Consultations
See the list below:
- Keratitis
- Infectious diseases specialist
- Ophthalmologist
- Granulomatous amebic encephalitis and disseminated disease
- Infectious diseases specialist
- Neurologist
The free-living amoebae that cause human infections include Acanthamoeba, Naegleria, Balamuthia mandrillaris, and, rarely, Sappinia. All 4 genera cause serious CNS or ocular infections. Distinct from enteric pathogenic protozoa, they all are usually soil/water commensals, have no human carrier state, involve no insect vector, and cause sporadic disease associated with specific behaviors and exposures.[1]
Acanthamoeba are among the most prevalent environmental protozoa and have been classified by 18s rDNA sequencing into at least 20 genotypes, designated T1-T20. The most common environmental and human pathogens belong to the T4 genotype. The following species of Acanthamoeba have been associated with human disease:[2]
The life cycle consists of 2 stages: a trophozoite (which is 14-40 µm in diameter) and a cyst (which has a double-layered wall with a diameter of 12-16 µm). Cysts are quite resistant to environmental and chemical insults.
Acanthamoeba was first established as a cause of human disease in the 1970s and might be considered an emerging infection. This genus causes 3 clinical syndromes: granulomatous amebic encephalitis (GAE), disseminated granulomatous amebic disease (eg, skin, sinus, and pulmonary infections), and, most commonly, amebic ocular keratitis. Individuals who develop GAE or disseminated disease are usually immunocompromised, whereas those with keratitis are usually immunocompetent. Disseminated disease and GAE carry a poor prognosis, and treatment strategies are not well defined; Acanthamoeba keratitis is a sight-threatening infection that carries a favorable prognosis when diagnosed and treated early.
Clinicians must be aware of the risk of ocular keratitis secondary to contamination of contact lenses so as to advise patients on preventive measures. Patients with contact lenses should be warned of exposure to water containing ubiquitous Acanthamoeba cysts, especially by swimming, showering, and using homemade lens-cleaning solutions.
Early recognition of the signs of keratitis (discomfort, blurred vision) are nonspecific but warrant prompt review of lens hygiene and aggressive diagnostic intervention. Therapies are most effective at the earliest stages of infection.
Severely immunosuppressed patients with subacute onset of headache, cognitive impairment, and focal neurologic signs should be considered at risk for granulomatous amebic encephalitis (GAE). While multiple ring enhancing lesions more commonly suggest toxoplasmosis, nocardia, and tuberculosis, exclusion of GAE requires biopsy.
Acanthamoeba keratitis occurs in patients who sustain minor corneal trauma. This is usually associated with wearing contact lenses for a longer duration than prescribed. Amoebae can be introduced through environmental exposures such as swimming[3] and showering while wearing contact lenses, contaminating lenses or cases with wet hands, "topping off" lens solution bottles, or using contaminated contact lens solutions, especially homemade solutions. Rare reports cite radial keratotomy preceding this infection.[4, 5]
GAE usually develops after hematogenous spread of the amoebae from pulmonary or skin lesions to the CNS. Organisms appear to disseminate via the middle cerebral and other arteries, producing widespread lesions most commonly in the frontal, temporal, parietal, and occipital lobes, as well as the cerebellum, brainstem, and basal ganglia.[6] GAE manifests as a chronic or subacute infection, mediated in part by host type IV hypersensitivity reaction, producing blood-brain barrier leak and neuronal damage.[7]
Disseminated disease may begin in the sinuses, skin, or lungs and disseminate from these locations in immunocompromised patients to other sites, including the brain, leading to GAE.
Acanthamoeba are ubiquitous organisms and have been isolated from natural and treated salt, brackish, and fresh water; soil; air; and dust. Most persons appear to have been exposed to this organism during their lifetime, as 50%-100% of healthy people have serum antibodies directed against Acanthamoeba. This amoeba has been isolated from the nasopharynx of healthy persons. Acanthamoeba has caused disease worldwide and appears of increasing interest, particularly in Asia.[8, 9, 10]
Acanthamoeba keratitis typically develops sporadically among people who wear water-contaminated contact lenses. Outbreaks are possible owing to manufacturing and distribution of lens cleaning solutions that are either contaminated or impotent.[11] Keratitis has been associated with wearing nondisposable contact lenses, using homemade sodium chloride solution to clean the lenses, and wearing lenses while swimming and showering. The isolation of Acanthamoeba cysts from swimming pool water is not unusual, as they resist chlorination. A higher percentage of isolates from swimming pools have been shown to be pathogenic than those isolated from natural fresh water.
