Cutis

Bowen disease (BD) of the nail unit has multiple clinical presentations, often making its diagnosis challenging. BD is a squamous cell carcinoma (SCC) in situ with various cited etiologic causes, including ionizing and nonionizing radiation, hydrocarbon exposure, trauma, arsenic ingestion, chronic paronychia, ectodermal dysplasia, and dyskeratosis congenita.1-4 Human papillomavirus (HPV) has been associated with the pathogenesis of BD and SCC of the anogenital, oral, and periungual regions.3-9 Specifically, HPV-16 is well recognized as the predominant type associated with periungual BD and SCC, though HPV-34, -35, and -73 also have been identified.2-8 We describe the case of a 25-year-old African American man with BD of the third right fingernail presenting as longitudinal melanonychia (LM), in which HPV-56 DNA was identified. back to top

CASE REPORT A 25-year-old African American man presented to our dermatology service for evaluation of a pigmented streak of the third right fingernail that had been present for several years. Findings from the examination revealed a band of LM on the right third fingernail associated with overlying linear dystrophy of the nail plate. There was no periungual extension of pigmentation onto the adjacent cuticle or the lateral nail fold (Figure 1).

A 3-mm punch biopsy of the proximal nail matrix was performed and revealed acanthosis, hyperkeratosis, and full-thickness epidermal atypia (Figure 2). Hypergranulosis and koilocytic changes were noted (Figure 3). MART-1 (melanoma antigen recognized by T cells 1) staining demonstrated a normal number and distribution of melanocytes.
Polymerase chain reaction amplification, with subsequent hybridization with probes specific to the DNA of HPV, showed strong positivity for HPV-56. Mohs micrographic surgery was performed to excise the tumor with clear margins (Figure 4). The wound was primarily closed using a modified running winch stitch (Figure 5). An anogenital examination performed during follow-up was negative for any verrucous lesions. back to top

Comment BD of the nail unit commonly has been described as wartlike but may present as periungual erythema with associated crusting, ulceration or fissuring, paronychia, onychocryptosis, or nail dystrophy, with eventual partial to complete degeneration of the nail.1,10 The digits of the hands are more commonly involved than the feet.10 In most cases, a single digit is involved, with the thumb being the most common. More invasive disease should be suspected in nodular cases and when bleeding and ulceration occur.5,10 LM is another presentation of BD involving the nail unit first described by Baran and Simon11 in 1988.

Sass et al2 described the first case of BD presenting as LM, in which HPV-16 was identified, and further demonstrated genomic integration of the viral DNA in the chromosomal host DNA. HPV infection, especially type 16, has been implicated both in the pathogenesis of anogenital and oral BD2-4,7 and in the development of BD or invasive SCC in the periungual area.1-4,6 In addition, HPV-34, -35, and -73 have been described.4,7,8

HPVs related to mucosal or genital lesions likely play an important role in the pathogenesis of BD and invasive SCC in the periungual region.3,5,7 Guitart et al5 described a case in which similar HPV genomes were detected in a uterine cervical neoplasia and a subungual SCC in the same patient. Similarly, Rudlinger et al12 described a patient with HPV-35 positive bowenoid papulosis in the anogenital region who presented 11 years later with bowenoid dysplasia of a verruca on the right ring finger with the same HPV type. The presence of the same HPV type in both anogenital and periungual regions occurring in the same patient could be explained through autoinoculation or direct contact.1,3,5,7 This is consistent with the observation that extragenital BD lesions are found more commonly in the upper extremities.1,3,7

Lorincz et al13 first reported HPV-56 in 1989 after having been detected in invasive cervical cancers. HPV-56 is included in the high-risk group of HPV types often detected in either cervical intraepithelial neoplasia or invasive cancers, or both.3,9,13 In 1999, Uezato et al3 reported the first case in which HPV-56 was found in extragenital BD. The lesion occurred on the first great toe of an 81-year-old Japanese woman who subsequently underwent surgery, including skin grafting, without evidence of recurrence. To our knowledge, our case represents the second report in which HPV-56 was found in a case of extragenital BD.

The prognosis for patients with BD involving the nail unit is good. In the case of invasive carcinoma of the nail unit, the reported incidence of local bone invasion ranges from 18% to 60%.14-16 The high rate of local invasion may reflect a delay in diagnosis due to patient neglect and/or confusion regarding the clinical presentation. Metastatic disease is rare. However, it has been reported in 4 cases, one of which is a patient with hereditary ectodermal dysplasia.4,15,17,18

Surgical removal is the preferred therapeutic intervention, with either simple excision followed by skin graft or healing by secondary intention.1,10,19 Mohs micrographic surgery is the treatment of choice, allowing for complete removal of the tumor with maximal preservation of normal tissue and physiologic function.1,10,19

In conclusion, our case represents the first report of BD of the nail unit associated with HPV-56. As new HPV subtypes are identified and classified according to their oncogenic potential, the well-established association among high-risk HPV types in both anogenital and nail unit neoplasias is reinforced by these reports. Recognition of LM as a presenting sign of nail unit BD may result in early diagnosis and treatment. back to top

Bowen disease (BD) of the nail unit has multiple clinical presentations, often making its diagnosis challenging. BD is a squamous cell carcinoma (SCC) in situ with various cited etiologic causes, including ionizing and nonionizing radiation, hydrocarbon exposure, trauma, arsenic ingestion, chronic paronychia, ectodermal dysplasia, and dyskeratosis congenita.1-4 Human papillomavirus (HPV) has been associated with the pathogenesis of BD and SCC of the anogenital, oral, and periungual regions.3-9 Specifically, HPV-16 is well recognized as the predominant type associated with periungual BD and SCC, though HPV-34, -35, and -73 also have been identified.2-8 We describe the case of a 25-year-old African American man with BD of the third right fingernail presenting as longitudinal melanonychia (LM), in which HPV-56 DNA was identified. back to top

CASE REPORT A 25-year-old African American man presented to our dermatology service for evaluation of a pigmented streak of the third right fingernail that had been present for several years. Findings from the examination revealed a band of LM on the right third fingernail associated with overlying linear dystrophy of the nail plate. There was no periungual extension of pigmentation onto the adjacent cuticle or the lateral nail fold (Figure 1).

