Multiple sclerosis (MS) is a chronic disorder of the central nervous system (CNS) in which the complex interplay between inflammation and neurodegeneration determines varying degrees of neurological disability. For this reason, it is very difficult to express an accurate prognosis based on purely clinical information in the individual patient at an early disease stage. Magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers are promising sources of prognostic information with a good potential of quantitative measure, sensitivity, and reliability. However, a comprehensive MS outcome prediction model combining multiple parameters is still lacking. Current relevant literature addressing the topic of clinical, MRI, and CSF markers as predictors of MS disability progression is reviewed here. 1. Introduction Multiple sclerosis (MS) is a chronic idiopathic disorder of the central nervous system (CNS) sustained by a multifocal inflammatory process predominantly affecting myelin-sheathed axons. Although traditionally viewed as a white matter (WM) demyelinating disorder, MS is characterized by acute and chronic axonal and neuronal loss, as shown for long by pathological and neuroimaging studies [1, 2]. Acute inflammation causes the development of plaques, characterized by blood-brain barrier (BBB) breakdown, perivascular cellular infiltration, demyelination, and axonal degeneration. Notably, axonal damage occurs not only in the acute phase but also in inactive MS lesions [3, 4]. Plaques represent the underlying pathological substrate of clinical events, with occurrence of focal/multifocal neurological symptoms and signs that eventually subside in many cases as inflammation ceases. Lesions may also involve the cortical gray matter (GM) in which case they are characterized by myelin/axonal injury and microglial activation but not BBB disruption [5] and less cellular infiltration compared to WM lesions [6, 7]. It is increasingly perceived that the severity of MS clinical outcome does not simply result from the extent of WM damage, but it rather represents a complex balance among WM and GM tissue damage, tissue repair, and cortical reorganisation [8–10]. The evidence that axonal loss highly correlates with neurological disability and disease progression [2] has spurred the search for reliable markers of axonal degeneration. Although MS aetiology still remains undetermined, genetic and environmental risk factors have been identified or are suspected (i.e., female gender, HLA-DRB1 allele, genome-wide association studies candidate genes, Epstein-Barr
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