Rapid Disability Progression Research Articles

Efficacy and safety of cladribine tablets in multiple sclerosis in real-world clinical practice

Cladribine has a well-defined activity against lymphocytes, leading to their selective depletion.Objective: to determine the efficacy and safety of cladribine in the treatment of multiple sclerosis (MS) in real-world clinical practice.Material and methods. The study involved 82 patients (57 women and 25 men, mean age 36.4±9.3 years) with a disease duration of 2.2±1.5 years. Seven (9%) patients had secondary progressive MS (SPMS), 6 (7%) had rapidly progressive MS (RPMS) and 69 (84%) had highly active MS (HAMS). According to the instructions for use, oral therapy with cladribine was administered in two short courses (up to 10 days per year) to achieve a long-term effect on the immune system. The dose of cladribine was calculated based on the body weight.Results. The average frequency of exacerbations per year before starting therapy was 1.6, while it decreased to 0.2 during cladribine therapy. An exacerbation was observed in 18 patients (22%) at the end of the first course of cladribine treatment and in one patient (2.6%) after the second treatment course. Thus, the number of exacerbations decreased by 78% after the first year of treatment and by 97.4% after the second year of treatment. The mean EDSS score was 3.2±2.5 points before the start of treatment, 3.6±2.5 points after the first course of treatment and 3.4±2.5 points after the second course (p>0.05). MRI results showed a decrease in disease activity by 83% after the first course of cladribine therapy and by 97.4% after the second course. No serious adverse events occurred in any of the patients.Conclusion. We demonstrated efficacy and safety of cladribine in real-life clinical practice in MS patients with frequent exacerbations and rapid disability progression (SPMS, RPMS, HAMS).

Lifetime exposure to smoking and substance abuse may be associated with late-onset multiple sclerosis: a population-based case-control study

BackgroundLate-onset multiple sclerosis (LOMS), defined as the development of MS after the age of 50, has shown a substantial surge in incidence rates and is associated with more rapid progression of disability. Besides, studies have linked tobacco smoking to a higher chance of MS progression. However, the role of smoking on the risk of developing LOMS remains unclear. This study aims to evaluate the possible association between lifetime exposure to cigarette and waterpipe smoking, drug abuse, and alcohol consumption and the risk of LOMS.MethodsThis population-based case-control study involved LOMS cases and healthy sex and age-matched controls from the general population in Tehran, Iran. The primary data for confirmed LOMS cases were obtained from the nationwide MS registry of Iran (NMSRI), while supplementary data were collected through telephone and on-site interviews. Predesigned questionnaire for multinational case-control studies of MS environmental risk factors was used to evaluate the LOMS risk factors. The study employed Likelihood ratio chi-square test to compare qualitative variables between the two groups and utilized two independent sample t-test to compare quantitative data. Adjusted odds ratio (AOR) for age along with 95% confidence intervals (CI) were calculated using matched logistic regression analysis in SPSS 23.ResultsTotally, 83 LOMS cases and 207 controls were included in the analysis. The female to male ratio in the cases was 1.5: 1. The mean ± SD age of 83 cases and 207 controls was 61.14 ± 5.38) and 61.51 ± 7.67 years, respectively. The mean ± SD expanded disability status scale (EDSS) score was 3.68 ± 2.1. Although the results of waterpipe exposure had no significant effect on LOMS development (P-value: 0.066), ever cigarette-smoked participants had a significantly higher risk of developing LOMS than those who never smoked (AOR: 2.57, 95% CI: 1.44–4.60). Furthermore, people with a history of smoking for more than 20 years had 3.45 times the odds of developing MS than non-smokers. Drug and alcohol abuse were both associated with LOMS in our study; of which opioids (AOR: 5.67, 95% CI: 2.05–15.7), wine (AOR: 3.30, 95% CI: 1.41–7.71), and beer (AOR: 3.12, 95% CI: 1.45–6.69) were found to pose the greatest risk of LOMS, respectively.ConclusionFor the first time, we identified smoking, drug, and alcohol use as potential risk factors for LOMS development. According to the global increase in cigarette smoking and alcohol use, these findings highlight the importance of conducting interventional approaches for prevention.

