Jelena Drulovic

The epidemiology of multiple sclerosis in Europe

Multiple sclerosis (MS) is a chronic and potentially highly disabling disorder with considerable social impact and economic consequences. It is the major cause of non‐traumatic disability in young adults. The social costs associated with MS are high because of its long duration, the early loss of productivity, the need for assistance in activities of daily living and the use of immunomodulatory treatments and multidisciplinary health care. Available MS epidemiological estimates are aimed at providing a measure of the disease burden in Europe. The total estimated prevalence rate of MS for the past three decades is 83 per 100 000 with higher rates in northern countries and a female:male ratio around 2.0. Prevalence rates are higher for women for all countries considered. The highest prevalence rates have been estimated for the age group 35–64 years for both sexes and for all countries. The estimated European mean annual MS incidence rate is 4.3 cases per 100 000. The mean distribution by disease course and by disability is also reported. Despite the wealth of epidemiological data on MS, comparing epidemiological indices among European countries is a hard task and often leads only to approximate estimates. This represents a major methodological concern when evaluating the MS burden in Europe and when implementing specific cost‐of‐illness studies.

Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders

BackgroundSerum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved.ResultsWe analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels.ConclusionsWe could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HR-NMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4-directed humoral immune response.

Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: A phase 2 study

Objectives: We present the first study to explore safety and efficacy of the human CD20 monoclonal antibody ofatumumab in relapsing-remitting multiple sclerosis (RRMS). Methods: In this randomized, double-blind, placebo-controlled study, patients received 2 ofatumumab infusions (100 mg, 300 mg, or 700 mg) or placebo 2 weeks apart. At week 24, patients received alternate treatment. Safety and efficacy were assessed. Results: Thirty-eight patients were randomized (ofatumumab/placebo, n = 26; placebo/ofatumumab, n = 12) and analyzed; 36 completed the study. Two patients in the 300-mg group withdrew from the study because of adverse events. No unexpected safety signals emerged. Infusion-related reactions were common on the first infusion day but not observed on the second infusion day. None of the patients developed human anti-human antibodies. Ofatumumab was associated with profound selective reduction of B cells as measured by CD19+ expression. New brain MRI lesion activity was suppressed (>99%) in the first 24 weeks after ofatumumab administration (all doses), with statistically significant reductions (p < 0.001) favoring ofatumumab found in new T1 gadolinium-enhancing lesions, total enhancing T1 lesions, and new and/or enlarging T2 lesions. Conclusions: Ofatumumab (up to 700 mg) given 2 weeks apart was not associated with any unexpected safety concerns and was well tolerated in patients with RRMS. MRI data suggest a clinically meaningful effect of ofatumumab for all doses studied. Results warrant further exploration of ofatumumab in RRMS. Classification of evidence: This study provides Class II evidence that in patients with RRMS, ofatumumab compared with placebo does not increase the number of serious adverse events and decreases the number of new MRI lesions.

Brain reserve and cognitive reserve protect against cognitive decline over 4.5 years in MS

Objective: Based on the theories of brain reserve and cognitive reserve, we investigated whether larger maximal lifetime brain growth (MLBG) and/or greater lifetime intellectual enrichment protect against cognitive decline over time. Methods: Forty patients with multiple sclerosis (MS) underwent baseline and 4.5-year follow-up evaluations of cognitive efficiency (Symbol Digit Modalities Test, Paced Auditory Serial Addition Task) and memory (Selective Reminding Test, Spatial Recall Test). Baseline and follow-up MRIs quantified disease progression: percentage brain volume change (cerebral atrophy), percentage change in T2 lesion volume. MLBG (brain reserve) was estimated with intracranial volume; intellectual enrichment (cognitive reserve) was estimated with vocabulary. We performed repeated-measures analyses of covariance to investigate whether larger MLBG and/or greater intellectual enrichment moderate/attenuate cognitive decline over time, controlling for disease progression. Results: Patients with MS declined in cognitive efficiency and memory (p < 0.001). MLBG moderated decline in cognitive efficiency (p = 0.031, ηp2 = 0.122), with larger MLBG protecting against decline. MLBG did not moderate memory decline (p = 0.234, ηp2 = 0.039). Intellectual enrichment moderated decline in cognitive efficiency (p = 0.031, ηp2 = 0.126) and memory (p = 0.037, ηp2 = 0.115), with greater intellectual enrichment protecting against decline. MS disease progression was more negatively associated with change in cognitive efficiency and memory among patients with lower vs higher MLBG and intellectual enrichment. Conclusion: We provide longitudinal support for theories of brain reserve and cognitive reserve in MS. Larger MLBG protects against decline in cognitive efficiency, and greater intellectual enrichment protects against decline in cognitive efficiency and memory. Consideration of these protective factors should improve prediction of future cognitive decline in patients with MS.

