Pathogenesis of Congenital Rubella Virus Infection in Human Fetuses: Viral Infection in the Ciliary Body Could Play an Important Role in Cataractogenesis.

BACKGROUND: Development of congenital rubella syndrome associated with rubella virus infection during pregnancy is clinically important, but the pathogenicity of the virus remains unclear. METHODS: Pathological examination was conducted on 3 aborted fetuses with congenital rubella infection. FINDINGS: At autopsy, all 3 aborted fetuses showed congenital cataract confirmed by gross observation. Rubella virus infection occurred via systemic organs including circulating hematopoietic stem cells confirmed by immunohistochemical and molecular investigations, and major histopathogical changes were found in the liver. It is noteworthy that the virus infected the ciliary body of the eye, suggesting a possible cause of cataracts. INTERPRETATION: Our study based on the pathological examination demonstrated that the rubella virus infection occurred via systemic organs of human fetuses. This fact was confirmed by immunohistochemistry and direct detection of viral RNA in multiple organs. To the best of our knowledge, this study is the first report demonstrating that the rubella virus infection occurred via systemic organs of the human body. Importantly, virus infection of the ciliary body could play an important role in cataractogenesis.

Risk of cataract among subjects with acquired immune deficiency syndrome free of ocular opportunistic infections.

PURPOSE: To evaluate the risk of cataract in the setting of AIDS. DESIGN: Prospective cohort study. PARTICIPANTS: Subjects with AIDS free of ocular opportunistic infections throughout catamnesis. METHODS: From 1998 through 2008, subjects 13 years of age or older were enrolled. Demographic characteristics and clinical characteristics were documented at enrollment and semiannually. MAIN OUTCOME MEASURES: Cataract was defined as high-grade lens opacity observed by biomicroscopy judged to be the cause of a best-corrected visual acuity worse than 20/40. Eyes that underwent cataract surgery during follow-up were considered to have developed cataract before the first visit when pseudophakia or aphakia was observed. RESULTS: Among 1606 participants (3212 eyes) at enrollment, 1.9% (95% confidence interval [CI]: 1.3%-2.7%) were observed to have cataract or prior cataract surgery. Among the 2812 eyes initially free of cataract and followed longitudinally (median follow-up, 4.6 years), the incidence of cataract was 0.37%/eye-year (95% CI: 0.26%-0.53%). In addition to age, significant cataract risk factors included prior cataract in the contralateral eye (adjusted hazard ratio [aHR], 21.6; 95% CI: 10.4-44.8), anterior segment inflammation (aHR, 4.40; 95% CI: 1.64-11.9), prior retinal detachment (aHR, 4.94; 95% CI: 2.21-11.0), and vitreous inflammation (aHR, 7.12; 95% CI: 2.02-25.0), each studied as a time-updated characteristic. Detectable human immunodeficiency virus RNA in peripheral blood was associated with lower risk of cataract at enrollment (adjusted odds ratio, 0.32; 95% CI: 0.12-0.80) but not of incident cataract (aHR, 1.58; 95% CI: 0.90-2.76). After adjustment for other factors, neither the then-current absolute CD4+ T-cell count nor antiretroviral therapy status showed consistent association with cataract risk, nor did an additive diagnosis of other comorbidities. Compared with the available population-based studies that used similar definitions of cataract, the age-specific prevalence of cataract in our cohort was higher than in 1 of 2 such studies, and the age-specific incidence of cataract surgery was higher. CONCLUSIONS: Our results suggest cataract may occur earlier among patients with AIDS free of ocular opportunistic infections than in the general population. Cataract risk was associated most strongly with age and with other ocular morbidity in this population. With improved survival, the burden of cataract likely will increase for persons with the human immunodeficiency virus or AIDS.

Cataracts in transgenic mice caused by a human papillomavirus type 18 E7 oncogene driven by KRT1-14.

Human papillomavirus type 18 (HPV18) is a common cause of cervical cancer. To create a mouse model for this common neoplastic disease, we used a human keratin 14 promoter to drive the HPV18 E7 oncogene to create transgenic mice. No mice up to a year of age developed cervical cancer. However, all transgenic mice and none of the controls developed progressive bilateral cortical cataracts. By 6 months of age, the cortex liquefied leaving the lens nucleus. Proliferation of lens epithelium formed multifocal nodules and free floating lens epithelial cells within the liquefied cortex. These cells were hyperplastic not neoplastic. Other HPV transgenic stocks develop cataracts suggesting this virus may have a broad cellular tropism.