Longitudinal trajectories of disability among Chinese adults: the role of cardiometabolic multimorbidity

BackgroundCardiometabolic multimorbidity (CM) has been found to be associated with higher mortality and functional limitations. However, few studies have investigated the longitudinal association between CM and disability in the Chinese population and whether these associations vary by smoking status.MethodsThe study included 16,754 participants from four waves (2011, 2013, 2015, and 2018) of China Health and Retirement Longitudinal Study (CHARLS) (mean age: 59, female: 51%). CM was assesed at baseline and defined as having two or more of diabetes, stroke, or heart disease. Disability was repeatedly measured by summing the number of impaired activities of daily living (ADL) and instrumental activities of daily living (IADL) during the 7-year follow-up. Linear mixed-effects model was used to determine the association of CM and trajectories of disability and to assess the modification effect of smoking status in these associations.ResultsParticipants with CM at baseline had a faster progression of disability compared to those without CM (CM: β = 0.13, 95% CI: 0.05 to 0.21). Current smokers with CM developed disability faster than their counterparts (Pinteraction for smoking=0.011). In addition, there was a significant association between CM and the annual change of disability in current smokers (β = 0.34, 95% CI: 0.17 to 0.50) while no such association was observed in current non-smokers (β = 0.08, 95% CI: -0.02 to 0.17).ConclusionCM was associated with more a rapid disability progression. Notably, being current smokers may amplify the adverse effects of CM on disability progression.

Rim lesions in MS at 3T: clinical correlation and possible radiological alternatives for daily practice at lower field strength

Background and purposeParamagnetic rim lesions (PRLs) have been described as an imaging feature specific to multiple sclerosis (MS) using high-field strength phase-sensitive MR imaging. These lesions are suggested to reflect chronic active inflammation associated with greater disease severity and a more rapid disability progression. The aim of our study is to investigate the relationship between PRLs, clinical parameters, other radiological findings and disease progression. Material and methodsThis cross-sectional study included MS patients treated with teriflunomide, fingolimod, natalizumab or ocrelizumab for at least 2 years. PRLs seen at 3T MRI were analysed and correlated with clinical data and radiological progression, defined as an increase of the T2/FLAIR-lesion load during therapy. In the search for alternatives for these PRLs, we defined two additional radiological markers: ‘FLAIR-bullet lesions’, and on post-contrast black-blood (BB) images, ‘BB-bullet lesions’. ResultsWe included 84 MS patients of whom 27 (32 %) had at least 1 PRL. PRLs were associated with radiological progression under therapy (p=0.039) and higher clinical disability scores, although only significant for 9-Hole Peg Test (p=0.023). Patients with FLAIR-bullet or BB-bullet lesions at 3T MRI had a higher chance of PRL (p<0.001) with a likelihood ratio of 13.2 for FLAIR-bullets and 12.6 for BB-bullet lesions, thanks to the high negative predictive value of respectively 83 % and 90 %. ConclusionPRLs are associated with an increase of T2/FLAIR-lesion load under therapy and unfavourable clinical outcome. Our newly defined ‘bullet lesions’ are associated with PRLs and might be an interesting MRI marker for centres without access to high-field SWI images.

Immunoablative therapy followed by autologous hematopoietic stem cell transplantation as the first-line disease-modifying therapy in patients with multiple sclerosis.

Immunoablative therapy followed by autologous hematopoietic stem cell transplantation (AHSCT) is one of the possible disease-modifying therapies (DMTs) for patients with multiple sclerosis (MS). In this case series, we would like to present six patients with MS, who underwent AHSCT as the first-line DMT. Six MS patients with a rapid progression of disability with or without relapses underwent AHSCT as the first-line DMT at the University Hospital Ostrava between 2018 and 2021. The conditioning regimens for AHSCT used were a medium-intensity regime BEAM (Carmustine, Etoposid, Cytarabin, Melphalan) and low-intensity regime based on Cyclophosphamide. Four out of six patients showed some disability progression after AHSCT, so the rapid progression of MS was just slowed down by AHSCT. One patient developed activity on magnetic resonance imaging three months after AHSCT, and two experienced mild relapses during the follow-up period. None of our patients developed grade 4 non-hematological toxicity; all infections were mild. In one patient, an allergic reaction probably to dimethyl sulfoxide was observed. Our case series of 6 patients shows that AHSCT is a promising therapeutic approach to slow down the rapid progression of clinical disability in MS patients with a good safety profile.

