main topic Wien Med Wochenschr (2014) 164:392–399 DOI 10.1007/s10354-014-0309-6
Sitting at the window to the world—ocular parasites Talin Barisani-Asenbauer
Received: 28 November 2013 / Accepted: 20 August 2014 / Published online: 31 October 2014 © Springer-Verlag Wien 2014
Summary Parasitic infections cause significant ophthalmic disease, both in developing countries and in the Western world. The parasitic infections Acanthamoeba keratitis, ocular toxoplasmosis, and ocular toxocariasis are responsible for a significant proportion of ocular pathology. Especially in light of the recent increase of immunocompromised (i.e. using immunosuppressants or HIV) and aged populations, parasitic infections of the eye are rising in number. This reviews aims to describe the pathogenesis, symptoms, diagnosis and management of infection, as well as preventative measures for these three parasitic ocular diseases. Keywords Acanthamoeba keratitis · Ocular toxoplasmosis · Ocular toxocariasis
Am Fenster der Welt – Okulare Parasiten Zusammenfassung Parasitische Infektionen sind global, sowohl in Entwicklungsländern als auch in der westlichen Welt die Ursache einer Vielzahl von Augenerkrankungen. Acanthamoen-Keratitis, okuläre Toxoplasmose und okuläre Toxocarose haben einen signifikanten Anteil an der Entstehung okulärer Pathologien. Bedingt durch die steigende Anzahl immunkompromitierter (durch immunsupressive Therapien oder HIV) und älterer Individuen in der Bevölkerung nehmen parasitische Erkrankungen des Auges in den letzten Jahren deutlich zu. Dieser Artikel fasst die Pathogenese, Symptome, Diagnosemethoden und Therapieansätze für diese drei parasitischen Erkrana.o. Univ. Prof. Dr. T. Barisani-Asenbauer () Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Kinderspitalgasse 15, 1090 Vienna, Austria e-mail: [email protected]
392 Sitting at the window to the world—ocular parasites
kungen zusammen und gibt einen Überblick über vorbeugende Maßnahmen zur Verhinderung einer Infektion. Schlüsselwörter Acanthamoen-Keratitis · Okuläre Toxoplasmose · Okuläre Toxocarose
Introduction Parasitic infections cause significant ophthalmic disease globally. Nevertheless, the epidemiology of parasitic ocular disease depends on the habitats of causative parasites as well as on the conduct and health status of individuals [1]. Therefore, the geographic location and cultural traditions are an important determining factor in the development of specific parasitic infections. For example, in developing countries, onchocerciasis affects millions of subjects and is recognized as second in the world only to trachoma as an infectious cause of blindness, whereas in the Western world, toxoplasmotic and Acanthamoeba infestations are accountable for a significant proportion of ocular morbidity [2]. Moreover, due to the recent increase in immunocompromised (i.e., using biologics or immunosuppressants, with human immunodeficiency virus (HIV), etc.) and aged populations, opportunistic infections of the eye, including parasitic infections, are rising [3]. This review is not comprehensive for the global community but focuses on disorders associated with more common ocular parasitic infections in Central Europe such as Acanthamoeba keratitis (AK), ocular toxoplasmosis (OT), and ocular toxocariasis.
Acanthamoeba keratitis Acanthamoebae are ubiquitous free-living amoebae. As opportunistic pathogens, they are the causative agents of
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AK, a sight-threatening, very painful corneal infection [4]. AK can carry a favorable prognosis when diagnosed and treated early in the disease course, but available treatment options can remain ineffective even when started early. AK is the most common Acanthamoeba infection, but with a prevalence of 0.2–0.3 per 10,000 contact lens wearers or 0.15–1.4 per million inhabitants (depending on the country) [5], it is still among the “orphan diseases.” Nevertheless, AK is a debilitating disease, and the management thereof poses two major challenges: the duly diagnosis of the disease and the effective eradication of cysts, which are resistant to most of the antimicrobial drugs [6]. In many cases, ophthalmologists may miss AK thinking of a bacterial or viral infection, which could delay the diagnosis.
Pathogenesis The pathogenesis of AK involves direct contact between the cornea and trophozoites. “Mini”-corneal injuries as seen in contact lens wearers facilitate the invasion of the parasite; however, acanthamoebae possess the capability to produce proteases that can degrade epithelial cell membranes without previous injury [7]. Contact lens
wear is seen as the leading risk factor for AK [8]; nevertheless, AK can also be seen in non-contact lens wearers [4, 9, 10].
Symptoms of the infection The predominant symptom of AK is pain! Subjects hardly can bear this pain that is often not explainable by the keratitis itself and serves as a valuable parameter to differentiate AK from herpetic stromal keratitis. Further symptoms can be very similar to the symptoms of other eye inflammations and infections. Nevertheless, in AK, these symptoms can last for several weeks or months: ●● ●● ●● ●● ●●
severe pain, excessive tearing, eye redness, blurred vision, and sensitivity to light.
Diagnosis of AK Clinical suspicion is the most critical step in the diagnosis of AK. Corneal scrapes for cultivation of amoebae, immunohistological staining, and/or polymerase chain reaction (PCR) analysis should be performed (Figs. 1 and 2). Where possible, confocal in vivo microscopy could help to diagnose the infection rapidly before laboratory results are available [11].
Management of AK
Fig. 1 Fresh lesion next to corneal scar in recurrent Acanthamoeba keratitis (contact lens wearer)
Fig. 2 Acanthamoeba keratitis in non-contact lens wearer. Subject had a corneal perforation
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There are currently no licensed drugs for the treatment of any of the Acanthamoeba infections. In AK, cure is usually achieved with a combination of biguanides such as polyhexamethylene biguanide or chlorhexidine, and diamidines such as propamidine isethionate (Brolene) or hexamidine (Desomedine) [9]. Treatment has to be applied aggressively at least hourly during the first days and subsequently several times a day for usually 6 months. However, sufficient efficacy is not always achieved, and resistance against propamidine is known to occur during long-term treatment [9]. Another major problem in treatment is amoebal encystation. Acanthamoebae, in contrast to most other amoebae, can encyst within the tissue, and Acanthamoeba cysts are significantly less susceptible to antimicrobials and disinfectants [12]. Thus, relapses may occur as soon as treatment is stopped. Recently, an immunocompromised but HIV-negative subject with disseminated Acanthamoeba infection was successfully treated with miltefosine. Miltefosine (hexadecylphosphocholine), an alkylphosphocholine, approved for the oral and topical treatment of leishmaniasis, proved also to be highly active against Acanthamoeba in vitro [13] and in vivo [14, 15]. For human AK,
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preliminary data on successful treatment with miltefosine of refractive cases are reported [16]. Moreover, collagen cross-linking is another new treatment modality for AK. Although in vivo studies could not show effectiveness, several clinical cases were treated successfully [17]. Finally, corneal transplantation could be required in cases where resulting corneal scarring reduces vision significantly [18]. Surgery should be performed in quiet eyes whenever possible to reduce the risk of corneal rejection, and deep lamellar keratoplasty where the corneal endothelium remains intact can not only help to improve graft survival but also serve as barrier against parasite invasion.
