable to the risk of development in the 2009-RIS group. The presence of new T2 or gadolinium-enhancing lesions on follow-up scans independently increased the risk of presenting with a clinical event (p < 0.001). The 2009-RIS subjects or Group 1-2 with at least 2 of the risk factors for a clinical event demonstrated better sensitivity (86.0%), negative predictive value (73.1%), accuracy (59.8%) and area under the curve (60.7%) compared to other criteria studied.
This large prospective cohort brings Class I evidence that subjects with fewer lesions than required in the 2009 RIS criteria evolve directly to a first clinical event at a similar rate when additional risk factors are present. Our results provide a rationale for revisions to existing RIS diagnostic criteria.
Objective:
The radiologically isolated syndrome (RIS) represents the earliest detectable pre-clinical phase of multiple sclerosis (MS). This study evaluated the impact of therapeutic intervention in preventing first symptom manifestation at this stage in the disease spectrum.
Methods:
We conducted a multi-center, randomized, double-blinded, placebo-controlled study involving people with RIS. Individuals without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with CNS demyelination were included. Within 12 MS centers in the U.S., participants were randomly assigned 1:1 to oral dimethyl fumarate (DMF) 240mg twice daily or placebo. The primary endpoint was the time to onset of clinical symptoms attributable to a CNS demyelinating event within a follow-up period of 96 weeks. An intention-to-treat analysis was applied to all participating individuals in the primary and safety investigations. The study is registered at ClinicalTrials.gov, NCT02739542 (ARISE).
Results:
Participants from 12 centers were recruited from March 9, 2016 to October 31, 2019 with 44 people randomized to dimethyl fumarate and 43 to placebo. Following DMF treatment, the risk of a first clinical demyelinating event during the 96-week study period was highly reduced in the unadjusted Cox proportional-hazards regression model (hazard ratio (HR)=0.18, 95% confidence interval (CI)=0.05-0.63, p=0.007). More moderate adverse reactions were present in the DMF (34 (32%)) than placebo groups (19 (21%)) but severe events were similar (DMF, 3 (5%); placebo, 4 (9%)).
Interpretation:
This is the first randomized clinical trial demonstrating the benefit of a disease-modifying therapy in preventing a first acute clinical event in people with RIS. This article is protected by copyright. All rights reserved.
Background
The rising costs associated with multiple sclerosis (MS) disease modifying therapies (DMTs) creates challenges for patients and the healthcare system in the United States (U.S.). Within a specialty medicine waste project, we quantified the magnitude of unused medications and corresponding value, the primary factors driving treatment switches and explored reasons for discontinuations by race and ethnicity.
Methods
Over one calendar year, MS DMTs were recovered from new and existing patients from a single neuroimmunologist within a tertiary MS care center. Baseline demographic and clinical information, including reasons for medication discontinuation or transitions were captured. Patients were stratified into three treatment transition categories: i) non-medical, ii) medical, or iii) tolerability reasons. Cause-specific Cox proportional hazard functions were fit for possible causes for treatment changes.
Results
A total of 422 patients (female: 73.2%, median age at diagnosis: 32.9 years (y)) comprised of 86.3% whites, 11.6% Black or African Americans, 1.4% Asians, and 0.7% Native Americans were included, representing 23% of patients evaluated within 2018, with a mean disease duration of 12.8 years (y) (standard deviation (SD): 8.2) and treatment duration of 2.9y (3.4). Women were more likely to switch due to injection fatigue or desire for an oral DMT when compared to men (95% CI [0.26, 0.78], p=0.01). Being Black or African American increased the hazard of switching treatment due to injection fatigue and desire for an oral medication relative to whites by 91% (95% CI [1.07, 3.42], p=0.03) and switching to a new DMT based on the subjective report of a perceived lack of efficacy was 221% greater (95% CI [1.04, 4.70], p=0.04), but not in relation to side effects, being 50% less likely to switch (95% CI [0.28, 0.90], p=0.02). In the passive recruitment phase over a single calendar year, DMTs with a retail value of $5.2 million (Average Wholesale Price (AWP)) were recovered. In the 1-month active recruitment phase within the same year involving 49 people with MS, unused MS DMTs of $1.1 million (AWP) were acquired. Of the 471 patients studied, 56.2% reported transitions in DMTs for reasons other than adequate disease control and tolerability at one point in their treatment history, underscoring the need for individualized therapy selections that enhance persistence and increase the likelihood of reducing further neurological disability.