The Bruton’s Tyrosine Kinase Inhibitor Evobrutinib Demonstrates Superior Efficacy in Targeting Compartmentalized Neuroinflammation Compared to Anti-CD20 Treatment. (S16.004)

<h3>Objective:</h3> To evaluate the efficacy of evobrutinib, a central nervous system (CNS)-penetrant Bruton’s tyrosine kinase inhibitor (BTKi), versus anti-CD20 treatment, on compartmentalized neuroinflammation and disease outcomes in a novel mouse model recapitulating key features of disease progression in multiple sclerosis (MS). <h3>Background:</h3> In MS, compartmentalized neuroinflammation often starts early and is characterized by an accumulation of persistent B cell rich aggregates. Compartmentalized neuroinflammation is predictive of both poor clinical outcomes and rapid disability progression. B cells within the CNS may be protected from established MS therapies such as anti-CD20 antibodies. CNS-penetrant small molecules directed against BTK – with its critical role in B cell activation, proliferation, and survival – have emerged to potentially target chronic neuroinflammation. <h3>Design/Methods:</h3> Preclinical assessments compared the therapeutic potential of evobrutinib and anti-CD20 antibodies on MS progression using the experimental autoimmune encephalomyelitis mouse model with features of progression (pEAE). Clinical outcomes and their correlation with CNS immunopathological parameters were assessed in pEAE mice to recapitulate key aspects of MS disease progression. <h3>Results:</h3> Evobrutinib, versus anti-CD20 (clone: SA271G2) treatment, reduced disease severity (65% reduction; P&lt;0.0001) and immunopathological parameters of disease (56% reduction; P&lt;0.01) in pEAE mice. The beneficial effects of BTKi were paralleled by body-weight gain and a decrease in maximum disease score versus anti-CD20 treatment. Evobrutinib lessened neuroinflammation by significantly reducing the number and activation of lymphoid and myeloid cells as well as the extent of submeningeal demyelination both in the brain (44% reduction; P&lt;0.01) and the spinal cord (42% reduction; P&lt;0.01). <h3>Conclusions:</h3> The improvements in clinical, immunological, and neuropathological parameters of disease observed in pEAE mice treated with evobrutinib illustrate the importance of compartmentalized neuroinflammation for disease progression. The limited effect of anti-CD20 treatment confirms the insufficient disease inhibition potential of antibody-based therapies when targeting intrathecal B cells. These findings support the notion that evobrutinib targets persistent neuroinflammation in MS. <b>Disclosure:</b> Ms. Kebir has received research support from Fonds de Recherche du Québec-Santé. Ms. Kebir has received intellectual property interests from a discovery or technology relating to health care. Cen Li has received research support from Chinese Scholarship Council. The institution of Michael May has received research support from NIH. Molly Church has nothing to disclose. Ursula Boschert has nothing to disclose. Jorge Alvarez has nothing to disclose.

Chronic obstructive pulmonary disease: an urgent problem of health saving of modern medicine

Chronic obstructive pulmonary disease is one of the most urgent problems of the modern medical community. Despite the introduction of constantly updated schemes of early diagnosis and treatment into practical medicine, there is still an upward trend in the number of cases, under-examined persons, and prognostically unfavorable outcomes. The review highlights the findings of epidemiological studies confirming the widespread prevalence of the disease, accompanied by rapid disability progression, high mortality, and significant economic damage. The review lists the main exogenous and endogenous risk factors for the development of chronic obstructive pulmonary disease, including occupational etiology. Attention is drawn to the possibility of disease prevention in a professional environment with the proper motivation of the patient and the application of economic efforts. The article discusses the main causes of underdiagnosis and late diagnosis of the disease. Lifestyle modification makes an undeniable contribution to the prevention of chronic obstructive pulmonary disease and improving prognosis in the developed disease. Certain psychological characteristics that reduce adherence to treatment of such patients should be considered in organizing the management of this category of persons and creating special schools. It is important to create a classification of endotypes of chronic obstructive pulmonary disease, as well as sufficient public awareness about this disease with the aim of the earliest possible diagnosis.

Circadian Rhythms of Endothelial Nitric Oxide Synthase and Toll-like Receptors 2 Production in Females with Rheumatoid Arthritis Depending on NOS3 Gene Polymorphism.

