Continuing Education Activity

Microsporidial keratitis, an infrequent and often overlooked type of corneal inflammation, results from exposure to contaminated water. Symptoms include redness, photophobia, and reduced vision. It typically presents as stromal keratitis or keratoconjunctivitis, distinguishable by disease progression and slit-lamp findings. Characteristic features include grayish-white epithelial lesions, conjunctivitis, and punctate keratopathy, potentially leading to nummular scars. This condition, historically linked to immunocompromised individuals, now affects immunocompetent patients. Despite shared presentations, therapy response varies.

This activity covers the etiology, epidemiology, pathophysiology, treatment, and management of ocular microsporidiosis, providing vital insights for healthcare professionals. Initially affecting mainly immunocompromised individuals, including those with HIV, microsporidial keratoconjunctivitis now impacts immunocompetent patients more frequently. Despite improved diagnostics, treatment approaches for microsporidial keratitis vary, with stromal keratitis often challenging to manage. The activity aims to equip healthcare providers with the knowledge and skills necessary to effectively diagnose and manage microsporidia-related ocular infections, thereby improving patient care outcomes.

Objectives:

• Differentiate microsporidial keratitis from other forms by understanding its unique risk factors and clinical findings.

• Implement appropriate diagnostic measures for confirming microsporidial keratitis in suspected cases.

• Apply evidence-based treatment strategies, considering topical, oral, and surgical interventions, for managing microsporidial keratitis per the latest clinical guidelines.

   

   

   

• Coordinate with healthcare teams and specialists to establish a comprehensive approach in managing microsporidial keratitis.

Introduction

Keratitis, an inflammation of the cornea accompanied by the infiltration of inflammatory cells, is predominantly caused by trauma or infection. Microspordial keratitis, originally termed "corneal nosematosis," is a rare form caused by microsporidia.[1][2] Microsporidia are obligate intracellular spore-forming parasites, similar to fungi that infect insects, birds, fish, and mammals.[1] Of the many known genera, only 7 infect humans.[3]

Microsporidia primarily causes gastrointestinal infections, but ocular, cerebral, and musculoskeletal infections are possible. Risk factors for ocular infection include contact lens use, trauma, eye surgery, topical corticosteroids, and exposure to soil, mud, dirty water, or thermal springs. Ocular infection with microsporidia typically manifests as keratoconjunctivitis or deep stromal keratitis.

The first documented case of microspordial keratitis was reported in a child from Sri Lanka in 1973. During the AIDS epidemic in the 1990s, the number of cases of microsporidial keratoconjunctivitis in patients who were immunocompromised increased. Since the early 2000s, cases of microspordial keratoconjunctivitis in immunocompetent hosts have continued to rise. Cases of microsporidial stromal keratitis occur primarily in immunocompetent hosts. Most cases of ocular microsporidia infection originate in Asia. Diagnosis and treatment of the disease may be challenging due to a lack of awareness among healthcare professionals regarding its diverse clinical presentations and disease progression. 

The robust spores persist in the environment for several months, remaining infectious. Human contraction of the infection can occur through ingestion, inhalation, or intimate activities. Although the method by which microsporidia infiltrate the human cornea remains elusive, the prevailing theory suggests contact with contaminated water or direct trauma.[1] Researchers have documented cases following exposure to floodwaters.

Diagnosis of microsporidial keratitis typically involves optical microscopy and polymerase chain reaction (PCR) to confirm the presence of the parasite. Treatment with topical medications yields varied success rates, and in some cases, surgical intervention may be necessary. Microsporidial keratitis can result in a significant decrease in visual acuity and a perforated corneal ulcer. With the exact transmission mechanism being unknown, prevention of infection is complicated. Healthcare professionals should consider microsporidial keratitis when evaluating patients with keratitis of unknown origin, particularly those who have traveled or returned from Asia, especially during the rainy season.

Etiology

Microsporidia are spore-forming intracellular organisms found nearly everywhere in nature. Traditionally classified under the kingdom Protista, they have been recently reclassified as fungi based on molecular studies.[4][5] With over 1700 species, the most common species involved in human infection are Enterocytozoon bieneusi and the Encephalitozoon species, primarily Encephalitozoon intestinalis. Microsporidium and Vittaforma corneae are the most common causes of microspordial stromal keratitis, and Encephalitozoon species are the most common cause of microspordial keratoconjunctivitis.[4]  

In addition to primitive genomes and ribosomes similar to protozoa, the absence of mitochondria, centrioles, and peroxisomes gives microsporidia its prokaryotic features. However, the presence of mitochondrial hsp70, mitosome, and alpha-beta tubulin has resulted in their reclassification to fungi.[6][7]