Conclusion
The magnitude of unused and wasted MS DMTs is staggering and these findings allude to a larger, more pervasive problem within the healthcare system with financial resources being applied to therapies that go unused.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system of unknown etiology. We tested the hypothesis that MS is caused by Epstein-Barr virus (EBV) in a cohort comprising more than 10 million young adults on active duty in the US military, 955 of whom were diagnosed with MS during their period of service. Risk of MS increased 32-fold after infection with EBV but was not increased after infection with other viruses, including the similarly transmitted cytomegalovirus. Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after EBV seroconversion. These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.
Objectives
To explore whether time to diagnosis, time to treatment initiation and age to reach disability milestones has changed in patients with clinically isolated syndrome (CIS) according to different multiple sclerosis (MS)-diagnostic criteria periods.
Methods
Retrospective study based on data prospective collected from the Barcelona-CIS cohort between 1994 and 2020. Patients were classified into five periods according to different MS criteria, and the time to MS diagnosis and treatment initiation were evaluated. The age at which MS patients reached an EDSS ≥3.0 was assessed by Cox regression analysis according to diagnostic criteria periods. Finally, in order to remove the classical “Will Rogers” phenomenon by which the use of different MS criteria over time might result on changes of prognosis, 2017 McDonald criteria were applied and age at EDSS ≥ 3.0 was also assessed by Cox regression.
Results
1174 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 EDSS ≥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. Early-treatment patients displayed an aHR of 0.53 (0.33-0.85) of reaching age at EDSS ≥3.0 compared to late-treatment. Changes in prognosis together with early-treatment effect were maintained after excluding possible bias derived from the use of different diagnostic criteria over time (so called, “Will Rogers” phenomenon)
Conclusion
A continuous decrease in the time to MS diagnosis and treatment initiation were observed across diagnostic criteria periods. Overall, patients diagnosed in more recent diagnostic criteria periods displayed a lower risk of reaching disability. Importantly, the prognostic improvement is maintained after discarding the “Will Rogers” phenomenon, and early treatment appears to be the most likely contributing factor.
Objective
We have previously identified male sex, younger age, and the presence of spinal cord lesions as independent factors that increase the 5‐year risk for evolution from radiologically isolated syndrome (RIS) to multiple sclerosis. We investigate here risk factors for the development of a clinical event using a 10‐year, multi‐national, retrospectively‐identified RIS dataset.
Methods
RIS subjects were identified according to 2009 RIS criteria and longitudinally followed as part of a worldwide cohort study. We analyzed data from 21 individual databases from 5 different countries. Associations between clinical and MRI characteristics, and the risk of developing a first clinical event were determined using multivariate Cox regression models.
Results
Additional follow‐up data was available in 277/451 RIS subjects (86% female). Mean age at RIS diagnosis was 37.2 y (range:11–74 y) with a median clinical follow‐up of 6.7 years. The cumulative probability of a first clinical event at 10 years was 51.2%. Age, positive CSF, infratentorial lesions on MRI, and spinal cord lesions, were baseline independent predictors associated with a subsequent clinical event. The presence of gadolinium enhancing lesions during follow‐up was also associated with the risk of a seminal event. Reason for MRI and gadolinium enhancing lesions at baseline did not influence the risk of a subsequent clinical event.
Interpretation
Approximately half of individuals with RIS experience a first clinical event within 10 years of the index MRI. The identification of independent predictors of risk for symptom onset may guide education and clinical management of individuals with RIS.
This article is protected by copyright. All rights reserved.
