Multiple sclerosis (MS) is an autoimmune, inflammatory, neurodegenerative, demyelinating disease of the central nervous system, predominantly involving myelinated neurons of the brain, spinal cord, and optic nerve. Optic neuritis is frequently associated with MS and often precedes other neurologic deficits associated with MS. A large number of patients experience visual defects and have abnormalities concomitant with neurologic abnormalities. Transgenic mice manifesting spontaneous neurologic and ocular disease are unique models that have revolutionized the study of MS. Spontaneous experimental autoimmune encephalomyelitis (sEAE) presents with spontaneous onset of demyelination, without the need of an injectable immunogen. This review highlights the various models of sEAE, their disease characteristics, and applicability for future research. The study of optic neuropathy and neurologic manifestations of demyelination in sEAE will expand our understanding of the pathophysiological mechanisms underlying MS. Early and precise diagnosis of MS with different noninvasive methods has opened new avenues in managing symptoms, reducing morbidity, and limiting disease burden. This review discusses the spectrum of available noninvasive techniques, such as electrophysiological and behavioral assessment, optical coherence tomography, scanning laser polarimetry, confocal scanning laser ophthalmoscopy, pupillometry, magnetic resonance imaging, positron emission tomography, gait, and cardiovascular monitoring, and their clinical relevance.