Early Phase Of Multiple Sclerosis Research Articles

Blood-Brain Barrier Disruption in Neuroimmunological Disease.

The blood-brain barrier (BBB) acts as a structural and functional barrier for brain homeostasis. This review highlights the pathological contribution of BBB dysfunction to neuroimmunological diseases, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), autoimmune encephalitis (AE), and paraneoplastic neurological syndrome (PNS). The transmigration of massive lymphocytes across the BBB caused by the activation of cell adhesion molecules is involved in the early phase of MS, and dysfunction of the cortical BBB is associated with the atrophy of gray matter in the late phase of MS. At the onset of NMOSD, increased permeability of the BBB causes the entry of circulating AQP4 autoantibodies into the central nervous system (CNS). Recent reports have shown the importance of glucose-regulated protein (GRP) autoantibodies as BBB-reactive autoantibodies in NMOSD, which induce antibody-mediated BBB dysfunction. BBB breakdown has also been observed in MOGAD, NPSLE, and AE with anti-NMDAR antibodies. Our recent report demonstrated the presence of GRP78 autoantibodies in patients with MOGAD and the molecular mechanism responsible for GRP78 autoantibody-mediated BBB impairment. Disruption of the BBB may explain the symptoms in the brain and cerebellum in the development of PNS, as it induces the entry of pathogenic autoantibodies or lymphocytes into the CNS through autoimmunity against tumors in the periphery. GRP78 autoantibodies were detected in paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome, and they were associated with cerebellar ataxia with anti-P/Q type voltage-gated calcium channel antibodies. This review reports that therapies affecting the BBB that are currently available for disease-modifying therapies for neuroimmunological diseases have the potential to prevent BBB damage.

Immunologic analysis of CSF in patients with de novo diagnosed RRMS. The role of chemokines in the early phase of the disease

Objectives: Multiple sclerosis (MS) is a chronic CNS autoimmune disease characterized by demyelination and neurodegeneration. Chemokines regulate leukocyte migration and inflammation in MS. In the present study, we evaluated selected chemokine levels in the cerebrospinal fluid of patients with multiple sclerosis diagnosed de novo compared to healthy controls.Methods: We measured EOTAXIN, IP-10, MCP-1, MIP-1a, MIP-1b and RANTES in the cerebrospinal fluid of 118 patients with de novo RRMS and 112 controls, analyzing correlations with time from symptom onset to diagnosis and changes in MRI.Results: Higher levels of EOTAXIN, IP-10, MIP-1B and RANTES, and lower MCP-1 were observed in MS patients compared to controls. MIP-1A did not show statistical significance. EOTAXIN and IP-10 concentrations increased with time. RANTES concentration correlated positively with T2 changes in MRI of the cervical spine, and EOTAXIN concentration correlated negatively with gadolinium (Gd+) changes in the cervical spine. There was no correlation with changes in the thoracic spine or brain.Conclusions: Chemokines play a significant role in the early phase of MS by influencing inflammatory activity. They may represent potential therapeutic targets for the treatment of this disease.

Gastrointestinal conditions in the multiple sclerosis prodrome.

To investigate gastrointestinal (GI)-related physician visits and drug dispensations in the 5 years preceding a first recorded demyelinating event or multiple sclerosis (MS) onset. Using linked administrative and clinical data from British Columbia (1996-2013), Canada, we identified an administrative cohort via a validated algorithm (n = 6863), a clinical cohort diagnosed at a MS clinic (n = 966), and matched controls (administrative cohort: n = 31,865; clinical cohort: n = 4534). In each cohort, the 5 years before a first demyelinating event or MS symptom onset (i.e., index date) were examined. We compared rates of GI-related physician visits and risk of ≥1 GI-related dispensation between MS cases and controls using negative binomial and robust Poisson models. Sex differences were tested using interaction terms. The administrative cohort MS cases had higher rates of physician visits related to gastritis and duodenitis (adjusted rate/risk ratio (aRR):1.42, 95% CI: 1.10-1.83) and diseases of the esophagus (aRR: 1.46, 95% CI: 1.06-2.02) prior to the index date. MS cases also had greater risk of at least one dispensation for several drug classes, including constipation-related (aRR: 1.82, 95% CI: 1.50-2.22), antiemetics/antinauseants (aRR: 1.64, 95% CI: 1.43-1.89), and propulsives (promotility drugs; aRR: 1.62, 95% CI: 1.47-1.79). Men had a disproportionally higher relative risk for propulsives than women (aRR: men = 2.32, 95% CI: 1.79-3.00; women = 1.54, 95% CI: 1.36-1.72). Several findings were similar in the smaller clinical cohort though none reached statistical significance. GI-related physician visits and drug dispensations were more common in the 5 years before the first demyelinating event versus matched controls. GI symptoms are a measurable feature of the prodromal or early phase of MS, with a sex difference evident.

