Continuing Education Activity

PTX exposure, and resulting toxicity, are most frequently associated with inhalation of vapors while cleaning or eradicating the coral from home aquariums. As a result of their rapid growth, unwanted zoanthids require removal from certain areas of the aquarium, which is most often done with boiling in water and/or scrubbing affected rocks. The resultant inhalation of steam or aerosolized droplets can lead to respiratory symptoms such as rhinorrhea, cough, and dyspnea. This activity will discuss the etiology, pathophysiology, and suggested management of toxic ocular exposure to palytoxin (PTX), leading to corneal toxicity as described in retrospective case reports of incidental contact. Additionally, it will review physical exam findings and prognosis of patients with presumed PTX associated keratoconjunctivitis. Finally, the role of the healthcare team in diagnosis and treatment will be discussed.

Objectives:

• Summarize the pathophysiology of palytoxin exposure keratitis.
• Outline the history and clinical symptoms associated with palytoxin keratitis.
• Identify the appropriate treatment for patients with suspected palytoxin keratitis.
• Identify the role of the healthcare team in the diagnosis and treatment of palytoxin exposure.

Introduction

Palytoxin (PTX) is a large naturally occurring toxin initially isolated from zoanthids (i.e., soft corals) in the genus Palythoa and has since been found in various marine life including microalgae.[1] PTX is a highly deadly polyhydroxylated and partially desaturated non-proteinaceous carbon backbone with a molecular weight of 2680 kilodaltons and a lethal dose (LD) of 150 ng/kg body weight in mice when given intravenously.[2] It is among the largest nonpolymeric natural products. It was first synthesized in totality in 1994, decades after its initial discovery. The toxin is released from organelles called nematocysts, which release spiral thread-like structures with ‘barbs’ that can pierce tissue upon contact.[3] These soft corals are often present in aquariums due to their beauty and relatively low maintenance. Though not all species are known to produce a toxin, the exact identification of the specific genus and species is often not possible; thus, all should be treated as toxic.[4]

Inhalation, ingestion, or cutaneous contact can lead to lethal systemic effects, but a small number of cases in recent years have described ophthalmic effects that range from superficial punctate epitheliopathy to bilateral corneal melt with subsequent perforation.[5][6]

Etiology

PTX exposure and resulting toxicity are most frequently associated with the inhalation of vapors while cleaning or eradicating the coral from home aquariums. As a result of their rapid growth, unwanted zoanthids require removal from specific areas of the aquarium. This process is most frequently accomplished by boiling in water and/or scrubbing affected rocks. The resultant inhalation of steam or aerosolized droplets can lead to respiratory symptoms such as rhinorrhea, cough, and dyspnea. Similarly, unprotected handling of PTX containing coral can lead to edema, erythema, and systemic symptoms in both broken and intact skin.[1]

Although less likely, PTX associated corneal toxicity results from environmental exposure as described in three different mechanisms: direct contact with contaminated water[3][7][8], rubbing the eye with a hand contaminated with PTX[4][6], or direct inoculation of the eye itself.[9][10]

Epidemiology

Zoantharia is currently commonly found in tropical and subtropical oceans, including Hawaii, along the western American coastline from Florida to Brazil, many Atlantic islands, Japan, and Australia. They live in shallow, hard-bottomed ocean floors up to 12 meters deep; thus, ocular exposure to the water shared with these animals can correlate with PTX exposure.[11] However, zoanthids are easily purchased online, and the majority of published cases are the result of aquarium enthusiasts worldwide.

Keratoconjunctivitis, or inflammation of the cornea and conjunctiva, has multiple etiologies. Epidemiologic data, therefore, is dependent on the underlying cause. Due to its relative rarity in the literature, PTX-associated keratoconjunctivitis has no epidemiological studies or estimates to our knowledge. 

Pathophysiology

Although the exact in vivo mechanism of toxicity remains unestablished, PTX is known to have vasoconstrictive, neurotoxic, and metabolic effects through dysregulation of ion pumps (e.g., the sodium-potassium ATPase, sodium-calcium exchangers, and sodium-hydrogen exchangers) which can lead to cell death.[5] Additionally, research has shown that the downstream cascade effects of PTX lead to actin filament system distortion.[9]

These molecular interactions likely cause corneal epithelial death upon exposure. Disruption of the corneal epithelium can lead to marginal ulcers and large ring-shaped inflammatory response and swelling of the stromal layer and associated keratitis. Additionally, during the wound healing process, corneal myofibroblasts express high levels of alpha-actin, which may be disrupted by PTX, slowing the body’s therapeutic process.[7][9] There is also a proposal that direct cytokine and proteolytic activity of PTX leads to peripheral degradation of collagen, keratocytes, and proteoglycans in the often seen immune system-related stromal ring leading to corneal thinning.[4]

