**2. Mustard gas-related ocular injuries**

Mustard gas-related ocular injuries can be divided into immediate, chronic, and delayedonset phases [12]. Acute manifestations of varying degrees, including eyelid erythema and edema, chemosis, subconjunctival hemorrhage, epithelial edema, punctate erosions, and corneal epithelial defects, develop in 75–90% of exposed individuals and can follow three different courses: complete resolution, persistent smoldering inflammation (chronic form), or reappearance of lesions after a latent period of quiescence (delayed form) [13, 14].

Late complications, developing after 1–40 years, can cause progressive and permanent reduction in visual acuity and even blindness, and they occur in approximately 0.5% of those initially severely wounded [6, 13]. A wide range of late ocular involvements have been reported, which include chronic blepharitis, dry eye, conjunctival vessel tortuosity, limbal ischemia and stem cell deficiency, corneal scarring and neovascularization, corneal thinning and perforation, epithelial irregularity, recurrent or persistent epithelial defects, and secondary degenerative changes including lipid/amyloid deposits (**Figure 1**) [5, 6, 12–17].

nerve agent in Yemen to support a coup against the Yemeni monarchy. During the Iran-Iraq war (1980–1988), Iraq used chemical weapons, including tabun and mustard gas, against Iran and Iraq's Kurdish minority. Iraq's use of chemical weapons was confirmed by the United

**1.2. Molecular formula of mustard gas and its biochemical mechanism of tissue injury**

vesicants because they cause vesicles, or blisters, on exposed skin. Pure sulfur mustard is odorless, colorless, and viscous liquid at room temperature. It is usually yellow-brown in color and has an odor resembling garlic, horseradish, or mustard plants when used as warfare agents, which is how it got its name. However, this compound has absolutely no relation

Mustard gas is a lipophilic, highly cytotoxic agent that rapidly penetrates tissue [5]. Exposed skin surfaces, eyes, the linings of both respiratory and gastrointestinal tracts, and renal systems as well as the bone marrow are all at risk. The risks increase dramatically under hot, humid conditions, and it can be lethal at sufficiently high doses [5, 6]. It has been demonstrated that 80% of sulfur mustard applied to the skin evaporates, 10% remains in the skin, and 10% gets absorbed systemically [7]. Susceptibility of the eyes to the toxic effects of mustard gas is due to moistness of the ocular surface, allowing activation of the agent. Additionally, corneal epithelial cells have a high turnover and metabolic rate that increase their vulnerability to the

Sulfur mustard is a cellular poison that triggers apoptosis as a cytotoxic mechanism. The acute toxic effects of mustard vesicants are usually attributed to the consequences of alkylation reactions with organic compounds including nucleoproteins such as DNA [9]. The ladder pattern of DNA fragmentation after cell exposure to mustard gas indicates internucleosomal cleavage of DNA. Alkylation reactions can result in genotoxic effects as well as physiological and metabolic disturbances that induce apoptosis [10]. In addition, mustard gas is a mutagen and is a known carcinogen that is associated with an increased risk of developing lung and

Mustard gas-related ocular injuries can be divided into immediate, chronic, and delayedonset phases [12]. Acute manifestations of varying degrees, including eyelid erythema and edema, chemosis, subconjunctival hemorrhage, epithelial edema, punctate erosions, and corneal epithelial defects, develop in 75–90% of exposed individuals and can follow three different courses: complete resolution, persistent smoldering inflammation (chronic form), or

Late complications, developing after 1–40 years, can cause progressive and permanent reduction in visual acuity and even blindness, and they occur in approximately 0.5% of those initially

reappearance of lesions after a latent period of quiescence (delayed form) [13, 14].

S) is one of a class of chemical warfare agents which are known as

Nations experts [3].

Sulfur mustard (C<sup>4</sup>

H8 Cl2

4 Causes and Coping with Visual Impairment and Blindness

whatsoever to culinary mustard [4].

other respiratory tract cancers [11].

**2. Mustard gas-related ocular injuries**

lipophilic sulfur mustard trapped into the oily tear layer [8].

Dry eye is a late ocular complication of exposure to mustard gas, the symptoms of which are often severe and persistent and can influence many aspects of intoxicated victims' lives [5, 6, 18, 19]. Although the exact pathophysiologic cause of dry eye syndrome after exposure to mustard gas is not known yet, most studies in this regard have revealed evidence for increased apoptosis in the conjunctival epithelium [20]. This apoptosis also occurs in goblet cells resulting in a significant decrease in goblet cell density thus reducing mucin production and tear film stability [20]. Additionally, dysfunction of lacrimal glands may occur secondary to lymphocytic infiltration of the glands [20].

