Early MS Patients Research Articles

Arm Swing Movements during Walking as an Early Predictor of Multiple Sclerosis Progression

Persons with Multiple Sclerosis (pwMS) are at a high risk of falling, with abnormal gait pattern. The upper limbs play an important role in postural control and gait stability. The presence of arm swing changes during walking in pwMS, especially in the early period, may be an indicator of balance problems. The current study aimed to assess arm swing during walking in early MS. A total of 18 pwMS were evaluated in two time points. The first time was after their first (stable) diagnosis (pre-evaluation) and the second time was 3 months after the pre-evaluation. In addition, 10 healthy controls were evaluated once. Arm swing analysis during walking, using video recording, was applied to both groups. Additionally, the MS group performed the Two-Minute Walk Test, Timed Up and Go, and Timed 25-Foot Walk Test. The pwMS showed similar joint angles at both the first and second evaluations. Only the elbow ROM value on the least affected side was lower in pwMS than healthy controls at the second evaluation (p = 0.027). The early MS patients showed altered arm swing pattern. As walking speed and mobility scores did not change over time, the decrease in elbow amplitude over a 3-month period indicates that the arm swing may present a pattern resulting from MS-specific disorders rather than being a compensatory mechanism in walking. From the earliest stages of the disease, variations in arm swing movements during walking may be considered as a disease progression-predictor for MS.

Prediction of high and low disease activity in early MS patients using multiple kernel learning identifies importance of lateral ventricle intensity.

BackgroundLack of easy-to-interpret disease activity prediction methods in early MS can lead to worse patient prognosis.ObjectivesUsing machine learning (multiple kernel learning – MKL) models, we assessed the prognostic value of various clinical and MRI measures for disease activity.MethodsEarly MS patients (n = 148) with at least two associated clinical and MRI visits were investigated. T2-weighted MRIs were cropped to contain mainly the lateral ventricles (LV). High disease activity was defined as surpassing NEDA-3 Criteria more than once per year. Clinical demographic, MRI-extracted image-derived phenotypes (IDP), and MRI data were used as inputs for separate kernels to predict future disease activity with MKL. Model performance was compared using bootstrapped effect size analysis of mean differences.ResultsA total of 681 visits were included, where 81 (55%) patients had high disease activity in a combined end point measure using all follow-up visits. MKL model discrimination performance was moderate (AUC ≥ 0.62); however, modelling with combined clinical and cropped LV kernels gave the highest prediction performance (AUC = 0.70).ConclusionsMRIs contain valuable information on future disease activity, especially in and around the LV. MKL techniques for combining different data types can be used for the prediction of disease activity in a relatively small MS cohort.

Functional connectivity dynamics reflect disability and multi-domain clinical impairment in patients with relapsing-remitting multiple sclerosis

Background & AimMultiple sclerosis (MS) is an autoimmune disease of the central nervous system associated with deficits in cognitive and motor functioning. While structural brain changes such as demyelination are an early hallmark of the disease, a characteristic profile of functional brain alterations in early MS is lacking. Functional neuroimaging studies at various disease stages have revealed complex and heterogeneous patterns of aberrant functional connectivity (FC) in MS, with previous studies largely being limited to a static account of FC. Thus, it remains unclear how time-resolved FC relates to variance in clinical disability status in early MS. We here aimed to characterize brain network organization in early MS patients with time-resolved FC analysis and to explore the relationship between disability status, multi-domain clinical outcomes and altered network dynamics. MethodsResting-state functional MRI (rs-fMRI) data were acquired from 101 MS patients and 101 age- and sex-matched healthy controls (HC). Based on the Expanded Disability Status Score (EDSS), patients were split into two sub-groups: patients without clinical disability (EDSS ≤ 1, n = 36) and patients with mild to moderate levels of disability (EDSS ≥ 2, n = 39). Five dynamic FC states were extracted from whole-brain rs-fMRI data. Group differences in static and dynamic FC strength, across-state overall connectivity, dwell time, transition frequency, modularity, and global connectivity were assessed. Patients’ impairment was quantified as custom clinical outcome z-scores (higher: worse) for the domains depressive symptoms, fatigue, motor, vision, cognition, total brain atrophy, and lesion load. Correlation analyses between functional measures and clinical outcomes were performed with Spearman partial correlation analyses controlling for age. ResultsPatients with mild to moderate levels of disability exhibited a more widespread spatiotemporal pattern of altered FC and spent more time in a high-connectivity, low-occurrence state compared to patients without disability and HCs. Worse symptoms in all clinical outcome domains were positively associated with EDSS scores. Furthermore, depressive symptom severity was positively related to functional dynamics as measured by state-specific global connectivity and default mode network connectivity with attention networks, while fatigue and motor impairment were related to reduced frontoparietal network connectivity with the basal ganglia. ConclusionsDespite comparably low impairment levels in early MS, we identified distinct connectivity alterations between patients with mild to moderate disability and those without disability, and these changes were sensitive to clinical outcomes in multiple domains. Furthermore, time-resolved analysis uncovered alterations in network dynamics and clinical correlations that remained undetected with conventional static analyses, showing that accounting for temporal dynamics helps disentangle the relationship between functional alterations, disability status, and symptoms in early MS.