Microsporidia are opportunistic waterborne pathogens commonly transmitted through contaminated water, like lakes, swamps, swimming pools, or spring water.[8][9][10] Among humans, microsporidia affects the gastrointestinal tract, brain, eyes, muscles, bones, and lungs.[11] While microspordial keratoconjunctivitis and microspordial stromal keratitis are the most prevalent ocular presentations, microsporidia also cause scleritis and endophthalmitis.[5][12][13] Historically, individuals who develop microsporidial keratoconjunctivitis were immunocompromised, often associated with HIV infection.[14][15] However, recent literature indicates that even immunocompetent patients can experience keratoconjunctivitis.[16][17][18] Conversely, deep stromal keratitis is primarily observed among immunocompetent individuals. 

Epidemiology

Endemic to Southeast and South Asian countries, ocular microsporidiosis is an infrequent but noteworthy contributor to infectious keratitis, with a prevalence of 0.4% observed in certain regions.[19] Specifically, Thailand, Taiwan, Singapore, and India are identified as endemic areas for microsporidial keratitis, marked by an upsurge in reported cases.[19] Adopting advanced diagnostic techniques, including various staining methods and PCR, has facilitated more accurate and timely diagnoses of this condition.

A notable study reveals that nearly 20% of all clinically diagnosed cases of infective keratitis in these regions are attributed to microsporidia, with incidences peaking during the rainy season. Moreover, a study conducted in South India involving over 10,000 patients with conjunctivitis unveils a significant proportion presenting with microsporidial keratoconjunctivitis among those who underwent corneal scraping. The underreporting of ocular microsporidia infection is likely due to the self-limited nature of microsporidial keratoconjunctivitis and the lack of comprehensive evaluations in patients with conjunctivitis. Clinicians often rely on clinical diagnosis due to these factors.[19] Large-scale epidemiological studies are imperative to clarify further endemic zones, geographical variation, and the mode of disease transmission.[19][20][21] 

Pathophysiology

Microsporidium is an obligate intracellular spore providing enhanced dispersion and protection against adverse environmental conditions. Its cell wall comprises a double envelope, with the outer portion containing glycoproteins and the inner part primarily chitin. The cytoplasm and nuclei form the infectious portion, known as sporoplasm. Changes in pH, exposure to certain cations, or low-dose ultraviolet radiation stimulate the polar filament to inject sporoplasm into the host.[22] Interestingly, spore intake occurs in cell cultures without releasing these polar tubules.

Factors inhibiting germination are magnesium chloride, ammonium chloride, minimal salt levels, sodium fluoride, ultraviolet exposure, temperatures >40 °C, and agents like itraconazole. Once inside the host cell, new spores form and infect neighboring cells. The symptoms and severity of microsporidiosis vary depending on the infecting species and the host's immune response, with severe cases often observed in significantly immunocompromised patients, particularly those with HIV.

Direct inoculation from contaminated water is the most likely cause of infection. Risk factors for acquiring microsporidial keratitis include contact lens usage, particularly inadequate hand hygiene or lens care practices, topical corticosteroid application, insect bites, ocular surgeries, and contact with domestic animals.[10] Immunosuppression remains a notable risk factor. The increased incidence during the rainy season suggests water contaminated with microsporidia or an increased insect population may contribute to transmission. The presence of risk factors among affected individuals varies widely, ranging from as low as 22.2% to as high as 100%.

The exact transmission route of ocular microsporidiosis remains unclear. While fecal-oral transmission is implicated in intestinal microsporidiosis, the viability of microsporidia spores against variable temperatures suggests alternative routes.[23] Certain pathogenic strains have been identified in both surface and groundwater, suggesting that unsanitary water sources, combined with subpar sanitary infrastructures, can be the nidus of infection.

Ocular trauma is another possible transmission route, as it can directly introduce these organisms into the corneal epithelium upon contact with soil or water-containing spores. The United States Environmental Protection Agency (EPA) recognizes microsporidia as a potential microbial waterborne contaminant.[24]

While the literature lacks a precise threshold, a CD4+ T-lymphocyte count below 100 cells/mm³ is commonly associated with increased susceptibility to microsporidial infection.[25][26]  Earlier research indicates a correlation between diminished CD4+ counts, often observed in individuals with AIDS, and the development of microsporidial keratoconjunctivitis. However, findings from Loh et al challenge this immunity-based theory, revealing a significant percentage of cases with normal CD4+ and CD8+ T-lymphocyte counts and negative serology.[27]  

Histopathology

The morphological identification of organisms on corneal tissue scrapings plays a crucial role in diagnosing microsporidial keratitis. The most helpful stain combines 10% potassium hydroxide (KOH) with 0.1% calcofluor white (KOH+CFW). A recent report by Mittal et al demonstrates that microsporidia spores are strongly acidic and heat fast. They stain strongly and most discretely when stained with the conventional Ziehl-Neelsen staining method using 20% sulphuric acid. A Gram stain reveals intraepithelial, gram-positive, oval-shaped spores on transmission electron microscopy. Characteristic periodic acid–Schiff-positive granules are identifiable at one end of mature microsporidia spores. However, the Giemsa stain is not considered useful due to its low sensitivity in detecting microsporidia. 