Rheumatoid Arthritis (RA) is an autoimmune polygenic disease characterized by rapid disability progression and high prevalence. Progression of RA is closely associated with chronobiological changes in the production of some hormones and inflammatory mediators, influencing the disease course and therapy efficacy. The main pathogenetic mechanism of RA is angiogenesis, which is controlled by biological clock-genes. Further investigation of circadian rhythms of angiogenic mediators production in RA patients may be considered as important and relevant. The aim of this study was to establish daily variability of serum endothelial Nitric Oxide Synthase (NOS3) and toll-like receptors 2 (sTLR2) levels in female RA patients depending on the NOS3 gene polymorphism. We examined 173 RA patients (100% female) aged 43.7 ± 7.35 years and 34 age-matched healthy women without joint diseases and autoimmune diseases (control). RA was diagnosed by ACR/EULAR 2010 criteria. Blood serum NOS3 and sTLR2 levels were determined at 08:00 and 20:00 using Cloud-Clone Corp kits (USA). NOS3 T-786С (rs2070744) polymorphism was determined by Real-Time PCR (Bio-Rad iCycler IQ5) using SNP-express kits. The SPSS22 software package was used for statistical processing of the results. Females with RA demonstrated oppositely directed serum NOS3 and sTLR2 daily changes: NOS3 level in the morning (08:00) was lower than in the evening (+ 45.5 ± 30.7%), and sTLR2 level in the evening (at 20:00) was lower than in the morning (-21.6 ± 13.1%). RA patients had differences in NOS3 and sTLR2 production depending on NOS3 T786C genotype. CC subjects had NOS3 level at 08:00, 20:00 and day average levels lower (16-25%), and sTLR2 level higher (24-27%) than those of TT subjects. RA patients, carriers of CC genotype, had higher chances of NOS3 and sTLR2 aberrant production compared to TT and TC genotype carriers (OR = 2.99 and 4.79, respectively). RA patients demonstrated oppositely directed circadian changes of serum NOS3 and sTLR2. CC genotype carriers had lower NOS3 and higher sTLR2 production rates than TT and TC genotype carriers.

Longitudinal Assessment of Multiple Sclerosis with the Brain-Age Paradigm.

During the natural course of multiple sclerosis (MS), the brain is exposed to aging as well as disease effects. Brain aging can be modeled statistically; the so-called "brain-age" paradigm. Here, we evaluated whether brain-predicted age difference (brain-PAD) was sensitive to the presence of MS, clinical progression, and future outcomes. In a longitudinal, multicenter sample of 3,565 magnetic resonance imaging (MRI) scans, in 1,204 patients with MS and clinically isolated syndrome (CIS) and 150 healthy controls (mean follow-up time: patients 3.41 years, healthy controls 1.97 years), we measured "brain-predicted age" using T1-weighted MRI. We compared brain-PAD among patients with MS and patients with CIS and healthy controls, and between disease subtypes. Relationships between brain-PAD and Expanded Disability Status Scale (EDSS) were explored. Patients with MS had markedly higher brain-PAD than healthy controls (mean brain-PAD +10.3 years; 95% confidence interval [CI] = 8.5-12.1] versus 4.3 years; 95% CI = 2.1 to 6.4; p < 0.001). The highest brain-PADs were in secondary-progressive MS (+13.3 years; 95% CI = 11.3-15.3). Brain-PAD at study entry predicted time-to-disability progression (hazard ratio 1.02; 95% CI = 1.01-1.03; p < 0.001); although normalized brain volume was a stronger predictor. Greater annualized brain-PAD increases were associated with greater annualized EDSS score (r = 0.26; p < 0.001). The brain-age paradigm is sensitive to MS-related atrophy and clinical progression. A higher brain-PAD at baseline was associated with more rapid disability progression and the rate of change in brain-PAD related to worsening disability. Potentially, "brain-age" could be used as a prognostic biomarker in early-stage MS, to track disease progression or stratify patients for clinical trial enrollment. ANN NEUROL 2020 ANN NEUROL 2020;88:93-105.

Natalizumab treatment reduces microglial activation in the white matter of the MS brain.