Measurement of neurofilaments improves stratification of future disease activity in early multiple sclerosis

Background: The added value of neurofilament light chain levels in serum (sNfL) to the concept of no evidence of disease activity-3 (NEDA-3) has not yet been investigated in detail. Objective: To assess whether combination of sNfL with NEDA-3 status improves identification of patients at higher risk of disease activity during the following year. Methods: We analyzed 369 blood samples from 155 early relapsing-remitting MS patients on interferon beta-1a. We compared disease activity, including the rate of brain volume loss in subgroups defined by NEDA-3 status and high or low sNfL (> 90th or < 90th percentile). Results: In patients with disease activity (EDA-3), those with higher sNFL had higher odds of EDA-3 in the following year than those with low sNFL (86.5% vs 57.9%; OR = 4.25, 95% CI: [2.02, 8.95]; p = 0.0001) and greater whole brain volume loss during the following year (β = −0.36%; 95% CI = [−0.60, −0.13]; p = 0.002). Accordingly, NEDA-3 patients with high sNfL showed numerically higher disease activity (EDA-3) in the following year compared with those with low sNfL (57.1% vs 31.1%). Conclusion: sNfL improves the ability to identify patients at higher risk of future disease activity, beyond their NEDA-3 status. Measurement of sNfL may assist clinicians in decision-making by providing more sensitive prognostic information.

The course of cervical spinal cord atrophy rate and its relationship with NEDA in relapsing remitting multiple sclerosis.

This study aimed to compare the annualized segmental cervical spinal cord atrophy rate (ASCAR) in the early and late stages of relapsing remitting multiple sclerosis (RRMS), and to investigate the relationship between ASCAR and no evidence of disease activity (NEDA) in RRMS. Participants in this study included early stage MS (EMSg) patients, late stage MS (LMSg) patients, and healthy controls. All of the included participants (n = 175 subjects) were followed up for 14months, and an MRI was performed on each participant at the beginning and at the end of the study. Cervical spinal cord average segmental area (CSCA) was measured by a semi-automated method, and ASCAR (mm2/year) was calculated. Data from the EMSg (n = 81 subjects) and LMSg (n = 94 subjects) patient groups were compared with each other and with the control group (n = 43 subjects). Examination of the initial CSCA values revealed that the baseline CSCA of the control group was larger than that of the EMSg (p < 0.001), and the baseline CSCA of the EMSg was larger than that of the LMSg (p < 0.001). The ASCAR of the control group, LMSg, and EMSg were 0.48, 0.93, and 1.81mm2 (p < 0.001), respectively. Regression analysis revealed that disability increase was associated with ASCAR, while MRI activity and relapse presence were unrelated to ASCAR. In both patient groups, ASCAR was slower in those who fulfilled NEDA but this relationship was not significant. Cervical spinal cord atrophy progression over time occurs at a greater rate in the early stages of RRMS disease compared to the late stages. ASCAR was unrelated to MRI activity and relapse, which are clinical markers of acute inflammation.