Mustard gas-related corneal involvements are completely different from those observed in other causes of corneal opacities that develop after trauma, infection, and acid or alkaline burns [18]. For example, corneal thinning and fragility is a striking feature in mustard gas-induced ocular injuries [18]. Such differences can be explained by the presence of other concomitant abnormalities such as limbal ischemia and vascular abnormalities [18]. Limbal ischemia causes scleral and corneal thinning, and the presence of leaking limbal vessels results in the accumulation of abnormal materials such as lipid and amyloid in the adjacent cornea [12]. Alterations of corneal stroma secondary to acute and chronic inflammation, stromal scar and fibrosis, and deposits make stromal layers too rigid to be separated by air. Therefore, deep anterior lamellar keratoplasty using the big-bubble technique is hard to perform in mustard gas-induced keratitis [12].

**Figure 1.** Abnormalities of the cornea, including surface irregularity, thinning, and intrastromal lipid and amyloid deposits, are evident in an eye suffering from mustard gas keratitis.

Although limbal stem cell deficiency has been reported in mustard gas-related ocular involvements, its clinical manifestations are completely different from those observed in other causes of stem cell deficiency such as acid or alkaline burns, thermal burns, Stevens–Johnson syndrome, ocular cicatricial pemphigoid, and multiple surgeries [18]. For example, conjunctivalization of the corneal surface, which is a striking feature in the latter conditions, is hardly observed in mustard gas-induced keratitis. Additionally, there is no correlation between the severity of corneal involvements and limbal stem cell deficiency in these eyes [12]. Limbal abnormalities observed in mustard gas-induced ocular involvements are contributed by the combined effects of limbal stem cell deficiency, limbal ischemia, and abnormally leaking vessels. However, one mechanism can be more prominent than the others in certain cases [12].

Preservative-free artificial tears and lubricants are one of the most prescribed drugs in the management of ocular symptoms in mustard gas-related corneal involvements. New formulas have been proposed for artificial tears, and can be used in the management of dry eye disease with any etiology. Recombinant human lubricin (proteoglycan 4), a natural substance [22], and hyaluronic acid with trehalose [23] are one of these new formulas, and have been found to be safe with a better patient satisfaction. Natural components of tear film such as anionic glycosaminoglycan polysaccharide in combination with polymers, hyaluronic acid, and carmellose sodium are quite effective in corneal epithelial staining [24]. Another new formula contains carmellose sodium, osmoprotectants, and hyaluronic acid and has been dem-

Corneal Blindness Caused by Mustard Gas http://dx.doi.org/10.5772/intechopen.70469 7

Curcumin is an anti-inflammatory agent with anti-cancer and anti-apoptotic properties [26, 27]. Dietary curcumin is found to decrease lens opacification in a rat model of naphthalene-induced cataract [28]. Curcumin is effective in the management of different respiratory and cutaneous symptoms in sulfur mustard-exposed casualties [29, 30]. This natural hydrophobic polyphenol is proposed as an alternative treatment for dry eye disease [31]. Maria et al. [32] have developed a formulated eye drop for curcumin with more aqueous solubility properties. This sustained-release drop may be appropriate for the management of different inflammatory ocular surface disorders encountered in sulfur mustard-exposed patients [32]. However, further animal studies and clinical trials are required to approve

Resolvin E1 (RvE1), a derivative of eicosapentaenoic acid, is an endogenous lipid mediator and can inhibit pro-inflammatory responses [33]. This drug has been used for the management of periodontitis, inflammatory bowel disease, and prevention of vascular inflammation [33, 34]. It has been shown that the topical administration of RvE1 significantly down regulates cyclooxygenase-2 (COX-2) expression and increases tear production, resulting in an increase in the density of superficial epithelial cells in a dry-eyed mouse model [35]. These features make RvE1 a potential therapeutic option in delayed ocular lesions induced by sulfur mustard. Similarly, thymosin β4 eye drops have been found to be effective in the treatment of dry eye disease and corneal vascularization and thus may have a role in the management of delayed ocular lesion in sulfur mustard-exposed victims [36]. There is no report of ocular

Diquafosol is a P2Y2 purinergic receptor agonist that stimulates the receptors in ocular tissues and thus increases mucin (conjunctival goblet cells stimulation) and the aqueous portion of tear film (conjunctival epithelial cells stimulation) [37]. Three percent diquafosol ophthalmic solution is effective for the treatment of dry eye disease through tear film stabilization and repair of corneal epithelial damages [38, 39]. Another P2Y2 receptor agonist is uridine. Oral uridine is reported to be beneficial for increasing mucin secretion and tear production [40].

Rebamipide is a mucosal protective agent with anti-inflammatory, immunosuppressive, and anti-apoptotic activities [41]. Corneal and conjunctival mucin can be effectively and safely increased by 2% rebamipide ophthalmic suspension [42]. The efficacy of diquafosol, rebamipide, and oral uridine in sulfur mustard-exposed patients should be investigated in clinical trials. Tretinoin (0.01% all-trans-retinoic acid) is effective in the treatment of dry eye disease [43]. Tretinoin improves tear film break-up time and Schirmer tear test results [43]. However, tretinoin cannot

onstrated to improve ocular symptoms in dry eye disease [25].

toxicity associated with the topical form of thymosin β4 [36].

the efficacy of this formulation.