Prevention
Fig. 3 Pathognomonic picture: fresh satellite next to old scar
To reduce the risk of AK contact lens wearers should
Ocular toxoplasmosis
●● wear and replace contact lenses as prescribed, ●● store reusable contact lenses as prescribed and never use tap water, ●● replace storage cases regularly, ●● not moisten contact lenses with either saliva or tap water, and ●● not wear contact lenses while swimming.
Although most toxoplasmosis infections remain asymptomatic—one-third of the world population is estimated to be seropositive—before progressing into a state of latent infection, they can result in severe ocular complications. The parasite typically persists in the retina, leading to recurring inflammation in the posterior segment of the eye. Current treatments can control active inflammation, but play a very limited role in the prevention of recurrences.
Fig. 4 Optical coherence tomography of fresh toxoplasmotic lesion before and after therapy. Note that final scar is much smaller than the inflammatory zone at the beginning
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main topic Ocular manifestation OT is the most frequent cause of posterior uveitis [19], an inflammation that occurs in the posterior pole of the eye. It can be congenitally transmitted or acquired after birth. Active ocular inflammation occurs when Toxoplasma cysts are present in the retina. Typical clinical findings are unilateral retinal lesions with involvement of the choroid. The lesions can either present as satellites to retinal scarring or multifocal or solitary lesions [20]. Other ocular symptoms include neuroretinitis, vasculitis, ocular vein occlusion, vitritis, and iritis. In immunocompetent patients, OT is almost always unilateral but can switch eyes from one episode to the other. Patients often describe unspecific symptoms, such as blurred vision, mild ocular pain, photophobia, and floaters in the active eye. Classic signs of activity include white-grayish lesions that are overlaid by vitreous cellular infiltrates. The fundus seems “cloudy.” Inactive lesions are characterized by their sharp pigmented margins, white center, and clear media. As a result of necrotizing retinitis, scars cicatrize from periphery to center. OT can heal spontaneously, but not without pigmented retinal scarring. This leads to more or less severe visual field impairment, depending on the location of the scar (Figs. 3 and 4). In congenital OT, lesions occur more often in the center of the macula (responsible for sharp central vision), which influences visual acuity severely and can lead to amblyopia, whereas in acquired OT, lesions are more often positioned in the periphery, thus resulting in a less significant loss of visual acuity and field. In most cases, OT is a reactivation of an acute infection not reflected by serological rise of antibodies. As systemic disease often occurs without symptoms, time elapsing between primary infection and ocular manifestations can vary extremely, making diagnosis even more difficult [21]. In immunocompromised individuals, OT is usually atypical and difficult to diagnose, as clinical picture can mimic many ocular infections and also tumors. The genetic makeup of Toxoplasma gondii is more complex than the three-strain theory, and unusual genotypes may contribute to various clinical outcomes of toxoplasmosis in different localities. Variant alleles have also been associated with the severity of pathology. The study of parasite genetic backgrounds is important for understanding the establishment of ocular disease [22].
Symptoms of OT Symptoms of OT include the following: ●● no pain (exception: pain due to ocular hypertension or iritis), ●● white eye (exception: due to ocular hypertension or iritis), ●● blurring, and ●● visual field defects.
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In contrast to the other forms of uveitis where vision impairments are caused by secondary complications, OT is commonly associated with vision problems depending on where the lesion is located. Predictably, lesions in the macular/perimacular areas had the poorest outcome but affected only 37.5 % of our patients. The vessel arcs not only were the most common site of lesions but were also characterized by a higher recurrence rate and shorter remission intervals. Furthermore, this group clearly showed a higher incidence of concomitant iritis.
Diagnosis of OT Ocular disease is diagnosed based on the appearance of the lesions in the eye, symptoms, and course of disease. Unfortunately, atypical clinical findings make clinical diagnosis more difficult, and at the moment, there is no reliable test known to diagnose OT. The presence of IgG T. gondii antibodies does not confirm the diagnosis (high prevalence in general population), but an absence in immunocompetent subjects usually rules out the possibility of OT. In cases where the diagnosis is uncertain, demonstration of anti-Toxoplasma antibody titers in the aqueous humor or vitreous can be helpful. PCR of aqueous, vitreous, and in rare cases retinal samples is another tool with high sensitivity and specificity [23]. The extent of the inflammation can be visualized using fluorescein and indocyanine green angiography, autofluorescence, and optical coherence tomography. These methods help to identify possible sequels such as epiretinal membrane, cystoid macular edema, neovascularization, vitreoretinal traction, and vasculitis. The outcome of the disease depends on many factors such as genotype and virulence of the parasite, inoculation, and immune system of the patient.
Management of OT The aim of treatment is twofold: first, to stop parasitic proliferation, and second, to reduce the sequels of inflammation. To do so, treatment of OT must be individualized; it depends on immune status, location of the lesions, severity of inflammation, and threat to eye sight. In immunocompetent patients, OT is self-limiting and can heal spontaneously after 1–3 months. When lesions are peripheral, symptoms are minimal, and neither the macula nor the optic disc is involved in the inflammation process, treatment is not required. Patients must simply be monitored. In all other cases, immediate treatment is necessary. Classic treatment consists of a “triple” therapy: 2–4-g loading dose of sulfadiazine followed by 1 g four times a day, with 75–100 mg of pyrimethamine loading dose followed by 25–50 mg a day, and corticosteroids for 4–6 weeks. Pyrimethamine can cause bone marrow depression, particularly leukopenia and thrombocytopenia.
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Folic acid 15 mg should be given three times weekly during the treatment to limit adverse effects. Clindamycin is sometimes added in severe cases, or used as a substitute in sulfadiazine allergy. A dose of 300 mg four times daily is recommended for 3–4 weeks followed by 150 mg four times daily for an additional 3–4 weeks. Azithromycin may also be used as a substitute [24, 25]. The combination of sulfamethoxazole, trimethoprim, and systemic corticosteroids is considered an effective alternative to the classic “triple” therapy. The 4–6 weeks’ treatment appears to be safe and has less severe side effects [26]. Intravitreal clindamycin plus dexamethasone is a novel approach that has shown comparable results to the classical OT management [27]. When anterior chamber activity is observed, topical steroids and hypotensive drops can be used to treat the resulting increase in intraocular pressure, if present. Reactivation of OT in pregnancy does not pose a risk to the fetus and should be managed considering the toxic and teratogenic potentials of the treatment. Intravitreal injections would reduce these risks.
