Two sisters with microphthalmia and anterior segment dysgenesis secondary to a PAX6 pathogenic variant with clinically healthy parents: a case of gonadal mosaicism?

PURPOSE: Genetic analysis of two siblings with complex microphthalmia, with clinically healthy parents. STUDY DESIGN: Clinical and experimental. METHODS: The patients underwent a detailed ophthalmic evaluation, including visual acuity, fundus examination, gonioscopy, ultrasound examination, and optical coherence tomography. Lensectomy with anterior vitrectomy was conducted in both patients. Additionally, in patient p1, electroencephalography analysis was performed. Genetic analysis was carried out using array comparative genomic hybridization (aCGH) and whole exome sequencing (WES). Bidirectional Sanger sequencing was conducted for validation and segregation analysis of the identified variant in the family. RESULTS: The aCGH results were normal. The heterozygous PAX6 variant c.52G>C (p.Gly18Arg) was identified in the proband (p1) through WES analysis. Sanger sequencing of exon 5 of PAX6 confirmed the presence of the variant in the other affected sibling (patient p2) but did not allow for identification of the variant in the parents' DNA isolated from leukocytes and buccal cells. CONCLUSIONS: The description of the variant in PAX6 in two siblings with clinically healthy parents who are negative for the mutation in DNA from leukocytes and buccal cells represents the possibility of parental gonadal mosaicism. Detection of germ cell mosaicism in the parents is essential to provide genetic counseling to the family regarding the risk of reoccurrence. Furthermore, we also report a pathogenic variant in PAX6 that to our knowledge has not so far been reported in patients with partial aniridia and therefore broadens the spectrum of the variants associated with aniridia.

Ocular loiasis affecting a child and its assessment by Anterior Segment Optical Coherence Tomography.

A 9-year-old girl from Equatorial Guinea presented to the emergency department complaining of foreign body sensation in her right eye. A thin and large, translucent, slowly moving, coiled worm was observed underneath the conjunctiva. Anterior segment optical coherence tomography revealed hyperreflective small areas surrounded by larger hyporeflective areas into the subconjunctival space. Loa loa microfilaria was evidenced on blood test. Surgical extraction of the subconjunctival worm was intended on slit lamp and under sedation in the operating room, but it was unsuccessful due to poor cooperation and rapid migration of the larva into the sub-Tenon's space. The patient received two cycles of oral albendazole and one cycle of diethylcarbamazine before achieving complete microfilaria seroconversion. Abbreviations: AS-OCT = Anterior Segment Optical Coherence Tomography, PCR = Polymerase Chain Reaction, DEC = diethylcarbamazine.

The involvement of anti-inflammatory protein, annexin A1, in ocular toxoplasmosis.

PURPOSE: The aim of this study was to evaluate the expression of the protein annexin A1 (ANXA1), a potent endogenous regulator of the inflammatory process, in ocular toxoplasmosis. METHODS: C57BL/6 female mice were infected using intravitreal injections of either 10(6) tachyzoites of Toxoplasma gondii (RH strain; T. gondii) or PBS only (control groups). After 24, 48, and 72 h, animals were sacrificed and their eyes were harvested for histopathological, immunohistochemical, and ultrastructural immunocytochemical analysis of ANXA1. Human retinal pigment epithelial (RPE) cells (ARPE-19) were infected in vitro with T. gondii and collected after 60, 120, 240 min, and 24 h. RESULTS: Compared with non-infected eyes, an intense inflammatory response was observed in the anterior (24 h after infection) and posterior segments (72 h after infection) of the infected eye, characterized by neutrophil infiltration and by the presence of tachyzoites and their consequent destruction along with disorganization of normal retina architecture and RPE vacuolization. T. gondii infection was associated with a significant increase of ANXA1 expression in the neutrophils at 24, 48, and 72 h, and in the RPE at 48 and 72 h. In vitro studies confirmed an upregulation of ANXA1 levels in RPE cells, after 60 and 120 min of infection with T. gondii. CONCLUSIONS: The positive modulation of endogenous ANXA1 in the inflammatory and RPE cells during T. gondii infection suggests that this protein may serve as a therapeutic target in ocular toxoplasmosis.