Relative efficiency of polymerase chain reaction and enzyme-linked immunosorbant assay in determination of viral etiology in congenital cataract in infants.

BACKGROUND: Perinatal viral infections of fetus are among the leading causes of congenital cataract and identifying the viral etiology is important. OBJECTIVES: To detect the presence of Rubella virus (RV), herpes simplex virus (HSV) and cytomegalovirus (CMV) in lens aspirate specimens obtained from patients with congenital cataract and relate the results with serology. SETTING AND DESIGN: Prospective study carried out in tertiary care hospital. MATERIALS AND METHODS: Fifty lens aspirates from 50 infants with congenital cataract were subjected to HSV, RV isolation and polymerase chain reaction (PCR) for detection of HSV and CMV. Reverse transcription polymerase chain reaction (RT-PCR) was applied for RV detection. Peripheral blood specimens were screened for anti-HSV, RV and CMV antibodies by enzyme-linked immunosorbant assay (ELISA). RESULTS: Rubella virus was detected in nine (18%) lens aspirates, by nRT-PCR which includes six positive by culture. HSV-2 DNA was detected in nine other lens aspirates, while CMV was not detected by PCR. Serological results did not correlate with the presence of viruses in the lens aspirates. This is the first report of detection of HSV-2 DNA in cases of congenital cataract. CONCLUSIONS: Cytomegalovirus may not be playing a significant role in causation of congenital cataract. The role of serology in identifying causative viral infection for congenital cataract needs to be re-evaluated.

[Relationship between rubella virus and Fuchs heterochromic uveitis; 2 patients]. / Samenhang tussen rubellavirus en fuchs-heterochromie-uveïtis; 2 patiënten.

Two otherwise healthy men, aged 26 and 29 years, were diagnosed with Fuchs heterochromic uveitis (FHU) on the basis of the presence of iris heterochromia or iris atrophy, stellate corneal precipitates, and/or cataract. Microbiological investigation of aqueous humour demonstrated intraocular antibody production against rubella virus, but not against Toxoplasma gondii, herpes simplex virus or varicella zoster virus. Microbial nucleic acid detection was negative for all pathogens. Some time later, both patients underwent cataract surgery, which improved their vision considerably. FHU is a chronic, generally unilateral iridocyclitis, accompanied by the above-mentioned ophthalmologic manifestations in the absence of systemic disease. Little is known about the pathogenesis ofFHU, but recent publications have provided evidence for the possible involvement of the rubella virus.

Prevalence of eye signs in congenital rubella syndrome in South India: a role for population screening.

PURPOSE: Congenital rubella syndrome (CRS) resulting from maternal rubella infection, especially in the first trimester, affects an estimated 100 000 infants each year worldwide. Immunisation has reduced its occurrence in the developed world, though it remains a problem in countries with poor immunisation coverage. This population-based study was aimed at screening children below 5 years of age for ocular signs suspicious of CRS. METHODS: Suspected CRS cases were recruited from hospital and outreach services of the Aravind Eye Care System over a 24-month period. Clinical confirmation was based on the fulfilment of the World Health Organization (WHO) definition, and laboratory confirmation was based on a positive test for IgM antibody. RESULTS: Children under 5 years of age (n = 51 548) with ocular complaints were screened for eye signs suspicious of CRS; CRS compatible signs were detected in 1.92% (1090) children. Of these suspects (299), 27.42% were subsequently confirmed clinically according to WHO definition, and (46) 4.2% were serologically (Laboratory) confirmed. Of all the eye signs evaluated for screening, cataracts were the most sensitive (80.43%). CONCLUSIONS: Cataracts among children have a high sensitivity for detecting CRS in India. It is the only clinical eye finding that has a high enough sensitivity and specificity to be useful as a screening tool for CRS.

Nested reverse transcription polymerase chain reaction for the detection of rubella virus in clinical specimens.