Multiple Sclerosis (MS) is a common cause of neurological disability among young adults and has a high economic burden. Currently there are 18 disease modifying agents for relapsing MS, which were tested in clinical trials versus placebo or an active comparator in a pairwise manner. However, there is currently no consensus on the fundamental principles of treatment approach and initial therapy selection. These factors result in variable use of disease modifying therapies. Here we describe the study protocol for Determining the Effectiveness of earLy Intensive Versus Escalation approaches for the Treatment of Relapsing-remitting Multiple Sclerosis (DELIVER-MS). The main objective of the study is to determine whether an early highly effective treatment approach, defined as use of one of four monoclonal antibodies as initial therapy, is more effective than an escalation treatment approach (any other approved medication as initial therapy with subsequent escalation to higher efficacy treatments guided by radiological and clinical evaluation). The primary endpoint of the study is reduction in normalized brain volume loss from baseline visit to month 36 visit using MRI. Brain volume loss was selected as the best short-term predictor of long-term clinical disability. A total of 400 participants will be randomized 1:1 using minimization to account for age and sex by site, and 400 will be enrolled into a parallel observational cohort. The study results will help guide overall treatment philosophy and will have important implications for patient choice, clinical practice, and treatment access.
Background
There is increasing evidence of prodromal multiple sclerosis (MS).
Objective
The aim of this study was to determine whether fatigue, sleep disorders, anaemia or pain form part of the MS prodrome.
Methods
This population-based matched cohort study used linked administrative and clinical databases in British Columbia, Canada. The odds of fatigue, sleep disorders, anaemia and pain in the 5 years preceding the MS cases’ first demyelinating claim or MS symptom onset were compared with general population controls. The frequencies of physician visits for these conditions were also compared. Modifying effects of age and sex were evaluated.
Results
MS cases/controls were assessed before the first demyelinating event (6863/31,865) or MS symptom onset (966/4534). Fatigue (adj.OR: 3.37; 95% CI: 2.76–4.10), sleep disorders (adj.OR: 2.61; 95% CI: 2.34–2.91), anaemia (adj.OR: 1.53; 95% CI: 1.32–1.78) and pain (adj.OR: 2.15; 95% CI: 2.03–2.27) during the 5 years preceding the first demyelinating event were more frequent among cases, and physician visits increased for cases relative to controls. The association between MS and anaemia was greater for men; that between MS and pain increased with age. Pre-MS symptom onset, sleep disorders (adj.OR: 1.72; 95% CI: 1.12–2.56) and pain (adj.OR: 1.53; 95% CI: 1.32–1.76) were more prevalent among cases.
Conclusion
Fatigue, sleep disorders, anaemia and pain were elevated before the recognition of MS. The relative anaemia burden was higher in men and pain more evident among older adults.
Individuals with radiologically isolated syndrome (RIS) have incidental magnetic resonance imaging (MRI) abnormalities suggestive of multiple sclerosis (MS).¹ Recent studies using susceptibility-based imaging have shown that a subgroup of chronic MS white matter lesions (WMLs) have a rim of paramagnetic susceptibility-associated signal loss at the lesion edge, the paramagnetic rim sign (PRS), that is associated with the presence of iron inside phagocytes, which indicates chronic, active demyelination.²,3 The objective of this study was to determine whether patients with RIS have WMLs that are positive for PRS (PRS+).
Importance
Unrecognized demyelinating events often precede the clinical onset of multiple sclerosis (MS). Identification of these events at the time of occurrence would have implications for early diagnosis and the search of causal factors for the disease.
Objective
To assess whether serum neurofilament light chain (sNfL) levels are elevated before the clinical MS onset.
Design, Setting, and Participants
Nested case-control study among US military personnel who have serum samples stored in the US Department of Defense Serum Repository. Serum samples were collected from 2000 to 2011; sNfL assays and data analyses were performed from 2018 to 2019. We selected 60 case patients with MS who either had 2 samples collected before onset (mean follow-up, 6.3 years) or 1 sample collected before and 1 after onset (mean follow-up, 1.3 years), among 245 previously identified case patients. For each case, we randomly selected 1 of 2 previously identified control individuals matched by age, sex, race/ethnicity, and dates of sample collection. The sample size was chosen based on the available funding.
Exposures
Serum NfL concentrations measured using an ultrasensitive single-molecule array assay (Simoa).
Main Outcomes and Measurements
Log-transformed sNfL concentrations in case patients and control individuals compared using conditional logistic regression and linear mixed models.