A multistate case control study conducted from 2008-2011 indicated the following risk factors (unadjusted matched odds ratios [mOR]) for acanthamebic keratitis among wearers of soft contact lenses:[5]
Significant risks factors under multivariable analysis included age older than 53 years, male sex, topping off, and using saline solution.[5]
A rabbit model of keratitis has been developed that utilizes diamond burr injury followed by use of soft lenses contaminated with 1000 amoebae/mm2 (90% trophozoites).[12] This model will be useful for understanding pathogenesis and improving therapy.
More than 90% of the approximately 150 reported cases of GAE have occurred among persons with a wide variety of immunocompromising conditions, including AIDS[13] , posttransplantation, cancer being treated with chemotherapy, systemic lupus erythematosus, steroid use, diabetes mellitus, malnutrition, or liver disease.[14] Children who are malnourished, but otherwise healthy, are also at increased risk. Likewise, persons with disseminated disease without CNS involvement are usually immunocompromised; this condition is most common among patients with AIDS who have low CD4 counts (eg, 15</ref>[16] In unusual cases, disseminated disease develops in immunocompetent children and adults. The incidence of GAE and disseminated disease appears to be rising, likely mirroring the increased number of persons worldwide who are living with immunocompromising conditions.
United States
Acanthamoeba keratitis cases substantially increased in the 1980s with the introduction of disposable soft contact lenses.[17] Some evidence shows that the rate has subsequently declined, especially with the introduction of multipurpose cleaning solutions. The estimated rate of Acanthamoeba keratitis is 1 per 250,000 people in the United States, although rates vary among studies: from 1.65-2.01 per million population up to 1 per 10,000 people who wear contact lenses.[18]
GAE and disseminated Acanthamoeba disease are very rare, but rates may be increasing given the rising number of persons living with immunocompromising conditions.
International
Acanthamoeba can cause keratitis, GAE, and disseminated disease worldwide. Data on the incidence rates of these infections internationally are not available since it is not a reportable disease.
Acanthamoeba keratitis is a local infection that does not lead to systemic infection or death but may be complicated by progressive visual loss, ulceration, secondary anterior uveitis with hypopyon, abscess formation, scleritis, glaucoma, cataract, and corneal melt and perforation. Ocular prognosis is worsened by delay in therapy for more than 3 weeks, use of steroids, and development of extracoronal manifestations.[19] Current drugs have limited efficacy unless applied early in the clinical course.
GAE carries a very high mortality rate (nearly 100%). Survivors of GAE have been described; these patients were treated with combination antimicrobial therapies. Disseminated disease also carries a high mortality rate, but it is lower than GAE if CNS involvement does not occur.
The prognosis of Acanthamoeba keratitis depends on the timing of recognition and therapy. Patients with symptoms that last for more than three weeks have a higher risk of long-term visual loss and complications.
The prognosis of GAE and disseminated disease is very poor and is worsened by late diagnosis, immunosuppression, and marginally effective therapies.
Patients who wear contact lenses should be educated about the risks of improper use and management of contact lenses. Clinical photographs might encourage better compliance with hygienic practices.