A 3-mm punch biopsy of the proximal nail matrix was performed and revealed acanthosis, hyperkeratosis, and full-thickness epidermal atypia (Figure 2). Hypergranulosis and koilocytic changes were noted (Figure 3). MART-1 (melanoma antigen recognized by T cells 1) staining demonstrated a normal number and distribution of melanocytes.
Polymerase chain reaction amplification, with subsequent hybridization with probes specific to the DNA of HPV, showed strong positivity for HPV-56. Mohs micrographic surgery was performed to excise the tumor with clear margins (Figure 4). The wound was primarily closed using a modified running winch stitch (Figure 5). An anogenital examination performed during follow-up was negative for any verrucous lesions. back to top

Comment BD of the nail unit commonly has been described as wartlike but may present as periungual erythema with associated crusting, ulceration or fissuring, paronychia, onychocryptosis, or nail dystrophy, with eventual partial to complete degeneration of the nail.1,10 The digits of the hands are more commonly involved than the feet.10 In most cases, a single digit is involved, with the thumb being the most common. More invasive disease should be suspected in nodular cases and when bleeding and ulceration occur.5,10 LM is another presentation of BD involving the nail unit first described by Baran and Simon11 in 1988.

Sass et al2 described the first case of BD presenting as LM, in which HPV-16 was identified, and further demonstrated genomic integration of the viral DNA in the chromosomal host DNA. HPV infection, especially type 16, has been implicated both in the pathogenesis of anogenital and oral BD2-4,7 and in the development of BD or invasive SCC in the periungual area.1-4,6 In addition, HPV-34, -35, and -73 have been described.4,7,8

HPVs related to mucosal or genital lesions likely play an important role in the pathogenesis of BD and invasive SCC in the periungual region.3,5,7 Guitart et al5 described a case in which similar HPV genomes were detected in a uterine cervical neoplasia and a subungual SCC in the same patient. Similarly, Rudlinger et al12 described a patient with HPV-35 positive bowenoid papulosis in the anogenital region who presented 11 years later with bowenoid dysplasia of a verruca on the right ring finger with the same HPV type. The presence of the same HPV type in both anogenital and periungual regions occurring in the same patient could be explained through autoinoculation or direct contact.1,3,5,7 This is consistent with the observation that extragenital BD lesions are found more commonly in the upper extremities.1,3,7

Lorincz et al13 first reported HPV-56 in 1989 after having been detected in invasive cervical cancers. HPV-56 is included in the high-risk group of HPV types often detected in either cervical intraepithelial neoplasia or invasive cancers, or both.3,9,13 In 1999, Uezato et al3 reported the first case in which HPV-56 was found in extragenital BD. The lesion occurred on the first great toe of an 81-year-old Japanese woman who subsequently underwent surgery, including skin grafting, without evidence of recurrence. To our knowledge, our case represents the second report in which HPV-56 was found in a case of extragenital BD.

The prognosis for patients with BD involving the nail unit is good. In the case of invasive carcinoma of the nail unit, the reported incidence of local bone invasion ranges from 18% to 60%.14-16 The high rate of local invasion may reflect a delay in diagnosis due to patient neglect and/or confusion regarding the clinical presentation. Metastatic disease is rare. However, it has been reported in 4 cases, one of which is a patient with hereditary ectodermal dysplasia.4,15,17,18

Surgical removal is the preferred therapeutic intervention, with either simple excision followed by skin graft or healing by secondary intention.1,10,19 Mohs micrographic surgery is the treatment of choice, allowing for complete removal of the tumor with maximal preservation of normal tissue and physiologic function.1,10,19

In conclusion, our case represents the first report of BD of the nail unit associated with HPV-56. As new HPV subtypes are identified and classified according to their oncogenic potential, the well-established association among high-risk HPV types in both anogenital and nail unit neoplasias is reinforced by these reports. Recognition of LM as a presenting sign of nail unit BD may result in early diagnosis and treatment. back to top

Bowen disease (BD) of the nail unit has multiple clinical presentations, often making its diagnosis challenging. BD is a squamous cell carcinoma (SCC) in situ with various cited etiologic causes, including ionizing and nonionizing radiation, hydrocarbon exposure, trauma, arsenic ingestion, chronic paronychia, ectodermal dysplasia, and dyskeratosis congenita.1-4 Human papillomavirus (HPV) has been associated with the pathogenesis of BD and SCC of the anogenital, oral, and periungual regions.3-9 Specifically, HPV-16 is well recognized as the predominant type associated with periungual BD and SCC, though HPV-34, -35, and -73 also have been identified.2-8 We describe the case of a 25-year-old African American man with BD of the third right fingernail presenting as longitudinal melanonychia (LM), in which HPV-56 DNA was identified. back to top

CASE REPORT A 25-year-old African American man presented to our dermatology service for evaluation of a pigmented streak of the third right fingernail that had been present for several years. Findings from the examination revealed a band of LM on the right third fingernail associated with overlying linear dystrophy of the nail plate. There was no periungual extension of pigmentation onto the adjacent cuticle or the lateral nail fold (Figure 1).