Laminar analysis of the cerebellar cortex shows widespread damage in early MS patients: A pilot study at 7T MRI.

BackgroundTo date, little is known about the presence and extent of cerebellar cortical pathology in early stages of MS.ObjectiveThe aims of this study were to (i) investigate microstructural changes in the normal-appearing cerebellar cortex of early MS patients by using 7 T MRI and (ii) evaluate the influence of those changes on clinical performance.MethodsEighteen RRMS patients and nine healthy controls underwent quantitative T1 and T2* measurement at 7 T MRI using high-resolution MP2RAGE and multi-echo gradient-echo imaging. After subtracting lesion masks, average T1 and T2* maps were computed for three layers in the cerebellar cortex and compared between groups using mixed effects models.ResultsThe volume of the cerebellar cortex and its layers did not differ between patients and controls. In MS patients, significantly longer T1 values were observed in all vermis cortical layers and in the middle and external cortical layer of the cerebellar hemispheres. No between-group differences in T2* values were found. T1 values correlated with EDSS, SDMT and PASAT.ConclusionsWe found MRI evidence of damage in the normal-appearing cerebellar cortex at early MS stages and before volumetric changes. This microstructural alteration appears to be related to EDSS and cognitive performance.

Evolution of Cortical and White Matter Lesion Load in Early-Stage Multiple Sclerosis: Correlation With Neuroaxonal Damage and Clinical Changes.

Introduction: Changes in cortical and white matter lesion (CL, WML) load are pivotal metrics to diagnose and monitor multiple sclerosis patients. Yet, the relationship between (i) changes in CL/WML load and disease progression and between (ii) changes in CL/WML load and neurodegeneration at early MS stages is not yet established. In this work, we have assessed the hypothesis that the combined CL and WML load as well as their 2-years evolution are surrogate markers of neurodegeneration and clinical progression at early MS stages. To achieve this goal, we have studied a group of RRMS patients and have investigated the impact of both CL and WML load on neuroaxonal damage as measured by serum neurofilament light chain (sNfL). Next, we have explored whether changes in CL/WML load over 2 years in the same cohort of early-MS are related to motor and cognitive changes.Methods: Thirty-two RRMS patients (<5 years disease duration) underwent: (i) 3T MRI for CL/WML detection and clinical assessment at baseline and 2-years follow-up; and (ii) baseline blood test for sNfL. The correlation between the number and volume of CL/WML and sNfL was assessed by using the Spearman's rank correlation coefficient and a generalized linear model (GLM). A GLM was also used to assess the relationship between (i) the number/volume of new, enlarged, resolved, shrunken, stable lesions and (ii) the difference in clinical scores between two time-points.Results: At baseline, sNfL levels correlated with both total CL count/volume (ρ = 0.6/0.7, Corr-P <0.017/Corr-P < 0.001) and with total WML count/volume (ρ = 0.6/0.6, Corr-P < 0.01 for both). Baseline sNfL levels also correlated with new WML count/volume (ρ = 0.6/0.5, Corr-P < 0.01/Corr-P < 0.05) but not with new CL. Longitudinal changes in CL and WML count and volume were significantly associated with (i) sustained attention, auditory information, processing speed and flexibility (p < 0.01), (ii) verbal memory (p < 0.01); (iii) verbal fluency (p < 0.05); and (iv) hand-motor function (p < 0.05).Discussion: Changes in cortical and white matter focal damage in early MS patients correlate with global neuroaxonal damage and is associated to cognitive performances.

The macrophage migration inhibitory factor pathway in human B cells is tightly controlled and dysregulated in multiple sclerosis.

In MS, B cells survive peripheral tolerance checkpoints to mediate local inflammation, but the underlying molecular mechanisms are relatively underexplored. In mice, the MIF pathway controls B‐cell development and the induction of EAE. Here, we found that MIF and MIF receptor CD74 are downregulated, while MIF receptor CXCR4 is upregulated in B cells from early onset MS patients. B cells were identified as the main immune subset in blood expressing MIF. Blocking of MIF and CD74 signaling in B cells triggered CXCR4 expression, and vice versa, with separate effects on their proinflammatory activity, proliferation, and sensitivity to Fas‐mediated apoptosis. This study reveals a new reciprocal negative regulation loop between CD74 and CXCR4 in human B cells. The disturbance of this loop during MS onset provides further insights into how pathogenic B cells survive peripheral tolerance checkpoints to mediate disease activity in MS.