Acanthamoeba keratitis is usually associated with a history of excessively long lens wear and/or contamination of the lens or lenses with unsterile water. Typical sources include swimming, showering, using nonsterile lens cleaners, contaminating lenses and cases by "topping off" or other unhygienic practices, and handling lenses with wet hands.[4, 5] The incubation period is a few days. Keratitis typically begins with a foreign-body sensation followed by pain, tearing, photophobia, blepharospasm, and blurred vision.[4, 19] Patients may have periods of symptom remission with a waxing and waning course. Bilateral involvement has been described in up to 11% of cases.[20]
Granulomatous amebic encephalitis (GAE) is a subacute diffuse meningoencephalitis, usually with an insidious onset. The incubation period is unknown but is probably weeks to months. The duration of illness until death ranges from 7-120 days (average, 39 days). Patients with GAE may have concurrent sinus, lung, or skin disease. Most patients present with focal neurologic deficits coupled with signs of increased intracranial pressure; other symptoms may include confusion, seizures, headache, focal weakness or ataxia, visual disturbances, and fever.
Skin disease may precede the onset of CNS manifestations by weeks to months and may include ulcers, nodules, or subcutaneous abscesses. Disseminated disease without CNS involvement may manifest as skin lesions, sinusitis, pneumonitis, or a combination. Other unusual manifestations of Acanthamoeba infections have included osteomyelitis, adrenalitis, and vasculitis.
Early physical findings in amebic keratitis include punctate keratopathy, pseudodendrites, epithelial or subepithelial infiltrates, and perineural infiltrates.[19] Confocal microscopy assists in identifying 5 stages of keratopathy, as described by Tu[21] : epitheliitis, epitheliitis with radial neuritis, anterior stromal disease, deep stromal keratitis, and ring infiltrates. Ring infiltrates are characteristic, but found in only 50% of cases. Early infection can mimic herpes keratitis, and late infection can mimic fungal keratitis. Perineural infiltrates are also highly suggestive of amebic keratitis.
The physical findings of GAE are highly dependent on location of lesions and result from increased intracranial pressure and focal neurological damage. These include abnormal mental status examination results, focal weakness or ataxia, and papilledema.
Disseminated disease without GAE may manifest as skin lesions that are typically hard erythematous nodules or skin ulcers. Other presentations of disseminated disease include pneumonitis and sinusitis.
Complications of Acanthamoeba keratitis include loss of visual acuity and necessity of corneal transplantation or enucleation.
GAE and disseminated infections are carry a very high mortality rate despite new and emerging antimicrobial regimens.
Diagnosis requires a high index of suspicion; an early diagnosis is critical for the retention of good visual acuity. The earliest clue to this infection is a dendriform pattern noted on the epithelium of the cornea.
Acanthamoeba trophozoites or cysts can be demonstrated with corneal scrapings or a biopsy sample via wet mount, stains, histopathologic examination, or culture.
Motile trophozoites may be seen in a wet-mount preparation.
Stain corneal scrapings with calcofluor white (stains cyst walls) and examine specimen with fluorescent microscopy.[22]
Cysts and trophozoites can be seen with a number of stains, including hematoxylin and eosin (H&E), Giemsa, and Wright.
Amoebae may be cultured on a buffered charcoal yeast extract or with a non-nutrient agar (NNA) overlaid with organisms such as Escherichia coli.
Conduct polymerase chain reaction (PCR) of biopsy specimens, if available (see below).
In addition, the use of tandem scanning confocal corneal microscopy has been described as a noninvasive method for diagnosis.[23]
If corneal specimens are unremarkable, consider culturing the contact lenses and saline solution for Acanthamoeba.
Suprainfecting bacteria can complicate the diagnosis; isolation of a bacterial pathogen does not exclude Acanthamoeba as the cause of the keratitis.
This condition is best diagnosed via brain biopsy. Sometimes cases are not recognized until postmortem evaluation.
Cerebrospinal fluid examination reveals an increased number of white blood cells (up to 800 cells/µL, primarily lymphocytes), elevated protein levels, and decreased glucose levels.
Examining the CSF for organisms is of very low yield.
Serologic studies are not useful.
Perform biopsy and culture areas of involvement.
CT scan should be obtained before a lumbar puncture is performed to ensure that this procedure is not contraindicated because of the herniation risk.
Findings on CT scan include multiple nonenhancing lesions in the cerebral cortex.
Obtain eye scrapings or biopsy samples. Corneal scrapping can be examined via a wet mount for motile trophozoites.
Perform lumbar puncture and brain biopsy.