Corneal button specimens in patients infected with Vittaforma corneae reveal oval-shaped spores measuring 3.5 to 5 µm and 11 to 13 coils in the polar tubule.[28] The spores of the Encephalitozoon species are 2 to 3 µm and contain 4 to 7 coils in the polar tubule.[28] Most notable with the Encephalitozoon species is the presence of a parasitophorous vacuole, a protective bubble made of plasma membrane surrounding microsporidia in the host. The spores are the only form that can survive outside the host cell. Histopathology reveals varying degrees of inflammation with a near absence of inflammatory cells in patients who are immunosuppressed.[29] Organisms commonly confused morphologically with microsporidia are Toxoplasma gondii, Leishmania spp., Histoplasma capsulatum, and Cryptosporidia spp.[30]

History and Physical

Examination for microsporidial keratitis involves a thorough evaluation of the patient's ocular symptoms, medical history, and risk factors for infection. Clinical examination typically includes a detailed assessment of visual acuity and slit-lamp biomicroscopy to inspect the cornea for characteristic findings such as epithelial lesions, stromal infiltrates, and conjunctival inflammation. Additionally, associated symptoms such as redness, tearing, photophobia, and foreign body sensation are noted.

Microsporidial Keratoconjunctivitis

Infection caused by Encephalitozoon species typically remains localized to the epithelial cells of the cornea and conjunctiva. In patients with microsporidial keratoconjunctivitis, symptoms usually appear 1 to 2 weeks after exposure. Patients often report exposure to contaminated water or trauma, mainly in the rainy season. Additionally, a history of exposure to pool water, natural springs, contaminated soil, topical steroid use, insect bites, contact with domestic animals, or participation in water sports may be present. 

Common complaints include redness, decreased visual acuity, tearing, eyelid swelling, eye pain, and a foreign body sensation. Initially, symptoms are typically unilateral but can progress to both eyes.[8] Bilateral involvement is more likely in patients with compromised immune systems, occurring in up to 32% of cases in healthy individuals. Both eyes may be affected simultaneously, or symptoms may develop in 1 eye first, followed by the other within 1 week to 3 months.

Clinical examination features include the following:[31][32]

• Multiple fine to coarse punctate, raised epithelial corneal lesions with a stuck-on appearance
• Lesions stain variably with fluorescein
• Lesions localize peripherally, paracentral, or diffusely
• Significant conjunctival congestion
• Typically not purulent
• Potential anterior chamber inflammation and keratic precipitates

Some cases present with multiple subepithelial punctate infiltrates, making microsporidial keratoconjunctivitis indistinguishable from adenoviral keratoconjunctivitis. Reports exist of a pseudomembrane forming on the conjunctiva.

The disease can be graded from grade 1 to 4 depending on the presenting features:

• Grade 1: The lesions are greyish-white, <10 in number, and distributed mainly in the peripheral cornea.
• Grade 2: The lesions are central, 10 to 20 in number, elevated epithelial lesions.
• Grade 3: The lesions are 21 to 40 in number.
• Grade 4: The lesions are primarily peripheral and have subepithelial infiltrates.

Disease progression can lead to outcomes like superficial punctate keratitis, which may eventually cause scarring beneath the epithelium. Atypical presentations of microsporidial keratoconjunctivitis can manifest as unique corneal patterns or conditions that mimic other eye diseases, such as Thygeson superficial punctate keratitis. [27]

Microsporidial Stromal Keratitis 

Microsporidial stromal keratitis occurs primarily in immunocompetent individuals and is commonly associated with infections caused by Vittaforma corneae and Microsporidium. This form of infection typically targets the corneal stroma, including the keratocytes. The clinical history and presentation are similar to microsporidial keratoconjunctivitis, but affected patients may have a history of multiple episodes of remission and recurrence.

