**4.3 Viral models**

Viral myelin damage models have been used to investigate the relationship of viruses in multiple sclerosis, and they have led to major breakthroughs in our understanding of the pathology of multiple sclerosis [67]. Both genetic and environmental factors have been implicated in MS, with greater importance attributed to the latter [68].

A possible role of viruses in the pathology of MS is suggested by epidemiological studies by the detection of viral antigens and virus-specific antibodies in the greater part of MS patients [69]. Several mechanisms can explain how viruses can induce demyelination and also involved in MS [70]. Damage may consequence either from an effect on neurons directly, known as a secondary event (the so-called inside-out model), or from a direct attack on myelin, in which case neurons die due to the lack of trophic support by myelin (the so-called outside-in model).In brief, the virus can damagethe CNS through direct infection of oligodendrocytes, which can be seen in progressive multifocal leukoencephalopathy and lately in MS patients following immunomodulatory therapies [71]. Moreover, viruses can irritate infected oligodendrocytes to attack the CNS. Through these direct effects, virus infection can affect myelin and neurons *via* multiple pathways [72].