A 3-mm punch biopsy of the proximal nail matrix was performed and revealed acanthosis, hyperkeratosis, and full-thickness epidermal atypia (Figure 2). Hypergranulosis and koilocytic changes were noted (Figure 3). MART-1 (melanoma antigen recognized by T cells 1) staining demonstrated a normal number and distribution of melanocytes.
Polymerase chain reaction amplification, with subsequent hybridization with probes specific to the DNA of HPV, showed strong positivity for HPV-56. Mohs micrographic surgery was performed to excise the tumor with clear margins (Figure 4). The wound was primarily closed using a modified running winch stitch (Figure 5). An anogenital examination performed during follow-up was negative for any verrucous lesions. back to top

Comment BD of the nail unit commonly has been described as wartlike but may present as periungual erythema with associated crusting, ulceration or fissuring, paronychia, onychocryptosis, or nail dystrophy, with eventual partial to complete degeneration of the nail.1,10 The digits of the hands are more commonly involved than the feet.10 In most cases, a single digit is involved, with the thumb being the most common. More invasive disease should be suspected in nodular cases and when bleeding and ulceration occur.5,10 LM is another presentation of BD involving the nail unit first described by Baran and Simon11 in 1988.

Sass et al2 described the first case of BD presenting as LM, in which HPV-16 was identified, and further demonstrated genomic integration of the viral DNA in the chromosomal host DNA. HPV infection, especially type 16, has been implicated both in the pathogenesis of anogenital and oral BD2-4,7 and in the development of BD or invasive SCC in the periungual area.1-4,6 In addition, HPV-34, -35, and -73 have been described.4,7,8

HPVs related to mucosal or genital lesions likely play an important role in the pathogenesis of BD and invasive SCC in the periungual region.3,5,7 Guitart et al5 described a case in which similar HPV genomes were detected in a uterine cervical neoplasia and a subungual SCC in the same patient. Similarly, Rudlinger et al12 described a patient with HPV-35 positive bowenoid papulosis in the anogenital region who presented 11 years later with bowenoid dysplasia of a verruca on the right ring finger with the same HPV type. The presence of the same HPV type in both anogenital and periungual regions occurring in the same patient could be explained through autoinoculation or direct contact.1,3,5,7 This is consistent with the observation that extragenital BD lesions are found more commonly in the upper extremities.1,3,7

Lorincz et al13 first reported HPV-56 in 1989 after having been detected in invasive cervical cancers. HPV-56 is included in the high-risk group of HPV types often detected in either cervical intraepithelial neoplasia or invasive cancers, or both.3,9,13 In 1999, Uezato et al3 reported the first case in which HPV-56 was found in extragenital BD. The lesion occurred on the first great toe of an 81-year-old Japanese woman who subsequently underwent surgery, including skin grafting, without evidence of recurrence. To our knowledge, our case represents the second report in which HPV-56 was found in a case of extragenital BD.

The prognosis for patients with BD involving the nail unit is good. In the case of invasive carcinoma of the nail unit, the reported incidence of local bone invasion ranges from 18% to 60%.14-16 The high rate of local invasion may reflect a delay in diagnosis due to patient neglect and/or confusion regarding the clinical presentation. Metastatic disease is rare. However, it has been reported in 4 cases, one of which is a patient with hereditary ectodermal dysplasia.4,15,17,18

Surgical removal is the preferred therapeutic intervention, with either simple excision followed by skin graft or healing by secondary intention.1,10,19 Mohs micrographic surgery is the treatment of choice, allowing for complete removal of the tumor with maximal preservation of normal tissue and physiologic function.1,10,19

In conclusion, our case represents the first report of BD of the nail unit associated with HPV-56. As new HPV subtypes are identified and classified according to their oncogenic potential, the well-established association among high-risk HPV types in both anogenital and nail unit neoplasias is reinforced by these reports. Recognition of LM as a presenting sign of nail unit BD may result in early diagnosis and treatment. back to top

Untitled Document Onchocerciasis (river blindness) is an infectious disease common in west and central Africa, Central and South America, and the Arabian Peninsula. Onchocerciasis is the second leading infectious cause of blindness worldwide. Approximately 18 million people are infected with Onchocerca volvulus, of which 99% are in Africa.1 O volvulus is a filarial nematode, the etiologic agent of onchocerciasis. The most common cutaneous manifestations of onchocerciasis are intense pruritus, subcutaneous nodules, and localized erythematous papules and plaques with induration. Ocular pathology in onchocerciasis manifests as uveitis, punctate keratitis, and glaucoma. Diagnosis is made through slitlamp examination, as well as by demonstration of filarial worms on wet mount and hematoxylin-eosin (H&E) stained sections. Patients are treated with oral or intravenous ivermectin at a dose of 150 mg/kg once every 6 months for up to 10 years.2

We present the case of a US Army soldier originally from west Africa who was initially treated over a period of 2 years for conjunctivitis, uveitis, and a labile refractory glaucoma. After referral to ophthalmology and dermatology, a diagnosis of onchocerciasis was made. back to top

CASE REPORT A 37-year-old African man presented to the glaucoma clinic for evaluation of refractory glaucoma in his right eye and for possible trabeculectomy. Numerous microfilariae were noted in the anterior chamber of both eyes on slitlamp examination. The diagnosis of onchocerciasis was made, and the patient was referred to the infectious diseases clinic, where further examination revealed subcutaneous nodules in his left buttock and left axilla. He then was referred to dermatology.

The patient was a poor historian and spoke limited English. His medical history was significant for ongoing flares of bilateral conjunctivitis and chronic uveitis. Originally from Sierra Leone, west Africa, he emigrated to the United States with his family 3 years previously and thereafter enlisted in the US Army. The patient reported intermittent blurred vision for many years and episodes of severely irritated watery eyes. He had no current complaints of rash or pruritus, but as a younger man he remembered having intermittent pruritus in his left inguinal area and in both eyes. He denied ever having a rash or other skin discoloration. His wife also complained of visual problems. He also recalled that in his village of Sierra Leone, most elderly people were blind. His 2 children, who were born in Sierra Leone, also reported a history of pruritic skin and blurry vision but were currently asymptomatic.

