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Ocular System

Acanthamoeba keratitis (AK)

Acanthamoeba keratitis (AK) is a potentially sight-threatening ocular infection that causes a progressive ulcerative keratitis and often carries a poor prognosis due to significant delays in diagnosis.

Perineural infiltrates in Acanthamoeba keratitis
Perineural infiltrates in Acanthamoeba keratitis | Carnt, N., Samarawickrama, C., White, A., & Stapleton, F. (2017). The diagnosis and management of contact lens-related microbial keratitis. Clinical and Experimental Optometry, 100(5), 482–493. https://doi.org/10.1111/cxo.12581

Acanthamoeba keratitis (AK) is a potentially sight-threatening ocular infection that causes a progressive ulcerative keratitis and often carries a poor prognosis due to significant delays in diagnosis.

Etiopathogeneis

Microbiology:

Acanthamoeba is a genus of protozoans that are ubiquitously present in various habitats, including water, air, soil, and dust. The most common species that cause AK are Acanthamoeba castellani and Acanthamoeba polyphaga
  • Acanthamoeba species exist in two forms, an active trophozoite or a dormant cyst.
    • Trophozoite form: Feeds on bacteria, algae, and yeasts. Trophozoites are also capable of slow locomotion and asexual reproduction.
    • Cystic form: Exhibits minimal metabolic activity and is capable of surviving adverse environmental conditions such as severe changes in temperature or pH, high doses of UV-light, food deprivation, or desiccation.
Schematics of Acanthamoeba-mediated corneal damage.
Schematics of Acanthamoeba-mediated corneal damage. “Blast” refers to damage. | Lorenzo-Morales, J., Khan, N. A., & Walochnik, J. (2015). An update on Acanthamoeba keratitis: diagnosis, pathogenesis and treatment. Parasite (Paris, France), 22, 10. https://doi.org/10.1051/parasite/2015010

Risk factors:

Causes of AK appear to be multifactorial, but most cases have been linked to contact lens wear and their cleaning solutions.
  • Contact lens wear (M/C cause)
  • Corneal injury
  • Exposure to dust, soil, or contaminated water

Presentation

Acanthamoeba keratitis usually presents unilaterally but may rarely occur in both eyes.

Excruciating pain (PATHOGNOMIC)

The characteristic finding of AK, even in the early stage, is pain out of proportion to clinical findings; there is a thought that this is due to the action of trophozoite-derived proteases.

Other features:

Symptoms may wax and wane between mild and severe.
  • Decreased vision
  • Eye redness
  • Foreign body sensation
  • Photophobia
  • Tearing, and discharge

Complications:

  • Common complications: Glaucoma, iris atrophy, broad-based anterior synechiae, cataract, and persistent endothelial defect
  • Rarer complications: Scleritis, sterile anterior uveitis, chorioretinitis, and retinal vasculitis

Diagnosis

Approximately 75 to 90% of patients with early acanthamoeba keratitis are initially misdiagnosed; therefore, a diagnosis of acanthamoeba keratitis should merit special consideration in patients with several weeks of symptoms that have not improved despite compliance with a daily regimen of topical antibiotics or antivirals. The clinician should consider bacterial superinfection if symptoms worsen despite the initiation of appropriate treatment.

Comprehensive ocular examination is also necessary for patients with suspected ocular infection.

Slit-lamp examination:

As many of these exam findings are non-specific, the clinician must have a high index of suspicion for AK in cases in which the history and other features are highly suggestive.
  • Early findings:
    • Epitheliopathy with punctuate keratopathy
    • Epithelial or subepithelial infiltrates
    • Pseudodendrites
    • Perineural infiltrates (> 60% cases): Highly suggestive for AK
  • Late-stage findings:
    • Characteristic featuresL “Ring-like” stromal infiltrate & radial keratoneuritis
    • Other findings: Satellite lesions, ulceration, abscess formation, anterior uveitis with hypopyon, and epithelial defects
    • Advanced disease: Stromal thinning and corneal perforation
Slit-lamp photographs: (A–D) Case S-2. (A) Filthy soft contact lens case, (B) ring ulcer at first visit, (C) disciform infiltrations with keratoprecipitates at 2 months after referral, and (D) corneal scar and mature cataract at 12 months after referral. (E–G) Case S-4. (E) Superficial punctate keratopathy at first visit, (F) ring infiltration with keratoprecipitates at 3 months after referral, and (G) corneal scar at 2 years after referral. (H and I) Case M-5. (H) Keratoneuritis and ciliary injection at first visit, and (I) clear cornea at 3 weeks after referral. | Shimmura-Tomita, M., Takano, H., Kinoshita, N., Toyoda, F., Tanaka, Y., Takagi, R., Kobayashi, M., & Kakehashi, A. (2018). Risk factors and clinical signs of severe Acanthamoeba keratitis. Clinical ophthalmology (Auckland, N.Z.), 12, 2567–2573. https://doi.org/10.2147/OPTH.S179360

Microbiological diagnosis:

Overview of the diagnostic procedure for Acanthamoeba keratitis. | Lorenzo-Morales, J., Khan, N. A., & Walochnik, J. (2015). An update on Acanthamoeba keratitis: diagnosis, pathogenesis and treatment. Parasite (Paris, France), 22, 10. https://doi.org/10.1051/parasite/2015010

Plate culture technique:

Gold standard for the detection of Acanthamoeba. Corneal scraping or biopsy is required to obtain a sample for culture. As Acanthamoeba trophozoites feed on bacteria, cultures will develop on 1.5% non-nutrient agar plates covered by E. Coli. The rate of positive culture result for Acanthamoeba in the setting of acanthamoeba keratitis is generally low, reported anywhere from 40-70%. Samples must be observed daily for up to one week before declaring a negative result.
Culture of Acanthamoeba on nonnutrient agar with an overlay of Escherichia coli.
Culture of Acanthamoeba on nonnutrient agar with an overlay of Escherichia coli. Clear tracks on the lawn of Escherichia coli suggests migrating trophozoites that feed on bacteria | Garg, P., Kalra, P., & Joseph, J. (2017). Non-contact lens related Acanthamoeba keratitis. Indian journal of ophthalmology, 65(11), 1079–1086. https://doi.org/10.4103/ijo.IJO_826_17

Polymerase chain reaction (PCR):

PCR has the advantages of being widely available, fast, and less labor-intensive. Thus, there is some reason to believe that PCR may become the new gold standard for the diagnosis of acanthamoeba keratitis in the near future.
  • 18s rRNA region: M/C employed to detect Acanthamoeba in clinical samples

In vivo confocal microscopy (IVCM):

IVCM is also an extremely useful tool that allows for the non-invasive examination of individuals cells of the cornea in real-time. IVCM will only reliably detect cysts, which will appear as well-defined, round, double-walled, hyper-reflective bodies. The pooled sensitivity and specificity of IVCM in one study were found to be 85.3% and 100%, respectively. IVCM may also be used to monitor disease progression and response to treatment. However, IVCM is expensive and often not readily available.
In vivo confocal microscopy image of Acanthamoeba keratitis involving superficial and deeper corneal layers
In vivo confocal microscopy image of Acanthamoeba keratitis involving superficial and deeper corneal layers: The typical “starry sky” appearance is depicted: Acanthamoeba spp. cysts appear as oval or round, double-walled, highly refractile structures with a polygonal inner wall and a total size of 12–25 microns | Grossniklaus H.E., Waring G.O., Akor C., Castellano-Sanchez A.A., Bennett K. Evaluation of hematoxylin and eosin and special stains for the detection of acanthamoeba keratitis in penetrating keratoplasties. Am. J. Ophthalmol. 2003;136:520–526. doi: 10.1016/S0002-9394(03)00322-2

Cytology:

Cytology smears is a viable method to detect Acanthamoeba cysts on corneal scrapings or biopsied tissue. Cytology smears have the advantage of being fast, easily performed, and readily available in most facilities. Cytology smears additionally do not require live organisms as with culture or intact DNA as required for PCR.
Microscopic features of Acanthamoeba cyst in corneal scraping – Gram stain (a) and calcofluor-white (b). Note hexagonal inner wall of the cysts
Microscopic features of Acanthamoeba cyst in corneal scraping – Gram stain (a) and calcofluor-white (b). Note hexagonal inner wall of the cysts | Garg, P., Kalra, P., & Joseph, J. (2017). Non-contact lens related Acanthamoeba keratitis. Indian journal of ophthalmology, 65(11), 1079–1086. https://doi.org/10.4103/ijo.IJO_826_17