ObjectiveTo evaluate whether natalizumab treatment reduces microglial activation in MS.MethodsWe measured microglial activation using the 18-kDa translocator protein (TSPO)-binding radioligand [11C]PK11195 and PET imaging in 10 patients with MS before and after 1 year treatment with natalizumab. Microglial activation was evaluated as the distribution volume ratio (DVR) of the specifically bound radioligand in brain white and gray matter regions of interest. MRI and disability measurements were performed for comparison. Evaluation was performed identically with 11 age- and sex-matched patients with MS who had no MS therapy.ResultsNatalizumab treatment reduced microglial activation in the normal-appearing white matter (NAWM; baseline DVR vs DVR after 1 year of treatment 1.25 vs 1.22, p = 0.014, Wilcoxon) and at the rim of chronic lesions (baseline DVR vs DVR after 1 year of treatment 1.24 vs 1.18, p = 0.014). In patients with MS with no treatment, there was an increase in microglial activation at the rim of chronic lesions (1.23 vs 1.27, p = 0.045). No alteration was observed in microglial activation in gray matter areas. In the untreated patient group, higher microglial activation at baseline was associated with more rapid disability progression during an average of 4 years of follow-up.ConclusionsTSPO-PET imaging can be used as a tool to assess longitudinal changes in microglial activation in the NAWM and in the perilesional areas in the MS brain in vivo. Natalizumab treatment reduces the diffuse compartmentalized CNS inflammation related to brain resident innate immune cells.

Obesity, Weight Loss, and Progression of Disability in Rheumatoid Arthritis.

Cross-sectional studies have demonstrated that obese patients with rheumatoid arthritis (RA) often report greater disability. The longitudinal effects of obesity, however, are not well-characterized. We evaluated associations between obesity, weight loss, and worsening of disability in patients of 2 large registry studies, which included patients who were followed for longer periods of time. This study included patients with RA from the National Data Bank for Rheumatic Diseases (FORWARD) (n = 23,323) and the Veterans Affairs RA (VARA) registry study (n = 1,697). Results of the Health Assessment Questionnaire (HAQ) or Multidimensional HAQ (MD-HAQ) were recorded through follow-up. Significant worsening of disability was defined as an increase of >0.2 in HAQ or MD-HAQ scores. The Cox proportional hazards model was used to evaluate the risk of worsening of disability from baseline and to adjust for demographics, baseline disability, comorbidity, disease duration, and other disease features. At enrollment, disability scores were higher among severely obese patients compared to those who were overweight both in FORWARD (β = 0.17 [95% confidence interval (95% CI) 0.14, 0.20]; P < 0.001) and in the VARA registry (β = 0.17 [95% CI 0.074, 0.27]; P = 0.001). In multivariable models, patients who were severely obese at enrollment had a greater risk of progressive disability compared to overweight patients in FORWARD (HR 1.25 [95% CI 1.18, 1.33] P < 0.001) and in the VARA registry (HR 1.33 [95% CI 1.07, 1.66]; P = 0.01). Weight loss following enrollment was also associated with a greater risk in both cohorts. In the VARA registry, associations were independent of other clinical factors, including time-varying C-reactive protein and swollen joint count. Severe obesity is associated with a more rapid progression of disability in RA. Weight loss is also associated with worsening disability, possibly due to it being an indication of chronic illness and the development of age-related or disease-related frailty.

Lower prevalence of multiple sclerosis in First Nations Canadians.

We compared the incidence and prevalence of multiple sclerosis (MS) between First Nations (FN) and non-FN populations in Manitoba. We applied previously validated algorithms to population-based administrative (health claims) data from Manitoba, Canada, to identify all persons with MS from 1984 to 2011. We identified FN individuals using the Municipality of Registration field held at Manitoba Health. We compared the incidence and prevalence of MS between the FN and non-FN populations using negative binomial models. From 1984 to 2011, 5,738 persons had MS, of whom 64 (1.1%) were of FN ethnicity. The average annual incidence rate per 100,000 population was 8.15 (95% confidence interval [CI] 5.98-11.1) in the FN population and 15.7 (95% CI 15.1-16.3) in the non-FN population (incidence rate ratio 0.52; 95% CI 0.38-0.71). In 1984, the crude prevalence of MS per 100,000 population was 35.8 (95% CI 14.9-86.1) in the FN population and 113.3 (95% CI 106.3-120.8) in the non-FN population. Between 1984 and 2011, the age-standardized prevalence of MS increased by 351% to 188.5 (95% CI 146.6-230.4) in the FN population. In contrast, the prevalence of MS per 100,000 general population increased by 225%-418.4% (95% CI 405.8-431.0). The incidence and prevalence of MS are twofold lower in the FN population than the non-FN population. Nonetheless, the prevalence of MS in FN Manitobans is higher than in other indigenous populations outside Canada. Given reports of more rapid disability progression among FN Canadians with MS, and the rising prevalence of MS in this population, attention should be directed to the needs of this population.