Two years before presentation, the patient was diagnosed with primary open-angle glaucoma. He had experienced atypical exacerbations and remissions. He reported right temporal field visual loss and cloudy vision bilaterally for 5 years. In addition, he had a history of hepatitis B, malaria, and a positive purified protein derivative (tuberculin) skin test, for which he was treated with isoniazid for 6 months. The patient denied any history of surgery. He had no known drug allergies, and his only medications were ophthalmic timolol, latanoprost, and dorzolamide. The remainder of his review of systems was unremarkable.

The patient was of normal height and weight, alert and oriented, and in no acute distress. Bilateral conjunctival injection without drainage or exudate was noted. Results of a cutaneous examination revealed 2 soft, mobile, nontender masses. One mass in the left axilla was superficial and measured 1.5 cm in diameter, while the other in the left buttock was deeper in the dermis and measured 3.0 cm in diameter. No lymphadenopathy or edema was detected. No acute or chronic papular dermatitis, excoriations, lichenifications, fine wrinkles, or depigmentation characteristic of onchocerciasis were appreciated.

Laboratory test results for liver function, prothrombin time, international normalized ratio, partial thromboplastin time, and chemistry panel were within normal limits. The complete blood count demonstrated a mild eosinophilia of 8.6%. Hepatitis panel was consistent with a chronic carrier state for subdeterminants of hepatitis B surface antigen (+), hepatitis B surface antibodies (–), and hepatitis B e antigen (–). Thick and thin peripheral blood smears performed in the afternoon and at midnight showed no other parasitic infections.

Excisional biopsy of the nodule in his buttock was performed and yielded a 1x2-cm diameter mass of fatty tissue with intertwined, white, hairlike worms encased in a thick fibrous capsule (Figure 1). The number of worms in the nodule and their lengths were not determined. Excisional biopsy of the axillary mass was performed, and results revealed a steatocystoma on standard H&E sections. Perilesional skin snips also were obtained.

Paraffin sections of an adult worm were prepared, placed on glass slides, and viewed at x100 magnification (Figure 2). Histopathology was typical of subcutaneous nodules, with outer walls of dense fibrous tissue extending between the worms. Skin biopsy specimens extending just into the dermis were obtained from the left buttock, embedded into paraffin, and stained with H&E (Figure 3). Eosinophils were present around degenerating microfilariae. Progressive fibrosis of the dermis was present, and the epidermis showed acanthosis and hyperkeratosis.
The patient was admitted to the hospital, treated intravenously with one dose of ivermectin 10,000 mg (150 mg/kg), and monitored overnight. To prevent a hypersensitivity reaction secondary to massive microfilarial death, he was treated orally with both 25 mg of diphenhydramine every 6 hours and 25 mg of hydroxyzine, as needed, for itching. The patient tolerated the treatment well and was told he should be treated with ivermectin biannually for the next several years. He was discharged the following day. back to top

Comment O volvulus is 1 of 8 filarial nematodes that can infect humans and is endemic to west and central Africa, Central and South America, and the Arabian Peninsula (Figure 4). It is estimated that 17.7 million people are infected with O volvulus. More than 99% of these infections occur in sub-Saharan Africa. Nearly 1 million people today can attribute their blindness or severe visual impairment to onchocerciasis.2,3 In areas near fast-moving water where the incidence of river blindness is high, villages cease to be economically viable and are deserted for less productive land, further away from the Simulium breeding sites.4

The parasite is spread among humans by the bite of an infected female Simulium blackfly, which breeds in fast-moving rivers. Once inside the human host, O volvulus larvae mature into adult worms (macrofilariae) and become encased in a soft tissue fibrotic nodule (onchocercoma). Inside the nodule, adult pairs mate and release 1300 to 1900 microfilariae per day for up to 9 to 11 years.5 These tiny offspring (250–300 mm long) migrate through the dermis and commonly invade the anterior chamber and uvea of the eye, as was observed in our patient.

Subcutaneous microfilariae live 6 to 24 months, then die and cause a cutaneous host inflammatory response, which is responsible for the majority of clinical symptoms.6 The initial dermatologic presentation includes intense pruritus, subcutaneous nodules, and localized discrete papules or plaques with erythema and induration. Chronic skin changes include areas of hyperpigmentation and hypopigmentation (“leopard skin”) and lichenification. The cutaneous inflammatory response to the microfilariae leads to breakdown of dermal collagen and elastic tissue. The skin becomes progressively atrophic and wrinkled, leading to gross disfigurement and skin laxity (eg, “hanging groin”).7

The common name for onchocerciasis, river blindness, is well deserved because of its potential for causing blindness in nearly one half of men and one third of women in some untreated, endemic areas.3 It is the fourth leading cause of blindness worldwide.8 Ocular pathology in onchocerciasis is caused by an intense eosinophilic and granulomatous response to dead and dying microfilariae. Frequently, this inflammatory process causes uveitis, which leads to glaucoma. Punctate keratitis is often present and, if left untreated, leads to sclerosing keratitis. Posterior segment lesions such as chorioretinitis and optic atrophy also have been observed.9 Our patient’s history of numerous episodes of conjunctivitis was related to irritation by microfilariae that were migrating to the cornea and the anterior chamber of the eye.3,6

Although our patient’s condition was discovered by slitlamp examination, cutaneous biopsies known as skin snips are the most common diagnostic tool because they are simple and provide definitive diagnosis. A razor blade is used to slice down to the dermal papillae to obtain a bloodless skin sample of 2 to 4 areas from the iliac crest or below.10,11 After placing the specimens in warm saline for 10 to 60 minutes, motile microfilariae are visualized on a wet mount, using low-power microscopy. Fixed and stained specimens, blood examination, excised nodules, and DNA amplification with polymerase chain reaction also can be used if diagnosis is still questionable.2,12

Histologically, onchocercal microfilariae are characterized by a cephalic free space, followed by anterior nuclei that are side by side, a caudal space free of nuclei, and a tail tapered to a fine point (Figure 3). These features readily differentiate O volvulus from Dipetalonema streptocerca, which are the only other microfilariae that live in dermal collagen throughout the body.13