BACKGROUND & OBJECTIVE: Rubella virus (RV) is one of the leading causes of childhood blindness in India. In this study we applied an optimized nested reverse transcription polymerase chain reaction (nRT-PCR) to detect RV in clinical specimens. METHODS: nRT-PCR was optimized using total RNA extracted from standard strain of RV using nested sets of primers specific for E1 open reading frame. nRT-PCR was applied onto 30 lens aspirates and corresponding peripheral blood leucocytes of 30 infants with congenital (29)/ developmental (01) cataract. Serology for anti-RV IgG and IgM antibodies was done. RV isolation was attempted using Vero and SIRC cell cultures. RESULTS: Optimized nRT-PCR was specific for RV and sensitive to detect 10 fg of RV RNA. Among 30 patients, nRT-PCR detected presence of RV in lens aspirates of 6 (20%) and 4 corresponding leucocytes. RV was isolated from 3 (10%) lens aspirates (nRT-PCR positive) of the 30 patients. Sera of these 6 patients showed presence of anti-RV IgG and IgM in one, only anti-RV IgG in 3 others and none in the other two. Of the remaining 24 patients, anti-RV IgG was detected in 3 and no anti-RV IgM antibodies in others. INTERPRETATION & CONCLUSION: Findings of our study showed that the nRT-PCR was a more sensitive and rapid technique to detect RV from lens aspirates compared to conventional methods of virus isolation and serology.

Congenital rubella cataract: a timely reminder in the new millennium?

Maternal infection with rubella in the first trimester is an important cause of congenital cataract. Any injury affecting the foetus following maternal rubella infection in the phase of organogenesis results in congenital defects collectively termed as congenital rubella syndrome (CRS). Although rubella embryopathy is a less common cause for congenital cataract than in the past, it is still seen. The number of cases reduced to one in 1997 after which there were no new cases till 2002. However, there have been two new cases of CRS in 2003. Herein another one in early 2004 is reported. Outbreaks of CRS will continue until the percentage of susceptible individuals is reduced to a minimum through immunization. The majority of rubella cases in Australia are confined to young female immigrants, many coming for marriage. We must continue to immunize children, identify and immunize vaccine failures and susceptible women before they become pregnant, and to screen pregnant women so they can be vaccinated after delivery.

Herpes simplex virus-1--associated congenital cataract.

PURPOSE: To report association of herpes simplex virus-type 1 (HSV-1) in four cases of congenital cataract. DESIGN: Prospective interventional case series. METHODS: Four infants younger than 12 months, presenting with unilateral or bilateral congenital cataract, were included. The cases were clinically evaluated by the pediatric ophthalmologist. The lens aspirates collected at the time of cataract surgery were processed for HSV-1 culture in rabbit corneal epithelial (SIRC) cell line and for HSV-1 DNA by polymerase chain (PCR). The sera of the children and the mother were tested for HSV-1 immunoglobulin (Ig) M and IgG by enzyme linked immunosorbent assay (ELISA). RESULTS: HSV-1 was isolated in tube cultures in three of four lens aspirates, and all four lens aspirates were positive for HSV-1 DNA by PCR. Serum HSV-1 IgM was positive in all babies and in three cases HSV-1 IgM was positive in the mother's serum. CONCLUSION: Based on a computerized literature search, we believe this may be the first report of HSV-1 associated congenital cataract.

Congenital nuclear cataracts and uveitis in HIV-transgenic mice.

PURPOSE: Patients infected with HIV-1 develop ocular manifestations, some due to opportunistic infections and others attributed to the virus itself. Among the latter are retinal microvasculopathy and uveitis. We have analysed the ocular phenotype in HIV-transgenic mice. METHODS: We have studied T26 transgenic mice which bear a gag-pol deleted HIV-1 genome. Transgene RNA was detected by Northern analysis. Ocular pathology was assessed by conventional histology, immunostaining for gp120 envelope protein, and in situ apoptosis detection with end-labelling. RESULTS: Abnormalities of lens epithelial cell development were detected as early as embryonic day 14.5. Histological changes included the malformation of an embryonal lens nucleus and poor closure of the lens suture lines. This resulted in congenital nuclear cataracts, as occur in congenital viral infections in human patients. In the adult animals, lenses were notable for extensive vacuolation, liquefaction, and degeneration of the cortex. Mild iridocyclitis and vitritis were also noted in adult transgenic mice. Immunostaining demonstrated the expression of gp 120 envelope protein within the lens epithelial and fibre cells. End-labelling with terminal deoxyribonucleotidyl transferase showed increased numbers of apoptotic cells in the adult lens. CONCLUSIONS: These findings suggest that one or more HIV-1 proteins are associated with congenital nuclear cataract formation and uveitis in HIV-transgenic mice.