Cigarette Smoking, Alcohol Consumption and Overweight in Multiple Sclerosis: Disability Progression

The rate at which disability progresses in multiple sclerosis (MS), and its severity, have been associated with modifiable lifestyle habits. To investigate the risk of disability progression in MS patients according to tobacco and alcohol consumption and to the presence of overweight. This was a follow-up of MS cases from a concluded case-control study (National Institute of Neurology and Neurosurgery, Mexico 2010-2013). The evolution in EDSS (Expanded Disability Scale Score) units was followed through a medical record review. Kaplan Meier statistics and multivariate Cox regression analysis were performed. Of 181 cases, 63.5% were women and 82.5% had relapsing remitting MS. Study duration was 19.95±15.24months. The disease progressed faster in daily smokers than in non-smokers (p=0.0168). In overweight patients, disability progressed faster than in normal weight patients (p=0.0249). Ex-consumers of alcohol had lower risk of progression than current consumers (HR=0.33 CI 95%=0.14-0.83, p=0.019) and both daily and ex-smokers presented higher risk of progression than non-smokers (HR=2.32 CI 95%=1.14-4.72, p=0.020 and HR=3.56, CI 95%=1.21-10.46, p=0.021). Stratifying by gender, the effects of smoking and overweight were only found in men. Smoking is associated with rapid disability progression in MS. Our results suggest that cessation of tobacco and alcohol consumption could be clinically beneficial. Although there is association between overweight and disability progression in men, a further exploration of gender differences is necessary to corroborate this finding.

Genetic variants in interleukin 7 receptor α chain (IL-7Ra) are associated with multiple sclerosis risk and disability progression in Central European Slovak population.

In this study, we determined the association between rs6897932 in interleukin 7 receptor α (IL7Ra) gene and the risk and disability progression of multiple sclerosis (MS) in 270 MS patients and 303 controls. We found allele C to be associated with the risk of MS and minor allele T to be protective against MS development. Moreover, we revealed for the first time that rs6897932 in IL7Ra gene is associated with the progression of MS, evaluated by MSSS scores. The minor allele T and genotype TT are protective against a rapid disability progression in MS in the Central European Slovak population.

PAIN IN NEUROMYELITIS OPTICA IS AN UNDER–RECOGNISED BUT DISABLING SYMPTOM

BackgroundNeuromyelitis Optica (NMO) is an autoimmune inflammatory demyelinating disorder of the central nervous system that affects the optic nerve and spinal cord: frequent relapses and the absence of full remission...

Aggressive relapsing multiple sclerosis characterized by rapid disability progression

BackgroundCriteria for identifying relapsing multiple sclerosis (RMS) patients with aggressive disease, which would be useful for clinical decision making, are currently unavailable. ObjectiveIdentify RMS patients with aggressive disease characterized by rapid disability progression. MethodsData from a 2-year, phase 3, double-blind, placebo-controlled trial with long-term follow-up evaluations of RMS patients taking either intramuscular interferon beta-1a (IM IFNβ-1a, 30μg) or placebo with baseline Expanded Disability Status Scale (EDSS) scores of 1.0–3.5 were retrospectively analyzed. Patients with a ≥2.0-point increase in EDSS score, resulting in a score ≥4.0 by study end, were considered to have aggressive RMS. The risk of a poor long-term outcome, defined as an EDSS score ≥8.0 at 8 years of follow-up, was calculated as an odds ratio from a logistic regression model comparing patients with and without aggressive RMS. ResultsOnly 25 patients met the criteria for aggressive RMS. Among these patients, mean disease duration was 5.1±3.85 years, mean baseline age was 37.2±6.35 years, and mean baseline EDSS score was 2.8±0.74. Fewer IM IFNβ-1a-treated than placebo-treated patients met the criteria for aggressive RMS at 2 years (7% vs 22% on placebo, p=0.0072). Thirteen patients reached the EDSS milestone of ≥8.0 by the end of the 8-year follow-up. The odds ratio for attaining severe disability was 86.4 (95% CI, 10.3–726.4; p<0.0001) for patients with aggressive RMS compared to patients without aggressive RMS. ConclusionsDefining aggressive RMS based on rapid EDSS progression was useful in identifying patients at risk for more severe disease course.