Onchocercomas measure on average 0.5 to 2 cm in diameter and often can be visualized or palpated.14 These nodules can be misdiagnosed up to 5% of the time by physicians in endemic areas. Most commonly, they are confused with lymph nodes, lipomas, intradermal cysts, cancer, and foreign body granulomas. Our patient demonstrated an onchocercoma deep in his left buttock. Cutaneous incision and blunt dissection of an additional subcutaneous mass of the left axilla of our patient demonstrated a steatocystoma. Because some onchocercomas are deep in tissue around bones and in muscle and cannot be detected, nodulectomy of all palpable nodules does not always cure the patient. Nevertheless, nodulectomy should always be considered in patients who live outside endemic areas, as they have a low risk of reinfection, and might be cured if they do not have occult nodules.5 Ultrasound has been effective in discovering nonpalpable lesions but only when technicians are trained in distinguishing onchocercoma morphology.15

The treatment of choice for onchocerciasis is one dose of oral ivermectin 150 mg/kg every 6 months for up to 10 years.16-18 The drug works at the γ-aminobutyric acid receptors, impairing the neuromuscular function of the microfilariae, which leads to paralysis and death of most of the microfilariae 2 to 3 days after the first dose. The most common adverse effects of the medication are myalgia, rash, node tenderness and swelling, pruritus, fever, chills, and localized edema. These result from a hypersensitivity reaction to massive microfilariae death. Most side effects are usually mild to moderate and occur in 9% of patients.19 Patients are treated semiannually, which is the lifespan of microfilariae. This optimizes the therapeutic benefit of the drug.16

Unfortunately, ivermectin does not kill adult worms that can continue to reproduce for many years. This is why nodulectomy is performed as an adjunct therapy semiannually. It is also why treatment may need to continue for up to 10 years—the lifespan of the adult worm. In vitro research on potential macrofilaricidal compounds has given some promising leads.20

Because onchocerciasis has a devastating impact on millions of impoverished people worldwide, Merck & Co., Inc., established the Mectizan Donation Program in 1987, providing ivermectin treatments free of charge to all endemic areas. Since then, more than 250 million doses of ivermectin have been administered.21 There is still no adequate vaccine. Only through continuous surveillance and treatment can this preventable cause of blindness be reduced or eliminated. back to top

Untitled Document Onchocerciasis (river blindness) is an infectious disease common in west and central Africa, Central and South America, and the Arabian Peninsula. Onchocerciasis is the second leading infectious cause of blindness worldwide. Approximately 18 million people are infected with Onchocerca volvulus, of which 99% are in Africa.1 O volvulus is a filarial nematode, the etiologic agent of onchocerciasis. The most common cutaneous manifestations of onchocerciasis are intense pruritus, subcutaneous nodules, and localized erythematous papules and plaques with induration. Ocular pathology in onchocerciasis manifests as uveitis, punctate keratitis, and glaucoma. Diagnosis is made through slitlamp examination, as well as by demonstration of filarial worms on wet mount and hematoxylin-eosin (H&E) stained sections. Patients are treated with oral or intravenous ivermectin at a dose of 150 mg/kg once every 6 months for up to 10 years.2

We present the case of a US Army soldier originally from west Africa who was initially treated over a period of 2 years for conjunctivitis, uveitis, and a labile refractory glaucoma. After referral to ophthalmology and dermatology, a diagnosis of onchocerciasis was made. back to top

CASE REPORT A 37-year-old African man presented to the glaucoma clinic for evaluation of refractory glaucoma in his right eye and for possible trabeculectomy. Numerous microfilariae were noted in the anterior chamber of both eyes on slitlamp examination. The diagnosis of onchocerciasis was made, and the patient was referred to the infectious diseases clinic, where further examination revealed subcutaneous nodules in his left buttock and left axilla. He then was referred to dermatology.

The patient was a poor historian and spoke limited English. His medical history was significant for ongoing flares of bilateral conjunctivitis and chronic uveitis. Originally from Sierra Leone, west Africa, he emigrated to the United States with his family 3 years previously and thereafter enlisted in the US Army. The patient reported intermittent blurred vision for many years and episodes of severely irritated watery eyes. He had no current complaints of rash or pruritus, but as a younger man he remembered having intermittent pruritus in his left inguinal area and in both eyes. He denied ever having a rash or other skin discoloration. His wife also complained of visual problems. He also recalled that in his village of Sierra Leone, most elderly people were blind. His 2 children, who were born in Sierra Leone, also reported a history of pruritic skin and blurry vision but were currently asymptomatic.

Two years before presentation, the patient was diagnosed with primary open-angle glaucoma. He had experienced atypical exacerbations and remissions. He reported right temporal field visual loss and cloudy vision bilaterally for 5 years. In addition, he had a history of hepatitis B, malaria, and a positive purified protein derivative (tuberculin) skin test, for which he was treated with isoniazid for 6 months. The patient denied any history of surgery. He had no known drug allergies, and his only medications were ophthalmic timolol, latanoprost, and dorzolamide. The remainder of his review of systems was unremarkable.

The patient was of normal height and weight, alert and oriented, and in no acute distress. Bilateral conjunctival injection without drainage or exudate was noted. Results of a cutaneous examination revealed 2 soft, mobile, nontender masses. One mass in the left axilla was superficial and measured 1.5 cm in diameter, while the other in the left buttock was deeper in the dermis and measured 3.0 cm in diameter. No lymphadenopathy or edema was detected. No acute or chronic papular dermatitis, excoriations, lichenifications, fine wrinkles, or depigmentation characteristic of onchocerciasis were appreciated.

Laboratory test results for liver function, prothrombin time, international normalized ratio, partial thromboplastin time, and chemistry panel were within normal limits. The complete blood count demonstrated a mild eosinophilia of 8.6%. Hepatitis panel was consistent with a chronic carrier state for subdeterminants of hepatitis B surface antigen (+), hepatitis B surface antibodies (–), and hepatitis B e antigen (–). Thick and thin peripheral blood smears performed in the afternoon and at midnight showed no other parasitic infections.