Prevention of OT Transmission can occur by ingesting oocysts, tachyzoites, tissue cysts, or bradyzoites. In addition to contaminated food, water source contamination is increasingly recognized as a source of infection. The disease can also be acquired by transfusion of whole blood or leukocytes, by organ transplant, or accidentally in laboratory workers. Preventive measures include the following: ●● To reduce risk from food –– Cook meat to safe temperatures –– Do not taste ground meat before cooking –– Peal and wash fruits and vegetables ●● To reduce risk from environment –– Avoid drinking untreated drinking water (travel!) –– Wear gloves when gardening or having contact with soil –– Change the litter box of cats daily –– If pregnant or immunosuppressed, do not change cat litter, keep cats indoors, and do not eat raw food, including food containing raw eggs (tiramisu, parfaits, etc.) and unwashed fruits and vegetables.
Conclusion OT is a complex disease of which not all concepts are understood. Diagnosis as well as therapy remains a challenge even for specialists. More clinical and epidemiologic studies are needed to understand the mechanisms involved in reactivation of infection and to find a more efficacious therapy.
Ocular toxocariasis—ocular larva migrans Human toxocariasis is usually an asymptomatic infestation with a common roundworm, Toxocara spp., that infects dogs, foxes, and cats. It encompasses several generalized major and minor syndromes and compartmentalized forms, including ocular toxocariasis (ocular larva migrans (OLM)). The characteristics of the infestation will depend on the number of parasites, site of infection, migratory behavior, and the host immunological response. Humans are primarily infected through the ingestion of soil and food contaminated with embryonated eggs. After the eggs are ingested, they develop into second-stage larvae in the small intestine. They then enter the portal circulation, following hematogenous and lymphatic routes to form cysts in tissue structures [29]. Humans are not the natural hosts of Toxocara, and the parasite cannot mature into an adult worm in the intestine [30]; however, it can survive as larvae in tissues for several years. Although toxocariasis is the most common helminthiasis in the world (surveys showing a 2–5 % positive rate in healthy adults from urban Western countries and 14.2–37 % in rural areas) [31, 32], toxocariasis belongs to the five neglected parasitic infections.
Risk factors Risk factors include the following: ●● contact with soil contaminated with dog feces; children are at greatest risk because they may ingest soil with contaminated eggs in playing areas, ●● cohabitation with dogs and cats, ●● eating without hand washing. ●● rural dwelling, and ●● travel to areas of high prevalence.
Therapy can control ocular inflammation and limit damage to the ocular tissue, but is very limited in preventing recurrences. In a clinical study, combination of 60 mg of trimethoprim and 160 mg of sulfamethoxazole were given every 3 days as prophylaxis against recurrences of OT. After 20 months, only 6.6 % of patients taking the prophylactic combination had recurrences, in comparison with 23.6 % of patients taking the placebo [28].
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main topic Ocular manifestation of OLM The parasites reach the eye through the retinal, ciliary, and choroidal circulation causing, in most cases, an inflammation in the posterior segment of the eye (posterior or panuveitis). Usually, a granuloma is formed at the posterior pole, accompanied by dense vitreous opacifications. Pathognomonic are fibrous bands connecting the granuloma to the optical nerve head. By traction, they can cause retinal detachment and visual loss. The inflammation can be so massive that the differential diagnosis against diffuse retinoblastoma can be difficult. OLM tends to occur either in older children and young adults but can be diagnosed in the adults and elderly as well [33]. As posterior uveitis does not cause red eyes, external symptoms of the infestations are usually missing making the primary diagnosis of OLM, especially in children, difficult. Up to 1 % of uveitis cases in Austria and the USA are related to Toxocara infestation [33, 34] Chronic endophthalmitis
Posterior granuloma
Peripheral granuloma
Frequency (%)
25
25–46
20–40
Mean age at onset (years)
2–8
6–14
6–40
Differential diagnoses
Retinoblastoma Coat’s disease Hyperplastic primitive vitreous Retinopathy of prematurity
Toxoplasmic retinochoroiditis Ocular histoplasmosis Idiopathic subretinal neovascular membranes
Congenital retinal folds Pars planitis Familiar exudative vitreoretinopathy
Blindness can be a result of: 1) direct damage caused by the retinal granuloma, 2) vitreous fibrous traction bands causing retinal detachment, or 3) intense inflammatory reactions. Symptoms of ocular toxocariasis include: blurry vision, floaters, loss of visual acuity, leukocoria, and retinal detachment. In the early stages, the granuloma is elevated above the retina and may resemble a neoplasm.
Diagnosis [34] Diagnosis can be made by: ●● distinct clinical features, ●● echography, ●● specific IgG antibodies by enzyme-linked immunosorbent assay, ●● Western blot analysis using Toxocara canis E/S antigen, and ●● serum/ocular fluids.
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main topic Treatment In OLM, immunologic—sight threatening—reactions due to dying larvae are feared. Therefore, anti-inflammatory therapy is the mainstay of treatment when intraocular inflammation is present. No clear guidelines exist regarding the use of antihelminthic therapy. Albendazole can be used in combination with steroids, as albendazole crosses the blood–brain barrier and has a proven potential for destroying larval stages of Toxocara spp. located in the tissues of the paratenic and final hosts [35]. The regimen used is albendazole at 10 mg/kg bid for 14 days in combination with steroids to suppress allergic reactions toward the dying larvae.
Prognosis and complications ●● In the ocular form, outcome is variable, but uniocular visual loss is not uncommon. ●● In the visceral form, outcome is usually good, but marked organ damage and even death can occur in extreme cases.
Prevention Prevention of toxocariasis is obviously preferable, but eradicating T. canis infection is difficult because of the complexity of its life cycle. Good hygiene practices, timely disposal of pet feces, and routine deworming of pets are strategies necessary to reduce ocular toxocariasis in humans [36]. ●● Ocular toxocariasis is a rare but sight-threatening eye disease. ●● In children, it is important to carry out differential diagnosis before enucleating eyes for retinoblastoma. Conflict of interest The author declares that there are no actual or potential conflicts of interest in relation to this article.
References 1. Hoti SL, Tandon V. Ocular parasitoses and their immunology. Ocul Immunol Inflamm. 2011 Dec;19(6):385–96. 2. Nimir AR, Saliem A, Ibrahim IA. Ophthalmic parasitosis: a review article. Interdiscip Perspect Infect Dis. 2012;2012:587402. 3. Otranto D, Eberhard ML. Zoonotic helminths affecting the human eye. Parasit Vectors. 2011 Mar 23;4:41. 4. Lorenzo-Morales J, Martín-Navarro CM, López-Arencibia A, et al. Acanthamoeba keratitis: an emerging disease gathering importance worldwide? Trends Parasitol. 2013 Apr;29(4):181–7. 5. Seal DV. Acanthamoeba keratitis update-incidence, molecular epidemiology and new drugs for treatment. Eye (Lond). 2003 Nov;17(8):893–905.