Results
Mean age at baseline was 27.5 years, and 92 of 120 participants (76.7%) were men. Serum NfL levels were higher in case patients with MS compared with their matched control individuals in samples drawn a median of 6 years (range, 4-10 years) before the clinical onset (median, 16.7 pg/mL; interquartile range [IQR], 12.6-23.1 pg/mL vs 15.2 pg/m; IQR, 10.3-19.9 pg/mL; P = .04). This difference increased with decreasing time to the case clinical onset (estimated coefficient for interaction with time = 0.063; P = .008). A within-person increase in presymptomatic sNfL levels was associated with higher MS risk (rate ratio for ≥5 pg/mL increase, 7.50; 95% CI, 1.72-32.80). The clinical onset was associated with a marked increase in sNfL levels (median, 25.0; IQR, 17.1-41.3 vs 45.1; IQR, 27.0-102.7 pg/mL for presymptomatic and postonset MS samples; P = .009).
Conclusions and Relevance
The levels of sNfL were increased 6 years before the clinical MS onset, indicating that MS may have a prodromal phase lasting several years and that neuroaxonal damage occurs already during this phase.
Background and purpose:
Radiologically isolated syndrome describes asymptomatic individuals with incidental radiologic abnormalities suggestive of multiple sclerosis. Recent studies have demonstrated that >40% of white matter lesions in MS (and often substantially more) have visible central veins on MR imaging. This "central vein sign" reflects perivenous inflammatory demyelination and can assist in differentiating MS from other white matter disorders. We therefore hypothesized that >40% of white matter lesions in cases of radiologically isolated syndrome would show the central vein sign.
Materials and methods:
We recruited 20 participants diagnosed with radiologically isolated syndrome after evaluation by a neurologist. We performed 3T MR imaging of the brain and cervical spinal cord. White matter lesions were analyzed for the central vein sign.
Results:
Of 391 total white matter lesions, 292 (75%) demonstrated the central vein sign (central vein sign+). The median proportion of central vein sign+ lesions per case was 87% (range, 29%-100%). When the "40% rule" that has been proposed to distinguish MS from other disorders was applied, of 20 participants, 18 cases of radiologically isolated syndrome (90%) had ≥40% central vein sign+ lesions (range, 55%-100%). Two participants (10%) had <40% central vein sign+ lesions (29% and 31%). When the simpler "rule of 6" was applied, 19 participants (95%) met these criteria. In multivariable models, the number of spinal cord and infratentorial lesions was associated with a higher proportion of central vein sign+ lesions (P = .002; P = .06, respectively).
Conclusions:
Most cases of radiologically isolated syndrome had a high proportion of central vein sign+ lesions, suggesting that lesions in these individuals reflect perivenous inflammatory demyelination. Moreover, we found correlations between the proportion of central vein sign+ lesions and spinal cord lesions, a known risk factor for radiologically isolated syndrome progressing to MS. These findings raise the possibility, testable prospectively, that the central vein sign may have prognostic value in distinguishing patients with radiologically isolated syndrome at risk of developing clinical MS from those with white matter lesions of other etiologies.
Some of the clinical manifestations of multiple sclerosis, such as memory impairment and depression, are, at least partly, related to involvement of the hippocampus. Pathological studies have shown extensive demyelination, neuronal damage, and synaptic abnormalities in the hippocampus of patients with multiple sclerosis, and improvements in MRI technology have provided novel ways to assess hippocampal involvement in vivo. It is now accepted that clinical manifestations related to the hippocampus are due not only to focal hippocampal damage, but also to disconnection of the hippocampus from several brain networks. Evidence suggests anatomical and functional subspecialisation of the different hippocampal subfields, resulting in variability between regions in the extent to which damage and repair occur. The hippocampus also has important roles in plasticity and neurogenesis, both of which potentially contribute to functional preservation and restoration. These findings underline the importance of evaluation of the hippocampus not only to improve understanding of the clinical manifestations of multiple sclerosis, but also as a potential future target for treatment.
Background:
The multiple sclerosis (MS) prodrome is poorly characterized.
Objective:
To phenotype the MS prodrome via health care encounters.
