Many disease-modifying therapies are currently available for adults with relapsing-remitting multiple sclerosis (MS) but none of them has been tested in pediatric MS in randomized placebo-controlled trials. At present, as suggested by observational studies and experts' guidelines, interferon-β and glatiramer acetate continue to be the standard first-line treatments for pediatric MS. Observational studies and some controlled unblinded trials have shown a positive effect of these meditations in reducing relapse rate and delaying disease progression, with an acceptable safety profile. The goal of this article is to provide an overview of current knowledge with regard to safety, tolerability, and efficacy of first-line treatment options for MS in the pediatric age group, with the aim of providing guidance for planning first-line treatment of MS in children and adolescents.

The management and treatment of multiple sclerosis (MS) is becoming more and more complex as many medications are now available, with different routes of administration, mechanisms of action, and effectiveness and safety profiles. The decision-making process to choose the right medication is a complex task requiring a careful evaluation of the results of clinical and post-marketing studies, and the capability to translate data from clinical studies to patients in everyday clinical practice. Two European neurological societies, the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and European Academy of Neurology (EAN), and the American Academy of Neurology (AAN) have recently delivered guidelines for MS treatment, helping neurologists to address the most common clinical issues related to this topic. The two guidelines offer a similar view and similar recommendations for the most relevant and common questions of clinical practice. For some aspects of MS treatment the statements are slightly different, in particular regarding pregnancy management in relation to treatments, the use of mitoxantrone, and the treatment of secondary progressive MS (SP-MS).

In this review the most important aspects of pediatric multiple sclerosis are presented and compared with the adult form. Some findings appear peculiar of pediatric MS: a. Clinical manifestations are similar in adolescents and adults with MS, however in very young subjects MS frequency at onset is similar in males and females, with a higher frequency of brainstem/cerebellar involvement and acute polysymptomatic/ADEM like onset; b. The course is relapsing-remitting in the large majority of patients, with a high relapse rate; c. Mild or severe disability is reached after a longer interval, but at a lower age compared to adult MS; d. The frequency of cognitive dysfunction is relatively high, with a quick deterioration but also the capability to partially recover with time; e. MRI is fundamental for diagnosis and prognosis: the pattern of MRI has some peculiar aspects in pediatric MS patients: i) the classic diagnostic criteria cannot be fulfilled, ii) lesion load is more relevant, iii) lesions are less destructive, have a more pronounced inflammatory pattern and have enhanced capability to recover with time; f. Diagnostic criteria of adults can be applied to patients with less than 18 years, but with limitations for subjects with less than 12 years and ADEM-like onset; g. The approach in differential diagnosis is particular complex and many disorders with clinical manifestations in the pediatric age must be considered: in this context it is important to pay attention to clinical, MRI and CSF red flags. Anti-MOG abs syndrome has been recently identified and should be carefully considered in patients with Acquired Demyelinating Syndrome; h. CSF oligoclonal bands are less frequent in pediatric MS patients, their presence in patients with Acquired Demyelinating Syndrome is strongly correlated to the risk of MS; i. The interplay between genetic and environmental factors determine the risk of developing MS; j. MS has a more pronounced inflammatory pattern (as suggested by the high relapse rate and the most relevant inflammatory pattern at brain MRI); k. The treatment is based on the approach used for adults: as MS has a strong impact on patients and their family the model of care should involve a team with specialized neurologists, pediatricians and neuro-pediatricians, nurses, psychologists, social workers and specialists of rehabilitative medicine.

Anti-CD20 therapies have established efficacy in the treatment of immune-mediated neurological and non-neurological diseases. Rituximab, one of the first B-cell-directed therapies, is relatively inexpensive compared to newer anti-CD20 molecules, is available in many countries, and has been used off-label in pediatric patients with neuroimmune conditions. The objective of this paper is to describe the experience with rituximab in pediatric multiple sclerosis and other inflammatory immune-mediated disorders of the central nervous system (CNS), and to define a protocol for its use in clinical practice, in particular addressing doses, interval of administration, duration of treatment, and tests to perform at baseline and during follow-up.

Many biological markers have been explored in multiple sclerosis (MS) to better quantify disease burden and better evaluate response to treatments, beyond clinical and MRI data. Among these, neurofilament light chain (Nf-L), although non-specific for this disease and found to be increased in other neurological conditions, has been shown to be the most promising biomarker for assessing axonal damage in MS, with a definite role in predicting the development of MS in patients at the first neurological episode suggestive of MS, and also in a preclinical phase. There is strong evidence that Nf-L levels are increased more in relapsing versus stable MS patients, and that they predict future disease evolution (relapses, progression, MRI measures of activity/progression) in MS patients, providing information on response to therapy, helping to anticipate clinical decisions in patients with an apparently stable evolution, and identifying patient non-responders to disease-modifying treatments. Moreover, Nf-L can contribute to the better understanding of the mechanisms of demyelination and axonal damage in adult and pediatric MS. A fundamental requirement for its clinical use is the accurate standardization of normal values, corrected for confounding factors, in particular age, sex, body mass index, and presence of comorbidities. In this review, a guide is provided to update clinicians on the use of Nf-L in clinical activity.