DYMUS-Hr self-assessment questionnaire (Croatian version) for dysphagia in multiple sclerosis-validity, reliability, and cross-cultural adaptation.

The prevalence of dysphagia in the early phases of multiple sclerosis is 30-40%, with an estimated of 30% of cases going undiagnosed cases. Such complications can lead to malnutrition, dehydration, and aspiration pneumonia and have a great impact on the quality of life and psychosocial status of a person with MS. The aim of this study was the validation of dysphagia in multiple sclerosis self-assessment questionnaire (DYMUS) in the Croatian language. The cross-cultural adaptation process included a back-forward translation technique of the English language version of DYMUS to the Croatian language, with pilot testing on 30 participants. The validity and reliability of the Croatian version of DYMUS (DYMUS-Hr) was applied to 106 MS patients, with comparison to the Eating Assessment Tool (EAT10), the Water Swallowing Test (WST), and a dichotomous self-assessment question. In the assessment of test-retest reliability, 99 MS patients were included. Internal consistency of DYMUS-Hr was very good (Cronbach's alpha-0.837); Cronbach's alpha was 0.819 for the "dysphagia for solids", and 0.562 for "dysphagia for liquids" subscale. A significant correlation (p < 0.001) was found between DYMUS-Hr and EAT10 (Spearman's rho-0.787), and WST (Spearman's rho-0.483). Construct validity was assessed with the self-assessment question and interpreted with the Mann-Whitney U test. Test-retest reliability showed moderate to substantial Cohen's Kappa reliability for each item. DYMUS-Hr is a valid and reliable screening assessment tool for patients with MS. There is a general lack of awareness about dysphagia symptoms among patients with MS; consequently, this disorder receives inadequate attention and often goes untreated.

Choroid plexus imaging to track neuroinflammation - a translational model for mouse and human studies.

Choroid plexus imaging to track neuroinflammation - a translational model for mouse and human studies.

IL-2, IL-6 and chitinase 3-like 2 might predict early relapse activity in multiple sclerosis.

The possibility to better predict the severity of the disease in a patient newly diagnosed with multiple sclerosis would allow the treatment strategy to be personalized and lead to better clinical outcomes. Prognostic biomarkers are highly needed. To assess the prognostic value of intrathecal IgM synthesis, cerebrospinal fluid and serum IL-2, IL-6, IL-10, chitinase 3-like 2 and neurofilament heavy chains obtained early after the onset of the disease. 58 patients after the first manifestation of multiple sclerosis were included. After the initial diagnostic assessment including serum and cerebrospinal fluid biomarkers, all patients initiated therapy with either glatiramer acetate, teriflunomide, or interferon beta. To assess the evolution of the disease, we followed the patients clinically and with MRI for two years. The IL-2:IL-6 ratio (both in cerebrospinal fluid) <0.48 (p = 0.0028), IL-2 in cerebrospinal fluid ≥1.23pg/ml (p = 0.026), and chitinase 3-like 2 in cerebrospinal fluid ≥7900pg/ml (p = 0.033), as well as baseline EDSS ≥1.5 (p = 0.0481) and age <22 (p = 0.0312), proved to be independent markers associated with shorter relapse free intervals. The IL-2:IL-6 ratio, IL-2, and chitinase 3-like 2 (all in cerebrospinal fluid) might be of value as prognostic biomarkers in early phases of multiple sclerosis.