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6. Panjwani N. Pathogenesis of acanthamoeba keratitis. Ocul Surf. 2010 Apr;8(2):70–9. 7. Cao Z, Jefferson DM, Panjwani N. Role of carbohydratemediated adherence in cytopathogenic mechanisms of Acanthamoeba. J Biol Chem. 1998 Jun 9;273(25):15838–45. 8. Qian Y, Meisler DM, Langston RH, Jeng BH. Clinical experience with Acanthamoeba keratitis at the cole eye institute, 1999–2008. Cornea. 2010 Sep;29(9):1016–21. 9. Clarke B, Sinha A, Parmar DN, et al. Advances in the diagnosis and treatment of acanthamoeba keratitis. J Ophthalmol. 2012;2012:484892. doi:10.1155/2012/484892. 10. Awwad ST, Petroll WM, McCulley JP, et al. Updates in Acanthamoeba keratitis. Eye Contact Lens. 2007 Jan;33(1):1–8. 11. Page MA, Mathers WD. Acanthamoeba keratitis: a 12-year experience covering a wide spectrum of presentations, diagnoses, and outcomes. J Ophthalmol. 2013;2013:670242. doi:10.1155/2013/670242. Epub 2013 Jun 12. PubMed PMID: 23840938; PubMed Central PMCID: PMC3694549. 12. Aksozek A, McClellan K, Howard K, et al. Resistance of Acanthamoeba castellanii cysts to physical, chemical, and radiological conditions. J Parasitol. 2002 Jun;88(3):621–3. 13. Walochnik J, Obwaller A, Gruber F, et al. Anti-acanthamoeba efficacy and toxicity of miltefosine in an organotypic skin equivalent. J Antimicrob Chemother. 2009 Sep;64(3):539–45. 14. Polat ZA, Obwaller A, Vural A, et al. Efficacy of miltefosine for topical treatment of Acanthamoeba keratitis in Syrian hamsters. Parasitol Res. 2012 Feb;110(2):515–20. 15. Aichelburg AC, Walochnik J, Assadian O, et al. Successful treatment of disseminated Acanthamoeba sp. infection with miltefosine. Emerg Infect Dis. 2008 Nov;14(11):1743–6. 16. Barisani-Asenbauer T, Walochnik J, Mejdoubi L, et al. Sucessful management of recurrent Acanthamoeba keratitis using topical and systemic miltefosine. 2012 EVER meeting abstracts, abstract # eF095. Accessed 5. May 2013. 17. Khan YA, Kashiwabuchi RT, Martins SA, et al. Riboflavin and ultraviolet light a therapy as an adjuvant treatment for medically refractive Acanthamoeba keratitis: report of 3 cases. Ophthalmology. 2011 Feb;118(2):324–31. 18. Parthasarathy A, Tan DT. Deep lamellar keratoplasty for acanthamoeba keratitis. Cornea. 2007 Sep;26(8):1021–3. 19. Dodds EM, Holland GN, Stanford MR, et al. Intraocular inflammation associated with ocular toxoplasmosis: relationships at initial examination. Am J Ophthalmol. 2008 Dec;146(6):856–65.e2. 20. Goldenberg D, Goldstein M, Loewenstein A, Habot-Wilner Z. Vitreal, retinal, and choroidal findings in active and scarred toxoplasmosis lesions: a prospective study by spectral-domain optical coherence tomography. Graefes Arch Clin Exp Ophthalmol. 2013 Aug;251(8):2037–45. 21. Vasconcelos-Santos DV. Ocular manifestations of systemic disease: toxoplasmosis. Curr Opin Ophthalmol. 2012 Nov;23(6):543–50. doi: 10.1097/ICU.0b013e328358bae5. 22. Vallochi AL, Goldberg AC, Falcai A, et al. Molecular markers of susceptibility to ocular toxoplasmosis, host and guest behaving badly. Clin Ophthalmol. 2008 Dec;2(4):837–48. 23. Sugita S, Ogawa M, Shimizu N, Morio T, Ohguro N, Nakai K, Maruyama K, Nagata K, Takeda A, Usui Y, Sonoda KH, Takeuchi M, Mochizuki M. Use of a comprehensive polymerase chain reaction system for diagnosis of ocular infectious diseases. Ophthalmology. 2013 Sep;120(9):1761–8. 24. Stanford MR, See SE, Jones LV, et al. Antibiotics for toxoplasmic retinochoroiditis: an evidence-based systematic review. Ophthalmology. 2003 May;110(5):926–31. 25. Rothova A, Bosch-Driessen LE, van Loon NH, et al. Azithromycin for ocular toxoplasmosis. Br J Ophthalmol. 1998 Nov;82(11):1306–8.
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main topic 26. Soheilian M, Sadoughi MM, Ghajarnia M, et al. Prospective randomized trial of trimethoprim/sulfamethoxazole versus pyrimethamine and sulfadiazine in the treatment of ocular toxoplasmosis. Ophthalmology. 2005 Nov;112(11):1876–82. 27. Lasave AF, Díaz-Llopis M, Muccioli C, et al. Intravitreal clindamycin and dexamethasone for zone 1 toxoplasmic retinochoroiditis at twenty-four months. Ophthalmology. 2010 Sep;117(9):1831–8. doi:10.1016/j.ophtha.2010.01.028. 28. Silveira C, Belfort R Jr, Muccioli C, Holland GN, Victora CG, Horta BL, Yu F, Nussenblatt RB. The effect of long-term intermittent trimethoprim/sulfamethoxazole treatment on recurrences of toxoplasmic retinochoroiditis. Am J Ophthalmol. 2002 Jul;134(1):41–6. 29. Despommier D. Toxocariasis: clinical aspects, epidemiology, medical ecology, and molecular aspects. Clin Microbiol Rev. 2003 Apr;16(2):265–72. 30. Azam D, Ukpai OM, Said A, et al. Temperature and the development and survival of infective Toxocara canis larvae. Parasitol Res. 2012 Feb;110(2):649–56. 31. Chomel BB, Kasten R, Adams C, et al. Serosurvey of some major zoonotic infections in children and teenagers in Bali, Indonesia. Southeast Asian J Trop Med Public Health. 1993 Jun;24(2):321–6.
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32. Magnaval JF, Michault A, Calon N, et al. Epidemiology of human toxocariasis in La Réunion. Trans R Soc Trop Med Hyg. 1994 Sep-Oct;88(5):531–3. 33. Barisani-Asenbauer T, Maca SM, Hauff W, Kaminski SL, Domanovits H, Theyer I, Auer H. Treatment of ocular toxocariasis with albendazole. J Ocul Pharmacol Ther. 2001 Jun;17(3):287–94. 34. Woodhall D, Starr MC, Montgomery SP, Jones JL, Lum F, Read RW, Moorthy RS. Ocular toxocariasis: epidemiologic, anatomic, and therapeutic variations based on a survey of ophthalmic subspecialists. Ophthalmology. 2012 Jun;119(6):1211–7. 35. de Visser L, Rothova A, de Boer JH, et al. Diagnosis of ocular toxocariasis by establishing intraocular antibody production. Am J Ophthalmol. 2008 Feb;145(2):369–74. 36. Centers for Disease Control and Prevention (CDC). Ocular toxocariasis—United States, 2009-2010. MMWR Morb Mortal Wkly Rep. 2011 Jun 10;60(22):734–6.