Excisional biopsy of the nodule in his buttock was performed and yielded a 1x2-cm diameter mass of fatty tissue with intertwined, white, hairlike worms encased in a thick fibrous capsule (Figure 1). The number of worms in the nodule and their lengths were not determined. Excisional biopsy of the axillary mass was performed, and results revealed a steatocystoma on standard H&E sections. Perilesional skin snips also were obtained.

Paraffin sections of an adult worm were prepared, placed on glass slides, and viewed at x100 magnification (Figure 2). Histopathology was typical of subcutaneous nodules, with outer walls of dense fibrous tissue extending between the worms. Skin biopsy specimens extending just into the dermis were obtained from the left buttock, embedded into paraffin, and stained with H&E (Figure 3). Eosinophils were present around degenerating microfilariae. Progressive fibrosis of the dermis was present, and the epidermis showed acanthosis and hyperkeratosis.
The patient was admitted to the hospital, treated intravenously with one dose of ivermectin 10,000 mg (150 mg/kg), and monitored overnight. To prevent a hypersensitivity reaction secondary to massive microfilarial death, he was treated orally with both 25 mg of diphenhydramine every 6 hours and 25 mg of hydroxyzine, as needed, for itching. The patient tolerated the treatment well and was told he should be treated with ivermectin biannually for the next several years. He was discharged the following day. back to top

Comment O volvulus is 1 of 8 filarial nematodes that can infect humans and is endemic to west and central Africa, Central and South America, and the Arabian Peninsula (Figure 4). It is estimated that 17.7 million people are infected with O volvulus. More than 99% of these infections occur in sub-Saharan Africa. Nearly 1 million people today can attribute their blindness or severe visual impairment to onchocerciasis.2,3 In areas near fast-moving water where the incidence of river blindness is high, villages cease to be economically viable and are deserted for less productive land, further away from the Simulium breeding sites.4

The parasite is spread among humans by the bite of an infected female Simulium blackfly, which breeds in fast-moving rivers. Once inside the human host, O volvulus larvae mature into adult worms (macrofilariae) and become encased in a soft tissue fibrotic nodule (onchocercoma). Inside the nodule, adult pairs mate and release 1300 to 1900 microfilariae per day for up to 9 to 11 years.5 These tiny offspring (250–300 mm long) migrate through the dermis and commonly invade the anterior chamber and uvea of the eye, as was observed in our patient.

Subcutaneous microfilariae live 6 to 24 months, then die and cause a cutaneous host inflammatory response, which is responsible for the majority of clinical symptoms.6 The initial dermatologic presentation includes intense pruritus, subcutaneous nodules, and localized discrete papules or plaques with erythema and induration. Chronic skin changes include areas of hyperpigmentation and hypopigmentation (“leopard skin”) and lichenification. The cutaneous inflammatory response to the microfilariae leads to breakdown of dermal collagen and elastic tissue. The skin becomes progressively atrophic and wrinkled, leading to gross disfigurement and skin laxity (eg, “hanging groin”).7

The common name for onchocerciasis, river blindness, is well deserved because of its potential for causing blindness in nearly one half of men and one third of women in some untreated, endemic areas.3 It is the fourth leading cause of blindness worldwide.8 Ocular pathology in onchocerciasis is caused by an intense eosinophilic and granulomatous response to dead and dying microfilariae. Frequently, this inflammatory process causes uveitis, which leads to glaucoma. Punctate keratitis is often present and, if left untreated, leads to sclerosing keratitis. Posterior segment lesions such as chorioretinitis and optic atrophy also have been observed.9 Our patient’s history of numerous episodes of conjunctivitis was related to irritation by microfilariae that were migrating to the cornea and the anterior chamber of the eye.3,6

Although our patient’s condition was discovered by slitlamp examination, cutaneous biopsies known as skin snips are the most common diagnostic tool because they are simple and provide definitive diagnosis. A razor blade is used to slice down to the dermal papillae to obtain a bloodless skin sample of 2 to 4 areas from the iliac crest or below.10,11 After placing the specimens in warm saline for 10 to 60 minutes, motile microfilariae are visualized on a wet mount, using low-power microscopy. Fixed and stained specimens, blood examination, excised nodules, and DNA amplification with polymerase chain reaction also can be used if diagnosis is still questionable.2,12

Histologically, onchocercal microfilariae are characterized by a cephalic free space, followed by anterior nuclei that are side by side, a caudal space free of nuclei, and a tail tapered to a fine point (Figure 3). These features readily differentiate O volvulus from Dipetalonema streptocerca, which are the only other microfilariae that live in dermal collagen throughout the body.13

Onchocercomas measure on average 0.5 to 2 cm in diameter and often can be visualized or palpated.14 These nodules can be misdiagnosed up to 5% of the time by physicians in endemic areas. Most commonly, they are confused with lymph nodes, lipomas, intradermal cysts, cancer, and foreign body granulomas. Our patient demonstrated an onchocercoma deep in his left buttock. Cutaneous incision and blunt dissection of an additional subcutaneous mass of the left axilla of our patient demonstrated a steatocystoma. Because some onchocercomas are deep in tissue around bones and in muscle and cannot be detected, nodulectomy of all palpable nodules does not always cure the patient. Nevertheless, nodulectomy should always be considered in patients who live outside endemic areas, as they have a low risk of reinfection, and might be cured if they do not have occult nodules.5 Ultrasound has been effective in discovering nonpalpable lesions but only when technicians are trained in distinguishing onchocercoma morphology.15

