doi: 10.1111/j.1365-4632.2009.04128.x
Report
External urethral stenosis: a latent effect of sulfur mustard two decades post-exposure Seyed Naser Emadi, MD, Alireza Hosseini-Khalili, MD, Mohammadreza Soroush, MD, Mohammadreza Khodaei Ardakani, MD, Mohammad Ghassemi-Broumand, MD, Seyed Masoud Davoodi, MD, Omolbanin Amirani, MSc, and David Haines, PhD
From the Janbazan Medical and Engineering Research Center, Baqiyatallah University of Medical Sciences (Research Center for Chemical Injuries and Department of Dermatology), University of Rehabilitation and Welfare Sciences, and Shahid Beheshti University of Medical Sciences, Tehran, Iran, and Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut Correspondence Seyed Naser Emadi, MD Janbazan Medical and Engineering Research Center No. 25, Farrokh st, Moghaddas ardebili St. Tehran Iran E-mail:
[email protected]
Abstract Background Sulfur mustard (SM), a chemical weapon used widely during World War I and against Iranians during the Iran–Iraq War of the 1980s, causes massive inflammatory tissue damage in the immediate post-exposure period, resulting in debilitating chronic disease in years to decades following contact with the agent. These syndromes most often are pathologies of the lungs, eyes, and skin, the primary target organs of SM. Typically, they are characterized by severe and increasingly painful inflammation, often accompanied by fibrosis and constriction of the anatomic channels needed for normal life, such as the small airways of the lungs and, in the present report, the urethra. Methods The present case study is a 43-year-old man with a history of heavy SM exposure to the groin in 1984. Result Within 1 year after exposure, the patient was found to have developed meatal stricture, occlusion of the external urethral meatus, and difficulty in urination. Two years post-exposure, he underwent ventral meatotomy and meatoplasty. Conclusion This case presents a unique example of the latent effects of SM exposure to the groin, and will be of value in the prevention of similar injury and complications to persons at risk of SM exposure in the future.
Introduction During the Iran–Iraq War (1980–88), the use of chemical weapons against Iranian civilians and military personnel by Baathist forces resulted in acute and chronic injury and disease among tens of thousands of exposed individuals.1–5 The most frequently used weapon during the conflict was sulfur mustard [SM, bis(2-chloroethyl) sulfide], a lipid-soluble and strongly nucleophilic compound that triggers a cascade of inflammatory processes resulting in massive tissue damage, principally blistering and necrosis of any organ coming into contact or penetrated by SM.6 Skin contact with liquid agent or vapor may result in mutagenic and toxicogenic effects to the epidermis, dermis, hypodermis, and adnexa (melanocytes, hair vessels, and follicles).7,8 Depending on the concentration of SM to which the skin is exposed, dermal effects range from erythema, at a vapor concentration of 100–400 mg/m3, to blister formation and further tissue degradation at more than 1000 mg/m3, or as a result of liquid agent contact.9,10 The severity of skin and mucosal injuries may also be enhanced by ª 2009 The International Society of Dermatology
various personal and environmental factors. For example, younger individuals and those with pale or greasy complexions or active infections are at increased risk of skin injury by SM.7,8,10 In addition, profuse sweating, particularly in areas of the body with a thin epidermis, such as axillary or groin areas, promotes SM skin injury.7,8,10 The evaluation of the acute skin injuries of Iranians exposed to mustard gas during the Iran–Iraq War demonstrated a four-stage progression of symptoms: (i) during 1–2 h post-exposure, the victim is typically asymptomatic; (ii) from 2 to 6 h post-exposure, erythema and itching may occur; (iii) 4–12 h post-exposure and lasting up to a few days, blister formation may occur; and (iv) 1–6 weeks post-exposure, changes in skin pigmentation may occur.4,11,12 At the time of writing, no reports were available in the open scientific literature describing the latent effects of SM toxicity on the glans penis and external urethral meatus. The present report describes a rare case in which these effects have occurred, together with complete obstruction of the meatus. The study was approved by the Ethics Committee of Janbazan Medical and Engineering Research Center, Tehran, Iran. International Journal of Dermatology 2009, 00, 1–4
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Figure 1 Bulla formation on the genital area 4 h post-exposure
to mustard gas in the battlefield, 1984 Figure 2 Pigmentation changes (hyperpigmentation and
Case Report This report describes the experience of a 43-year-old Iranian army veteran exposed to SM at the age of 23 years in 1984. The victim was wearing a mask and chemical protective overgarments at the time of the attack; however, his trousers ripped and, as the SM concentration at the site of contamination was fairly high, he received direct dosing by liquid agent to the genitalia, but was fortunate to avoid contamination of other commonly affected target tissues, such as the eyes and lungs. Within 6 h post-exposure, he experienced increasingly severe burning sensations and itching in the groin area. Subsequently, he was dispatched to a referral hospital in Tehran and was provided with treatment for the acute symptoms, principally erythema, edema, and bulla in the affected area (Fig. 1). Approximately 1 year following exposure, the patient developed late complications, including hypo- and hyperpigmentation on the glans and extensive depigmentation of the external meatus, and delayed urination and increasing pain as a result of progressive obstruction of the urethral canal. In the second year post-exposure, the patient experienced severe narrowing of the urethra, progressing to stenosis, owing to fibroid tissue and scar formation. Cystoscopic examination was normal from the fossa navicolaris of the urethra to the bladder; however, mild dilatation of the bladder cavity with thickening of the mucosa was observed on the bladder cavity. Surgical remediation for these conditions was undertaken, including ventral meatotomy and meatoplasty (Fig. 2). After surgery, because of hesitancy, dribbling, and intermittency, the patient has been using a urethral catheter (clear intermittent catheterization). Despite a little discomfort during intercourse, the penile erection is normal. Discussion The effectiveness of SM as a chemical weapon is substantially a result of its ability to rapidly penetrate the mucosa and skin, International Journal of Dermatology 2009, 00, 1–4