Platelet-derived growth factor predicts prolonged relapse-free period in multiple sclerosis

BackgroundIn the early phases of relapsing-remitting multiple sclerosis (RR-MS), a clear correlation between brain lesion load and clinical disability is often lacking, originating the so-called clinico-radiological paradox. Different factors may contribute to such discrepancy. In particular, synaptic plasticity may reduce the clinical expression of brain damage producing enduring enhancement of synaptic strength largely dependent on neurotrophin-induced protein synthesis. Cytokines released by the immune cells during acute inflammation can alter synaptic transmission and plasticity possibly influencing the clinical course of MS. In addition, immune cells may promote brain repair during the post-acute phases, by secreting different growth factors involved in neuronal and oligodendroglial cell survival. Platelet-derived growth factor (PDGF) is a neurotrophic factor that could be particularly involved in clinical recovery. Indeed, PDGF promotes long-term potentiation of synaptic activity in vitro and in MS and could therefore represent a key factor improving the clinical compensation of new brain lesions. The aim of the present study is to explore whether cerebrospinal fluid (CSF) PDGF concentrations at the time of diagnosis may influence the clinical course of RR-MS.MethodsAt the time of diagnosis, we measured in 100 consecutive early MS patients the CSF concentrations of PDGF, of the main pro- and anti-inflammatory cytokines, and of reliable markers of neuronal damage. Clinical and radiological parameters of disease activity were prospectively collected during follow-up.ResultsCSF PDGF levels were positively correlated with prolonged relapse-free survival. Radiological markers of disease activity, biochemical markers of neuronal damage, and clinical parameters of disease progression were instead not influenced by PDGF concentrations. Higher CSF PDGF levels were associated with an anti-inflammatory milieu within the central nervous system.ConclusionsOur results suggest that PDGF could promote a more prolonged relapse-free period during the course of RR-MS, without influencing inflammation reactivation and inflammation-driven neuronal damage and likely enhancing adaptive plasticity.

Relationship between Social Cognition and traditional cognitive impairment in Progressive Multiple Sclerosis and possible implicated neuroanatomical regions

BackgroundCognitive impairment is a relevant contributor of the medical and social burden in Progressive MS. Social Cognition, the neurocognitive processes underlying social interaction, has been explored mainly in European and North American cohorts, influencing social aspects of quality of life (QOL) of early MS patients and families. Few studies have studied Social Cognition in Progressive MS and the literature on its neuroanatomical bases or brain atrophy measurements is still scarce. ObjectivesTo explore the relationship between Social Cognition performance and its correlations with traditional cognitive domains, brain atrophy and QOL in primary and secondary Progressive MS patients. MethodsCross-sectional analysis including: mini-Social-Cognition-and-Emotional-Assessment (mini-SEA), neuropsychological battery, disability, depression, fatigue, QOL, and brain volume. ResultsForty-three MS patients, 23 primary and 20 secondary Progressive, 65% women, mean age and disease duration of 57.2 and 15.7 years, respectively, with high levels of disability (median EDSS 6.0) and a widespread impairment in traditional domains (mostly episodic verbal/visual and working memories) were assessed. The Mini-SEA score was correlated with executive functions (cognitive shifts Rho:0.55; p = 0.001) analyzing the whole group, and with visual episodic memory (Rho:0.58, p = 0.009) in the primary Progressive MS group. Mini-SEA score was also correlated with total normalized grey matter volume (Rho:0.48; p = 0.004). Particularly, atrophy within bilateral cortical regions of orbitofrontal, insula and cerebellum, and right regions of fusiform gyrus and precuneus were significantly associated with higher Social Cognition impairment. In this cohort, QOL was not correlated with Social Cognition, but with EDSS, fatigue and depression. ConclusionsIn Progressive MS, Social Cognition is directly correlated with traditional cognitive domains such as executive function and episodic memory. It is also associated with global grey matter atrophy and regional atrophy within associative visual and executive cortical areas, but no correlations with QOL were found in this cohort. These findings may contribute to the understanding of the pathological bases behind Social Cognition in Progressive MS.