Methods:
Using data from a population-based cohort study linking administrative and clinical data in four Canadian provinces, we compared physician and hospital encounters and prescriptions filled (via International Classification of Diseases chapters, physician specialty or drug classes) for MS subjects in the 5 years before the first demyelinating claim in an administrative cohort or the clinical symptom onset in an MS clinic-derived cohort, to age-, sex- and geographically matched controls. Rate ratios (RRs), 95% confidence intervals (95% CIs) and proportions were estimated.
Results:
The administrative and clinical cohorts included 13,951/66,940 and 3202/16,006 people with and without MS (cases/controls). Compared to controls, in the 5 years before the first demyelinating claim or symptom onset, cases had more physician and hospital encounters for the nervous (RR (range) = 2.31; 95% CI: 1.05-5.10 to 4.75; 95% CI: 3.11-7.25), sensory (RR (range) = 1.40; 95% CI: 1.34-1.46 to 2.28; 95% CI: 1.72-3.02), musculoskeletal (RR (range) = 1.19; 95% CI: 1.07-1.33 to 1.70; 95% CI: 1.57-1.85) and genito-urinary systems (RR (range) = 1.17; 95% CI: 1.05-1.30 to 1.59; 95% CI: 1.48-1.70). Cases had more psychiatrist and urologist encounters (RR (range) = 1.48; 95% CI: 1.36-1.62 to 1.80; 95% CI: 1.61-2.01), and higher proportions of musculoskeletal, genito-urinary or hormonal-related prescriptions (1.1-1.5 times higher, all p < 0.02). However, cases had fewer pregnancy-related encounters than controls (RR = 0.78; 95% CI: 0.71-0.86 to 0.88; 95% CI: 0.84-0.92).
Conclusion:
Phenotyping the prodrome 5 years before clinical recognition of MS is feasible.
Background:
Multiple sclerosis (MS) management has changed over time, but changes in health care utilization by MS patients remain understudied. We estimated physician services utilization in the five-year periods before and after MS diagnosis, and over the period 1984-2008.
Methods:
Using administrative data we identified 4092 persons with MS and a matched general population (GPOP) cohort of 21,446 persons. Using general linear models we compared physician visits between the MS and GPOPs for the period 1984-2008, the year of MS diagnosis, and for the five-year periods pre- and post-diagnosis.
Results:
From 1984 to 2008, 98% of the MS population averaged ≥1 physician visits/year versus 87% of the GPOP. In 2008, the MS population had 12.9 physician visits/person-year while the GPOP had 8.4 (rate ratio (RR) 1.53; 95% confidence interval (CI): 1.52-1.55). Five years pre-MS diagnosis, the MS population had more physician visits than the GPOP (RR 1.15; 95% CI; 1.10-1.21). The number of visits peaked the year of MS diagnosis (19.0), decreasing thereafter, but remaining elevated versus the pre-diagnosis period.
Conclusion:
The MS population uses more physician services than the GPOP, starting at least five years pre-MS diagnosis. A better understanding of the reasons for these higher utilization rates may ultimately improve outcomes in MS.
Incidentally identified anomalies within the CNS that are highly suggestive of demyelinating disease have been extensively described in neuropathological series, and are increasingly being detected during premortem investigations. With the exception of studies that focused specifically on the prevalence of this entity, the observed anomalies are unanticipated and unrelated to the intended purpose of the examination. The discovery of MRI technology, and its subsequent widespread adoption in the clinic, has facilitated the identification of such cases. The natural course of individuals with incidentally identified demyelinating anomalies is unknown at present. This Review focuses on the history and nosology of unexpected demyelinating pathology, encompassing both autopsy data and MRI-based antemortem investigations of large cohorts, as well as family members at high risk of developing multiple sclerosis. Longitudinal clinical data acquired from prospectively followed cohorts will also be reviewed. In addition, I discuss the estimated prevalence of demyelinating pathology, the currently proposed criteria for its identification, implications for therapeutic intervention, and predictors of disease progression.
Natural history of patients with incidentally discovered lesions that fulfill magnetic resonance imaging (MRI) criteria for multiple sclerosis (MS) in the absence of objective clinical symptoms suggestive of central nervous system (CNS) inflammatory-demyelinating disease is not well defined.
We evaluated the risk of developing symptomatic MS in patients with radiologically uncovered asymptomatic possible inflammatory-demyelinating disease (RAPIDD).
