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Acanthamoeba Keratitis

DR SARANSH JAIN 08/06/2015

INTRODUCTION

• Belong suborder Acanthopodina and the genus Acanthamoeba

• Family of free-living cyst-forming protozoans that are ubiquitous in air, soil, dust and water.

• 11 species of which A. Castellanii and A. polyphaga are the most common in keratitis

• Life cycle consist of motile trophozoite and dormant cyst stages.Dart JK, Saw VP, KilvingtonS. Acanthamoebakeratitis: diagnosis and treatment

update 2009. Am J Ophthalmol2009;148:487-99 e2

MICRO-BIOLOGY• Free-living organisms• Commonly found in water

and soil• Prey on other microbes• Exist in 2 forms • More vulnerable, freely

mobile TROPHOZOITE• Characteristic double-

walled CYST extremely resistant to extremes of temperature, desiccation, irradiation, antimicrobial agents, and other changes in environment

Trophozoite of Acanthamoeba species displaying numerous delicate hyaline acanthopodia, a large contractile vacuole, and nucleus

Double-walled cysts of Acanthamoeba demonstrating the wrinkled outer ectocyst and rounded or polygonal inner endocyst

EPIDEMIOLOGY• Acanthamoeba Keratitis first description in 1975, by Jones

• Generally rare infection characterized by periodic outbreaks

• Incidence of 1.49–2.01 cases per million contact lens users per yr, approximately 90% of cases occurring in contact lens wearers

• Contact lens-related microbial keratitis occurs in 1–25 cases per 10 000 wearers per year, primarily dependent on wear regimen

• In India, Acanthamoeba was identified in 1% of all patients cultured for possible infectious keratitis regardless of etiology.

RISK FACTORS• Contact lens wear (>90%

cases of AK)

• Both soft and rigid lens wearers-

1. Trauma

2. Swimming in lenses

3. Noncompliance with CL disinfection systems

• Associated with an increased

risk of Acanthamoeba keratitis

Dart JK, Saw VP, KilvingtonS. Acanthamoebakeratitis: diagnosis and treatment update 2009. Am J Ophthalmol2009;148:487-99 e2

• Usually unilateral.

• Contact lens types:• Soft lenses carry a higher risk compared to daily-wear

rigid lenses.

• Planned-replacement soft contact lenses, which require daily cleaning and overnight storage higher risk than daily disposable lenses.

• Orthokeratologylenses, also shown to be associated with AK.

• Development of AK in contact lens users very strongly related to poor lens hygiene and contaminated water.

• The systems most effective against both forms of the amoeba are heat and hydrogen peroxide disinfection, specifically the two-step type which ensures extended disinfectant exposure time prior to neutralization.

• Cysts are highly resistant to chlorine and most current multipurpose solutions (MPS).

• Consequently, the use of one-step hydrogen peroxide systems,chlorine-based disinfection and most recently, AMO Complete MoisturePlus, an MPS, have been associated with an increased risk of Acanthamoeba keratitis

PATHOPHYSIOLOGY

Centers for Disease Control and Prevention Life Cycle of AcanthamoebaSpp., 2004

PATHOGENESIS

Clarke DW, NiederkornJY. The pathophysiologyof Acanthamoebakeratitis. Trends Parasitol2006;22:175-80

• Initial attachment- facilitated by expression of a mannose-binding protein(MBP), it binds to corneal epithelial cell-expressed mannosylated glycoprotein

• Corneal injury such as contact lens wear may increase its expression as well as measured cytopathic effects

• Once bound, acanthamoebae then express proteases such as MIP-133 which degrade both corneal epithelium and corneal stroma, promoting invasion and ulceration

• The organism can proliferate, subsisting on bacterial prey or, possibly, resident keratocytes

• Precise mechanism of CL induced risk for Acanthamoeba infection – Unclear, it is known that significant immunedeviation of the ocular surface permit binding of microorganisms, and promote biofilm formation on the lens and lens paraphernalia