Brain volume in early MS patients with and without IgG oligoclonal bands in CSF

BackgroundOligoclonal bands of IgG (OB) are proposed as an early prognostic factor of the disease. Growing attention is directed towards brain volume evaluation as a possible marker of the severity of MS. Previous studies found that MS patients lacking OB have less brain atrophy. Aimto evaluate a possible relationship between OB and cerebral volume in a cohort of early MS patients. MethodsInclusion criteria were: diagnosis of relapsing-remitting MS; CSF analysis and MRI acquired simultaneously and within 12 months from clinical onset. A total of 15 healthy controls underwent MRI. ResultsIn 20 MS patients, CSF analysis did not show OB synthesis (OB negative group). A control group of 25 MS patients in whom OB was detected was also randomly recruited (OB positive group). T test showed a significant difference in NWV between the OB positive and OB negative groups (P value = 0.01), and between the OB positive group and the healthy controls (P value = 0.001). No differences were detected between OB negative group and healthy controls.Multivariable linear regression showed a relationship between NWV and OB synthesis (P value = 0.02) controlling for age, gender, and EDSS. ConclusionsOur preliminary results suggest that OB positive patients show more atrophy of white matter since early phases of the disease, supporting the role of CSF analysis as a prognostic factor in MS.

Early disturbances in multimodal evoked potentials as a prognostic factor for long-term disability in relapsing-remitting multiple sclerosis patients.

The aim of this study was to investigate whether early alterations in evoked potentials (EPs) have a prognostic value in relapsing-remitting multiple sclerosis (RRMS). We retrospectively selected 108 early MS patients with a neurological follow-up ranging from 5 to 15years, in whom multimodal EPs (visual, brainstem auditory, somatosensory and motor) were performed at diagnosis. A conventional ordinal score was used to quantify the observed abnormalities. The extent of change in the composite EP score was well correlated to the Expanded Disability Status Scale (EDSS) at ten years (Y10) and up to 15years (Y11-15) after disease onset. Analysis of the predictive value of the EP score showed an increased risk of disability progression at Y10 and Y11-15 of 60% (p<0.0001) and 73% (p<0.0001) respectively in patients with an EP score >4. Conversely, the risk of disability progression at Y10 and Y11-15 associated with a lower EP score (⩽4) was reduced to 16% and 20% respectively. Our data support the good predictive value for long-term disability progression of multimodal EPs performed early after disease onset in RRMS patients. This study, performed in a homogeneous RRMS cohort with long term follow-up, demonstrates the value of an early comprehensive neurophysiological assessment as a marker for future disability.

Sympathetic cardiovascular and sudomotor functions are frequently affected in early multiple sclerosis.

The aim of this study was to determine the prevalence of autonomic dysfunction using the composite autonomic scoring scale (CASS) and heart rate variability (HRV) in patients with clinically isolated syndrome (CIS) and to correlate autonomic dysfunction with other measures of MS disease activity. CASS, HRV and plasma catecholamines during supine and tilted phase were performed in 104 CIS patients. MRI findings were analyzed for total number of lesions and the presence of brainstem and cervical spinal cord lesions. Autonomic dysfunction (CASS >1) was present in 59.8% of patients, parasympathetic dysfunction in 5%, sympathetic in 42.6% and sudomotor in 32.7% of patients. Patients with autonomic dysfunction on CASS had lower level of norepinephrine in the supine position compared to patients without autonomic dysfunction (1.06±0.53 vs. 1.37±0.86, p=0.048). The CASS score showed positive correlation with s-HF (r=0.226, p=0.031), s-SDNN (r=0.221, p=0.035), t-HF (r=0.225, p=0.032), and t-HFnu (r=0.216, p=0.04), and a negative correlation with t-LF/HF (r=-0.218, p=0.038). More patients with MRI brainstem lesions had a positive adrenergic index (p=0.038). Patients with MRI brainstem lesions also had a lower t-SDNN (26.2±14.2 vs. 32±13.3, p=0.036) and a lower t-LF (median 415.0 vs. 575.5, p=0.018) compared to patients without these lesions. Patients with adrenergic index ≥1 had a significantly higher standing heart rate compared to patients with an adrenergic index of 0 (96±13.5 vs. 90±12, p=0.032). Autonomic (primarily sympathetic) dysfunction is present in a large proportion of early MS patients and it seems to be related to brainstem involvement.