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Sitting at the window to the world—ocular parasites Talin Barisani-Asenbauer
Received: 28 November 2013 / Accepted: 20 August 2014 / Published online: 31 October 2014 © Springer-Verlag Wien 2014
Summary Parasitic infections cause significant ophthalmic disease, both in developing countries and in the Western world. The parasitic infections Acanthamoeba keratitis, ocular toxoplasmosis, and ocular toxocariasis are responsible for a significant proportion of ocular pathology. Especially in light of the recent increase of immunocompromised (i.e. using immunosuppressants or HIV) and aged populations, parasitic infections of the eye are rising in number. This reviews aims to describe the pathogenesis, symptoms, diagnosis and management of infection, as well as preventative measures for these three parasitic ocular diseases. Keywords Acanthamoeba keratitis · Ocular toxoplasmosis · Ocular toxocariasis
Am Fenster der Welt – Okulare Parasiten Zusammenfassung Parasitische Infektionen sind global, sowohl in Entwicklungsländern als auch in der westlichen Welt die Ursache einer Vielzahl von Augenerkrankungen. Acanthamoen-Keratitis, okuläre Toxoplasmose und okuläre Toxocarose haben einen signifikanten Anteil an der Entstehung okulärer Pathologien. Bedingt durch die steigende Anzahl immunkompromitierter (durch immunsupressive Therapien oder HIV) und älterer Individuen in der Bevölkerung nehmen parasitische Erkrankungen des Auges in den letzten Jahren deutlich zu. Dieser Artikel fasst die Pathogenese, Symptome, Diagnosemethoden und Therapieansätze für diese drei parasitischen Erkrana.o. Univ. Prof. Dr. T. Barisani-Asenbauer () Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Kinderspitalgasse 15, 1090 Vienna, Austria e-mail: [email protected]
392 Sitting at the window to the world—ocular parasites
kungen zusammen und gibt einen Überblick über vorbeugende Maßnahmen zur Verhinderung einer Infektion. Schlüsselwörter Acanthamoen-Keratitis · Okuläre Toxoplasmose · Okuläre Toxocarose
Introduction Parasitic infections cause significant ophthalmic disease globally. Nevertheless, the epidemiology of parasitic ocular disease depends on the habitats of causative parasites as well as on the conduct and health status of individuals [1]. Therefore, the geographic location and cultural traditions are an important determining factor in the development of specific parasitic infections. For example, in developing countries, onchocerciasis affects millions of subjects and is recognized as second in the world only to trachoma as an infectious cause of blindness, whereas in the Western world, toxoplasmotic and Acanthamoeba infestations are accountable for a significant proportion of ocular morbidity [2]. Moreover, due to the recent increase in immunocompromised (i.e., using biologics or immunosuppressants, with human immunodeficiency virus (HIV), etc.) and aged populations, opportunistic infections of the eye, including parasitic infections, are rising [3]. This review is not comprehensive for the global community but focuses on disorders associated with more common ocular parasitic infections in Central Europe such as Acanthamoeba keratitis (AK), ocular toxoplasmosis (OT), and ocular toxocariasis.
Acanthamoeba keratitis Acanthamoebae are ubiquitous free-living amoebae. As opportunistic pathogens, they are the causative agents of
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AK, a sight-threatening, very painful corneal infection [4]. AK can carry a favorable prognosis when diagnosed and treated early in the disease course, but available treatment options can remain ineffective even when started early. AK is the most common Acanthamoeba infection, but with a prevalence of 0.2–0.3 per 10,000 contact lens wearers or 0.15–1.4 per million inhabitants (depending on the country) [5], it is still among the “orphan diseases.” Nevertheless, AK is a debilitating disease, and the management thereof poses two major challenges: the duly diagnosis of the disease and the effective eradication of cysts, which are resistant to most of the antimicrobial drugs [6]. In many cases, ophthalmologists may miss AK thinking of a bacterial or viral infection, which could delay the diagnosis.
Pathogenesis The pathogenesis of AK involves direct contact between the cornea and trophozoites. “Mini”-corneal injuries as seen in contact lens wearers facilitate the invasion of the parasite; however, acanthamoebae possess the capability to produce proteases that can degrade epithelial cell membranes without previous injury [7]. Contact lens
wear is seen as the leading risk factor for AK [8]; nevertheless, AK can also be seen in non-contact lens wearers [4, 9, 10].
Symptoms of the infection The predominant symptom of AK is pain! Subjects hardly can bear this pain that is often not explainable by the keratitis itself and serves as a valuable parameter to differentiate AK from herpetic stromal keratitis. Further symptoms can be very similar to the symptoms of other eye inflammations and infections. Nevertheless, in AK, these symptoms can last for several weeks or months: ●● ●● ●● ●● ●●
severe pain, excessive tearing, eye redness, blurred vision, and sensitivity to light.
Diagnosis of AK Clinical suspicion is the most critical step in the diagnosis of AK. Corneal scrapes for cultivation of amoebae, immunohistological staining, and/or polymerase chain reaction (PCR) analysis should be performed (Figs. 1 and 2). Where possible, confocal in vivo microscopy could help to diagnose the infection rapidly before laboratory results are available [11].
Management of AK
Fig. 1 Fresh lesion next to corneal scar in recurrent Acanthamoeba keratitis (contact lens wearer)
Fig. 2 Acanthamoeba keratitis in non-contact lens wearer. Subject had a corneal perforation
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There are currently no licensed drugs for the treatment of any of the Acanthamoeba infections. In AK, cure is usually achieved with a combination of biguanides such as polyhexamethylene biguanide or chlorhexidine, and diamidines such as propamidine isethionate (Brolene) or hexamidine (Desomedine) [9]. Treatment has to be applied aggressively at least hourly during the first days and subsequently several times a day for usually 6 months. However, sufficient efficacy is not always achieved, and resistance against propamidine is known to occur during long-term treatment [9]. Another major problem in treatment is amoebal encystation. Acanthamoebae, in contrast to most other amoebae, can encyst within the tissue, and Acanthamoeba cysts are significantly less susceptible to antimicrobials and disinfectants [12]. Thus, relapses may occur as soon as treatment is stopped. Recently, an immunocompromised but HIV-negative subject with disseminated Acanthamoeba infection was successfully treated with miltefosine. Miltefosine (hexadecylphosphocholine), an alkylphosphocholine, approved for the oral and topical treatment of leishmaniasis, proved also to be highly active against Acanthamoeba in vitro [13] and in vivo [14, 15]. For human AK,
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preliminary data on successful treatment with miltefosine of refractive cases are reported [16]. Moreover, collagen cross-linking is another new treatment modality for AK. Although in vivo studies could not show effectiveness, several clinical cases were treated successfully [17]. Finally, corneal transplantation could be required in cases where resulting corneal scarring reduces vision significantly [18]. Surgery should be performed in quiet eyes whenever possible to reduce the risk of corneal rejection, and deep lamellar keratoplasty where the corneal endothelium remains intact can not only help to improve graft survival but also serve as barrier against parasite invasion.
