Histopathological and Radiological Studies – Early Multiple Sclerosis Is Not Silent
Axonal pathology in MS was described as early as the 19th century. However, it was only in the late 1990s that methodologically advanced histopathological studies led to a reappraisal of the concept of irreversible axonal damage underlying persistent disability.

A series of elegant studies demonstrated that axonal transection occurs early during the disease and is at least initially associated with ongoing tissue inflammation.¹ Using different non-conventional magnetic resonance (MR) techniques, such as magnetisation transfer and MR spectroscopy, widespread tissue damage and axonal dysfunction can also be identified radiologically during early MS, even in areas without overt lesions on conventional MR imaging (MRI).

Functional re-organisation of neuronal networks and/or compensation by redundant mechanisms are thought to contribute to rapid clinical recovery after CIS, again emphasising widespread alterations during this early disease phase.² This initially subclinical tissue damage can accumulate over time and pose a substantial risk for disease progression and disability during later disease stages. Clinically, this may be reflected by the impact of the early course of established MS on long-term prognosis. Thus, several longitudinal natural history studies demonstrate that the number of relapses during the first two to five years is associated with the rate of accrual of permanent disability, with greater numbers of early episodes leading to a shorter interval to reach disability landmarks.³

Surrogate Parameters – Initial Cranial Magnetic Resonance Imaging Identifies Clinically Isolated Syndrome Patients Who Are ‘At Risk’
While the majority of CIS patients experience further relapses, defining MS, the disease remains monophasic in a proportion of patients. Given this population on the one hand, but early irreversible tissue damage in other patients, a major aim is to identify parameters that can predict risk of further relapses and accrual of disability after CIS. Currently, cranial (c)MRI is the best validated method of identifying CIS patients with a high risk of experiencing further relapses. Long-term observation of a CIS cohort reported by the group from the National Hospital for Neurology and Neurosurgery (NHNN) at Queen’s Square, London corrobated the predictive value of the initial cMRI. Here, the risk of suffering further relapses is related to the initial cMRI lesion load, which may also be associated with the degree of long-term disability.⁴

Similar findings have been reported for other cohorts. Thus far, no other biological markers characterising CIS patients who are ‘at risk’ have been unequivocally identified. Initial high expectations after a report on the value of serum antibodies against components of central myelin to predict the risk of suffering further relapses after CIS were not met due to lack of reproduction of these findings in other cohorts.^5,6 However, the role of antimyelin antibodies as surrogate parameters and optimal detection methods and their potential pathogenetic implications are currently still under investigation.