On average, patients experience symptoms 1 month to 2 years before presentation.[33][34] Clinical manifestations include multifocal, mid to deep stromal infiltrates with the overlying epithelium remaining intact. The stromal infiltrates are nonspecific and associated with edema with or without deep stromal vascularization. The infiltrate can be ulcerative at times.[35]

In cases where patients present with a history of chronic culture-negative stromal keratitis, clinicians should consider including microsporidial stromal keratitis in the differential diagnosis.[34] This form of keratitis can often be overlooked due to its atypical presentation and the challenges associated with its diagnosis.

Evaluation

Scrapings or biopsies of the conjunctiva or cornea typically serve as the primary diagnostic method for confirming microsporidial keratitis. These samples are subjected to various laboratory tests to facilitate the visualization of microsporidia spores.

Transmission Electron Microscopy

Historically, transmission electron microscopy (TEM) played a crucial role in elucidating the classification and comprehension of human microsporidia infections, including those impacting the eye. The distinctive polar tubule, observed through TEM, plays a vital role in identifying and classifying the organism within the Microspora phylum. Despite TEM remaining the gold standard for confirming and identifying microsporidia species, its complex procedure and limited accessibility restrict its practical utility in clinical diagnostics.[36]

Smear Diagnosis

Optical microscopy is a primary method for diagnosing microsporidiosis, as microsporidia are obligate intracellular organisms that cannot be cultured in routine media and require cell cultures for growth. Due to the challenges in consistently culturing microsporidia, direct smear findings become essential. Corneal abnormalities in patients with microsporidial keratoconjunctivitis appear raised and superficial. Clinicians typically scrape off these lesions with a 15-scalpel blade after applying topical anesthetic, and the samples undergo staining to identify microsporidia spores.

Smears initially used for Gram staining can be reused by decolorizing and reapplying a Ziehl-Neelsen stain, thus eliminating the necessity for additional scrapings.[37] Several staining methods are available for verifying the diagnosis of microsporidial keratoconjunctivitis from corneal and conjunctival samples. The combined 10% potassium hydroxide (KOH) with 0.1% calcofluor white (KOH+CFW) staining is the most preferred due to its superior detection rate, closely followed by the modified Ziehl-Neelsen stain, particularly when a fluorescence microscope is not available. The Gram stain follows, with Giemsa staining being the least preferred.

Some researchers have successfully used the modified trichrome staining method when diagnosing microsporidial keratoconjunctivitis.[38] Identification by staining does not allow for identification of the specific species involved. PCR is more commonly used for species-specific identification than electron microscopy.

Due to the presence of deep stromal infiltrates, diagnosing microsporidial stromal keratitis poses greater challenges. Corneal scrapings may not provide sufficient diagnostic information in this condition. A corneal biopsy or therapeutic penetrating keratoplasty in chronic culture-negative keratitis is a valid option to reach the diagnosis. The biopsy or excised corneal button is subjected to histopathological evaluation for a tissue diagnosis. 

Molecular Techniques in Diagnosis

PCR is a powerful tool for diagnosing microsporidial infections and determining the species involved. This molecular technique targets pathogen DNA by binding to a specifically designed set of primers and amplifying it repeatedly in the presence of free nucleotides by a thermostable polymerase enzyme. Utilizing known sequenced pan-microsporidia primers, PCR amplifies a fragment of 16S rRNA, offering a sensitivity of 83% and specificity of 98%.[39] 

Nucleic acids extracted from corneal scrapings or biopsies typically undergo a pan-microsporidian PCR followed by DNA sequencing and a Basic Local Alignment Search Tool (BLAST) search for species-specific identification. Recently, a duplex PCR method has emerged, incorporating pan-microsporidian primers and species-specific ones for Vittaforma corneae.[40] Despite the availability of specific primers for ocular microsporidia species since 1994, they have not gained significant traction in clinical microbiology. Compared to earlier methods, a notable absence of commercial kits specifically designed for diagnosing ocular microsporidiosis exists. 

Introduced in 1996, PCR combined with Southern analysis has successfully distinguished Encephalitozoon species in urine samples. However, its widespread adoption for ocular infections has been limited thus far. Nonetheless, PCR remains a valuable tool for various microsporidia infections across diverse clinical specimens. For example, a 2004 study by Conners et al detailed a PCR method using specific rRNA primers, followed by sequencing to identify microsporidia in corneal samples.

Other studies indicate the utility of real-time PCR assays and multiplex PCR in different contexts, showing potential for broad applications, including the diagnosis of microsporidial keratoconjunctivitis. A newly reported oligonucleotide microarray also seems promising, showcasing the ability to detect multiple species. Its efficacy in ocular sample diagnostics is yet to be determined.[41]

Cell Cultivation Techniques

Due to their intracellular nature, microsporidia can only propagate in cell culture systems. During the early 1990s, researchers successfully adapted 3 microsporidia isolates, specifically Encephalitozoon hellem, from corneal tissue and conjunctival samples of patients with AIDS to Madin-Darby Canine kidney epithelial (MDCK) cells.