Ocular cysticercosis of the anterior segment.

A 6-year-old girl presented with signs of severe anterior uveitis. After initiating treatment, a cyst like lesion was observed in the anterior chamber that led to the diagnosis of ocular cysticercosis that was ultimately confirmed with histopathologic analysis. Ocular cysticercosis usually affects the extraocular muscle. Infection of the anterior chamber has been described, although to a lesser extent. Because of the usually poor visual prognosis and the controversy in treatment, physicians should be aware of this disease and its different variants of presentation.

Ultrasound biomicroscopy in the diagnosis and management of intraocular gnathostomiasis.

PURPOSE: To describe the use of ultrasound biomicroscopy in the identification of an intraocular nematode in a case of suspected nematode-induced uveitis DESIGN: Observational case report. METHOD: UBM was performed under topical anesthesia in a patient with acute painful uveitis suspected to result from an intraocular nematode. Clinical examination did not reveal the nematode. RESULTS: Over a 6-minute time span, serial UBM examinations revealed the nematode to move from the iris root into the posterior chamber through the zonules. Subsequently, it was seen adhering to the cornea and could be removed surgically, resulting in symptom relief. CONCLUSION: UBM is a useful tool in diagnosis and management of parasitic uveitis.

Ophthalmological study of the lesions induced by the filarial worm with dermal microfilariae, Monanema martini, in its murid hosts.

The filaria Monanema martini with skin-dwelling microfilariae induces in its natural murid hosts lesions similar to those in human onchocerciasis. This was demonstrated by histo-pathological studies but it appeared useful to evaluate the model by a clinical investigation. An ophthalmological analysis was performed on the two species of hosts, inoculated by one, two, or multiple doses of larvae, and with infections of at least one year duration. A total of 140 eyes was examined (anterior and posterior segments). We established a system for enumerating the different types and severities of lesions. We prepared a file for each eye and attempted to quantify our observations. The significant lesions were different in the two host species. In Arvicanthis niloticus, in which motile microfilariae were seen in the anterior segment, punctate keratitis was predominant. In Lemniscomys striatus, the posterior segment showed complete chorioretinal atrophy, similar to the final stage of onchocercal chorioretinitis in humans. M. martini represents in its natural hosts two complementary models for the study of the pathogenesis and treatment of human onchocerciasis.

Effects of repeated doses of ivermectin on ocular onchocerciasis: community-based trial in Sierra Leone.

Ivermectin seems to be a safe and effective treatment for onchocerciasis when given in a single dose, but less is known about the effects of repeated doses. Also, there seem to be differences in its effectiveness in anterior and posterior segment ocular disease. The ocular effects of ivermectin were studied in 586 villagers who were taking part in a double-blind, placebo-controlled, randomised trial in Sierra Leone. Only those who had received four doses, with 6-month intervals, of ivermectin or placebo were eligible. The 296 ivermectin-treated subjects and the 272 who received placebo were comparable with respect to age, sex, Onchocerca infection, blindness, and visual impairment before treatment. After treatment, the ivermectin group had less anterior segment disease than the placebo group, with significantly lower prevalences of microfilariae in the anterior chamber and cornea, and punctate keratitis (all p less than 0.001), and iritis (p less than 0.05). There was no significant difference in the prevalence of sclerosing keratitis, optic atrophy, or chorioretinitis between the groups. Visual acuities tended to be better in the ivermectin group, but the difference was not significant. There was a small but significant (p less than 0.01) excess of vascular sheathing in the ivermectin group. These differences persisted when subjects who were blind or visually impaired at baseline were excluded from analysis. The long-term effects of ivermectin, particularly on posterior segment disease, need further evaluation. In the mean time, the mass distribution of ivermectin should be promoted for all communities with hyperendemic onchocerciasis at risk of anterior segment disease.

Ocular manifestations of onchocerciasis in a rain forest area of west Africa.

