cases have led to the proposal of a "viking gene" hypothesis for the dissemination of the disease. augustus frederick d'este (1794–1848), son of prince augustus frederick, duke of sussex and lady augusta murray and a grandson of george iii of the united kingdom, almost certainly had ms. d'este left a detailed diary describing his 22 years living with the disease. his diary began in 1822 and ended in 1846, although it remained unknown until 1948. his symptoms began at age 28 with a sudden transient visual loss (amaurosis fugax) after the funeral of a friend. during his disease, he developed weakness of the legs, clumsiness of the hands, numbness, dizziness, bladder disturbance and erectile dysfunction. in 1844, he began to use a wheelchair. despite his illness, he kept an optimistic view of life. another early account of ms was kept by the british diarist w. n. p. barbellion, pen name of bruce frederick cummings (1889–1919), who maintained a detailed log of his diagnosis and struggle. his diary was published in 1919 as the journal of a disappointed man. charles dickens, a keen observer, described possible bilateral optic neuritis with reduced contrast vision and uhthoff phenomenon in the main female character of bleak house (1852–1853), esther summerville. research main article: multiple sclerosis research epstein-barr virus ongoing studies as of 2022, the pathogenesis of ms as it relates to ebv is actively investigated, as are disease-modifying therapies; understanding of how risk factors combine with ebv to initiate ms is sought. whether ebv is the only cause of ms might be better understood if an ebv vaccine is developed and shown to prevent ms as well. even though a variety of studies showed the connection between an ebv infection and a later development of multiple sclerosis, the mechanisms behind this correlation are still not completely clear. though there are some leading theories which are explaining the relationship between the two diseases closer. it is expected that the involvement of ebv-infected b-cells and the involvement of anti-ebna antibodies, which appear to be significantly higher in multiple sclerosis patients, play a crucial role in the development of the disease. this is supported by the fact that with treatment against b-cells, e.g. through ocrelizumab therapy, the course of multiple sclerosis symptoms will be improved. annual relapses will appear in a minor rate and disability progression is slower. a study led by a stanford research unit which was published in 2022, has shown that during an ebv infection, molecular mimicry can occur, where the immune system will produce antibodies against the ebna1 protein, which at the same time is able to bind to glialcam in the myelin. additionally, they observed a phenomenon which is uncommon in healthy individuals but often detected in multiple sclerosis patients – b-cells are trafficking to the brain and spinal cord, where they are producing oligoclonal antibody bands. a majority of these oligoclonal bands do have an affinity to the viral protein ebna1, which is cross-reactive to glialcam. these antibodies are abundant in approximately 20–25% of multiple sclerosis patients and worsen the autoimmune demyelination which leads consequently to an pathophysiologocal exacerbation of the disease. furthermore, the intrathecal oligoclonal expansion with a constant somatic hypermutation is unique in multiple sclerosis when compared to other neuroinflammatory diseases. in the study there was also the abundance of antibodies with ighv 3–7 genes measured, which appears to be connected to the disease progress. antibodies which are ighv3–7-based are binding with a high affinity to ebna1 and glialcam. this process is actively thriving the demyelination. it is probable that b-cells, expressing ighv 3–7 genes entered the csf and underwent there affinity maturation after facing glialcam, which led consequently to the production of high affinity anti-glialcam antibodies. this was additionally shown in the eae mouse model where immunization with ebna1 lead to a strong b-cell response against glialcam, which worsened the eae. medications medications that influence voltage-gated sodium ion channels are under investigation as a potential neuroprotective strategy because of hypothesized role of sodium in the pathological process leading to axonal injury and accumulating disability. there is insufficient evidence of an effect of sodium channel blockers for people with ms. pathogenesis ms is a clinically defined entity with several atypical presentations. some auto-antibodies have been found in atypical ms cases, giving birth to separate disease families and restricting the previously wider concept of ms. anti-aqp4 autoantibodies