Additionally, various other cell types were evaluated for cultivating microsporidia, such as E6, HLF, MRC-5, RK-13, HeLa, Vero, SIRC, and fetal bovine lung fibroblasts. The Vero cell line proved the most effective when comparing the Vero, HeLa, and SIRC cell lines for growing 4 distinct microsporidia species.[42] Despite these advancements, the method of nurturing these organisms in cell lines has not been streamlined for the routine diagnosis of microsporidial keratoconjunctivitis.[42]

Antigen Detection Techniques

In clinical microbiology, antigen detection using various specimens is a common way to identify numerous infectious conditions. This method frequently involves the use of either monoclonal or polyclonal antibodies. Specific antibodies, especially those targeting the spore wall or polar tubule, are available for multiple microsporidia species.[43] Research from the early 20th century indicates the effective application of immunofluorescent antibody techniques to identify ocular microsporidia using species-specific antisera.[40] 

Many researchers feel antigen detection techniques are less sensitive than PCR and, if used, should be used as a supplement to conventional histological methods. Indirect immunofluorescence assay is neither widely available on the market nor regularly used in diagnosing ocular microsporidiosis. In addition, testing for specific antibodies against microsporidia in blood for diagnostic purposes in cases of ocular microsporidiosis is not endorsed and remains inaccessible.[43]

Imaging Techniques

Anterior segment optical coherence tomography (AS-OCT) offers a contact-free, high-definition method to visualize cross-sections of the cornea. A study by Thanathanee et al reveals the following changes in patients with microsporidia keratoconjunctivitis:

• Hyperreflective dots are limited to the epithelial layers of the cornea
• No extension into the stromal layer 
• Hyperreflective dots are slightly raised above the epithelial surface in most cases

These features distinguish microsporidia lesions from the nummular scars caused by adenovirus, which present as more prominent subepithelial anomalies, manifesting milder reflectivity and a smoother epithelial surface. Coupled with microbiological analyses, AS-OCT may offer diagnostic clarity and a means to track treatment progress. Further studies are necessary.[44]

In Vivo Confocal Microscopy 

In vivo confocal microscopy (IVCM) is a ground-breaking tool for diagnosing ocular infections. Using IVCM, the lesions of microsporidial keratoconjunctivitis appear as epithelial clusters accompanied by bright, pinpoint-shaped spores. Clinicians can distinguish from adenovirus keratoconjunctivitis based on the presence of a bright basal epithelium, dendritic cells, and active keratocytes in the superficial stroma at the center of the cornea. Additionally, IVCM can potentially assess treatment efficacy and evaluate for deeper stromal penetration. However, its adoption remains limited due to significant interobserver variability and high cost.[45]

Impression Cytology

Impression cytology involves the application of cellulose acetate filter paper to the eye's surface, allowing for the collection of superficial layers lining the ocular surface. Once collected, clinicians can do histological, immunohistological, or molecular analyses of the cells. This test offers a less invasive method and an alternative to corneal smear tests.

Limited documentation of its use exists in the literature, and its potential accuracy in terms of sensitivity and specificity requires further exploration. Through this technique, intracellular and extracellular spores, without inflammatory cells, have been identified, mirroring the findings of smear tests.[46]

Treatment / Management

No consensus exists regarding the management of microsporidial keratitis. The various treatment options are listed below:

Topical Therapy

Superficial infections are self-limited or treated medically. Deeper stromal involvement often requires corneal transplantation to eradicate the infection and improve vision.[47][35] Lubricants are effective for symptomatic relief. In a randomized controlled trial, lubricants are as effective as biguanides.[48] The frequency of lubricant application depends on the severity of patient symptoms, with more frequent dosing in more symptomatic patients. 