• This provides a stable microorganism-rich food supply to encourage proliferation and extend contact time of the amoeba with corneal epithelium, increasing chances of successful binding. Numerous studies have shown increased pathogenicity of Acanthamoeba when co-cultured with organisms commonly associated with human disease and also when incorporated inside the amoeba as endosymbionts

CLINICAL FEATURES

• High index of clinical suspicion

• bilateral in 7–11% Any age may be affected and no sex predilection

• h/o chronicity, multiple physician referrals, culture-negative scrapings, resistance to antimicrobial agents (bacterial, fungal, and viral), and previous corticosteroid use, are related to the indolent nature of the disease and misdiagnosis or delayed diagnosis rather than being an integral feature of the disease

• Manifest as a nonspecific foreign body sensation, photophobia, sometimes escalating to severe, intractable pain with visual acuity similarly unpredictable in the early stages

• One of the specific and important symptoms of Acanthamoeba keratitis is the severity of the pain in the early stage of infection

EARLY DISEASE (<1month)

Epitheliopathy

Punctate keratopathy

Epithelial or Sub-epithelial infiltrates

Pseudodendrites

Radial Keratoneuritis

EPITHELITIS

• Epitheliitis - predominantly epithelial infestation which may present with a mild foreign body sensation ranging to moderate pain and mild loss of visual acuity.

• Its flat, diffuse microcystic form exhibits relative perilimbal sparing and may be confused with dry eye or contact lens-associated surface toxicity

Pseudodendrites (rose bengal) Epithelial Ridges

• Perineuralinfiltrates in a radial distribution.

• Clustering of acanthamoeba trophozoites around corneal stromalnerves resulting in swelling of nerves.

• Trophozoites kill nerve cells by direct cytolysis and apoptosis, explainingthe severe pain experienced in AK.

LATE DISEASE (>1month)

• Ring infiltrates

• Frank ulceration

• Secondary sterile anterior uveitis, sometimes with hypopyon

• Corneal melt

• Corneal perforation

RING ABSCESS CORNEAL MELT

sterile anterior uveitis

• Extreme photophobia related possibly to its neurotrophic nature, its ability to synthesize certain prostaglandins, and the host's reactive immune response

• Visible ring infiltrate represents an immune hypersensitivity response

• Accurate diagnosis with these signs of infection is probable, but, with the exception of radial keratoneuritis, represents advanced disease

Extracorneal manifestations

• Limbitis• scleritis • uveitis • eyelid edema• dacryoadenitis

DIFFERENTIAL DIAGNOSIS

• Viral Keratitis eg. Herpetic stromal keratitis

• Fungal Keratitis

• Toxic Keratopathy

• Bacterial Keratitis eg. Mycobacterium

noncontiguous or multifocal pattern of granular epitheliopathy and subepithelial opacities (unlike the contiguous, dendritic pattern in HSV keratitis)

DIAGNOSIS• Early diagnosis and prompt delivery of

appropriate medical therapy is essential to secure a good prognosis.

• If effective therapy is delayed for 3 weeks or more, prognosis deteriorates.

• AK should be considered in any case of corneal trauma complicated by exposure to soil or contaminated water and in all contact lens wearers.

• Diagnosis is made by visualizing amebae in stained smears or by culturing organisms obtained from corneal scrapings.

• Culture yield is laboratory-dependent, with larger studies reporting only 35%- 50% positivity

• A significant number of cases are treated based on clinical presentation and/or confocal microscopy findings.

• Lamellar corneal biopsy may be required to establish the diagnosis in some cases.

• Contact lenses and related paraphernalia can be examined, but significant contamination without disease has been demonstrated.

LAB DIAGNOSIS

1. CORNEAL SCRAPINGS

Epithelial scrapings for Light Microscopy

Various stains can be used including:• Haematoxylin and Eosin• Giemsa• Periodic acid Schiff• Calcofluorwhite• Acridineorange stains

STAINING

Corneal smear showing Acanthamoeba cyst, trophozoite, and epithelial cells (Papinicolau, x400

PSEUDOPOD like projections of trophozoite with GIEMSA stain

CORNEAL BIOPSY

Cysts of Acanthamoeba species stained with the optical whitening agent calcofluor white and examined using ultraviolet epifluorescence

Corneal biopsy showing Acanthamoeba cysts (Periodic Acid Schiff)c

CONFOCAL MICROSCOPY

• Double walled cysts within stroma.• Bright structures with spindle-like pseudopodia

visualised within basal epithelium consistent with Acanthamoeba trophozoites.

