## 3 Vitamin B and Dry Eye Disease  
Vitamin B complexes are a group of water-soluble vitamins that mostly have coenzyme activities which might be helpful for the maintenance of ocular surface homeostasis and prevention of DED [16]. Several micronutrients in the vitamin B group were shown to be associated with DED, particularly DED related to neuropathic ocular pain (NOP) [12; 13; 23; 24; 35; 63; 64]. Vitamin B1 (thiamine; molecular formula C\({}_{12}\)H\({}_{17}\)N\({}_{4}\)OS+) has an anti-oxidative function and promotes the metabolism of carbohydrates, the synthesis of proteins, and the production of neurotransmitters [16]. Vitamin B2 (riboflavin; molecular formula C\({}_{17}\)H\({}_{20}\)N\({}_{4}\)O\({}_{6}\)) also has anti-oxidant activity and was shown to have protective effects against cataracts [65]. Vitamin B6 (pyridoxine; molecular formula C\({}_{8}\)H\({}_{11}\)NO\({}_{3}\)) is important for immune system regulation and the production of neurotransmitters [16]. Vitamin B12 (cobalamin; molecular formula C\({}_{63}\)H\({}_{88}\)CoN\({}_{14}\)O\({}_{14}\)P) can facilitate nerve regeneration and remyelination [16]. Thus, deficiency in these vitamins can result in impaired nerve survival and regeneration, leading to peripheral and central sensitization and neuropathic pain leading to dry eye symptoms [16]. Accumulated stress and repetitive noxious nerve injury may result in maladaptive neuroplastic changes in somatosensory pathways that lead to neuropathic pain caused by the sensitization of peripheral and central somatosensory pathways [2; 66; 67; 68]. Previous studies have indicated that abnormalities in the neurossensory system may play an important role in the pathophysiology of DED, [2; 67; 68; 69] and that the dry eye workshop II (DEWS II) included neurosensory abnormalities in the definition of DED in 2017. [1] NOP can develop in association with pathologic changes in the peripheral and central nervous systems that result from chronic nerve damage caused by insults, including ocular surface damage and tear film instability [66; 70]. Discrepancies between dry eye signs and symptoms are frequently observed in patients with DED [66; 67; 68], and NOP may, at least in part, explain this phenomenon [67; 68; 69]. These findings suggest that vitamin B deficiency may have an influence on DED associated with NOP, and the supplementation of micronutrients can improve DED, particularly NOP-associated DED [12; 13; 14; 23; 64]. An experimental study showed that vitamin B12 might be important for the trophic regulation of nerve regeneration [14]. [PERSON] et al. [35] introduced a case of NOP recalcitrant to the conventional treatment of DED, including artificial tears and topical cyclosporine, in which vitamin B12 deficiency was incidentally detected and where parenteral vitamin B12 administration resulted in a dramatic improvement in NOP. [PERSON] et al. [23] also reported that vitamin B12 supplementation for 3 months in patients with vitamin B12 deficiency and NOP led to improvements in ocular surface disease index (OSDI) scores, tear secretion, and tear film stability, and that the efficacy of vitamin B12 was superior to that of conventional treatments, such as artificial tears and cyclosporine. These findings suggest that vitamin B12 deficiency may play a role in neurosensory abnormalities leading to DED, and supplementation with vitamin B12 can be effective for NOP [12; 23]. Moreover, several studies have reported an association between vitamin B12 deficiency and [PERSON] syndrome [24; 63; 71], suggesting the possible existence of other mechanisms underlying the association between vitamin B12 and DED. [PERSON] et al. [64] reported that oral vitamin B1 and mecobalamin, a form of vitamin B12, improved both dry eye symptoms and signs [64]. [PERSON] et al. [72] showed that the nebulization of vitamin B (twice a week for 3 months) onto the ocular surface led to decreased OSDI, increased TBUT, and improved corneal staining scores.