A multicenter assessment of cervical cord atrophy among MS clinical phenotypes.

Objective: In this multicenter study, a new semiautomatic method for segmenting the cervical cord from C2 to C5 was used to investigate the correlation between cord atrophy and clinical disability in a large sample of patients with multiple sclerosis (MS). Methods: T2 and 3-dimensional T1-weighted cervical cord scans and dual-echo brain scans were acquired from 143 healthy controls, 22 patients with clinically isolated syndromes (CIS), 101 patients with relapsing-remitting MS (RRMS), 79 patients with secondary progressive MS (SPMS), 58 patients with benign MS (BMS), and 75 patients with primary progressive MS (PPMS) in 3 European centers. Normalized cervical cord cross-sectional area (CSAn) was measured by an active surface cord model. Between-group comparisons were performed using linear mixed-effect models. A nonparametric kernel estimator was used to obtain smoothed plots of CSA along the cervical cord. Results: Cord CSAn was significantly lower in PPMS vs healthy controls, BMS vs RRMS, SPMS vs BMS, and RRMS. From C2 to C5, a net separation and definition of the plots of patients with BMS, PPMS, and SPMS was seen with respect to those of the other study groups. CSAn was correlated with Expanded Disability Status Scale (r = −0.49, p < 0.0001), with a differential effect among disease clinical phenotypes: no association in either CIS or in BMS; association in RRMS (r = −0.30, p = 0.001), SPMS (r = −0.34, p = 0.001), and PPMS (r = −0.27, p = 0.01). Conclusions: Cervical cord atrophy provides a relevant and useful marker for the characterization of clinical heterogeneity of patients with MS. The stability of this measure among different centers supports its use as potential outcome measure to monitor disease progression in multicenter trials.

The impact of sexual dysfunction on the quality of life measured by MSQoL-54 in patients with multiple sclerosis:

Objective Sexual dysfunction (SD) is a common but often overlooked symptom in multiple sclerosis (MS). The aim of this study was to estimate the frequency, type, and intensity of SD in our patients with MS and to investigate its influence on all the domains of quality of life. Methods The study population comprised a cohort of 109 patients with MS (McDonalds criteria, 2001). SD was quantified by a Szasz sexual functioning scale. Health-related quality of life was measured by a disease-specific instrument MSQoL-54 (Serbian version). Results The presence of at least one symptom of SD was found in about 84% of the men and in 85% of the women. The main complaints in women were reduced libido, difficulties in achieving orgasm, and decreased vaginal lubrication; in men, the main complaints were reduced libido, incomplete erections, and premature ejaculation. In women, statistically significant negative correlations between the presence and level of SD and quality of life domains were reached for all subscales (P < 0.01), except for the Pain subscale (P = 0.112). In men, negative correlations were also observed for all domains, but they were statistically significant for physical health, physical role limitations, social function, health distress, sexual function, and sexual function satisfaction (P < 0.01). We found that the presence of all the analyzed types of sexual problems statistically significantly lowered scores on the sexual function and the sexual function satisfaction subscales in both men and women (P < 0.01). The most prominent impact on both domains was observed for the total loss of erection in men and for anorgasmia in women. Conclusions Our results reveal that frequent occurrence of SD in MS patients prominently affects all aspects of their quality of life.