The treatment of choice for onchocerciasis is one dose of oral ivermectin 150 mg/kg every 6 months for up to 10 years.16-18 The drug works at the γ-aminobutyric acid receptors, impairing the neuromuscular function of the microfilariae, which leads to paralysis and death of most of the microfilariae 2 to 3 days after the first dose. The most common adverse effects of the medication are myalgia, rash, node tenderness and swelling, pruritus, fever, chills, and localized edema. These result from a hypersensitivity reaction to massive microfilariae death. Most side effects are usually mild to moderate and occur in 9% of patients.19 Patients are treated semiannually, which is the lifespan of microfilariae. This optimizes the therapeutic benefit of the drug.16

Unfortunately, ivermectin does not kill adult worms that can continue to reproduce for many years. This is why nodulectomy is performed as an adjunct therapy semiannually. It is also why treatment may need to continue for up to 10 years—the lifespan of the adult worm. In vitro research on potential macrofilaricidal compounds has given some promising leads.20

Because onchocerciasis has a devastating impact on millions of impoverished people worldwide, Merck & Co., Inc., established the Mectizan Donation Program in 1987, providing ivermectin treatments free of charge to all endemic areas. Since then, more than 250 million doses of ivermectin have been administered.21 There is still no adequate vaccine. Only through continuous surveillance and treatment can this preventable cause of blindness be reduced or eliminated. back to top

Untitled Document Onchocerciasis (river blindness) is an infectious disease common in west and central Africa, Central and South America, and the Arabian Peninsula. Onchocerciasis is the second leading infectious cause of blindness worldwide. Approximately 18 million people are infected with Onchocerca volvulus, of which 99% are in Africa.1 O volvulus is a filarial nematode, the etiologic agent of onchocerciasis. The most common cutaneous manifestations of onchocerciasis are intense pruritus, subcutaneous nodules, and localized erythematous papules and plaques with induration. Ocular pathology in onchocerciasis manifests as uveitis, punctate keratitis, and glaucoma. Diagnosis is made through slitlamp examination, as well as by demonstration of filarial worms on wet mount and hematoxylin-eosin (H&E) stained sections. Patients are treated with oral or intravenous ivermectin at a dose of 150 mg/kg once every 6 months for up to 10 years.2

We present the case of a US Army soldier originally from west Africa who was initially treated over a period of 2 years for conjunctivitis, uveitis, and a labile refractory glaucoma. After referral to ophthalmology and dermatology, a diagnosis of onchocerciasis was made. back to top

CASE REPORT A 37-year-old African man presented to the glaucoma clinic for evaluation of refractory glaucoma in his right eye and for possible trabeculectomy. Numerous microfilariae were noted in the anterior chamber of both eyes on slitlamp examination. The diagnosis of onchocerciasis was made, and the patient was referred to the infectious diseases clinic, where further examination revealed subcutaneous nodules in his left buttock and left axilla. He then was referred to dermatology.

The patient was a poor historian and spoke limited English. His medical history was significant for ongoing flares of bilateral conjunctivitis and chronic uveitis. Originally from Sierra Leone, west Africa, he emigrated to the United States with his family 3 years previously and thereafter enlisted in the US Army. The patient reported intermittent blurred vision for many years and episodes of severely irritated watery eyes. He had no current complaints of rash or pruritus, but as a younger man he remembered having intermittent pruritus in his left inguinal area and in both eyes. He denied ever having a rash or other skin discoloration. His wife also complained of visual problems. He also recalled that in his village of Sierra Leone, most elderly people were blind. His 2 children, who were born in Sierra Leone, also reported a history of pruritic skin and blurry vision but were currently asymptomatic.

Two years before presentation, the patient was diagnosed with primary open-angle glaucoma. He had experienced atypical exacerbations and remissions. He reported right temporal field visual loss and cloudy vision bilaterally for 5 years. In addition, he had a history of hepatitis B, malaria, and a positive purified protein derivative (tuberculin) skin test, for which he was treated with isoniazid for 6 months. The patient denied any history of surgery. He had no known drug allergies, and his only medications were ophthalmic timolol, latanoprost, and dorzolamide. The remainder of his review of systems was unremarkable.

The patient was of normal height and weight, alert and oriented, and in no acute distress. Bilateral conjunctival injection without drainage or exudate was noted. Results of a cutaneous examination revealed 2 soft, mobile, nontender masses. One mass in the left axilla was superficial and measured 1.5 cm in diameter, while the other in the left buttock was deeper in the dermis and measured 3.0 cm in diameter. No lymphadenopathy or edema was detected. No acute or chronic papular dermatitis, excoriations, lichenifications, fine wrinkles, or depigmentation characteristic of onchocerciasis were appreciated.

Laboratory test results for liver function, prothrombin time, international normalized ratio, partial thromboplastin time, and chemistry panel were within normal limits. The complete blood count demonstrated a mild eosinophilia of 8.6%. Hepatitis panel was consistent with a chronic carrier state for subdeterminants of hepatitis B surface antigen (+), hepatitis B surface antibodies (–), and hepatitis B e antigen (–). Thick and thin peripheral blood smears performed in the afternoon and at midnight showed no other parasitic infections.

Excisional biopsy of the nodule in his buttock was performed and yielded a 1x2-cm diameter mass of fatty tissue with intertwined, white, hairlike worms encased in a thick fibrous capsule (Figure 1). The number of worms in the nodule and their lengths were not determined. Excisional biopsy of the axillary mass was performed, and results revealed a steatocystoma on standard H&E sections. Perilesional skin snips also were obtained.