The auto-reactive profile of B cells from early MS patients

Abstract My lab’s recent work has led to the discovery that antibodies expressed by memory B cells in the cerebrospinal fluid (CSF) of patients with Multiple Sclerosis recognize neurons and astrocytes in the brain. Genetic analysis further revealed that only certain heavy chain genes accommodate binding to these brain targets, and that memory B cells from control cohorts rarely express these antibody genes. In fact, in a recent clinical trial, we demonstrated that the prevalence of these antibody genes expressed by memory B cells in the CSF support identification of patients who either have MS or will develop MS in the future with 89–94% accuracy. This Antibody Gene Signature (AGS) is a novel biomarker that heralds the advent of antibody genetics as a means to support categorization of patients early in their disease course. Our goal for this project was to determine whether antibodies expressed by activated memory B cells that have initiated antibody production (called “plasmablasts”) in the peripheral blood of MS patients also recognize neurons and astrocytes. We cloned and expressed more than 50 antibodies expressed by peripheral plasmablasts of early MS patients and control cohorts. We found that antibodies expressed by peripheral plasmablasts from patients who develop MS bind to neurons and astrocytes in the brain. Those plasmablasts that did not express antibody heavy chains associated with the AGS did not bind to brain targets. Interestingly, only those patients in our cohort who have an elevated frequency of peripheral plasmablasts continue to accumulate brain MRI activity. It is possible that brain-reactive peripheral plasmablasts contribute to the brain damage associated with MS.

Characterizing Disability in Early Onset MS Patients: Correlation of Clinical Parameters with Retinal Nerve Fibre Layer Thickness (P01.165)

Characterizing Disability in Early Onset MS Patients: Correlation of Clinical Parameters with Retinal Nerve Fibre Layer Thickness (P01.165)

Vitamin D has a direct immunomodulatory effect on CD8+ T cells of patients with early multiple sclerosis and healthy control subjects

Little is known on a putative effect of vitamin D on CD8+ T cells. Yet, these cells are involved in the immmunopathogenesis of MS. We assessed the cytokine profile of EBV-specific CD8+ T cells of 10 early MS patients and 10 healthy control subjects with or without 1,25(OH)2D3 and found that, with 1,25(OH)2D3, these cells secreted less IFN-γ and TNF-α and more IL-5 and TGF-β. CD4+ T cell depletion or even culture with CD8+ T cells only did not abolish the immunomodulatory effect of 1,25(OH)2D3 on CD8+ T cells, suggesting that 1,25(OH)2D3 can act directly on CD8+ T cells.

Intrathecal immune responses to EBV in early MS

EBV has been consistently associated with MS, but its signature in the CNS has rarely been examined. In this study, we assessed EBV-specific humoral and cellular immune responses in the cerebrospinal fluid (CSF) of patients with early MS, other inflammatory neurological diseases (OIND) and non-inflammatory neurological diseases (NIND). The neurotropic herpesvirus CMV served as a control. Virus-specific humoral immune responses were assessed in 123 consecutive patients and the intrathecal recruitment of virus-specific antibodies was expressed as antibody indexes. Cellular immune responses tested in the blood of 55/123 patients were positive in 46/55. The CD8(+) CTL responses of these 46 patients were assessed in the blood and CSF using a CFSE-based CTL assay. We found that viral capsid antigen and EBV-encoded nuclear antigen-1, but not CMV IgG antibody indexes, were increased in early MS as compared with OIND and NIND patients. There was also intrathecal enrichment in EBV-, but not CMV-specific, CD8(+) CTL in early MS patients. By contrast, OIND and NIND patients did not recruit EBV- nor CMV-specific CD8(+) CTL in the CSF. Our data, showing a high EBV-, but not CMV-specific intrathecal immune response, strengthen the association between EBV and MS, in particular at the onset of the disease.

