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Currently, a comprehensive assessment of EAE pathogenesis with respect to inflammatory and degenerating neuronal elements is lacking. By using Fluoro\u2010jade histochemistry to mark neurodegeneration and dual immunostaining to follow T\u2010cell, microglial, and vascular responses, the time course and distribution of pathological events in EAE was surveyed. C57BL\/6J mice were killed at 7, 10, 14, 21 or 35 days after vaccination with the myelin oligodendrocyte glycoprotein peptide MOG<jats:sub>35\u201355<\/jats:sub>. Disease onset occurred at day 14 and peaked at day 21. Early T\u2010cell infiltration and microglial activation in periventricular and superficial white matter structures adjacent to meninges suggested initial recruitment of effector T cells via the cerebrospinal fluid and choroid plexus. This was associated with microglial activation at distal sites along the same white matter tracts, with subsequent vascular recruitment of T cells associated with further injury. Systematic examination of the entire CNS supported this two\u2010step model of EAE pathogenesis, with inflammation and neurodegeneration commencing at similar times and affecting multiple levels of predominantly sensory central pathways, including their terminal fields. This included aspects of the visual, auditory\/vestibular, somatosensory (lemniscal), and proprioceptive (spinocerebellar) systems. The early targeting of visual and periventricular structures followed by more widespread CNS involvement is consistent with common presenting signs in human MS patients and suggestive of a similar basis in neuropathology. J. Comp. 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