We identified and longitudinally followed a cohort of 22 patients from two tertiary care MS centers: Istanbul University, Cerrahpasa School of Medicine, Istanbul, Turkey, and Mayo Clinic, Rochester, Minnesota, after an initial MRI study fulfilling the Barkhof-Tintore MRI criteria completed for other reasons unrelated to MS.
Eight of 22 patients developed an objective clinical symptom consistent with a CNS inflammatory-demyelinating syndrome and fulfilled dissemination in space and time criteria for definite MS. Median age at the time of diagnosis of MS was 44.8 years (range 28.3-71.4 years). Time taken for the development of definite MS was studied by survival analysis. Cumulative event rates were; 12 months: 9%, 24 months: 15%, 36 months: 30.4%, and 60 months: 44.6%. Six of 22 patients were followed beyond 60 months. Two of these six patients developed MS later (at 66 and 112 months, respectively). Three patients remained asymptomatic despite follow-up of 10 years.
with RAPIDD develop MS at a similar rate to treated patients (and less frequently than placebo groups) with clinically isolated syndromes from prior randomized controlled studies. Some patients with RAPIDD continue to have radiological evolution of subclinical disease without MS symptoms despite long follow-up periods.
The discovery and broad application of MRI in medicine has led to an increased awareness in the number of patients with incidental white matter pathology in the CNS. Routinely encountered in clinical practice, the natural history or evolution of such individuals with respect to their risk of developing multiple sclerosis (MS) is unclear.
To investigate the natural history of patients who exhibit incidental imaging findings highly suggestive of MS pathology.
Detailed clinical and radiologic data were obtained from asymptomatic patients with MRI anomalies suggestive of MS.
The cohort consisted of 41 female and 3 male subjects (median age = 38.5, range: 16.2-67.1). Clinical evaluations were performed in 44 patients at the time of initial imaging; longitudinal clinical follow-up occurred for 30 patients, and longitudinal MRI data were acquired for 41 patients. Neurologic examination at the time of the initial MRI scans was normal in nearly all cases. While radiologic progression was identified in 59% of cases, only 10 patients converted to either clinically isolated syndrome or definite MS. The presence of contrast-enhancing lesions on the initial MRI was predictive of dissemination in time on repeat imaging of the brain (hazard ratio [HR] = 3.4, 95% confidence interval [1.3, 8.7], p = 0.01).
Individuals with MRI anomalies highly suggestive of demyelinating pathology, not better accounted for by another disease process, are very likely to experience subsequent radiologic or clinical events related to multiple sclerosis. Additional studies will be necessary to fully define this risk.
The concept of preclinical multiple sclerosis is now well recognised, and a diagnosis of silent brain T2 lesions is frequent because of the ease of performing MRI. Nevertheless, patients with incidental brain MRI fulfilling Barkhof- Tintoré criteria are more rare. We report a descriptive retrospective study of clinical and 5 year MRI follow-up in patients with subclinical demyelinating lesions fulfilling MRI Barkhof-Tintoré criteria with a normal neurological examination. 30 patients were identified and the first brain MRI was performed for various medical events: headaches (n = 14), migraine with (n = 2) or without (n = 4) aura, craniocerebral trauma (n = 3), depression (n = 3), dysmenorrhoea (n = 2), epilepsy (n = 1) and cognitive changes (n = 1). Mean time for the second brain MRI was 6 months (range 3-30). 23 patients had temporospatial dissemination (eight with gadolinium enhancement). 11 patients had clinical conversion: optic neuritis (n = 5), brainstem (n = 3), sensitive symptoms (n = 2) and cognitive deterioration (n = 1). Eight (72%) already had criteria of dissemination to space and time before the clinical event. Mean time between the first brain MRI and clinically isolated syndrome (CIS) was 2.3 years. To our knowledge, this is the first cohort of CIS with preclinical follow-up. Early treatment should be discussed in view of the predictive value on conversion of the MRI burden of the disease.
- L M Weiss
- D O'malley
- Benign Lymphadenopathies
Weiss LM and O'Malley D. Benign
lymphadenopathies. Mod Pathol 2013; 26(Suppl. 1):
S88-S96.