Oxidative Stress Markers in Cerebrospinal Fluid of Newly Diagnosed Multiple Sclerosis Patients and Their Link to Iron Deposition and Atrophy.

Oxidative stress has been implied in cellular injury even in the early phases of multiple sclerosis (MS). In this study, we quantified levels of biomarkers of oxidative stress and antioxidant capacity in cerebrospinal fluid (CSF) in newly diagnosed MS patients and their associations with brain atrophy and iron deposits in the brain tissue. Consecutive treatment-naive adult MS patients (n = 103) underwent brain MRI and CSF sampling. Healthy controls (HC, n = 99) had brain MRI. CSF controls (n = 45) consisted of patients with non-neuroinflammatory conditions. 3T MR included isotropic T1 weighted (MPRAGE) and gradient echo (GRE) images that were processed to quantitative susceptibility maps. The volume and magnetic susceptibility of deep gray matter (DGM) structures were calculated. The levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), 8-iso prostaglandin F2α (8-isoPG), neutrophil gelatinase-associated lipocalin (NGAL), peroxiredoxin-2 (PRDX2), and malondialdehyde and hydroxyalkenals (MDA + HAE) were measured in CSF. Compared to controls, MS patients had lower volumes of thalamus, pulvinar, and putamen, higher susceptibility in caudate nucleus and globus pallidus, and higher levels of 8-OHdG, PRDX2, and MDA + HAE. In MS patients, the level of NGAL correlated negatively with volume and susceptibility in the dentate nucleus. The level of 8-OHdG correlated negatively with susceptibility in the caudate, putamen, and the red nucleus. The level of PRDX2 correlated negatively with the volume of the thalamus and both with volume and susceptibility of the dentate nucleus. From MRI parameters with significant differences between MS and HC groups, only caudate susceptibility and thalamic volume were significantly associated with CSF parameters. Our study shows that increased oxidative stress in CSF detected in newly diagnosed MS patients suggests its role in the pathogenesis of MS.

Quantitative 7-Tesla Imaging of Cortical Myelin Changes in Early Multiple Sclerosis.

Cortical demyelination occurs early in multiple sclerosis (MS) and relates to disease outcome. The brain cortex has endogenous propensity for remyelination as proven from histopathology study. In this study, we aimed at characterizing cortical microstructural abnormalities related to myelin content by applying a novel quantitative MRI technique in early MS. A combined myelin estimation (CME) cortical map was obtained from quantitative 7-Tesla (7T) T and T1 acquisitions in 25 patients with early MS and 19 healthy volunteers. Cortical lesions in MS patients were classified based on their myelin content by comparison with CME values in healthy controls as demyelinated, partially demyelinated, or non-demyelinated. At follow-up, we registered changes in cortical lesions as increased, decreased, or stable CME. Vertex-wise analysis compared cortical CME in the normal-appearing cortex in 25 MS patients vs. 19 healthy controls at baseline and investigated longitudinal changes at 1 year in 10 MS patients. Measurements from the neurite orientation dispersion and density imaging (NODDI) diffusion model were obtained to account for cortical neurite/dendrite loss at baseline and follow-up. Finally, CME maps were correlated with clinical metrics. CME was overall low in cortical lesions (p = 0.03) and several normal-appearing cortical areas (p < 0.05) in the absence of NODDI abnormalities. Individual cortical lesion analysis revealed, however, heterogeneous CME patterns from extensive to partial or absent demyelination. At follow-up, CME overall decreased in cortical lesions and non-lesioned cortex, with few areas showing an increase (p < 0.05). Cortical CME maps correlated with processing speed in several areas across the cortex. In conclusion, CME allows detection of cortical microstructural changes related to coexisting demyelination and remyelination since the early phases of MS, and shows to be more sensitive than NODDI and relates to cognitive performance.

Common Peripheral Immunity Mechanisms in Multiple Sclerosis and Alzheimer's Disease.