Identifying Patients with Relapsing-Remitting Multiple Sclerosis Who Have Aggressive Disease Characterized by Rapid Disability Progression (P05.093)

Objective: Identify relapsing multiple sclerosis (RMS) patients with aggressive disease characterized by rapid disability progression. Background Criteria for identifying RMS patients with aggressive disease, which would be useful for clinical decision making and trial design, are currently unavailable. Design/Methods: The Multiple Sclerosis Collaborative Research Group (MSCRG) study was a phase 3, double-blind, placebo-controlled trial of intramuscular interferon beta-1a (IM IFNβ-1a) in patients with RMS. Patients received IM IFNβ-1a 30 μg or placebo once weekly for up to 2 years. Patients were required to have a baseline Expanded Disability Status Scale (EDSS) score of 1.0–3.5. Patients with a ≥2.0-point increase in EDSS score resulting in a score ≥4.0 by study end were considered to have aggressive RMS. The risk of a poor long-term outcome, defined as an EDSS score ≥8.0 at 8 years of follow-up, was calculated as an odds ratio from a logistic regression model comparing patients with and without aggressive RMS. Results: Few patients (n=39) had EDSS ≥4.0 over 2 years. Only 25 patients met the criteria for aggressive RMS. Among these patients, mean disease duration was 5.1±3.85 years, mean baseline age was 37.2±6.35 years, and mean baseline EDSS was 2.8±0.74. More patients in the placebo group (22%) than in the IM IFNβ-1a group (7%) met the criteria for aggressive RMS at 2 years ( P =0.0072). Thirteen patients reached the EDSS milestone of 8.0 (severe disability) by the end of the 8-year follow-up. The odds ratio for attaining severe disability was 31.4 (95% confidence interval, 7.7–127.8; P Conclusions: The proposed definition for aggressive RMS characterized by rapid EDSS progression appeared to be useful in identifying patients at high risk for a more severe long-term disease course with greater accumulation of physical disability. Supported by: Biogen Idec Inc. Disclosure: Dr. Scott has received personal compensation for activities with Novartis, Biogen Idec, Teva Neuroscience, and Genzyme as a consultant or speaker. Dr. Scott has received research support from the Pittsburgh Foundation. Dr. Laforet has received personal compensation for activities with Biogen Idec Inc. as an employee.Dr. Laforet holds stock and/or stock options in Biogen Idec Inc., which sponsored research in which Dr. Laforet was involved as an investigator. Dr. You has received personal compensation for activities with Biogen Idec as an employee.

Clinical &amp;amp; Neuropsychological profile in patients with Parkinson&amp;rsquo;s disease and Parkinson&amp;rsquo;s Plus syndromes: study from a tertiary care referral centre in a developing country

Clinical & Neuropsychological profile in patients with Parkinson’s disease and Parkinson’s Plus syndromes: study from a tertiary care referral centre in a developing country Abu Zafar Ansari,1 Deepika Joshi,1 Vijay Nath Mishra,1 Rameshwar Nath Chaurasia,1 Shailesh Gupta,2 Baidanath Kumar,1 Vijay Nandmer,1 Arun Kumar1 1Dept. of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India; 2Dept. of Cl. Neurophysiology, Department of Physiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India Background: Cognitive dysfunction is an important cause of disability in Parkinson’s disease (PD) and Parkinson’s Plus syndrome (PD Plus). The development of dementia in PD has significant impact on the natural history of disease with rapid progression of disability and increased mortality. The present study aimed to evaluate the clinical and neuropsychological profile in patients with PD and PD Plus syndromes. Methods: Forty-one patients with a diagnosis of probable PD, and Parkinson’s Plus syndromes with minimum of fifth standard education were enrolled. They were evaluated with the UPDRS, Hoehn & Yahr staging, MMSE and AIIMS comprehensive neuropsychological battery in Hindi (adult form) using the eight lobar scales for the right and left hemisphere. Patients were then compared with age and gender matched controls. Results: Parkinson’s disease (85.4%) comprised the majority of cases followed by PSP (12.2%) and CBGD (2.4%). The MMSE scores were significantly reduced in the patients as compared to controls. Neuropsychological testing revealed that the mean T scores of the lobar scales (both right and left hemispheres) in patient group (LF – 77.33; LSM 76.57; LPO – 79.26; LT- 82.74; RF – 95.14; RSM – 92.05; RPO – 73.86; RT- 74.45) were higher & remarkably significant as compared to the controls (p

