Multiple Sclerosis - Predicting The Next Attack

__Abstract__ MS is a complex disease characterized by a large heterogeneity in radiological and pathological findings but also in clinical disease course and treatment response. Prognostic factors are needed to. reliably counsel patients about their prognosis, differentiate between CIS/MS and other causes of the symptoms, . be able to start the appropriate treatment at the right moment in the right patient, and . gain more insight into the pathogenesis of MS (and . to try to prevent MS in some cases, knowing that the incidence of MS is increasing, probably caused by a, so far unknown, environmental factor). This thesis focuses on predictive factors in patients with CIS and relapsing-remitting MS (RRMS). In this introduction, an overview of the known prognostic factors is given, including clinical and bedside factors as well as genetics and body fluid biomarkers. First, an overview of risk factors for MS in the general population is given. Second, predictive factors for the next attack are described for patients with CIS and RRMS. For patients with CIS, the next attack is disease-defining, leading to the diagnosis of clinically definite MS (CDMS). In patients with RRMS, there is some controversy regarding the importance of relapses. Because the progressive phase of the disease (see figure 1) causes most of the long-term disability in MS patients, and this is independent of the location, severity and recovery of previous relapses, some people feel that relapses do not matter in relation to long-term disability. However, it is also known that relapses are associated with residual neurological deficit in 40-50% of cases, and that relapses early in the disease course (year 1 and 2) do seem to affect later disability. Furthermore, relapses have physical, emotional and financial consequences, and may lead to hospitalization and time away from work and home. Especially in early disease, relapses are the main cause of disability in MS patients. Because relapses are also the main target for all current MS therapies, it is an important topic in MS research. Because progressive MS was not investigated in the research described in this thesis, these MS subtypes are not discussed here

Vitamin A is not associated with exacerbations in multiple sclerosis

Background Vitamin A is a multifunctional vitamin that can inhibit the formation of Th17 cells, which are probably involved in the development of relapses in MS. Furthermore, it promotes Treg formation. Therefore, vitamin A can be hypothesized to be lower in patients than in healthy controls, and to decrease relapse risk in relapsing-remitting MS (RRMS) patients. Objective To compare vitamin A levels in MS patients and controls, and to investigate whether vitamin A levels are associated with relapse risk. Methods In a case-control study all-trans-retinol levels were compared between 31 RRMS patients and 29 matched controls. In a prospective longitudinal study in 73 RRMS patients, serum samples for all-trans-retinol measurements were taken every eight weeks. Associations between all-trans-retinol concentrations and relapse rates were calculated using Poisson regression with the individual serum levels as time-dependent variable. Associations between vitamin A and vitamin D were calculated. Results Mean vitamin A levels were lower in patients (2.16 μmol/l) than in controls (2.44 μmol/l) but with borderline significance (p=0.05). In the longitudinal study, during follow-up (mean 1.7 years), 58 patients experienced a total of 139 relapses. Monthly moving averages of all-trans retinol levels were categorized into tertiles: a low (3.7 μmol/l). Relapse rates were not associated with serum all-trans retinol levels (p>0.2), in univariate nor in multivariate analysis. Serum concentrations of all-trans-retinol and 25-OH-vitamin D were positively correlated, although this correlation was weak (r=0.15). Conclusion We did not find evidence for a role for vitamin A in the disease course of RRMS. We did find an association between vitamin A and D levels in the RRMS patients, possibly explained by dietary products that contain both fat-soluble vitamins

Smoking at time of CIS increases the risk of clinically definite multiple sclerosis

Background: Cigarette smoking is a modifiable risk factor that influences the disease course of patients with multiple sclerosis (MS). However, in patients with a clinically isolated syndrome (CIS), there are conflicting results about the association between smoking and the risk of a subsequent MS diagnosis. The aim of this study was to determine the risk of clinically definite MS (CDMS) in smoking and non-smoking patients at time of a first demyelinating event. Methods: Two hundred and fifty patients, aged 18–50 years, were included in our prospective CIS cohort. At time of the first neurological symptoms, patients completed a questionnaire about smoking habits. Cox regression analyses were performed to calculate univariate and multivariate hazard ratios for CDMS diagnosis in smoking and non-smoking CIS patients. Results: One hundred and fourteen (46%) CIS patients were diagnosed with CDMS during a mean follow-up of 58 months. In total, 79 (32%) patients smoked at time of CIS. Sixty-seven % of the smoking CIS patients were diagnosed with CDMS during follow-up compared to 36% of the non-smoking CIS patients (p < 0.001). Smoking at time of CIS was an independent predictor for CDMS diagnosis (HR 2.3; p = 0.002). Non-smoking CIS patients who had a history of smoking did not have a higher risk for CDMS than those who had never smoked. Conclusions: Smoking at time of CIS was an independent risk factor for a future CDMS diagnosis. This is an additional argument to quit smoking at time of the first attack of suspected MS

Fatigue after a first attack of suspected multiple sclerosis

Background: Fatigue is reported by more than 75% of multiple sclerosis (MS) patients. In an earlier study, we showed that fatigue is not only a common symptom in patien

High neurofilament levels are associated with clinically definite multiple sclerosis in children and adults with clinically isolated syndrome

__Background:__ A promising biomarker for axonal damage early in the disease course of multiple sclerosis (MS) is neurofilament light chain (NfL). It is unknown whether NfL has the same predictive value for MS diagnosis in children as in adults. __Objective:__ To explore the predictive value of NfL levels in cerebrospinal fluid (CSF) for MS diagnosis in paediatric and adult clinically isolated syndrome (CIS) patients. Methods: A total of 88 adult and 65 paediatric patients with a first attack of demyelination were included and followed (mean follow up-time in adults: 62.8 months (standard deviation (SD) ±38.7 months) and 43.8 months (SD ±27.1 months) in children). Thirty control patients were also included. Lumbar puncture was done within 6 months after onset of symptoms. NfL was determined in CSF using enzyme-linked immunosorbent assay (ELISA). COX regression analyses were used to calculate hazard ratios (HR) for clinically definite multiple sclerosis (CDMS) diagnosis. __Results:__ After adjustments for age, oligoclonal bands (OCB), and asymptomatic T2 lesions on baseline magnetic resonance imaging (MRI), increased NfL levels in both paediatric and adult CIS patients were associated with a sh