Neurodegenerative diseases are closely related to inflammatory and autoimmune events, suggesting that the dysregulation of the immune system is a key pathological factor. Both multiple sclerosis (MS) and Alzheimer's disease (AD) are characterized by infiltrating immune cells, activated microglia, astrocyte proliferation, and neuronal damage. Moreover, MS and AD share a common pro-inflammatory signature, characterized by peripheral leukocyte activation and transmigration to the central nervous system (CNS). MS and AD are both characterized by the accumulation of activated neutrophils in the blood, leading to progressive impairment of the blood–brain barrier. Having migrated to the CNS during the early phases of MS and AD, neutrophils promote local inflammation that contributes to pathogenesis and clinical progression. The role of circulating T cells in MS is well-established, whereas the contribution of adaptive immunity to AD pathogenesis and progression is a more recent discovery. Even so, blocking the transmigration of T cells to the CNS can benefit both MS and AD patients, suggesting that common adaptive immunity mechanisms play a detrimental role in each disease. There is also growing evidence that regulatory T cells are beneficial during the initial stages of MS and AD, supporting the link between the modulatory immune compartments and these neurodegenerative disorders. The number of resting regulatory T cells declines in both diseases, indicating a common pathogenic mechanism involving the dysregulation of these cells, although their precise role in the control of neuroinflammation remains unclear. The modulation of leukocyte functions can benefit MS patients, so more insight into the role of peripheral immune cells may reveal new targets for pharmacological intervention in other neuroinflammatory and neurodegenerative diseases, including AD.

Peripheral levels of selected adipokines in patients with newly diagnosed multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. The exact aetiology is unknown. However, genetic and environmental factors are suggested to be involved in the pathogenesis of MS. Improper diet, resulting in obesity and metabolic syndrome, can contribute to this disease. Adipokines, secreted by adipose tissue, link the metabolism and immune system. We aimed to assess plasma levels of selected adipokines in newly diagnosed, treatment-naïve individuals with multiple sclerosis. Our group comprised 58 individuals (31 MS patients and 27 controls, matched for age and BMI) without diabetes, hypertension, or dyslipidaemia. Circulating adiponectin and all adiponectin fractions, visfatin, and omentin concentrations were measured. Metabolic parameters were also assessed. In MS individuals we observed the following results: higher concentrations of visfatin, lower levels of omentin, and no differences in adiponectin array. There were also correlations between some adipokines and metabolic parameters. After adjustment to BMI, a significant decrease in total adiponectin, high-molecular weight (HMW) adiponectin and omentin, and an increase in medium-molecular-weight (MMW) adiponectin were observed in the group of MS patients when compared to those of the controls. Our results indicate that adiponectin with its fractions, visfatin, and omentin cannot be considered as causative factors in the early phase of multiple sclerosis. However, the potential role of adipokines in MS is possible because they might be involved in the pathogenesis of MS, regarded as an autoimmune disorder.

The Role of fMRI in the Assessment of Neuroplasticity in MS: A Systematic Review

Neuroplasticity, which is the ability of the brain to adapt to internal and external environmental changes, physiologically occurs during growth and in response to damage. The brain's response to damage is of particular interest in multiple sclerosis, a chronic disease characterized by inflammatory and neurodegenerative damage to the central nervous system. Functional MRI (fMRI) is a tool that allows functional changes related to the disease and to its evolution to be studied in vivo. Several studies have shown that abnormal brain recruitment during the execution of a task starts in the early phases of multiple sclerosis. The increased functional activation during a specific task observed has been interpreted mainly as a mechanism of adaptive plasticity designed to contrast the increase in tissue damage. More recent fMRI studies, which have focused on the activity of brain regions at rest, have yielded nonunivocal results, suggesting that changes in functional brain connections represent mechanisms of either adaptive or maladaptive plasticity. The few longitudinal studies available to date on disease evolution have also yielded discrepant results that are likely to depend on the clinical features considered and the length of the follow-up. Lastly, fMRI has been used in interventional studies to investigate plastic changes induced by pharmacological therapy or rehabilitation, though whether such changes represent a surrogate of neuroplasticity remains unclear. The aim of this paper is to systematically review the existing literature in order to provide an overall description of both the neuroplastic process itself and the evolution in the use of fMRI techniques as a means of assessing neuroplasticity. The quantitative and qualitative approach adopted here ensures an objective analysis of published, peer-reviewed research and yields an overview of up-to-date knowledge.