The association of rubella virus in congenital cataract - a hospital-based study in India.

BACKGROUND: The association of rubella virus (RV) with congenital cataract has been well established. Since the data on association of RV with congenital cataract in India are scanty, a study was done based on virus isolation from lens aspirates in patients undergoing therapeutic lensectomy and serology. OBJECTIVE: To determine the incidence of the association of rubella virus with congenital cataract. STUDY DESIGN: The lens aspirates collected during the 9-year period (from 1990 to 1998), from 70 children up to 12 years of age with congenital cataract were processed for the isolation of rubella virus by conventional viral isolation culture method using BHK-21 and Vero cell lines. Identification of the virus was confirmed by immunofluorescence using human anti-rubella virus specific hyperimmune serum. Serum samples were collected from 55 out of these 70 children and the presence of antibodies to RV was detected by ELISA test. RESULTS: RV was isolated from lens aspirates in seven (10%) out of the 70 children with congenital cataract. Of the 55 sera tested, 22 had both anti-rubella IgM and IgG antibodies, in 13 only anti-RV IgG antibodies, in seven only IgM antibodies and the rest of the 13 samples did not have detectable levels of rubella antibodies. Among the children who had IgM antibodies, 12 (24.5%) were below the age of 6 months. CONCLUSION: It can be concluded based on virus isolation that 10% of patients with congenital cataract were due to rubella infection and the detection of 24.5% anti-RV IgM antibodies in children below 6 months old shows the possible association of rubella virus with congenital cataract.

Laboratory investigations on viral and Chlamydia trachomatis infections of the eye: Sankara Nethralaya experiences.

PURPOSE: To review our experiences on the laboratory investigations of viral and chlamydial conjunctivitis, congenital cataract and acute retinal inflammations seen from 1990 to 1998 at Sankara Nethralaya, Chennai, India. METHODS: Conjunctival swabs/scrapings from 1061 patients with conjunctivitis were investigated. Nested polymerase chain reaction (nPCR) and restriction fragment length polymorphism (RFLP) techniques were applied on 74 conjunctival swabs during the 1996 outbreak of acute viral conjunctivitis. The occurrence of Rubella virus in 86 lens aspirates of congenital cataract was investigated. Tests were performed for the association of Herpes simplex virus (HSV), Varicella zoster virus (VZV) and Cytomegalovirus (CMV) with acute retinal inflammation in 32 patients. RESULTS: The causative agents of conjunctivitis were Adenovirus in 13.8%, HSV in 2.2% and C. trachomatis in 20.9% of the patients. Epidemics were due to Adenovirus type 4 in 1991, type 3 in 1992-93 and type 7a in 1996. PCR was 37.9% more sensitive in detecting Adenovirus than virological methods. RFLP identified the conjunctivitis epidemic strain of 1996 as Adenovirus 7a. Rubella virus was isolated from 8.1% of lens aspirates from congenital cataract. Nineteen of the 32 patients with acute retinitis had confirmed virus infections (VZV: 8; HSV: 5; and CMV: 6) and the rapid detection of the virus agent helped institute specific chemotherapy resulting in useful vision in some patients. CONCLUSION: Laboratory investigations for diagnosis of viral and C. trachomatis ocular infections were useful in establishing the aetiology and determining the incidence of causative agents of specific ocular diseases.

[Ocular manifestations of hepatitis B]. / Manifestari oculare la bolnavi cu hepatita cu virus B.

We have examined 87 patients with chronic diffuse liver diseases with viral etiology and 20 healthy patients with ophthalmological, immunological and biochemical methods. It was established that liver pathology produced by hepatitis B virus give exchanges in the conjunctival and perilimbic circulation of the corneal sensitivity, retinal and optic nerve dysfunctions and also complicated cataract. Clinical symptoms in ophthalmopathology are amplify with the liver pathology progression and it is associated with the autoimmune reactions development, underlined by the antigens against eye tissues, and by the biochemical seric and local (lacrimal) parameters. The changes in eye structures were found at young and middle age patients, fact which indicate the social aspect of the problem and the necessity of their observation. In the vasoactive product "Cavinton" used in the complex treatment of the liver viral pathology it was established the possibility of pharmacologic correction of the pathologic changes in the ocular microcirculation and optic system.