The epidemiology and natural history of onchocerciasis and its ocular complications in rain forest areas are poorly understood. The present study was conducted on a rubber plantation in a hyperendemic area in the rain forest of Liberia, West Africa, where 800 persons were examined. The prevalence of infection was 84% overall 29% had intraocular microfilariae, and 2.4% were blind in one or both eyes. Onchocerciasis was the cause of all binocular blindness and one-third of all visual impairment. Over half of the visual impairment caused by onchocerciasis was due to posterior segment diseases. Chorioretinal changes were present in 75% of people, and included intraretinal pigment clumping in 52% and retinal pigment epithelium atrophy in 32%. Atrophy of the retinal pigment epithelium was associated with increasing age and severity of infection. Intraretinal pigment was strongly associated with anterior uveitis. There was a strong correlation between uveitis and the inflammatory chorioretinal sequelae: retinitis, intraretinal pigment, subretinal fibrosis, and optic neuropathy. These findings indicate that considerable visual impairment associated with rain forest onchocerciasis is common and is due largely to chorioretinal disease.

Changes in ocular onchocerciasis four and twelve months after community-based treatment with ivermectin in a holoendemic onchocerciasis focus.

The impact of ivermectin mass treatment on ocular onchocerciasis was studied in a holoendemic focus of blinding onchocerciasis in Ghana. A cohort of 417 persons, 369 of whom were treated, was followed up at 4 and 12 months after treatment. The mean ocular microfilarial load in the anterior chamber of the eye and in the cornea of treated persons was reduced to less than 20% and 10% of the pretreatment levels respectively at the 4 months follow-up but had increased significantly by 12 months. Lesions of the eye at the advanced stage of development remained stable. There was significant regression of early lesions of the anterior segment of the eye, particularly iridocyclitis, after ivermectin treatment. In view of the substantial increase of ocular microfilarial loads after 12 months, 6-monthly treatment may be indicated in such highly endemic foci. However, long-term observation is needed to give a correct estimate of the full benefit to be derived from mass treatment with ivermectin.

Ocular onchocerciasis and intensity of infection in the community. II. West African rainforest foci of the vector Simulium yahense.

A novel method of analysis was used to describe community patterns of ocular onchocerciasis in relation to the intensity of infection in West African forest villages where S. yahense is the sole vector. The pattern is completely different from that found in the savanna, even after correction for the intensity of infection as measured by the Community Microfilarial Load (CMFL). Lesions of the anterior segment of the eye as well as onchocercal blindness either do not occur or occur only sporadically with increasing CMFL in the Yahense forest whilst a steep linear relation exists between the prevalence of these lesions and the CMFL in the savanna. Lesions of the posterior segment of the eye are also less common in the Yahense forest. For a given skin microfilarial load, the ocular microfilarial load is lower in the Yahense forest. For a given ocular microfilarial load, a lower prevalence of eye lesions is found in the Yahense forest compared to the savanna. It is concluded that microfilariae of Onchocerca volvulus in the Yahense forest are less eye invasive than microfilariae from the savanna. Furthermore, they appear to be also less pathogenic to the eye. These findings explain why ocular onchocerciasis is relatively mild in the Yahense forest, in spite of the high intensities of O. volvulus infection in the community.

Ophthalmological results from a placebo controlled comparative 3-dose ivermectin study in the treatment of onchocerciasis.

One hundred and ninety eight patients with moderate to heavy infection with Onchocerca volvulus and with eye involvement in most, were allocated randomly to treatment with 100, 150 or 200 mcg/kg body weight of ivermectin or placebo given as a single oral dose in a double-blind dose finding study. The patients were drawn from an area under over ten years of vector control in Northern Ghana by the Onchocerciasis Control Programme, OCP. They underwent detailed clinical, laboratory and ophthalmological examination before treatment and in the review period of one year in hospital. Ivermectin given in a dose of 100, 150 or 200 mcg/kg eliminated microfilariae similarly slowly over 3-6 months and was associated with inflammatory reaction in the anterior segment which resolved without treatment. No changes in the fundus of the eye was detected by fluorescein angiography and no no-table other adverse eye reaction was observed. The ceiling of therapeutic activity of ivermectin in the eye is therefore put at 100 mcg/kg which is lower than the level fo 150 mcg/kg found in the skin. The apparent discrepancy may be due to different dose requirements on account of different mechanisms of action of ivermectin at the two sites. In the skin there is active killing while in the eye it is presumed there is a passive elimination of microfilariae.