were found in neuromyelitis optica (nmo), which was previously considered a ms variant. a spectrum of diseases named nmosd (nmo spectrum diseases) or anti-aqp4 diseases has been accepted. some cases of ms were presenting anti-mog autoantibodies, mainly overlapping with the marburg variant. anti-mog autoantibodies were found to be also present in adem, and a second spectrum of separated diseases is being considered. this spectrum is named inconsistently across different authors, but it is normally something similar to anti-mog demyelinating diseases. a third kind of auto-antibodies is accepted. they are several anti-neurofascin auto-antibodies which damage the ranvier nodes of the neurons. these antibodies are more related to the peripheral nervous demyelination, but they were also found in chronic progressive ppms and combined central and peripheral demyelination (ccpd, which is considered another atypical ms presentation). in addition to the significance of auto-antibodies in ms, four different patterns of demyelination have been reported, opening the door to consider ms as a heterogeneous disease. disease biomarkers mri brain scan produced using a gradient-echo phase sequence showing an iron deposit in a white matter lesion (inside green box in the middle of the image; enhanced and marked by red arrow top-left corner) since disease progression is the result of degeneration of neurons, the roles of proteins showing loss of nerve tissue such as neurofilaments, tau, and n-acetylaspartate are under investigation. improvement in neuroimaging techniques such as positron emission tomography (pet) or mri carry a promise for better diagnosis and prognosis predictions. regarding mri, there are several techniques that have already shown some usefulness in research settings and could be introduced into clinical practice, such as double-inversion recovery sequences, magnetization transfer, diffusion tensor, and functional magnetic resonance imaging. these techniques are more specific for the disease than existing ones, but still lack some standardization of acquisition protocols and the creation of normative values. this is particularly the case for proton magnetic resonance spectroscopy, for which a number of methodological variations observed in the literature may underlie continued inconsistencies in central nervous system metabolic abnormalities, particularly in n-acetyl aspartate, myoinositol, choline, glutamate, gaba, and gsh, observed for multiple sclerosis and its subtypes. there are other techniques under development that include contrast agents capable of measuring levels of peripheral macrophages, inflammation, or neuronal dysfunction, and techniques that measure iron deposition that could serve to determine the role of this feature in ms, or that of cerebral perfusion. covid-19 the hospitalization rate was found to be higher among individuals with ms and covid-19 infection, at 10%, while the pooled infection rate is estimated at 4%. the pooled prevalence of death in hospitalized individuals with ms is estimated as 4%. other emerging theories one emerging hypothesis, referred to as the hygiene hypothesis, suggests that early-life exposure to infectious agents helps to develop the immune system and reduces susceptibility to allergies and autoimmune disorders, including ms. germ-free mice infected with transplanted fecal matter from ms patients exhibit an increased risk of developing eae, an animal model of ms. it has also been proposed that certain bacteria found in the gut use molecular mimicry to infiltrate the brain via the gut-brain axis, initiating an inflammatory response and increasing blood-brain barrier permeability. vitamin d levels have also been correlated with ms; lower levels of vitamin d correspond to an increased risk of ms, suggesting a reduced prevalence in the tropics – an area with more vitamin d-rich sunlight – strengthening the impact of geographical location on ms development. ms mechanisms begin when peripheral autoreactive effector cd4+ t cells get activated and move into the cns. antigen-presenting cells localize the reactivation of autoreactive effector cd4-t cells once they have entered the cns, attracting more t cells and macrophages to form the inflammatory lesion. in ms patients, macrophages and microglia assemble at locations where demyelination and neurodegeneration are actively occurring, and microglial activation is more apparent in the normal-appearing white matter of ms patients. astrocytes generate neurotoxic chemicals like nitric oxide and tnfα, attract neurotoxic inflammatory monocytes to the cns, and are responsible for astrogliosis, the scarring that prevents the spread of neuroinflammation and kills neurons inside the scarred area.