History and Physical

The symptoms of PTX-associated keratoconjunctivitis are non-specific and include severe ocular pain, red eye, decreased visual acuity, metallic taste, photophobia, and a foreign body sensation.[4][6] A detailed history should be elicited from all patients with suspected toxic ocular exposure. Particular attention should be given to inquiring about risk factors, as listed above. History details, including hobbies and recent travel, should not be overlooked or omitted as they are critical to obtaining a correct diagnosis.

A comprehensive ocular examination is also warranted for all patients with symptoms suspicious of toxic ocular exposure. Findings vary from case to case, but the most commonly seen manifestation has been reported as conjunctival injection, followed by a ring-shaped inflammatory infiltrate on initial examination and Descemet's membrane folds.[3][4][6][7][9][10] Furthermore, there are reports of other ocular findings on the slit-lamp exam, including:

• Eyelid swelling and diffuse punctate epithelial erosions[9]
• Corneal erosion
• Anterior chamber reactions
• Partially avascular conjunctiva[10]
• Iritis
• Bullae rupture and epithelial defect[6]
• Limbal stem cell failure with resultant conjunctival overgrowth and corneal melting[12]
• Diffuse bilateral punctate epithelial erosions and corneal epithelial infiltrates with “crystalline-appearing” foreign bodies[3]
• Anterior chamber inflammatory changes[7]
• Whitish spots on the limbus[13]
• Punctate bulbar and tarsal conjunctival hemorrhages[8]

Due to the wide variety of presentation and general rarity of clinical presentation, a strong history, and clinical suspicion is needed for an accurate diagnosis.

Evaluation

Diagnosis of PTX keratoconjunctivitis has no confirmatory study or imaging and is a clinical diagnosis based on symptomatology with a clear history of preceding exposure to water likely containing PTX. Though the compound has been isolated through high-performance liquid chromatography in some public health cases, at present, there is no qualitative or quantitative test for human toxicity (i.e., PTX is not isolated in the patient for diagnosis).[14][15] Most published reports indicate negative cultures for an infectious cause and a temporal relationship to PTX exposure.[4][6][7]

In one case, the pH of the affected eye was elevated (8.5 OD and 7.5 OS), which decreased to 7.5 and 7.0 after rinsing with an aqueous solution containing amphoteric salts[10]; however, other reports indicate a neutral (7.0) pH in the eye.[4][9] One case reported testing for autoimmune associations, which were also negative.[6]

Due to possible systemic effects from ocular inoculation, and the potential for lethality with systemic exposure, additional testing should be considered in patients complaining of a bitter or metallic taste, lethargy, nausea, vomiting, muscle cramping, or shortness of breath. These may include an electrocardiogram and respiratory monitoring. One patient demonstrated elevated creatine kinase and a myoglobin positive urine sample indicative of possible rhabdomyolysis.[10]

Treatment / Management

There are no treatment protocols or guidelines for medical or surgical management in cases of PTX associated keratoconjunctivitis due to limited case reports in the literature. However, due to the inflammatory changes and good response to corticosteroids observed in most cases, some recommendations have been made.

Initial therapy should include the removal of the toxin from the eye by rinsing or instillation of artificial tears.[7] Ruiz et al. add that each eye should undergo irrigation individually. Their report describes a case in which toxin was squirted only into the right eye, following which the patient immediately irrigated their eye with tap water for several minutes and then developed bilateral symptoms. They concluded that irrigating the right eye potentially brought the skin and left eye into contact with the toxin.[10] Also, there have been suggestions that the concentration of, and exposure time to PTX increases with contact lens usage[4]; thus, immediate clean removal of contact lenses is likely beneficial.