Prevention
Fig. 3 Pathognomonic picture: fresh satellite next to old scar
To reduce the risk of AK contact lens wearers should
Ocular toxoplasmosis
●● wear and replace contact lenses as prescribed, ●● store reusable contact lenses as prescribed and never use tap water, ●● replace storage cases regularly, ●● not moisten contact lenses with either saliva or tap water, and ●● not wear contact lenses while swimming.
Although most toxoplasmosis infections remain asymptomatic—one-third of the world population is estimated to be seropositive—before progressing into a state of latent infection, they can result in severe ocular complications. The parasite typically persists in the retina, leading to recurring inflammation in the posterior segment of the eye. Current treatments can control active inflammation, but play a very limited role in the prevention of recurrences.
Fig. 4 Optical coherence tomography of fresh toxoplasmotic lesion before and after therapy. Note that final scar is much smaller than the inflammatory zone at the beginning
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main topic Ocular manifestation OT is the most frequent cause of posterior uveitis [19], an inflammation that occurs in the posterior pole of the eye. It can be congenitally transmitted or acquired after birth. Active ocular inflammation occurs when Toxoplasma cysts are present in the retina. Typical clinical findings are unilateral retinal lesions with involvement of the choroid. The lesions can either present as satellites to retinal scarring or multifocal or solitary lesions [20]. Other ocular symptoms include neuroretinitis, vasculitis, ocular vein occlusion, vitritis, and iritis. In immunocompetent patients, OT is almost always unilateral but can switch eyes from one episode to the other. Patients often describe unspecific symptoms, such as blurred vision, mild ocular pain, photophobia, and floaters in the active eye. Classic signs of activity include white-grayish lesions that are overlaid by vitreous cellular infiltrates. The fundus seems “cloudy.” Inactive lesions are characterized by their sharp pigmented margins, white center, and clear media. As a result of necrotizing retinitis, scars cicatrize from periphery to center. OT can heal spontaneously, but not without pigmented retinal scarring. This leads to more or less severe visual field impairment, depending on the location of the scar (Figs. 3 and 4). In congenital OT, lesions occur more often in the center of the macula (responsible for sharp central vision), which influences visual acuity severely and can lead to amblyopia, whereas in acquired OT, lesions are more often positioned in the periphery, thus resulting in a less significant loss of visual acuity and field. In most cases, OT is a reactivation of an acute infection not reflected by serological rise of antibodies. As systemic disease often occurs without symptoms, time elapsing between primary infection and ocular manifestations can vary extremely, making diagnosis even more difficult [21]. In immunocompromised individuals, OT is usually atypical and difficult to diagnose, as clinical picture can mimic many ocular infections and also tumors. The genetic makeup of Toxoplasma gondii is more complex than the three-strain theory, and unusual genotypes may contribute to various clinical outcomes of toxoplasmosis in different localities. Variant alleles have also been associated with the severity of pathology. The study of parasite genetic backgrounds is important for understanding the establishment of ocular disease [22].
Symptoms of OT Symptoms of OT include the following: ●● no pain (exception: pain due to ocular hypertension or iritis), ●● white eye (exception: due to ocular hypertension or iritis), ●● blurring, and ●● visual field defects.
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In contrast to the other forms of uveitis where vision impairments are caused by secondary complications, OT is commonly associated with vision problems depending on where the lesion is located. Predictably, lesions in the macular/perimacular areas had the poorest outcome but affected only 37.5 % of our patients. The vessel arcs not only were the most common site of lesions but were also characterized by a higher recurrence rate and shorter remission intervals. Furthermore, this group clearly showed a higher incidence of concomitant iritis.
Diagnosis of OT Ocular disease is diagnosed based on the appearance of the lesions in the eye, symptoms, and course of disease. Unfortunately, atypical clinical findings make clinical diagnosis more difficult, and at the moment, there is no reliable test known to diagnose OT. The presence of IgG T. gondii antibodies does not confirm the diagnosis (high prevalence in general population), but an absence in immunocompetent subjects usually rules out the possibility of OT. In cases where the diagnosis is uncertain, demonstration of anti-Toxoplasma antibody titers in the aqueous humor or vitreous can be helpful. PCR of aqueous, vitreous, and in rare cases retinal samples is another tool with high sensitivity and specificity [23]. The extent of the inflammation can be visualized using fluorescein and indocyanine green angiography, autofluorescence, and optical coherence tomography. These methods help to identify possible sequels such as epiretinal membrane, cystoid macular edema, neovascularization, vitreoretinal traction, and vasculitis. The outcome of the disease depends on many factors such as genotype and virulence of the parasite, inoculation, and immune system of the patient.
Management of OT The aim of treatment is twofold: first, to stop parasitic proliferation, and second, to reduce the sequels of inflammation. To do so, treatment of OT must be individualized; it depends on immune status, location of the lesions, severity of inflammation, and threat to eye sight. In immunocompetent patients, OT is self-limiting and can heal spontaneously after 1–3 months. When lesions are peripheral, symptoms are minimal, and neither the macula nor the optic disc is involved in the inflammation process, treatment is not required. Patients must simply be monitored. In all other cases, immediate treatment is necessary. Classic treatment consists of a “triple” therapy: 2–4-g loading dose of sulfadiazine followed by 1 g four times a day, with 75–100 mg of pyrimethamine loading dose followed by 25–50 mg a day, and corticosteroids for 4–6 weeks. Pyrimethamine can cause bone marrow depression, particularly leukopenia and thrombocytopenia.
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Folic acid 15 mg should be given three times weekly during the treatment to limit adverse effects. Clindamycin is sometimes added in severe cases, or used as a substitute in sulfadiazine allergy. A dose of 300 mg four times daily is recommended for 3–4 weeks followed by 150 mg four times daily for an additional 3–4 weeks. Azithromycin may also be used as a substitute [24, 25]. The combination of sulfamethoxazole, trimethoprim, and systemic corticosteroids is considered an effective alternative to the classic “triple” therapy. The 4–6 weeks’ treatment appears to be safe and has less severe side effects [26]. Intravitreal clindamycin plus dexamethasone is a novel approach that has shown comparable results to the classical OT management [27]. When anterior chamber activity is observed, topical steroids and hypotensive drops can be used to treat the resulting increase in intraocular pressure, if present. Reactivation of OT in pregnancy does not pose a risk to the fetus and should be managed considering the toxic and teratogenic potentials of the treatment. Intravitreal injections would reduce these risks.