Neuropsychiatric assessments in patients with multiple sclerosis in early phases and with low disability.

BackgroundIn the early phases of multiple sclerosis (MS), patients exhibit slight neuropsychiatric deficits that can only be detected using reliable tools.AimThe present investigation aimed to examine neuropsychological performance in 35 patients with incipient MS.Patients and methodsFor the MS group, the inclusion criteria included time of disease <3 years and low disability. The neuropsychological battery consisted of Rey Auditory Learning Test, Controlled Oral Word Association Test, Hooper Visual Organization Test, and Symbol Digit Modalities Test (SDMT).ResultsAfter correction for the educational level, no significant effect of MS on performance was found for all the tests except for the number of errors of the SDMT (NE-SDMT). Higher levels of education were associated with better performances in all tests, except for the NE-SDMT. MS patients made more errors than the controls.ConclusionThe effect on the NE-SDMT may reflect difficulties in the ability to inhibit inadequate responses. Patients may exhibit impulsive control disorders in incipient MS, independent of their educational level.

Axisymmetric solutions for a chemotaxis model of Multiple Sclerosis

In this paper we study radially symmetric solutions for our recently proposed reaction–diffusion–chemotaxis model of Multiple Sclerosis. Through a weakly nonlinear expansion we classify the bifurcation at the onset and derive the amplitude equations ruling the formation of concentric demyelinating patterns which reproduce the concentric layers observed in Balo sclerosis and in the early phase of Multiple Sclerosis. We present numerical simulations which illustrate and fit the analytical results.

Peripheral blood monocyte count at onset may affect the prognosis in multiple sclerosis

Multiple sclerosis (MS) is a demyelinating neurological disease with unknown causes. In this study, we comprehensively studied blood cell counts in the early phase of MS and compared their values with eventual prognostic variables. We found that the blood monocyte count in the early phase of MS was robustly associated with the clinical severity of MS (rho = 0.64; p = 0.0002) but that the counts of the other blood cells were not associated with severity. This correlation between monocyte count and severity was not observed in neuromyelitis optica. In conclusion, blood monocytes could be a candidate for the prognostic prediction of MS.

Cognitive impairment at diagnosis predicts 10-year multiple sclerosis progression

Background: Cognitive impairment occurs from the early phases of multiple sclerosis (MS), and more frequently affects secondary progressive (SP) subjects than relapsing–remitting (RR). Objective: To investigate relationships between cognitive dysfunctions in newly diagnosed RRMS, and long-term MS-related outcomes. Methods: The present 10-year retrospective longitudinal study included 155 RRMS subjects, tested with the Rao Brief Repeatable Battery at MS diagnosis. The reaching of Expanded Disability Status Scale (EDSS) 4.0, and the SP conversion were recorded. Results: 67 subjects (43.2%) reached EDSS 4.0, and 34 subjects (21.9%) converted to SP during a follow-up period of 10.0±1.8 years. Subjects with cognitive impairment at diagnosis had a rate of reaching EDSS 4.0 more than three times greater (p<0.001; HR=3.183), and a rate of SP conversion more than two times greater, as compared to cognitively preserved subjects (p=0.008; HR=2.535). In particular, better scores in the Selective Reminding Test-Delayed Recall and in the Symbol Digit Modalities Test at baseline were associated with lower SP conversion rates during the follow-up period (p=0.018; HR=0.835; and p=0.001; HR=0.941, respectively). Conclusion: Cognitive impairment, with particular involvement of processing speed and memory, predicts disability progression and SP conversion in newly diagnosed RRMS, highlighting the importance of cognitive assessment from the beginning of MS.