depigmentation) and meatal stenosis with ventral meatotomy on the glans of the penis
particularly in warm and moist areas, such as the groin, which retain toxicants for longer time periods than other areas of the skin surface.13–15 SM toxicity arises from the formation of a highly reactive intermediate under physiologic conditions that alkylates DNA, proteins, and other macromolecules essential for normal homeostatic function.13,14 The subject of this case study suffered very severe effects as a result of intense contamination of the groin area and the long interval between SM contact and decontamination. The effect of the agent was further aggravated by scratching of the affected area in an attempt to alleviate itching in the early post-exposure period, with consequent pruritus and inflammatory tissue damage. In this case, the adverse medical consequences of exposure to the agent were exacerbated by the thin epidermis of the glans and external urethral canal.13 Because of the particular vulnerability of the groin area to toxicant-mediated injury, even light SM contamination of this part of the body may result in deep destructive consequences to the epithelium, capillaries, and veins, resulting in the activation of fibroblasts and recruitment of inflammatory cells, which, in turn, induce fibrosis and continuing inflammatory tissue damage.16 During the first days of hospitalization for the acute effects of SM exposure, this patient was catheterized so as to alleviate edema of the urethral canal and restore the ability to void; however, as catheterization is known, in many cases, to injure the urethral mucosa, this procedure may have increased the penetration and tissue distribution of SM, ultimately contributing to increased severity of the latent effects described in this report. Obstruction of the urethral meatus can occur with different etiologies, including calculi, strictures, tumors, and physical and chemical factors (i.e. trauma, surgery, catheterization, radiation, chemical toxins, acids and alkali agents), as well as dermatologic dermatosis (i.e. lichen sclerosus, lichen ª 2009 The International Society of Dermatology
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of catheterization of such persons prior to voiding to minimize further damage to the external urethral canal; (iv) the meatal area should be washed with normal saline, gently, to avoid exacerbating the penetration of the agent and inflammatory tissue damage; and (v) individuals who become exposed to SM in the groin area should refrain from touching the affected skin until full-body decontamination has been accomplished. Depending on the etiology and staging (acute and chronic) of meatal stricture, the treatment differs from patient to patient. Buccal graft meatoplasty is a surgical technique used for meatal stenosis, and is applied to chemically injured patients. Acknowledgments Figure 3 Histologic view of mustard scar on the glans of the
penis showed partial flattening of the rete ridges and acanthosis with variable hyperpigmentation in the basal layer in the epidermis, and loss of skin appendage and sclerotic reaction with collagen deposit (sclerodermoid changes) in the dermis (hematoxylin and eosin; original magnification, ·40)
planus, Crohn’s disease, cicatricial pemphigoid, recurrent fixed drug eruption, Behcet’s disease, and epidermolysis bullosa).17 In the present case, progressive stenosis of the meatus after 1 year of exposure can be explained by neutrophilic migration, hyperactivity of fibroblasts, with collagen and mucoprotein production, and consequently fibroid and scleroderma tissue formation (Fig. 3).18,19 Depigmented patches were noted on the external urethral orifice and glans of the penis, which are indications of high-dose SM exposure, with consequent destruction of melanocytes, sclerodermal changes, and fibrotic obstruction (Fig. 2).18,20,21 Previous investigators have described in detail the effect of SM on keratinocytes and melanocytes.18–21 Consequently, a major descriptive focus of the present report is the changes in structure and pigmentation of the dermis and epidermis – an area in which less information is publicly available. Conclusions The examination of cases such as ours yields an enhanced understanding of how certain types of toxicant exposure result in unique clinical outcomes. The present case allows conclusions to be drawn that may be useful in the design of strategies to minimize SM toxicity to groin areas for individuals who are at risk of, or who have sustained, groin exposures. These include: (i) the importance of shielding vulnerable parts of the skin from direct contamination, in particular those areas that sweat profusely and have a thin epidermis; (ii) rapid voiding following exposure may help to decrease the extent of damage to the urethral mucosa and genitalia; (iii) the avoidance ª 2009 The International Society of Dermatology
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