Prevention of OT Transmission can occur by ingesting oocysts, tachyzoites, tissue cysts, or bradyzoites. In addition to contaminated food, water source contamination is increasingly recognized as a source of infection. The disease can also be acquired by transfusion of whole blood or leukocytes, by organ transplant, or accidentally in laboratory workers. Preventive measures include the following: ●● To reduce risk from food –– Cook meat to safe temperatures –– Do not taste ground meat before cooking –– Peal and wash fruits and vegetables ●● To reduce risk from environment –– Avoid drinking untreated drinking water (travel!) –– Wear gloves when gardening or having contact with soil –– Change the litter box of cats daily –– If pregnant or immunosuppressed, do not change cat litter, keep cats indoors, and do not eat raw food, including food containing raw eggs (tiramisu, parfaits, etc.) and unwashed fruits and vegetables.
Conclusion OT is a complex disease of which not all concepts are understood. Diagnosis as well as therapy remains a challenge even for specialists. More clinical and epidemiologic studies are needed to understand the mechanisms involved in reactivation of infection and to find a more efficacious therapy.
Ocular toxocariasis—ocular larva migrans Human toxocariasis is usually an asymptomatic infestation with a common roundworm, Toxocara spp., that infects dogs, foxes, and cats. It encompasses several generalized major and minor syndromes and compartmentalized forms, including ocular toxocariasis (ocular larva migrans (OLM)). The characteristics of the infestation will depend on the number of parasites, site of infection, migratory behavior, and the host immunological response. Humans are primarily infected through the ingestion of soil and food contaminated with embryonated eggs. After the eggs are ingested, they develop into second-stage larvae in the small intestine. They then enter the portal circulation, following hematogenous and lymphatic routes to form cysts in tissue structures [29]. Humans are not the natural hosts of Toxocara, and the parasite cannot mature into an adult worm in the intestine [30]; however, it can survive as larvae in tissues for several years. Although toxocariasis is the most common helminthiasis in the world (surveys showing a 2–5 % positive rate in healthy adults from urban Western countries and 14.2–37 % in rural areas) [31, 32], toxocariasis belongs to the five neglected parasitic infections.
Risk factors Risk factors include the following: ●● contact with soil contaminated with dog feces; children are at greatest risk because they may ingest soil with contaminated eggs in playing areas, ●● cohabitation with dogs and cats, ●● eating without hand washing. ●● rural dwelling, and ●● travel to areas of high prevalence.
Therapy can control ocular inflammation and limit damage to the ocular tissue, but is very limited in preventing recurrences. In a clinical study, combination of 60 mg of trimethoprim and 160 mg of sulfamethoxazole were given every 3 days as prophylaxis against recurrences of OT. After 20 months, only 6.6 % of patients taking the prophylactic combination had recurrences, in comparison with 23.6 % of patients taking the placebo [28].
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main topic Ocular manifestation of OLM The parasites reach the eye through the retinal, ciliary, and choroidal circulation causing, in most cases, an inflammation in the posterior segment of the eye (posterior or panuveitis). Usually, a granuloma is formed at the posterior pole, accompanied by dense vitreous opacifications. Pathognomonic are fibrous bands connecting the granuloma to the optical nerve head. By traction, they can cause retinal detachment and visual loss. The inflammation can be so massive that the differential diagnosis against diffuse retinoblastoma can be difficult. OLM tends to occur either in older children and young adults but can be diagnosed in the adults and elderly as well [33]. As posterior uveitis does not cause red eyes, external symptoms of the infestations are usually missing making the primary diagnosis of OLM, especially in children, difficult. Up to 1 % of uveitis cases in Austria and the USA are related to Toxocara infestation [33, 34] Chronic endophthalmitis
Posterior granuloma
Peripheral granuloma
Frequency (%)
25
25–46
20–40
Mean age at onset (years)
2–8
6–14
6–40
Differential diagnoses
Retinoblastoma Coat’s disease Hyperplastic primitive vitreous Retinopathy of prematurity
Toxoplasmic retinochoroiditis Ocular histoplasmosis Idiopathic subretinal neovascular membranes
Congenital retinal folds Pars planitis Familiar exudative vitreoretinopathy
Blindness can be a result of: 1) direct damage caused by the retinal granuloma, 2) vitreous fibrous traction bands causing retinal detachment, or 3) intense inflammatory reactions. Symptoms of ocular toxocariasis include: blurry vision, floaters, loss of visual acuity, leukocoria, and retinal detachment. In the early stages, the granuloma is elevated above the retina and may resemble a neoplasm.
Diagnosis [34] Diagnosis can be made by: ●● distinct clinical features, ●● echography, ●● specific IgG antibodies by enzyme-linked immunosorbent assay, ●● Western blot analysis using Toxocara canis E/S antigen, and ●● serum/ocular fluids.
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main topic Treatment In OLM, immunologic—sight threatening—reactions due to dying larvae are feared. Therefore, anti-inflammatory therapy is the mainstay of treatment when intraocular inflammation is present. No clear guidelines exist regarding the use of antihelminthic therapy. Albendazole can be used in combination with steroids, as albendazole crosses the blood–brain barrier and has a proven potential for destroying larval stages of Toxocara spp. located in the tissues of the paratenic and final hosts [35]. The regimen used is albendazole at 10 mg/kg bid for 14 days in combination with steroids to suppress allergic reactions toward the dying larvae.
Prognosis and complications ●● In the ocular form, outcome is variable, but uniocular visual loss is not uncommon. ●● In the visceral form, outcome is usually good, but marked organ damage and even death can occur in extreme cases.
Prevention Prevention of toxocariasis is obviously preferable, but eradicating T. canis infection is difficult because of the complexity of its life cycle. Good hygiene practices, timely disposal of pet feces, and routine deworming of pets are strategies necessary to reduce ocular toxocariasis in humans [36]. ●● Ocular toxocariasis is a rare but sight-threatening eye disease. ●● In children, it is important to carry out differential diagnosis before enucleating eyes for retinoblastoma. Conflict of interest The author declares that there are no actual or potential conflicts of interest in relation to this article.
References 1. Hoti SL, Tandon V. Ocular parasitoses and their immunology. Ocul Immunol Inflamm. 2011 Dec;19(6):385–96. 2. Nimir AR, Saliem A, Ibrahim IA. Ophthalmic parasitosis: a review article. Interdiscip Perspect Infect Dis. 2012;2012:587402. 3. Otranto D, Eberhard ML. Zoonotic helminths affecting the human eye. Parasit Vectors. 2011 Mar 23;4:41. 4. Lorenzo-Morales J, Martín-Navarro CM, López-Arencibia A, et al. Acanthamoeba keratitis: an emerging disease gathering importance worldwide? Trends Parasitol. 2013 Apr;29(4):181–7. 5. Seal DV. Acanthamoeba keratitis update-incidence, molecular epidemiology and new drugs for treatment. Eye (Lond). 2003 Nov;17(8):893–905.