Longitudinal Mixed-Effect Model Analysis of the Association between Global and Tissue-Specific Brain Atrophy and Lesion Accumulation in Patients with Clinically Isolated Syndrome.

The relationship between lesion formation and brain atrophy development in the early phase of multiple sclerosis is unclear. We investigated the association between new lesion accumulation and brain atrophy progression in patients with clinically isolated syndrome over 48 months. Patients with clinically isolated syndrome (n = 210) were evaluated with 1.5T MR imaging at baseline and at 6, 12, 24, 36, and 48 months as part of a multicenter observational study of early administration of intramuscular interferon β-1a. Mixed-effect model analyses, adjusted for age, sex, and treatment status, investigated the association between accumulation of contrast-enhancing and T2 lesions and brain-volume percent changes in a 48-month period. In patients with clinically isolated syndrome, the average whole-brain volume decreased 2.5%, the mean lateral ventricle volume increased 16.9%, and a mean of 7.7 new/enlarging T2 lesions accumulated over the follow-up period. Patients with clinically isolated syndrome who showed greater percentages of change in whole-brain, white and gray matter, cortical, and lateral ventricle volumes over the follow-up period had more severe lesion outcomes at baseline (all P < .007). There were significant associations between decreased individual brain-volume measures at baseline and greater percentages of change during follow-up (P < .05). We found a significant association between the total cumulative number of new/enlarging T2 lesions and the evolution of whole-brain (P < .001), lateral ventricle (P = .007), gray matter and thalamic (P = .013), subcortical deep gray matter (P = .015), and cortical (P = .036) volumes over the follow-up period. Lesion accumulation and brain-volume changes occur simultaneously in the early phase of clinically isolated syndrome. More severe lesion and brain-volume outcomes at baseline were associated with greater development of brain atrophy over the follow-up period in patients with clinically isolated syndrome.

The multiple sclerosis visual pathway cohort: understanding neurodegeneration in MS.

BackgroundMultiple Sclerosis (MS) is an immune-mediated disease of the Central Nervous System with two major underlying etiopathogenic processes: inflammation and neurodegeneration. The latter determines the prognosis of this disease. MS is the main cause of non-traumatic disability in middle-aged populations.FindingsThe MS-VisualPath Cohort was set up to study the neurodegenerative component of MS using advanced imaging techniques by focusing on analysis of the visual pathway in a middle-aged MS population in Barcelona, Spain. We started the recruitment of patients in the early phase of MS in 2010 and it remains permanently open. All patients undergo a complete neurological and ophthalmological examination including measurements of physical and disability (Expanded Disability Status Scale; Multiple Sclerosis Functional Composite and neuropsychological tests), disease activity (relapses) and visual function testing (visual acuity, color vision and visual field). The MS-VisualPath protocol also assesses the presence of anxiety and depressive symptoms (Hospital Anxiety and Depression Scale), general quality of life (SF-36) and visual quality of life (25-Item National Eye Institute Visual Function Questionnaire with the 10-Item Neuro-Ophthalmic Supplement). In addition, the imaging protocol includes both retinal (Optical Coherence Tomography and Wide-Field Fundus Imaging) and brain imaging (Magnetic Resonance Imaging). Finally, multifocal Visual Evoked Potentials are used to perform neurophysiological assessment of the visual pathway.DiscussionThe analysis of the visual pathway with advance imaging and electrophysilogical tools in parallel with clinical information will provide significant and new knowledge regarding neurodegeneration in MS and provide new clinical and imaging biomarkers to help monitor disease progression in these patients.