Antimicrobial agents

Topical fumagillin and fluoroquinolones are important antimicrobials frequently used in treating microsporidial ocular infections.[4][49] Fluoroquinolones target the topoisomerase and DNA gyrase enzymes. Among fluoroquinolones, ciprofloxacin 0.3%, gatifloxacin 0.5%, moxifloxacin 0.5%, levofloxacin 0.5%, norfloxacin 0.3%, and ofloxacin 0.5% are effective against microsporidia dosed hourly with or without oral albendazole. However, the results are mainly anecdotal, from in vivo and in vitro studies, and not supported by randomized clinical trials.[16][27][16][49][50]

On the other hand, fumagillin is a mycotoxin produced by Aspergillus and treats microsporidia by inhibiting RNA synthesis.[4] Fumagillin may also act by inhibiting the proteinase, type 2 methionine aminopeptidase. Some reports suggest a potential for relapse after treatment cessation. The concentration of bicyclohexyl ammonium fumagillin is 0.113 mg/ml.[16][51][52]

Biguanides

Polyhexamethylene biguanide (PHMB) 0.02% and chlorhexidine gluconate 0.02% are 2 biguanides effective in treating microsporidial keratitis when combined with debridement.[17] Both PHMB and chlorhexidine are disinfectant antiseptics requiring reconstitution to 0.02% as they are not commercially available in the given concentration. Dosing is as frequent as every 30 to 60 minutes.[48]

Diamidines

Sparse reports have highlighted compounds such as propamidine isethionate and hexamidine isethionate 0.1% as part of combination treatments. Currently, in vitro susceptibility testing for these cationic antiseptics does not exist.[53]

Immune modulation and steroids

Patients with persistent or recurrent disease warrant a short course of topical steroids or steroid-sparing agents like tacrolimus 0.3% and cyclosporine 0.5%.[54][55][56] Tacrolimus and cyclosporine modulate and suppress corneal inflammatory responses. Apart from this, patients who develop endotheliitis, limbitis, and anterior chamber reactions warrant topical steroids.[19][21][19][27] Some studies suggest that the early application of topical steroids can prevent complications when dealing with specific types of keratitis. However, unlike adenovirus, studies have not conclusively shown steroids' impact on microsporidia multiplication.

Antifungal agents

Microsporidia are related to fungi. Azoles treat fungi by inhibiting ergosterol synthesis in the plasma membrane of fungi. Research published by Agatha and others involving 550 patients reveals that fluconazole 0.3%, dosed 4 times daily until symptom resolution, effectively achieves over 95% visual recovery.[21][57]  

Oral Therapy

Antifungals

Itraconazole, an oral antifungal medication, has been administered to treat specific infections without any relapses. However, its definitive efficacy is still under scrutiny.[58] Oral Itraconazole 200 mg/d is effective for disseminated diseases; however, the effectiveness of an oral antifungal in treating microsporidial keratitis has not been established.[59]

Antiprotozoal and antihelminthic medications

Albendazole is an antiprotozoal effective in treating microsporidial keratoconjunctivitis.[60] It exerts its action by inhibiting microtubules, thus impeding cell division. Albendazole is most effective against Encephalitozoon species, with a recommended dose of 400 mg twice daily.[49] 

Corneal Swabbing and Surgical Management

In microsporidial keratoconjunctivitis, the debridement of the corneal epithelium serves dual purposes: collecting samples for microbiological evaluation and reducing the microbial load. This procedure typically involves using a 15-blade or 26-gauge needle, and the affected area normally heals without scarring.[17] Debridement can be utilized alone or with antimicrobial and lubricating agents. However, debridement is not superior to conservative management and increases the risk of superimposed infection. Therefore, it is advisable to reserve debridement for severe cases.[61] 

Repeated corneal swabbing using cotton swabs is another effective, relatively less invasive procedure proposed by Fan and colleagues. This method involves repetitive swabbing of the cornea using cotton swabs, which is less intrusive, causes minimal discomfort, is generally well-received by patients. Moreover, results are typically evident within a week of the procedure.[19] 

The outlook for stromal disease is less optimistic. While some case reports describe successful medical treatment, the efficacy varies. Medications used alone or in combination include topical polyhexamethylene biguanide, chlorhexidine, and voriconazole with or without oral itraconazole or albendazole. However, one study revealed that less than half of the patients responded to medical therapy consisting of topical polyhexamethylene biguanide and chlorhexidine, with or without oral albendazole. Ultimately, 25 of the 34 patients required keratoplasty. Therapeutic penetrating keratoplasty often emerges as the only viable option for patients with corneal stromal involvement.[34][62]

Differential Diagnosis

The differential diagnoses for microsporidial keratoconjunctivitis include:[55]

• Adenoviral keratoconjunctivitis
• Thygeson superficial punctate keratitis
• Dry eye disease
• Filamentary keratitis
• Vesicular stage of herpes simplex virus epithelial keratitis
• Acanthamoeba keratitis
• Atypical mycobacterial keratitis
• Viral keratoconjunctivitis 
• Bacterial conjunctivitis

Thygeson superficial punctate keratitis typically presents bilaterally, featuring coarse raised epithelial lesions predominantly located centrally. This condition responds favorably to treatment with topical steroids.