Paraffin sections of an adult worm were prepared, placed on glass slides, and viewed at x100 magnification (Figure 2). Histopathology was typical of subcutaneous nodules, with outer walls of dense fibrous tissue extending between the worms. Skin biopsy specimens extending just into the dermis were obtained from the left buttock, embedded into paraffin, and stained with H&E (Figure 3). Eosinophils were present around degenerating microfilariae. Progressive fibrosis of the dermis was present, and the epidermis showed acanthosis and hyperkeratosis.
The patient was admitted to the hospital, treated intravenously with one dose of ivermectin 10,000 mg (150 mg/kg), and monitored overnight. To prevent a hypersensitivity reaction secondary to massive microfilarial death, he was treated orally with both 25 mg of diphenhydramine every 6 hours and 25 mg of hydroxyzine, as needed, for itching. The patient tolerated the treatment well and was told he should be treated with ivermectin biannually for the next several years. He was discharged the following day. back to top

Comment O volvulus is 1 of 8 filarial nematodes that can infect humans and is endemic to west and central Africa, Central and South America, and the Arabian Peninsula (Figure 4). It is estimated that 17.7 million people are infected with O volvulus. More than 99% of these infections occur in sub-Saharan Africa. Nearly 1 million people today can attribute their blindness or severe visual impairment to onchocerciasis.2,3 In areas near fast-moving water where the incidence of river blindness is high, villages cease to be economically viable and are deserted for less productive land, further away from the Simulium breeding sites.4

The parasite is spread among humans by the bite of an infected female Simulium blackfly, which breeds in fast-moving rivers. Once inside the human host, O volvulus larvae mature into adult worms (macrofilariae) and become encased in a soft tissue fibrotic nodule (onchocercoma). Inside the nodule, adult pairs mate and release 1300 to 1900 microfilariae per day for up to 9 to 11 years.5 These tiny offspring (250–300 mm long) migrate through the dermis and commonly invade the anterior chamber and uvea of the eye, as was observed in our patient.

Subcutaneous microfilariae live 6 to 24 months, then die and cause a cutaneous host inflammatory response, which is responsible for the majority of clinical symptoms.6 The initial dermatologic presentation includes intense pruritus, subcutaneous nodules, and localized discrete papules or plaques with erythema and induration. Chronic skin changes include areas of hyperpigmentation and hypopigmentation (“leopard skin”) and lichenification. The cutaneous inflammatory response to the microfilariae leads to breakdown of dermal collagen and elastic tissue. The skin becomes progressively atrophic and wrinkled, leading to gross disfigurement and skin laxity (eg, “hanging groin”).7

The common name for onchocerciasis, river blindness, is well deserved because of its potential for causing blindness in nearly one half of men and one third of women in some untreated, endemic areas.3 It is the fourth leading cause of blindness worldwide.8 Ocular pathology in onchocerciasis is caused by an intense eosinophilic and granulomatous response to dead and dying microfilariae. Frequently, this inflammatory process causes uveitis, which leads to glaucoma. Punctate keratitis is often present and, if left untreated, leads to sclerosing keratitis. Posterior segment lesions such as chorioretinitis and optic atrophy also have been observed.9 Our patient’s history of numerous episodes of conjunctivitis was related to irritation by microfilariae that were migrating to the cornea and the anterior chamber of the eye.3,6

Although our patient’s condition was discovered by slitlamp examination, cutaneous biopsies known as skin snips are the most common diagnostic tool because they are simple and provide definitive diagnosis. A razor blade is used to slice down to the dermal papillae to obtain a bloodless skin sample of 2 to 4 areas from the iliac crest or below.10,11 After placing the specimens in warm saline for 10 to 60 minutes, motile microfilariae are visualized on a wet mount, using low-power microscopy. Fixed and stained specimens, blood examination, excised nodules, and DNA amplification with polymerase chain reaction also can be used if diagnosis is still questionable.2,12

Histologically, onchocercal microfilariae are characterized by a cephalic free space, followed by anterior nuclei that are side by side, a caudal space free of nuclei, and a tail tapered to a fine point (Figure 3). These features readily differentiate O volvulus from Dipetalonema streptocerca, which are the only other microfilariae that live in dermal collagen throughout the body.13

Onchocercomas measure on average 0.5 to 2 cm in diameter and often can be visualized or palpated.14 These nodules can be misdiagnosed up to 5% of the time by physicians in endemic areas. Most commonly, they are confused with lymph nodes, lipomas, intradermal cysts, cancer, and foreign body granulomas. Our patient demonstrated an onchocercoma deep in his left buttock. Cutaneous incision and blunt dissection of an additional subcutaneous mass of the left axilla of our patient demonstrated a steatocystoma. Because some onchocercomas are deep in tissue around bones and in muscle and cannot be detected, nodulectomy of all palpable nodules does not always cure the patient. Nevertheless, nodulectomy should always be considered in patients who live outside endemic areas, as they have a low risk of reinfection, and might be cured if they do not have occult nodules.5 Ultrasound has been effective in discovering nonpalpable lesions but only when technicians are trained in distinguishing onchocercoma morphology.15

The treatment of choice for onchocerciasis is one dose of oral ivermectin 150 mg/kg every 6 months for up to 10 years.16-18 The drug works at the γ-aminobutyric acid receptors, impairing the neuromuscular function of the microfilariae, which leads to paralysis and death of most of the microfilariae 2 to 3 days after the first dose. The most common adverse effects of the medication are myalgia, rash, node tenderness and swelling, pruritus, fever, chills, and localized edema. These result from a hypersensitivity reaction to massive microfilariae death. Most side effects are usually mild to moderate and occur in 9% of patients.19 Patients are treated semiannually, which is the lifespan of microfilariae. This optimizes the therapeutic benefit of the drug.16

Unfortunately, ivermectin does not kill adult worms that can continue to reproduce for many years. This is why nodulectomy is performed as an adjunct therapy semiannually. It is also why treatment may need to continue for up to 10 years—the lifespan of the adult worm. In vitro research on potential macrofilaricidal compounds has given some promising leads.20

Because onchocerciasis has a devastating impact on millions of impoverished people worldwide, Merck & Co., Inc., established the Mectizan Donation Program in 1987, providing ivermectin treatments free of charge to all endemic areas. Since then, more than 250 million doses of ivermectin have been administered.21 There is still no adequate vaccine. Only through continuous surveillance and treatment can this preventable cause of blindness be reduced or eliminated. back to top