After initial eye washing to remove as much toxin as possible, Farooq et al. recommend early aggressive corticosteroid treatment (e.g., 1% prednisolone acetate at least six times daily) and prophylactic antibiotic therapy for mild cases[6]; this has support from the fact that all published mild cases with early steroid intervention resulted in positive outcomes. In more moderate or severe cases, Farooq et al. and Barbany et al. recommend prophylactic antibiotics with prednisolone acetate 1% on an hourly schedule and consideration of oral steroids, oral doxycycline, and ascorbic acid.[6][7]

For severe exposure, other recommendations on management are made on a case-by-case basis with patients often receiving some surgical intervention in addition to medical management. Amniotic membrane transplant, tarsorrhaphy, or epithelialization stimulating eyedrops may be helpful in cases with persistent epithelial defects; corneal transplant may be a consideration in cases of corneal ulceration that result in perforation. In instances with residual scarring, ridged/scleral contact lenses, or a corneal transplant may be a possibility.[7] Finally, in two cases of corneal perforation, urgent bilateral sequential penetrating keratoplasty was documented in one, and an anterior lamellar patch grafting was completed in the other.[6]

Differential Diagnosis

As presenting complaints are often nonspecific, the differential diagnosis can be extensive. However, high on the list should be infectious keratoconjunctivitis, and the clinician can rule it out with appropriate cultures. These can include bacterial, viral PCR, fungal, and amoebic cultures. The literature documents, however, that even in the case of positive cultures, a temporal correlation between exposure and symptoms can lead to a diagnosis of PTX-associated corneal toxicity.[6]

Other considerations should include other toxic exposures. In one instance, a patient was noted to have exposure to water from his coral fish tanks and plant debris (Epipremnum aureum, better known as golden pothos or devil’s ivy) sap.[16] The literature also notes that the presentation of PTX toxic keratitis is also similar to that of ophthalmia nodosa from caterpillar or tarantula hair lodging in the eye. This condition differs in its mechanism of action by causing mechanical, not toxic, and inflammatory trauma.[3] Of note, topical non-steroidal anti-inflammatory drugs (NSAIDs) use-related toxic keratolysis may also present with stromal ulceration seen in some cases of ocular PTX exposure.[6]

• Ophthalmia nodosa from mechanical irritants
• Infectious keratoconjunctivitis
• Topical NSAID toxic keratolysis

Prognosis

Prognosis is heavily influenced by initial exposure and a decrease in visual acuity as well as time to treatment with steroids. Patients with mild exposure and minimal symptoms who were treated early with steroids all improved within days to months. Patients with severe exposure, systemic effects, visual acuity worse than 20/200, or requiring surgical intervention faired much worse; with reported cases of persistent corneal scarring and neovascularization, limbal cell failure with conjunctival overgrowth and permanent vision loss, and best-corrected visual acuity worse than or equal to 20/100 after treatment.[9][12][6]

Complications

Undiagnosed or poorly managed PTX keratoconjunctivitis can lead to permanent visual defects, including corneal perforation and limbal stem cell failure. These complications result mainly from the extent of the initial exposure and delay in diagnosis (as noted above), where most cases present as mild exposure with no permanent defects.[8][12]

Deterrence and Patient Education

Most buyers and sellers seem to be unaware of potential exposure, though some understanding of potential toxicity is present in aquarium enthusiast forums and blogs found online.[6][7][10] In an attempt to prevent cutaneous, ocular, or inhalational exposure, those enjoying these beautiful animals should use eye protection, thick rubber gloves that will not break with potential exposure to sharp aquarium rocks, and an air mask with activated charcoal filters when handling them. In addition to personal protective equipment, there have been recommendations to turn off any protein skimmers, air bubblers, or other pumps associated with the aquarium while handling or manipulating the coral to reduce the potential for aerosolization of the toxin. Finally, some have proposed that the best approach to zoanthids in a home aquarium is their removal by a trained professional. Following removal and disposal, aquarium water can be cleared of over 99% of PTX with activated carbon treatment.[17][18]

Public health initiatives focusing on education, or legal oversight of the buying and selling of these organisms, may increase awareness of this potential complication and decrease future cases.

Pearls and Other Issues

• Palytoxin (PTX) is an ocular irritant potentially found in various soft corals (e.g., zoanthids) and other marine life commonly found in saltwater home aquariums.
• It is difficult to determine which soft coral species harbor PTX, and all should be assumed toxic.
• A careful history is necessary to assess for exposure to the toxin as the diagnosis is clinical.
• An ocular examination may be nonspecific but most often shows conjunctival injection, a ring-shaped inflammatory infiltrate, and folds in Descemet's membrane.
• Eye irrigation alongside topical corticosteroid use (e.g., prednisolone acetate 1% at least six times a day) and prophylactic antibiotics are the recommended treatment, though no definitive guidelines are available. Most patients recover well.

Enhancing Healthcare Team Outcomes

Though not always specified, published cases indicate that the majority of cases will likely present to the emergency department within days of exposure. Prompt ophthalmologic consultation is necessary to prevent delays in obtaining appropriate treatment and assessment of the need for surgical intervention. Close follow-up is required to adjust medical management and assure the best visual outcomes. [Level 5]