The differential diagnoses for microsporidial stromal keratitis include:

• Herpetic stromal keratitis
• Fungal corneal ulcer
• Bacterial corneal ulcer

Prognosis

Microsporidial stromal keratitis often follows a pattern of remission and recurrence until surgically removed via penetrating keratoplasty. Conversely, microsporidial keratoconjunctivitis typically resolves without any long-term sequelae or residual effects. In a study involving 332 patients treated for microsporidial keratoconjunctivitis, 49 returned for reevaluation at 6 weeks. Among the returning patients, 16 individuals (4.8%) returned for symptoms of microsporidial keratoconjunctivitis, and the remaining patients had non-microsporidial keratoconjunctivitis eye complaints like refractive error and dacrocystitis. The 3 manifestations of persistence were superficial punctate keratitis, sub-epithelial infiltrates, and uveitis. The 16 patients with symptoms of microsporidial keratoconjunctivitis underwent further treatment and achieved disease resolution. Some of them experienced recurrences at a later date. Visual acuity typically returns following successful treatment, with recovery rates ranging from 70% to 100%. However, unresolved subepithelial infiltrates may lead to worsening vision.[19]

Complications

Nummular scars can persist in cases of inadequately treated microsporidial keratoconjunctivitis. In cases of stromal keratitis, corneal scars and edema usually increase with each recurring episode of inflammation.[55] Increased intraocular pressure due to topical corticosteroid use is an additional medication-related complication. Other potential sequelae are limbitis, endotheliitis, and keratic precipitates.[55] These can be treated with topical steroids.[54]

Postoperative and Rehabilitation Care

Postoperative and rehabilitation care following microsporidial keratitis treatment is crucial for optimal recovery and visual outcomes. This comprehensive care regimen typically includes diligent monitoring of the surgical site, regular administration of prescribed medications, and adherence to specific postoperative instructions provided by the healthcare provider. Care consists of the following:

• Medications
  • The first-line treatment for microsporidial keratitis is topical fumagillin, although its availability may be limited.
  • Alternative medications include oral albendazole, itraconazole, and topical propamidine isethionate.
  • Avoid corticosteroids or use them cautiously, as they can exacerbate the infection. When used, administer along with appropriate antifungal therapy to control inflammation.[55]

• Regular monitoring
  • Regular repeat evaluations are crucial to monitor the healing process, check for any complications, and assess the effectiveness of the treatment.
  • Slit-lamp examinations aid in monitoring the resolution of the keratitis.[63]

• Visual rehabilitation
  • Once the infection has cleared, some patients may have residual corneal scarring, which can affect vision.
  • A corrective spectacle prescription or contact lenses may be necessary
  • For severe scarring, corneal transplantation or keratoplasty may restore vision.[23]

• Protective measures
  • Post-infection, sunglasses can help in reducing light sensitivity 
  • Using protective eyewear in environments that put individuals at risk can prevent future episodes, especially in agricultural settings or where the risk of trauma is high.[63]

• Patient education
  • Educate patients regarding the importance of completing the medication regimen even if symptoms improve.
  • Inform patients about the potential risk factors and preventive measures to prevent microsporidial keratitis.[63]

• Physical therapy
  • If a patient has been incapacitated or bedridden due to severe infection or another concurrent medical condition, physical rehabilitation may be necessary to regain muscle strength and function.[63]

• Counseling and mental health
  • Dealing with visual impairment or a significant ocular condition can be stressful. Providing counseling or mental health resources can be beneficial for some patients.[63]

• Nutritional support
  • Adequate nutrition is essential for healing. Ensure the patient maintains a balanced diet to support the healing process.[63]

Consultations

Consultations for treatment of microsporidial keratitis include the following:

• Ophthalmologist: An eye specialist should be consulted to diagnose, monitor, and treat the condition.

• Infectious disease specialist: For patients who are immunocompromised or have a suspicion of systemic involvement.

• Cornea specialist: If the keratitis does not resolve with standard treatments, surgical intervention, like a corneal transplantation, becomes necessary.