Uric acid levels in sera from patients with multiple sclerosis

Abstract The levels of uric acid (UA), a natural peroxynitrite scavenger, were measured in sera from 240 patients with multiple sclerosis (MS) and 104 sex- and age-matched control patients with other neurological diseases (OND). The mean serum UA concentration was lower in the MS than in the OND group, but the difference did not reach the level of statistical significance (P=0.068). However, the mean serum UA level from patients with active MS (202.6+67.1 μmol/l) was significantly lower than that in inactive MS patients (226.5+78.6 μmol/l; P=0.046) and OND controls (P=0.007). We found a significant inverse correlation of serum UA concentration with female gender (P=0.0001), disease activity (P=0.012) and duration (P=0.017), and a trend towards an inverse correlation with disability as assessed by EDSS score, which did not reach statistical significance (P=0.067). Finally, multivariate linear regression analyses showed that UA concentration was independently correlated with gender (P=0.0001), disease activity (P=0.014) and duration of the disease (P=0.043) in MS patients. These findings suggest that serum UA might serve as a possible marker of disease activity in MS. They also provide support to the potential beneficial therapeutic effect of radical-scavenging substances in MS.

Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis.

The choice of appropriate control group(s) is critical in cerebrospinal fluid (CSF) biomarker research in multiple sclerosis (MS). There is a lack of definitions and nomenclature of different control groups and a rationalized application of different control groups. We here propose consensus definitions and nomenclature for the following groups: healthy controls (HCs), spinal anesthesia subjects (SASs), inflammatory neurological disease controls (INDCs), peripheral inflammatory neurological disease controls (PINDCs), non-inflammatory neurological controls (NINDCs), symptomatic controls (SCs). Furthermore, we discuss the application of these control groups in specific study designs, such as for diagnostic biomarker studies, prognostic biomarker studies and therapeutic response studies. Application of these uniform definitions will lead to better comparability of biomarker studies and optimal use of available resources. This will lead to improved quality of CSF biomarker research in MS and related disorders.

Lifestyle Factors and Multiple Sclerosis: A Case-Control Study in Belgrade

The aim of this case-control study was to assess the risk of developing multiple sclerosis (MS) associated with certain lifestyle factors (cigarette smoking and coffee and alcohol consumption). The study groups consisted of 210 cases with clinically proven and/or laboratory-confirmed MS (Poser’s criteria) and an identical number of sex- and age-matched hospital controls. In the MS patients, cigarette smoking was significantly more frequent than in the controls (OR = 1.6, p = 0.021). A dose-response relationship between the risk of MS and both duration (years) of smoking (p = 0.027) and number of cigarettes smoked daily (p = 0.021) was observed. Coffee consumption was significantly more frequent in the MS group (OR = 1.7, p = 0.047), with dose-response relationships. The analysis of alcohol drinking showed a significant association between consumption of hard liquor per day and risk of MS (OR = 6.7, p = 0.026). In multivariate logistic regression analysis, smoking was detected to be a significant independent risk factor for MS (OR = 2.4, p = 0.004).

Interleukin-12 and tumor necrosis factor-α levels in cerebrospinal fluid of multiple sclerosis patients

Concentrations of interleukin (IL)-12 and tumor necrosis factor-alpha (TNF-alpha) in cerebrospinal fluid (CSF) were measured in patients with multiple sclerosis (MS) and control patients with non-inflammatory neurological diseases (NIND) by an enzyme-linked immunosorbent assay. TNF-alpha was detectable in the CSF of 60% of the patients with active MS, none of those with inactive MS and 29% of patients with NIND. CSF concentrations of TNF-alpha correlated with the degree of disability in MS patients (P < 0.05). Detectable levels of IL-12 were found in 10% of the MS CSF samples and 18% of NIND CSF samples. There was a significant relationship between CSF concentrations of IL-12 and those of TNF-alpha in MS patients (P < 0.05); no relationship was observed between the presence of IL-12 and disease activity or severity. These findings further stress the involvement of T helper 1 type-response within the central nervous system in MS.