Primary retinal pathology in multiple sclerosis as detected by optical coherence tomography

Optical coherence tomography studies in multiple sclerosis have primarily focused on evaluation of the retinal nerve fibre layer. The aetiology of retinal changes in multiple sclerosis is thought to be secondary to optic nerve demyelination. The objective of this study was to use optical coherence tomography to determine if a subset of patients with multiple sclerosis exhibit primary retinal neuronopathy, in the absence of retrograde degeneration of the retinal nerve fibre layer and to ascertain if such patients may have any distinguishing clinical characteristics. We identified 50 patients with multiple sclerosis with predominantly macular thinning (normal retinal nerve fibre-layer thickness with average macular thickness < 5th percentile), a previously undescribed optical coherence tomography defined phenotype in multiple sclerosis, and compared them with 48 patients with multiple sclerosis with normal optical coherence tomography findings, 48 patients with multiple sclerosis with abnormal optical coherence tomography findings (typical for multiple sclerosis) and 86 healthy controls. Utilizing a novel retinal segmentation protocol, we found that those with predominant macular thinning had significant thinning of both the inner and outer nuclear layers, when compared with other patients with multiple sclerosis (P < 0.001 for both), with relative sparing of the ganglion cell layer. Inner and outer nuclear layer thicknesses in patients with non-macular thinning predominant multiple sclerosis were not different from healthy controls. Segmentation analyses thereby demonstrated extensive deeper disruption of retinal architecture in this subtype than may be expected due to retrograde degeneration from either typical clinical or sub-clinical optic neuropathy. Functional corroboration of retinal dysfunction was provided through multi-focal electroretinography in a subset of such patients. These findings support the possibility of primary retinal pathology in a subset of patients with multiple sclerosis. Multiple sclerosis-severity scores were also significantly increased in patients with the macular thinning predominant phenotype, compared with those without this phenotype (n = 96, P=0.006). We have identified a unique subset of patients with multiple sclerosis in whom there appears to be disproportionate thinning of the inner and outer nuclear layers, which may be occurring as a primary process independent of optic nerve pathology. In vivo analyses of retinal layers in multiple sclerosis have not been previously performed, and structural demonstration of pathology in the deeper retinal layers, such as the outer nuclear layer, has not been previously described in multiple sclerosis. Patients with inner and outer nuclear layer pathology have more rapid disability progression and thus retinal neuronal pathology may be a harbinger of a more aggressive form of multiple sclerosis.

Intrathecal IgM synthesis in pediatric MS is not a negative prognostic marker of disease progression: quantitative versus qualitative IgM analysis

Background: Intrathecal IgM synthesis is reported to be associated with a worse prognosis in adults with multiple sclerosis (MS). Objective: To study the predictive value of intrathecal IgM synthesis for the clinical course of pediatric MS. Methods: Seventy children with onset of MS before the age of 16 years and followed for a median period of 10.4 years (range: 0.4–22.8 years) were studied. The two subgroups with (n = 44) or without (n = 26) intrathecal IgM synthesis were distinguished by a new, very sensitive, evaluation of quantitative analysis in cerebrospinal fluid (CSF)/serum quotient diagrams (Reibergrams). The clinical course and EDSS (Expanded Disability Status Scale) scores at five and ten years were compared with IgM frequencies between both groups with a new statistics program for CSF data. Results: The cohort of children without intrathecal IgM production had higher numbers of attacks in the first two years and shorter time intervals between first and second attack, although this was not statistically significant (p = 0.04, p = 0.15 respectively). In addition there was also a trend for girls without intrathecal IgM synthesis to have a higher EDSS score after 10 years compared with the group with IgM synthesis. Conclusion: Intrathecal IgM synthesis is not associated with a more rapid progression of disability in pediatric MS. Reevaluation of data from previous reports about the negative predictive value of intrathecal IgM synthesis in adult MS with a CSF statistics tool show that the apparent contradiction is due to a methodological bias in the qualitative detection of ‘oligoclonal’ IgM or linear IgM index.