Lumbar puncture may be contraindicated if signs of increased intracranial pressure are present.
If skin lesions are present, perform skin biopsy.
Obtain biopsy samples of the involved sites (eg, skin, sinuses).
In keratitis, amebic cysts and trophozoites are found within the cornea. An acute or mixed inflammatory infiltrate may contain giant cells. Corneal revascularization may occur.
Individuals with GAE have moderate-to-severe cerebral edema. Necrotizing granulomas that contain perivascular trophozoites and cysts are usually located in the cerebellum, mid brain, and brain stem. Multinucleated giant cells may be present within the granulomas. Granulomas are usually noted among immunocompetent patients. On biopsy specimens, angiitis with perivascular cuffing with lymphocytes may be seen. The leptomeninges are spared except when they directly overlie areas of cortical involvement.
Based on animal models, polymerase chain reaction (PCR) testing appears to be a promising method of rapid keratitis diagnosis.[24]
Medical therapy for Acanthamoeba infection is not well established. Early diagnosis and treatment are paramount for improving outcome. Listed below are treatments that have been reported in the literature.
Successful treatment of keratitis consists of early diagnosis and aggressive surgical and medical therapies.[25, 26]
Medical treatment consists of topical antimicrobial agents, which can achieve high concentrations at the site of the infection.
Because the cyst form may be highly resistant to therapy, a combination of agents is generally used.[19, 27]
Many authorities recommend a combination of chlorohexidine (0.02%) and polyhexamethylene biguanide (PHMB, 0.02%) for treating both the trophozoites and cysts.[26, 27]
These topical antimicrobials are administered every hour immediately after corneal debridement or for the first several days of therapy. These agents are then continued hourly during waking hours for 3 days (at least 9 times/day is recommended) depending on clinical response. The frequency is then reduced to every 3 hours. Two weeks may be required before a response is observed, and the total duration of therapy is a minimum of 3-4 weeks. Some advocate treating for 6-12 months. When therapy is discontinued, close observation is warranted to rule out recurrent disease.
No clear consensus exists about use of steroids. Most authorities recommend that steroid use is probably best avoided but might be used judiciously if anterior-chamber inflammation is present.[19] Patients receiving steroids should continue antiamebic therapy for several weeks after the steroids are stopped.
Treatment is not standardized and is limited. Most use a combination of therapies for the treatment of GAE, which should be urgently administered.
Early therapy with a multidrug regimen is the best approach. If possible, immunosuppression should be reversed. A combination of pentamidine, an azole (fluconazole or itraconazole), a sulfadiazine, and flucytosine can be considered.
In vitro and in vivo data suggest that the following medications have activity against Acanthamoeba:
Other potential regimens have included several combinations of the above agents.
Two immunocompetent children survived with treatment that consisted of ketoconazole, rifampin, and trimethoprim-sulfamethoxazole. A recent case reported discussed the use of this combination, but the patient ultimately relapsed and died of progressive leukemia.[29] . A heart transplant recipient was successfully treated with a combination of flucytosine, fluconazole, miltefosine, and decreased immunosuppression.[30]
Other potential regimens include (1) fluconazole and sulfadiazine or (2) pentamidine, amphotericin, flucytosine, rifampin, itraconazole, and chlorhexidine.
A case that involved only the skin was treated with intravenous pentamidine, topical chlorhexidine gluconate, and 2% ketoconazole cream, followed by oral itraconazole.
Because of the severity of these infections and the difficulty in killing both cysts and trophozoites without cellular toxicity, a wide range of new therapies are being evaluated in animals and humans.[31] These include both new and old technologies, as well as drugs with new delivery systems, such as liposomes, and new mechanism of action, such as small inhibitory RNA molecules[32] and agents designed to activate programmed death pathways.[33]
Acanthamoeba keratitis: The abnormal epithelium is débrided. Penetrating keratoplasty/corneal transplantation may be necessary in cases that do not respond to medical therapy.[34, 19]
See the list below:
Acanthamoeba keratitis may be prevented by scrupulous and appropriate use of contact lenses.