CULTURE METHODS

MANAGEMENT

TREATMENT

• Early diagnosis is the most important prognostic indicator of a successful treatment outcome

• Many cases treated initially for herpetic keratitis• Persistent infection is related to the presence of

acanthamoeba cysts.• Goals of medical therapy in AK include:– Eradication of viable cysts and trophozoites– Rapid resolution of associated inflammatory response

ANTI-AMOEBIC MEDICATIONS

Biguanides (polyhexamethylenebiguanide, PHMB, and chlorhexidine0.02%)

Interact with cytoplasmic membrane, resulting in loss of cellular components and inhibition of respiratory enzymes

Only Anti-Amoebic Medication shown to have consistent in vitro and clinical efficacy against both cysts and trophozoites, with the others primarily effective against trophozoites.

mainstay of pharmacologic treatment used early in the course of therapy, although successful resolution can be achieved

Diamidines(hexamidine0.1%)

• Cationic surface-active properties inducing structural membrane changes affecting cell permeability

• Molecules then penetrate into amoebic cytoplasm resulting in denaturation of cytoplasmic proteins and enzymes

• Effective against both trophozoite and cysts forms of acanthamoeba

• Monotherapy not recommended due to clinically resistant isolates being reported

Imidazoles/triazoles

• Topical imidazole shown to be effective against trophozoites but not cysts

• Systemic anti-amoebic therapy with itraconazole useful adjunct to prevent potential spread of trophozoites into adjacent tissues in cases with associated limbitis and scleritis

• Voriconazole treatment has been shown to be efficacious in some recalcitrant cases

• Should be never be used as monotherapy

Aminoglycosides(Neomycin)

• Has been shown to be ineffective against cysts in vitro

• Also toxic to corneal epithelium and may result in indolent corneal ulceration that may be attributed to disease activity

• Minimal role in modern therapy

Use of steroids in AK

• Controversial• Steroids result in improvement of clinical signs and

symptoms due its anti-inflammatory effect.

• However,– Treatment of acanthamoeba cysts with dexamethasone

hastens maturation and excystment resulting in a 4-to 10-fold increase in number of trophozoites.

– Acceleration of trophozoite proliferation was observed.

SURGICAL TREATMENT

• Epithelial debridement– Extensive debridement of affected area of corneal epithelium may

be therapeutic if performed early when disease is intraepithelial

• Penetrating keratoplasty– Indications:

• Therapy resistant infection (Therapeutic PK)– Severe stromal melting with threatened perforation– Fulminant corneal abscess

Generally poor results due to:– Relatively large grafts with higher risk of rejection– Recurrence of disease in graft due to residual viable cyst

• Visual rehabilitation (Optical PK)– Residual corneal scarring

Better visual prognosis compared to therapeutic PK

SUMMARY

• Acanthamoeba is difficult to treat with a prolonged course and requiring multiple toxic antiseptic drugs.

• Most common differential diagnoses is herpetic keratitis.

• Early diagnoses of acanthamoeba is crucial for effective treatment of AK.

• Pain disproportionate to clinical signs in early presentation. In late presentation, patient may be painless.

• In fulminant late AK, therapeutic keratoplasty may be indicated

REFERENCES !!

• Cornea, 3rd Edition- Jay H. Krachmer, Mark J. Mannis and Edward J. Holland

• Principles & Practices Of Ophthalmology- Albert Jackobiec, VOL1, 3rd Edition

• Clinical Ophthalmology: Systemic Approach- 7th Edition- Jack J. Kanski and Brad Bowling

• Ophthalmology – 4th Edition- Myron Yanoff & Jay S. Duker

• External Disease and Cornea- AAO- Basic and Clinical Science Course – Section 8