Mood and coping in clinically isolated syndrome and multiple sclerosis

Few studies have examined behavioural changes in the early phase of multiple sclerosis (MS). The aim of the study is to investigate mood alterations and to explore coping strategies regarding patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS). The communication of diagnosis was made by one neurologist using a standardized approach. Depression, anxiety and coping questionnaires were filled in within 1month from the diagnosis and at 3, 6, 12, 18 and 24months subsequently. Thirty-nine patients were examined (11 CIS, 28 RRMS), also 39 healthy controls. At entry, patients showed a lower degree of hostile behaviour and a higher level of depression than the controls. At follow-up, a reduction in depression, anxiety and a better coping adjustment was observed. A higher reliance on 'Accepting responsibilities' coping score was seen in patients with higher levels of depression and anxiety. No significant differences were revealed by group comparisons between CIS and RRMS. This study highlights transient mood alterations and an improving of adaptive coping over a period of time in patients with CIS and RRMS. Similar emotional reactions and coping in clinical subgroups suggest that these factors are independent from the type of information provided during the communication of the diagnosis.

Comparison of functional exercise capacity, pulmonary function and respiratory muscle strength in patients with multiple sclerosis with different disability levels and healthy controls

To compare functional exercise capacity, pulmonary function and respiratory muscle strength in fully ambulatory patients with multiple sclerosis with different disability levels and healthy controls, and to elucidate the determinant factors of functional exercise capacity. Forty-three fully ambulatory patients with multiple sclerosis and 30 healthy controls were included in the study. Patients were grouped according to Expanded Disability Status Scale (EDSS); Group I (EDSS 0-2), Group II (EDSS 2.5-4.5). Functional exercise capacity was evaluated using a six-minute walk test, and measurement of pulmonary function, and maximal inspiratory and expiratory pressures (MIP, MEP). The Pulmonary Index was used as a clinical predictor of respiratory dysfunction. Respiratory muscle strength was lower in multiple sclerosis groups compared with controls, but the difference in MIP and %MIP did not reach statistical significance in Group I. The six-minute walk test distance was significantly shorter and peak expiratory flow was lower in multiple sclerosis groups (p < 0.05). Of the variance in the six-minute walk test distance, 75% was explained by EDSS (R2 = 0.55, p < 0.001), difference in heart rate (R2 = 0.06, p = 0.007), age (R2 = 0.05, p = 0.009) and gender (R2 = 0.09, p = 0.003). Respiratory muscles are weakened, functional exercise capacity is reduced and pulmonary function is affected even in the early phase of multiple sclerosis. Ambulatory patients with multiple sclerosis who have a higher level of disability have lower pulmonary function, respiratory muscle strength and functional capacity than less disabled ones and controls. Neurological disability level, age, gender and heart rate difference on exertion are the determinants of functional exercise capacity.

The association of intrathecal immunoglobulin synthesis and cortical lesions predicts disease activity in clinically isolated syndrome and early relapsing–remitting multiple sclerosis

Background: The intrathecal production of immunoglobulin (Ig) is a major biological feature of multiple sclerosis (MS), and immunopathological studies have suggested a primary role of the humoral immune response in causing irreversible brain damage. Objective: To evaluate whether, in the early phases of MS, intrathecal Ig synthesis correlates with the presence of cortical lesions (CLs), and if their association could predict the clinical course of the disease. Methods: Eighty-six patients presenting with symptoms and signs suggestive of MS underwent a diagnostic work-up that included magnetic resonance imaging and cerebrospinal fluid examination. The risk ratios (RR) for conversion to MS and for a new disease activity were calculated. Results: Patients with clinically isolated syndromes (CIS) having CLs and intrathecal synthesis of Ig had the highest risk of conversion to MS (RR = 3.4; Wald 95% CI = 1.7–7.0, p < 0.001) whereas CIS patients without CLs and intrathecal synthesis of Ig had the lowest risk of conversion to MS (RR = 0.1, Wald 95% CI = 0.02–0.7, p < 0.001). The highest risk of having disease-related activity during the follow-up was observed in CIS and relapsing–remitting MS patients showing CLs and intrathecal Ig synthesis (RR = 2.1; Wald 95% CI = 1.5–3.1, p < 0.001) while the lowest in CIS and relapsing–remitting MS patients without CLs and intrathecal Ig synthesis (RR = 0.3; Wald 95% CI = 0.1–0.7, p < 0.001). Conclusion: We observed that the association of intrathecal immunoglobulin synthesis and CLs was highly predictive of an earlier CIS conversion to MS as well as of a higher disease activity.