Deterrence and Patient Education

Microsporidia are a rare and commonly misdiagnosed cause of corneal infection. Ocular infection typically presents as keratoconjunctivitis or stromal keratitis. Patients must understand how to reduce their risk of infection. The following is a list of recommendations to help reduce the risk of infection:

• Avoid contaminated water sources

• Use protective eyewear while swimming or participating in water sports

• Frequently wash hands with soap and water, especially after handling soil, gardening, or coming in contact with animals

• Avoid touching the eyes with dirty hands.[64] 

Patients with contact lenses should:

• Always wash their hands before handling lenses
• Use sterile lens solutions for cleaning and storing contact lenses
• Clean the lens storage case daily and replace it regularly
• Do not sleep in contact lenses unless they are approved for overnight use [65]

Patients should understand that the symptoms of microsporidial keratitis are redness, pain, tearing, photophobia, blurred vision, and a foreign body sensation. Various treatment options are available, from topical and oral medications to surgical interventions. The majority of patients with microsporidial keratoconjunctivitis will have self-limited disease, and treatment options are removal of the microbes with a cotton swab and symptomatic treatment with lubricants, topical antimicrobials, and oral antifungals and anthelmintic medications.

The stromal disease has a less optimistic prognosis, and corneal transplantation may be necessary. Patients must understand the importance of completing the entire course of treatment, returning at regularly scheduled intervals, and calling with any evidence of recurrence.[3]

Encourage patients to share information about microsporidial keratitis with family and friends, especially those at risk. Proper deterrence strategies and patient education minimize the risk of infection, and outcomes can be improved. Regular consultation with healthcare professionals is essential for early detection and effective management.[66]

Pearls and Other Issues

Key facts to keep in mind about microsporidial keratitis include the following:

• Clinical presentation: Patients typically present with symptoms of a painful red eye, photophobia, tearing, a foreign body sensation, and decreased visual acuity. The clinical picture may resemble viral or fungal keratitis.

• Slit-lamp examination: On slit-lamp examination, microsporidial stromal keratitis appears as diffuse multifocal mid- to deep stromal infiltrates with mild to moderate conjunctival injection, stromal edema, and endothelial exudates. Microsporidial keratoconjunctivitis has variable presentations, which likely signify different disease stages. Mild to severe nonpurulent conjunctivitis and grayish-white, coarse, multifocal, raised epithelial lesions resolve after 1 week. Next, central epithelial lesions and superficial punctate keratopathy develop. After 2 to 4 weeks, subepithelial infiltrates or a haze may form. 

• Laboratory diagnosis: The diagnosis can be confirmed by scraping the affected corneal epithelium and examining the sample under a microscope. Specimens stained with KOH+CFW, Ziehl-Neelsen, or Graham stains are best for visualizing microsporidia. Transmission electron microscopy can provide a definitive diagnosis but may not be readily available.

• PCR testing: PCR assays can be beneficial in diagnosing microsporidial infections by making a diagnosis and identifying the specific species involved. 

• Antifungal medications: Microsporidia are closely related to fungi and respond to some antifungal medications. Topical fumagillin is effective but only sometimes readily available. Alternatives are oral itraconazole or albendazole.

• Debridement: Superficial debridement of the infected epithelium can help reduce the parasitic load and enhance the penetration of topical medications.

• Avoid steroids: The use of corticosteroids may exacerbate the infection. Consider using tacrolimus or cyclosporin alone.

• Missed diagnosis: Diagnosis can be challenging due to the rarity of the disease and the overlap of clinical features with more common forms of keratitis.

• Lack of specific medication: A lack of readily available and specific treatment guidelines for microsporidial keratitis can make management challenging.

• Recurrence: Despite successful treatment, recurrence can happen, and proper long-term care is necessary.

Enhancing Healthcare Team Outcomes

Patients experiencing ocular microsporidia infections face the risk of recurrence, vision loss, and potential corneal transplantation. Given the self-limiting nature of microsporidial keratoconjunctivitis and the absence of consensus on medical management for microsporidial keratoconjunctivitis and microsporidial stromal keratitis, an interdisciplinary approach becomes crucial for optimal patient care.

Early identification and effective management of microsporidial stromal keratitis are essential to minimize morbidity. Primary care, ophthalmology, and infectious disease clinicians must possess crucial clinical skills and knowledge for diagnosing and managing ocular microsporidia infections. Clinicians must recognize clinical presentations, understand potential overlaps with more common ocular conditions, and navigate the challenges of establishing accurate diagnoses.

Given the condition's rarity, the treatment approach must be strategic. Clinicians must use evidence-based therapies and rely on colleagues' expertise. Microsporidial ocular infections are uncommon. Each healthcare professional must contribute unique knowledge to the patient's care plan while engaging in effective interpersonal communication. Effective interprofessional communication allows for vital exchange of information and collaborative decision-making among the team members.

Patient education ensures proper long-term care, improved quality of life, and reduced morbidity. By embracing these principles of skill, strategy, responsibilities, and interprofessional communication, healthcare professionals can deliver the best possible patient care, ultimately improving patient outcomes and enhancing team performance in managing microsporidial ocular infections.