Newer diagnostic procedures:

  • Loop-mediated isothermal amplification (LAMP)
  • Novel, non-invasive imaging techniques:
  • Heidelberg retina tomography II (HRT II)
  • Nuclear magnetic resonance (NMR) spectroscopy

Differential diagnosis:

  • Contact lens associated keratitis
  • Conjunctivitis 
  • Dry eye
  • Herpes simplex virus keratitis
  • Recurrent corneal erosion
  • Staph marginal keratitis

Management

Acanthamoeba trophozoites are frequently sensitive to a variety of medications, including antibiotics, antiseptics, antifungals, and antiprotozoals. However, Acanthamoeba is resistant to most of the listed treatments in the cystic form, thereby allowing for prolonged infection. Both medical and surgical options may be considerations in the setting of treatment-resistant AK.

Proposed therapeutic strategy for Acanthamoeba keratitis
Proposed therapeutic strategy for Acanthamoeba keratitis. An initial aggressive approach to treatment involves hourly topical eye drops (polyhexamethylene biguanide (PHMB) 0.02% and propamidine isethionate 0.1%), followed by tapering to maintenance therapy using PHMB and propamidine 3–4 times per day for 6 weeks. A stable clinical exam after a 2-week antiamoebic free period reduces the risk of medication toxicity and can also unmask the continued presence of trophozoites or cysts. If the infection is still present, the treatment protocol must be repeated. Topical low-dose and low-frequency steroid eye drops (such as loteprednol etabonate and fluorometholone acetate) have been suggested in cases of severe ocular pain, limbitis, or scleritis, and must be used with extreme caution. Topical steroids should only be used with concomitant antiamoebic therapy. | Varacalli, G., Di Zazzo, A., Mori, T., Dohlman, T. H., Spelta, S., Coassin, M., & Bonini, S. (2021). Challenges in Acanthamoeba Keratitis: A Review. Journal of clinical medicine, 10(5), 942. https://doi.org/10.3390/jcm10050942

Antiamebics:

The goals of medical therapy include the eradication of viable cysts and trophozoites and rapid resolution of the associated inflammatory response. Diamidines and biguanides are two classes of antiamebics that are often the first-line therapy for acanthamoeba keratitis due to their proven cysticidal effects. Topical treatment should continue for up to one year after PK.
  • Epithelial debridement can be performed to allow for improved penetration of topical medications
List of Anti-acanthamoeba drugs and doses
List of Anti-acanthamoeba drugs and doses | Garg, P., Kalra, P., & Joseph, J. (2017). Non-contact lens related Acanthamoeba keratitis. Indian journal of ophthalmology, 65(11), 1079–1086. https://doi.org/10.4103/ijo.IJO_826_17

Extra corneal manifestations:

The development of extra corneal manifestations such as scleritis or limbitis indicates a worse outcome and warrants treatment with anti-inflammatory medications. These medications may warrant continuation for several months to control inflammation and eradicate the pathogen.
  • NSAIDs: Oral flurbiprofen (50-100 mg, 2-3x daily)
  • High-dose systemic steroids: Prednisolone 1 mg/kg/day
  • Systemic immunosuppressants: Cyclosporine (3.0 to 7.5 mg/kg/day)

Surgical management:

If acanthamoeba keratitis remains unresponsive to topical conservative treatment, various surgical options remain available. Notably, PK used to be the first-line therapy for AK before biguanides and diamidines. Now, PK is generally only for patients with significant cataract, fulminant corneal abscess, corneal perforation, or therapy-resistant ulceration with peripheral neovascularization.
  • Penetrating keratoplasty (PK)
  • Corneal cryoplasty
  • Amniotic membrane transplantation
  • Riboflavin-UVA crosslinking

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