By Caroline W. Chung, MD, Eric J. Shiuey, MD, MS, and Stephen Armenti, MD, PhD
Edited by Jeremiah P. Tao, MD, FACS
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Researchers began noticing an uptick in mpox in humans in May 2022, resulting in the declaration of a Public Health Emergency of International Concern in July of that year.1,2 Mpox, initially called monkeypox and renamed in November 2022 by the World Health Organization,2 was first identified in monkeys, but the reservoir species is thought to be an unknown rodent species. Mpox can cause numerous health complications, including serious eye issues.
The outbreak that started in 2022 has affected 110 countries, and, as of July 2023, about 88,000 mpox cases have been reported worldwide, with 30,583 cases in the United States. During the outbreak, 44 deaths in the United States have been attributed to mpox—almost 90% of deaths have been in Black men.3 The current outbreak has approximately a 99% survival rate and has disproportionately affected younger men (median age 38), particularly men who have sex with men and men who are immunocompromised.2 The outbreak may be related to the global loss of vaccine-derived immunity following discontinuation of the smallpox vaccination.1
While the disease infrequently affects the eyes, patients with ocular mpox are more likely to experience severe systemic disease or require hospitalization, suggesting that ocular findings may predict mpox disease severity.4 In general, with diagnostic precision and timely care, many of the long-term sequelae that can manifest from this potentially disfiguring condition can be minimized.
Etiology
Mpox is caused by the monkeypox virus (MPXV), a double-stranded DNA virus that belongs to the Orthopoxvirus genus, which also includes variola (smallpox), vaccinia (smallpox vaccine), and cowpox.1 MPXV is historically endemic to central and west Africa and was found in only seven countries. It is divided into two clades. Clade I (formerly the Congo Basin clade) is known to cause more severe disease and is highly infectious and transmissible. Clade II (formerly the West African clade) includes the ongoing outbreak.1,2
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INITIAL PRESENTATION. Isolated temporal conjunctival ulceration of the left eye with no extension onto the cornea. The patient has a cosmetic contact lens in place.
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RECURRENCE. New ulcerated margin-involving left upper eyelid lesion with no clear central umbilication or vesicle, and an inferonasal conjunctival ulceration extending 4 mm onto the peripheral cornea with haze, mild thinning, and epithelial loss.
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Symptoms and Findings
Systemic. Mpox infection symptoms consist of a two- or three-day febrile prodrome with headache, chills, and muscle aches followed by a vesiculopustular rash affecting the skin and mucosa. The rash, which can involve anywhere from 20 to 500 lesions, typically distributes in a centrifugal pattern, with the greatest density of lesions on the face, extremities, and anogenital region. Mpox, like smallpox, features lesions that are typically in the same stage of healing. (This contrasts with the rash of chicken pox, which tends to present with lesions in variable stages of healing.) A frequent subsequent complication is severe scarring of affected areas. Other complications of mpox include encephalitis, bronchopneumonia, gastroenteritis, sepsis, and ocular manifestations.2
Ocular. During the current outbreak, ocular involvement has been reported in 1% to 5% of mpox cases.1,2 In these cases, the disease most often presents as external skin lesions (periorbital and eyelid lesions) and ocular surface lesions (blepharoconjunctivitis, conjunctival lesions, and corneal ulcerative lesions). Transmission of the virus to the eye is thought to occur via autoinoculation of a periocular lesion or the contiguous spread of a lesion into the eye, as opposed to a primary conjunctival lesion as part of regional eruption of the virus. Periocular or lid margin lesions may be considered high-risk lesions, which may predispose patients to ocular disease.2
Conjunctival involvement can present variably, with a conjunctival follicular reaction, discrete conjunctival lesions, pseudomembranes, or subconjunctival nodules. There have been no cases of intraocular involvement (e.g., uveitis, optic neuritis), as has been described previously in smallpox cases. Corneal involvement can present as corneal ulceration or stromal keratitis and can cause significant scarring and bacterial superinfection, which may lead to temporary or permanent visual impairment.4,5
Differential Diagnosis
Although the majority of ocular mpox cases present with additional nonocular findings that render the diagnosis easily discernable, workup for ocular lesions would typically include a broad differential for infectious, autoimmune, or drug-related etiologies. Infectious diseases that can present similarly include varicella, herpes zoster, herpes simplex, variola, vaccinia, cowpox, and molluscum contagiosum. Scabies and syphilis may also present with similar periocular lesions. Inflammatory and drug-related etiologies in the differential include peripheral ulcerative keratitis from rheumatoid arthritis, granulomatosis with polyangiitis, polyarteritis nodosa, mucus membrane pemphigoid, and Stevens-Johnson syndrome.
Diagnostic testing for mpox begins with a high index of clinical suspicion in patients who present with the characteristic rash anywhere on the body or have had known exposure to the virus. The CDC has provided case definitions6 for the 2022 mpox outbreak and provides instructions for reporting cases.7 The gold standard to confirm mpox disease includes a lesion swab for PCR testing or culture, or both. When ocular mpox is present, a sample from the ocular surface may also be taken and sent for PCR testing.2
Case Study: Severe Ocular Mpox Infection
A 43-year-old man presented to a tertiary medical center with left eye redness for one day and with one week of worsening painful skin lesions. His medical history was significant for AIDS (CD4 count 53) and latent syphilis, and he had been treated for systemic mpox infection one month prior to his visit, with no previous ocular involvement. Ocular history was notable for cosmetic contact lens wear. Visual acuity was 20/20 in both eyes. Slit-lamp examination revealed an isolated ulcer on his temporal conjunctiva with minimal mucoid discharge (Fig. 1). He also had diffuse umbilicated lesions on his face, oral mucosa, extremities, and anogenital area but no eyelid or corneal lesions and no intraocular inflammation.