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6. Panjwani N. Pathogenesis of acanthamoeba keratitis. Ocul Surf. 2010 Apr;8(2):70–9. 7. Cao Z, Jefferson DM, Panjwani N. Role of carbohydratemediated adherence in cytopathogenic mechanisms of Acanthamoeba. J Biol Chem. 1998 Jun 9;273(25):15838–45. 8. Qian Y, Meisler DM, Langston RH, Jeng BH. Clinical experience with Acanthamoeba keratitis at the cole eye institute, 1999–2008. Cornea. 2010 Sep;29(9):1016–21. 9. Clarke B, Sinha A, Parmar DN, et al. Advances in the diagnosis and treatment of acanthamoeba keratitis. J Ophthalmol. 2012;2012:484892. doi:10.1155/2012/484892. 10. Awwad ST, Petroll WM, McCulley JP, et al. Updates in Acanthamoeba keratitis. Eye Contact Lens. 2007 Jan;33(1):1–8. 11. Page MA, Mathers WD. Acanthamoeba keratitis: a 12-year experience covering a wide spectrum of presentations, diagnoses, and outcomes. J Ophthalmol. 2013;2013:670242. doi:10.1155/2013/670242. Epub 2013 Jun 12. PubMed PMID: 23840938; PubMed Central PMCID: PMC3694549. 12. Aksozek A, McClellan K, Howard K, et al. Resistance of Acanthamoeba castellanii cysts to physical, chemical, and radiological conditions. J Parasitol. 2002 Jun;88(3):621–3. 13. Walochnik J, Obwaller A, Gruber F, et al. Anti-acanthamoeba efficacy and toxicity of miltefosine in an organotypic skin equivalent. J Antimicrob Chemother. 2009 Sep;64(3):539–45. 14. Polat ZA, Obwaller A, Vural A, et al. Efficacy of miltefosine for topical treatment of Acanthamoeba keratitis in Syrian hamsters. Parasitol Res. 2012 Feb;110(2):515–20. 15. Aichelburg AC, Walochnik J, Assadian O, et al. Successful treatment of disseminated Acanthamoeba sp. infection with miltefosine. Emerg Infect Dis. 2008 Nov;14(11):1743–6. 16. Barisani-Asenbauer T, Walochnik J, Mejdoubi L, et al. Sucessful management of recurrent Acanthamoeba keratitis using topical and systemic miltefosine. 2012 EVER meeting abstracts, abstract # eF095. Accessed 5. May 2013. 17. Khan YA, Kashiwabuchi RT, Martins SA, et al. Riboflavin and ultraviolet light a therapy as an adjuvant treatment for medically refractive Acanthamoeba keratitis: report of 3 cases. Ophthalmology. 2011 Feb;118(2):324–31. 18. Parthasarathy A, Tan DT. Deep lamellar keratoplasty for acanthamoeba keratitis. Cornea. 2007 Sep;26(8):1021–3. 19. Dodds EM, Holland GN, Stanford MR, et al. Intraocular inflammation associated with ocular toxoplasmosis: relationships at initial examination. Am J Ophthalmol. 2008 Dec;146(6):856–65.e2. 20. Goldenberg D, Goldstein M, Loewenstein A, Habot-Wilner Z. Vitreal, retinal, and choroidal findings in active and scarred toxoplasmosis lesions: a prospective study by spectral-domain optical coherence tomography. Graefes Arch Clin Exp Ophthalmol. 2013 Aug;251(8):2037–45. 21. Vasconcelos-Santos DV. Ocular manifestations of systemic disease: toxoplasmosis. Curr Opin Ophthalmol. 2012 Nov;23(6):543–50. doi: 10.1097/ICU.0b013e328358bae5. 22. Vallochi AL, Goldberg AC, Falcai A, et al. Molecular markers of susceptibility to ocular toxoplasmosis, host and guest behaving badly. Clin Ophthalmol. 2008 Dec;2(4):837–48. 23. Sugita S, Ogawa M, Shimizu N, Morio T, Ohguro N, Nakai K, Maruyama K, Nagata K, Takeda A, Usui Y, Sonoda KH, Takeuchi M, Mochizuki M. Use of a comprehensive polymerase chain reaction system for diagnosis of ocular infectious diseases. Ophthalmology. 2013 Sep;120(9):1761–8. 24. Stanford MR, See SE, Jones LV, et al. Antibiotics for toxoplasmic retinochoroiditis: an evidence-based systematic review. Ophthalmology. 2003 May;110(5):926–31. 25. Rothova A, Bosch-Driessen LE, van Loon NH, et al. Azithromycin for ocular toxoplasmosis. Br J Ophthalmol. 1998 Nov;82(11):1306–8.
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main topic 26. Soheilian M, Sadoughi MM, Ghajarnia M, et al. Prospective randomized trial of trimethoprim/sulfamethoxazole versus pyrimethamine and sulfadiazine in the treatment of ocular toxoplasmosis. Ophthalmology. 2005 Nov;112(11):1876–82. 27. Lasave AF, Díaz-Llopis M, Muccioli C, et al. Intravitreal clindamycin and dexamethasone for zone 1 toxoplasmic retinochoroiditis at twenty-four months. Ophthalmology. 2010 Sep;117(9):1831–8. doi:10.1016/j.ophtha.2010.01.028. 28. Silveira C, Belfort R Jr, Muccioli C, Holland GN, Victora CG, Horta BL, Yu F, Nussenblatt RB. The effect of long-term intermittent trimethoprim/sulfamethoxazole treatment on recurrences of toxoplasmic retinochoroiditis. Am J Ophthalmol. 2002 Jul;134(1):41–6. 29. Despommier D. Toxocariasis: clinical aspects, epidemiology, medical ecology, and molecular aspects. Clin Microbiol Rev. 2003 Apr;16(2):265–72. 30. Azam D, Ukpai OM, Said A, et al. Temperature and the development and survival of infective Toxocara canis larvae. Parasitol Res. 2012 Feb;110(2):649–56. 31. Chomel BB, Kasten R, Adams C, et al. Serosurvey of some major zoonotic infections in children and teenagers in Bali, Indonesia. Southeast Asian J Trop Med Public Health. 1993 Jun;24(2):321–6.
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32. Magnaval JF, Michault A, Calon N, et al. Epidemiology of human toxocariasis in La Réunion. Trans R Soc Trop Med Hyg. 1994 Sep-Oct;88(5):531–3. 33. Barisani-Asenbauer T, Maca SM, Hauff W, Kaminski SL, Domanovits H, Theyer I, Auer H. Treatment of ocular toxocariasis with albendazole. J Ocul Pharmacol Ther. 2001 Jun;17(3):287–94. 34. Woodhall D, Starr MC, Montgomery SP, Jones JL, Lum F, Read RW, Moorthy RS. Ocular toxocariasis: epidemiologic, anatomic, and therapeutic variations based on a survey of ophthalmic subspecialists. Ophthalmology. 2012 Jun;119(6):1211–7. 35. de Visser L, Rothova A, de Boer JH, et al. Diagnosis of ocular toxocariasis by establishing intraocular antibody production. Am J Ophthalmol. 2008 Feb;145(2):369–74. 36. Centers for Disease Control and Prevention (CDC). Ocular toxocariasis—United States, 2009-2010. MMWR Morb Mortal Wkly Rep. 2011 Jun 10;60(22):734–6.
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