Natural Naive CD4+CD25+CD127low Regulatory T Cell (Treg) Development and Function Are Disturbed in Multiple Sclerosis Patients: Recovery of Memory Treg Homeostasis during Disease Progression

Patients with relapsing-remitting multiple sclerosis (RR-MS) show a suboptimal CD4(+)CD25(+) regulatory T cell (Treg) function, whereas no Treg alterations are observed in secondary progressive MS (SP-MS) patients. To clarify the difference in Treg activity between early and chronic disease stages in MS, we analyzed the functional capacity and homeostatic parameters of naive CD4(+)CD25(+)CD127(low)CD45RA(+) Tregs (nTregs) and their memory counterparts CD4(+)CD25(+)CD127(low)CD45RO(+) Tregs (mTregs) in untreated MS patients and healthy controls. Interestingly, whereas the suppressive capacity of FACS-sorted nTregs was impaired in both early and chronic MS patients, only the latter group showed a restored mTreg function. Consistent with this observation, chronic MS patients had increased numbers of mTregs as compared with age-matched early MS patients, whereas nTreg frequencies did not differ significantly. TCR excision circle numbers were reduced in nTregs of early MS patients, suggestive of a diminished nTreg thymic output. Moreover, a decreased number of CD31(+) mTregs were observed in early vs chronic MS patients, indicating that inflammatory processes drive the homeostatic turnover of mTregs during the early disease stage. Additionally, early MS patients showed a more restricted nTreg and mTreg TCR BV gene profile as compared with healthy controls and chronic MS patients. Finally, analysis of IFN-beta and glatiramer acetate-treated MS patients showed that these immunomodulatory drugs modify nTreg homeostasis. Taken together, this study provides strong evidence for a disturbed thymic nTreg development and function in MS patients. Moreover, memory Treg but not naive Treg homeostasis recovers during disease progression.

Patterns of neurologic involvement in multiple sclerosis.

Specific patterns of neurologic involvement within the 8 Functional Systems (Pyramidal, Cerebellar, Brain Stem, Sensory, Bowel & Bladder, Visual, Cerebral, Other) in a well-documented series of early MS patients have been presented in rank order of expected frequency. The first 35 and the first 86 of the 256 possible patterns comprised respectively 71% and 90% of all cases expected or observed. Patterns with increasingly higher rank orders provided increasingly greater likelihood for the diagnosis of MS. For 1 of the 4 most common patterns, the likelihood of MS was 17 times that without consideration of any pattern. In this series, the occurrence of any of the first 35 patterns was well above expectations, while patterns ranked beyond 86 were highly unlikely.

Viral antibodies in cerebrospinal fluid of multiple sclerosis and control patients: comparison between radioimmunoassay and conventional techniques

Cerebrospinal fluid antibodies to measles, rubella, vaccinia, herpes simplex, and varicella-zoster viruses in four patient study groups (clinically definite multiple sclerosis [MS], early probable MS, optic neuritis, and control patients with other neurological diseases) were assayed by radioimmunoassay, complement fixation, hemagglutination-inhibition, or complement-enhanced plaque reduction methods. Antibodies were more frequently found and at higher dilutions by radioimmunoassay than by other techniques. Measles virus antibody, the most frequently found antibody, was present in the cerebrospinal fluid of 72% of MS patients and 5% of control patients. The differences between the numbers of MS patients and control patients with antibodies to other viruses were not as marked. Thus, 58% of MS patients versus 21% of control patients had antibody to rubella virus, 20 versus 3% had antibody to vaccinia virus, 50 versus 33% had antibody to herpes simplex virus, and 25 versus 8% had antibody to varicella virus. Sixty-seven percent of MS patients and 26% of control patients had antibodies to two or more viruses in their cerebrospinal fluid.