The patient was admitted to a tertiary medical center in Philadelphia. Conjunctival and skin PCR tests for mpox and herpes viruses were both positive. He was treated with IV acyclovir and a 14-day course of IV tecovirimat and discharged on oral tecovirimat and biweekly IV cidofovir infusions. Ocular treatment included a seven-day course of trifluridine drops and erythromycin ointment, and he was advised to stop wearing contact lenses. His conjunctival lesion improved within one week.
A recurrence. One month later, he presented with new left eye pain, photophobia, and redness for one day, with worsening painful skin lesions on his face. He reported adherence to his outpatient therapy and said he had not worn contact lenses. Visual acuity was 20/20 in the right eye and 20/30 in the left eye. He had a new left inferonasal 4-mm peripheral corneal ulceration involving the adjacent conjunctiva and a new margin-involving left upper eyelid lesion (Fig. 2).
He was readmitted to the hospital. Conjunctival and skin PCR tests for mpox were again both positive, but PCR tests for herpes viruses were negative. He was empirically treated with another 10-day course of IV tecovirimat, oral Valtrex (valaciclovir), and he continued on biweekly IV cidofovir. Ocular treatment included trifluridine drops 6×/day, preservative-free artificial tears 6×/ day, and erythromycin ointment nightly. Within two days of treatment, the lesion reepithelialized, and he reported significant improvement in his pain. He was discharged on oral tecovirimat and biweekly IV cidofovir.
When we saw him two weeks later, he had very mild corneal epithelial irregularity with haze and no edema. Visual acuity improved to 20/20 in both eyes. He was instructed to complete a three-week course of trifluridine as well as to continue using artificial tears. The patient required systemic therapy for a minimum of three months and has had no recurrence of ocular disease. He is following up closely with an infectious disease specialist.
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Management
Systemic disease. First-line treatment for systemic mpox is symptom management. The disease is typically self-limited and should not recur unless the patient is immunocompromised.
Treatment. Those who warrant systemic therapy include immunocompromised individuals, children, and people who are pregnant. Also, ocular or periorbital mpox infections are categorized as severe and warrant systemic therapy because of the possible risk of visual compromise. Antivirals including tecovirimat (Tpoxx), brincidofovir (Tembexa), cidofovir (Vistide), and IV vaccinia immune globulin may be used for systemic management. Animal models have shown decreased mortality and shortened illness duration with IV tecovirimat.8,9 There are no data on ocular penetration of these systemic medications, and it is important for physicians to discuss the risks of these medications with immunocompromised patients, children, and pregnant individuals. To date, there have been no published randomized control trials demonstrating efficacy of any ocular mpox treatments in humans.
Ocular treatment. Aggressive topical lubrication has been the mainstay treatment for ocular mpox. For corneal epithelial involvement, topical antibacterial prophylaxis may be used to prevent bacterial superinfection. Prevention is most important, and patients should be advised to wash their hands frequently, avoid eye rubbing, and limit contact lens use.10,11
Trifluridine (Viroptic), a nucleoside analogue that interferes with viral DNA replication, may have a role in ocular mpox. Conventionally used for HSV keratitis, trifluridine has been used in case reports to treat vaccinia keratitis and has shown in vitro activity against orthopoxviruses.12 The CDC recommends using trifluridine eyedrops in cases of mpox keratitis and considering its use for mpox conjunctivitis and for prophylaxis in margin-involving lid lesions, which may be higher risk for inoculation.13 There is no gold standard duration of treatment, but typically it should be used for less than three weeks, as the benefits must be balanced with ocular surface toxicity.
Conclusion
Ocular involvement in the current mpox outbreak is rare. Patients with systemic mpox should, however, be advised to wash their hands frequently, avoid eye rubbing, and limit contact lens use to reduce accidental autoinoculation. Ocular mpox presents as lid/periorbital lesions and ocular surface and corneal lesions. Ocular involvement is an indication for systemic treatment, and tecovirimat is first line. The CDC recommends treating with trifluridine drops for cases of keratitis, and trifluridine may also be considered in cases of conjunctivitis or for prophylaxis in patients with high-risk lesions.
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1 Ci Ng FY et al. Ocul Surf. 2023;27:13-15.
2 Kaufman AR et al. JAMA Ophthalmol. 2023;141(1):78-83.
3 Riser AP et al. MMWR Morb Mortal Wkly Rep. 2023;72(15):404-410.
4 Huhn GD et al. Clin Infect Dis. 2005;41(12):1742-1751.
5 Thornhill JP et al. N Engl J Med. 2022;387:679-691.
6 CDC. Case definitions for use in the 2022 monkeypox response. www.cdc.gov/poxvirus/mpox/clinicians/case-definition.html. Accessed July 5, 2023.
7 CDC. Case reporting recommendations for health departments. www.cdc.gov/poxvirus/mpox/health-departments/case-reporting.html. Accessed July 5, 2023.
8 Sherwat A et al. N Engl J Med. 2022;387:579-581.
9 Yu J, Raj SM. Global Biosecurity. 2019;1(1).
10 Ly-Yang F et al. JAMA Ophthalmol. 2022;140(10):1022-1024.
11 Rai RS et al. JAMA Ophthalmol. 2022; 140(12):1244-1246.
12 Altmann S et al. J Infect Dis. 2011;203(5):683-690.
13 Cash-Goldwasser S et al. MMWR Morb Mortal Wkly Rep. 2022;71(42):1343-1347.
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Dr. Chung is a resident and Dr. Armenti is Assistant Professor of Ophthalmology. Both are at the University of Pennsylvania in Philadelphia. Dr. Shiuey is a resident at Sinai Hospital of Baltimore. Financial disclosures: None.