Although unproven, nasal irrigation with unsterile water is probably inappropriate for severely immunocompromised hosts.
Because of the chronicity of Acanthamoeba diseases, they require long-term monitoring for relapse.
No specific guidelines currently exist for management of amebic keratitis or GAE. A 2015 Cochrane review of medical interventions for keratitis was inconclusive.
The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications.
Clinical Context: Imidazole broad-spectrum antifungal agent. Inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death.
Clinical Context: Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.
Clinical Context: Inhibits growth of protozoa by blocking oxidative phosphorylation and inhibiting incorporation of nucleic acids into RNA and DNA, causing inhibition of protein and phospholipid synthesis.
Clinical Context: Converted to fluorouracil after penetrating fungal cells. Inhibits RNA and protein synthesis. Active against Candida and Cryptococcus and generally used in combination with amphotericin B.
Clinical Context: Nonabsorbable imidazole. Broad-spectrum synthetic antifungal agent that inhibits growth of yeasts and fungal growth by altering cell membrane permeability, which causes fungal cell death.
Therapy is directed at the underlying condition, with the goal of minimizing symptoms and preventing complications.
Clinical Context: Available in oral and parenteral forms. FDA approved for esophageal candidiasis and candidemia. Used clinically for serious candidal infections refractory to amphotericin B. Voriconazole has been found to be active against C glabrata and C krusei, as well as isolates that have developed resistance to fluconazole.
Clinical Context: Inhibits biosynthesis of ergosterol, damaging fungal cell wall membrane, which results in fungal cell death.
Clinical Context: Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. Has little affinity for mammalian cytochromes, which is believed to explain its low toxicity. Available as tablets for oral administration, as a powder for oral suspension, and as a sterile solution for IV use. Has fewer adverse effects and better tissue distribution than older systemic imidazoles. Daily dose varies with indication.
Fluconazole penetrates the cerebrospinal fluid, kidneys, and liver well. It is concentrated and excreted by the kidneys in its active form so is effective against urinary tract infections.
The mechanism of action of these agents may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.
Clinical Context: Consists of an amebicidal and antibacterial aminoglycoside obtained from a strain of Streptomyces rimosus that is active in intestinal amebiasis. It is poorly absorbed and is active only against the intraluminal form of amebiasis.
Clinical Context: Developed as an anti-leishmanial therapy, it appears to have some activity and has been used successfully in a number of cases of GAE. It can be orally administered and has mild to moderate gastrointestinal side effects as major toxicity.
Biochemical pathways in the parasite are sufficiently different from those in the human host to allow selective interference by chemotherapeutic agents in relatively small doses.
Clinical Context: Through a competitive antagonism of para-aminobenzoic acid (PABA), this agent interferes with microbial growth. It is commonly used for meningococcal prophylaxis.
Clinical Context: Trimethoprim-sulfamethoxazole inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. One double-strength tablet contains trimethoprim (TMP) 160 mg and sulfamethoxazole (SMX) 800 mg.
Clinical Context: Also called rifampicin. Inhibits RNA synthesis in bacteria by binding to beta subunit of DNA-dependent RNA polymerase, which, in turn, blocks RNA transcription.
Clinical Context: Causes leakage of intracellular components by binding to phospholipids, altering permeability and damaging the bacterial cytoplasmic membrane.
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.
Clinical Context: Binds to negatively charged bacterial cell walls and extramicrobial complexes. It has bacteriostatic and bactericidal effects.
Avoid using homemade sodium chloride solutions and swimming while wearing contacts.
Follow manufacturer's guidelines regarding cleaning contact lenses.
Heat disinfect or use benzalkonium-preserved saline for cleaning contact lenses.
See the list below:
Keratitis usually responds to medical therapy. The disease process may affect visual acuity.
GAE carries a high mortality rate (nearly 100%). Most cases are fatal in 7-120 days (mean, 39 d).
Disseminated disease with skin involvement (no CNS disease) is associated with a mortality rate (73%).
Contact lens wearers should avoid using homemade sodium chloride solutions and swimming while wearing contact lenses. Patients should consult manufacturer's guidelines regarding cleaning instructions.